WO2010117796A2 - Processes for the preparation of alpha-chloroketones from carboxylic acids - Google Patents

Processes for the preparation of alpha-chloroketones from carboxylic acids Download PDF

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WO2010117796A2
WO2010117796A2 PCT/US2010/029222 US2010029222W WO2010117796A2 WO 2010117796 A2 WO2010117796 A2 WO 2010117796A2 US 2010029222 W US2010029222 W US 2010029222W WO 2010117796 A2 WO2010117796 A2 WO 2010117796A2
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alkyl
formula
compound
group
cycloalkyl
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WO2010117796A3 (en
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Steven J. Collier
Jack Liang
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Codexis, Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/44—Nitrogen atoms not forming part of a nitro radical
    • C07D233/50—Nitrogen atoms not forming part of a nitro radical with carbocyclic radicals directly attached to said nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/63—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/095—Compounds containing the structure P(=O)-O-acyl, P(=O)-O-heteroatom, P(=O)-O-CN
    • C07F9/096—Compounds containing the structure P(=O)-O-C(=X)- (X = O, S, Se)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • compositions and methods for the preparation of ⁇ -chloroketones from carboxylic acids are provided.
  • Alpha-chloroketones have intrinsic activity as enzyme inhibitors and are also useful as intermediates for the preparation of a number of clinically and commercially important compounds.
  • chiral alpha-chloroketones derived from amino acids are useful for the preparation of chirally pure therapeutic agents, including, for example, inhibitors of renin, angiotensin converting enzyme (ACE), and HIV proteases, see e.g., Wang et al. (2004) J. Org. Chem. 69: 1629-1633.
  • ⁇ -chloroketones can be used as synthetic intermediates.
  • Atazanavir Nelfmavir, Cefovecin, Indacaterol, Ziprasidone, Lumefantrine, Mauladrine, and numerous antifungals (including e.g., Itraconazole, Bromuconazole, Chlorfenvinphos, Econazole, Enilconazole, Fenticonazole, Hexaconazole, Itraconazole, Ketoconazole, Sulconazole, Terconazole.
  • ⁇ -chloroketones including Nugent et al.
  • the present disclosure is directed to processes for the preparation of ⁇ -chloroketones from carboxylic acids, and, more particularly, to processes for the preparation of substantially chirally pure and chirally pure ⁇ -chloroketones derivatives of amino acids.
  • the carboxyl group of a compound of Formula (II) is activated by contact with a chloroformate reagent, of Formula (III) to provide an activated ester intermediate of Formula (IV).
  • the activated ester intermediate of Formula (IV) is contacted with a sulfoxonium ylide of Formula (V) to provide the keto ylide intermediate of Formula (VI), which, in turn, is contacted with anhydrous HCl to provide the ⁇ -chloroketone of Formula (I).
  • each of the -(C 3 -C 6 )CyC loalkyl, -phenyl, and -(5- to 10-membered)heteroaryl may also be unsubstituted or may be substituted with at least one moiety selected from the group consisting of hydrogen, -OH, -CH 2 OH, -CH 2 CH 2 OH -NH 2 , -halo, -CN, -NO 2 , -C(O)NH 2 ,-(Ci-C 6 )alkyl, -C(O)NH(Ci -C 4 ))alkyl, -C(O)N((Ci-C 4 )alkyl) 2 , and -(Ci-C 4 )alkyl.
  • R 2 is an alkyl, alkenyl, aryl, or heteroaryl group selected from the group consisting of phenyl, benzyl, vinyl, -(Ci-C 2 )alkyl, -(Ci- C 3 )alkyl, -(Ci-C 4 )alkyl, -(Ci-C 6 )alkyl, and -(Ci-Cio)alkyl, where each alkyl group may be unsubstituted or may be substituted with at least one moiety selected from the group consisting of -(C 3 -C 7 )cycloalkyl, -phenyl, and -(5- to 10-membered)heteroaryl.
  • R 2 is selected from the group consisting of phenyl, benzyl, vinyl, methyl, and isobutyl. In particular embodiments, R is isobutyl.
  • R 3 and R 4 are each independently selected from the group consisting of -(C r C 2 )alkyl, -(C r C 3 )alkyl, -(C r C 4 )alkyl, -(C r C 6 )alkyl, -(C r Cio)alkyl, where each alkyl group may be unsubstituted or may be substituted with at least one moiety selected from the group consisting of -(C 3 -Ci 0 )cycloalkyl, -(C 3 -C 6 )cycloalkyl, -phenyl, and -(5- to 10-membered)heteroaryl.
  • each -(C 3 -Ci 0 )cycloalkyl, -(C 3 -C 6 )cyc loalkyl , -phenyl, and -(5- to 10-membered)heteroaryl may also be unsubstituted or may be substituted with at least one moiety selected from the group consisting of -(Ci-C 2 )alkyl, -(Ci-C 3 )alkyl, and -(Ci-C 4 )alkyl.
  • R 3 and R 4 are both methyl.
  • each -(C 3 - Cio)cycloalkyl, -(C 3 -C 6 )cycloalkyl , -phenyl, and -(5- to 10-membered)heteroaryl may also be unsubstituted or it may be substituted with at least one moiety selected from the group consisting of hydrogen, -OH, -CH 2 OH, -CH 2 CH 2 OH -NH 2 , -halo, -CN, -NO 2 , -C(O)NH 2 ,-(Ci-C 6 )alkyl, -C(O)NH(Ci -C 4 ))alkyl, -C(O)N((Ci-C 4 )alkyl) 2 , and -(Ci-C 4 )alkyl.
  • R 6 is a nitrogen protecting group.
  • R 6 is selected from the group consisting of benzyloxycarbonyl (Cbz), 9- fluorenylmethoxycarbonyl (FMOC), and t-butoxycarbonyl (BOC).
  • R 6 is t- butoxycarbonyl (BOC).
  • the sulfoxonium methylide reagent of Formula V is prepared and isolated before use as a reagent in reaction 2 of Scheme 1 above (as well as in reactions 5, 8, 11, 14, 17, 20, and 22 of Schemes 2-7, and 10 below).
  • an appropriate sulfoxide i.e. (R 3 )(R 4 )S(O)
  • methyl iodide e.g., dimethylsulfoxide
  • methyl iodide salt e.g., dimethylsulfoxide
  • a strong base in an organic solvent to provide the dialkyl sulfoxonium methylide of Formula (V).
  • the activated ester product of Formula (IV), formed in Reaction 1 and the reaction mixture in which the sulfoxonium ylide reagent of Formula (V) is formed are directly combined, i.e., without purification of either product.
  • the activated ester product of Formula (IV) is collected, resuspended, and added directly to the reaction mixture in which the sulfoxonium ylide reagent of Formula (V) is formed.
  • the activated ester product of Formula (IV) is collected, resuspended, and added in multiple aliquots directly to the reaction mixture in which the sulfoxonium ylide reagent of Formula (V) is formed.
  • the HCl used in reaction 1 for conversion of keto ylide compounds of Formula (VI) to compounds of Formula (I) is anhydrous HCl.
  • the anhydrous HCl is provided in situ by contacting a chloride salt and an organic acid in an organic solvent.
  • the chloride salt is LiCl.
  • the organic acid is methanesulfonic acid.
  • the organic solvent is anhydrous.
  • the general process of Scheme 1 can be carried out wherein rather than using a chloro formate compound of Formula (III), the compound of Formula (II) is activated by contact with an acyl chloride reagent of Formula (XII) or a carboxylic acid anhydride reagent of Formula (XXXI) to provide an activated intermediate of Formula (XIII).
  • R 1 to R 6 are as described above regarding Scheme 1.
  • R is tert-butyl and, therefore the compound of Formula (XII) is compound (7) (pivaloyl chloride):
  • the carboxylic acid anhydride compound of Formula (XXXI) is compound (27), pivaloyl anhydride, is used in reaction 4 of Scheme 2 (in place of pivaloyl chloride (7)) to provide the activated ester of Formula (XIII).
  • the carboxyl group of a compound of Formula (VIII) is activated by contact with a chloroformate reagent of Formula (III) to provide an activated intermediate of Formula (IX).
  • the activated intermediate of Formula (IX) is contacted with a sulfoxonium ylide of Formula (V) to provide the keto ylide intermediate of Formula (X), which, in turn is contacted with anhydrous HCl (e.g., produced by LiCl and methanesulfonic mixture) to provide the ⁇ -chloroketone of Formula (VII).
  • anhydrous HCl e.g., produced by LiCl and methanesulfonic mixture
  • the product of Scheme 3 is a substantially chirally pure compound of Formula (VII). In certain embodiments, the product of Scheme 3 is a chirally pure compound of Formula (VII).
  • the process of Scheme 3 (i.e. reactions 7, 8, and 9) can be carried out using, as starting material, a substantially chirally pure or chirally pure L-amino acid compound of Formula (XIVa), or a substantially chirally pure or chirally pure D-amino acid compound of Formula (XIVb).
  • the product of Scheme 3 is a substantially chirally pure compound of Formula (XVa) or compound of Formula (XVb). In certain embodiments, the product of Scheme 3 is a chirally pure compound of Formula (XVa) or compound of Formula (XVb).
  • the present disclosure also provides methods for the preparation of an ⁇ -chloroketone derivative of N-protected amino acid compounds of Formula (VII) (e.g., compound (6)) according to the process depicted in Scheme 4, below:
  • the carboxyl group of compound (1) is activated by contact with the chloroformate reagent isobutyl chloroformate, compound (2), to provide the activated ester intermediate, compound (3).
  • the activated ester intermediate, compound (3) is contacted with a sulfoxonium ylide, compound (4), to provide the keto ylide intermediate, compound (5), which, in turn, is contacted with anhydrous HCl to provide the ⁇ -chloroketone, compound (6).
  • the product of Scheme 4 is substantially chirally pure compound (6). In certain embodiments, the product of Scheme 4 is chirally pure compound (6).
  • the starting material is not a chirally pure compound; e.g., where the starting material is mixture (e.g., a racemic mixture) comprising both an N-protected-D-amino acid and an N-protected-L-amino acid.
  • mixture e.g., a racemic mixture
  • Examples of each are, respectively, compounds of Formula (XVI) and (VIII).
  • the chemical processes described herein can be depicted as in Scheme 5 below:
  • the commercially available activated ester of Formula (XX) (derived from N-hydroxysuccinimide) is contacted with a sulfoxonium ylide of Formula (V) to provide the keto ylide intermediate of Formula (VI), which in turn, is contacted with anhydrous HCl to provide the ⁇ -chloroketone of Formula (I), as depicted in Scheme 6, below:
  • the general process of Scheme 1 can be carried out wherein rather than using a chloro formate compound of Formula (III), the carboxyl group of a compound of Formula (II) is activated by contact with a dialkyl or diaryl halophosphate of Formula (XXI) to provide the activated ester intermediate of Formula (XXII), as depicted in the process disclosed in Scheme 7 below.
  • the activated ester intermediate of Formula (XXII) is contacted with a sulfoxonium ylide of Formula (V) to provide the keto ylide intermediate of Formula (VI), which as in the general process of Scheme 1, then is contacted with anhydrous HCl to provide the ⁇ -chloroketones of Formula (I).
  • R 1 to R 6 are as described above in connection with Scheme 1, and R 7 and R 8 are each independently selected from the group consisting Of (Ci-C 6 ) alkyl and aryl and X is Br, Cl, or I.
  • R 7 and R 8 are each independently selected from the group consisting of -methyl, -ethyl, -propyl, -isopropyl, -butyl, -iso-butyl, -?-butyl, and phenyl.
  • R 7 and R 8 are both ethyl.
  • X is Cl.
  • a compound of Formula (II) is activated with CDI to provide compounds (22), and (23) shown below:
  • the activated ester compounds prepared using CDI, R 5 is a phenyl moiety and R 6 is a Boc protecting group, thereby providing compound (24) and compound (25), depicted below:
  • the disclosure provides an activated ester compound useful for preparing an ⁇ -chloroketone compound of Formula (I), with R ! -R 6 defined as in connection with Scheme 1 , wherein the compound is selected from the compounds having the following structural formulas depicted herein: Formula (IV), Formula (IX), Formula (XIII), Formula (XVII), Formula (XX), Formula (XXII), Formula (XXIII), Formula (XXIV), Formula (XXV), Formula (XXVI), Formula (XXVII), Formula (XXVIII), Formula (XXIX), and Formula (XXX).
  • the disclosure provides an activated ester compound useful for preparing an ⁇ -chloroketone of Formula (I), wherein the compound is selected from the list of compounds having the following numbered structures disclosed herein: compound (3), compound (11), compound (13), compound (15), compound (17), compound (18), compound (19), compound (20), compound (21), compound (24), compound (25), and compound (26).
  • the disclosure provides a keto sulfoxonium ylide compound useful for preparing an ⁇ -chloroketone of Formula (I), wherein the compound is selected from the compounds having the following structural formulas depicted herein: Formula (VI), Formula (X), and Formula (XVIII).
  • the disclosure provides a keto sulfoxonium ylide compound useful for preparing an ⁇ -chloroketone of Formula (I), wherein the compound has the structure of compound (5) as disclosed herein.
  • the present disclosure concerns processes for the preparation of ⁇ -chloroketones from carboxylic acids, particularly for the preparation of substantially chirally pure ⁇ -chloroketone derivatives of amino acids and chirally pure ⁇ -chloroketone derivatives of amino acids. Included herein is disclosure of the condensation reaction of a carboxylic acid with a chloro formate reagent which provides an activated ester intermediate that can be readily converted to a keto sulfoxonium ylide by reaction with an appropriate sulfoxonium ylide.
  • a carboxylic acid with an acyl chloride, a dialkyl or diaryl halophosphate, a carboxylic acid anhydride, N-hydroxysuccinimide, or N,N-carbonyl diimidazole to provide an activated ester intermediate that can be converted by reaction with an appropriate sulfoxonium ylide to a keto sulfoxonium ylide.
  • the keto sulfoxonium ylide can be converted to a desired ⁇ -chloroketone by contact with chloride in the presence of a suitable organic acid, e.g., anhydrous HCl provided by LiCl in the presence of methanesulfonic acid.
  • Alkyl means a straight chain or branched non cyclic hydrocarbon.
  • the term alkyl encompasses, inter alia, "(C r C 10 )alkyl,” “(C r C 6 )alkyl,” “(CrC 4 )alkyl,” “(CrC 3 )alkyl,” “(C r C 2 )alkyl,” “(C 2 -C 4 )alkyl,” and “(C 2 -C 6 )alkyl.”
  • (Ci-Cio)alkyl means a straight chain or branched non-cyclic hydrocarbon having from 1 to 10 carbon atoms.
  • Representative straight chain -(Ci-Cio)alkyls include -methyl, ethyl, -n propyl, -n- butyl, -n-pentyl, -n-hexyl, -n-heptyl, -n-octyl, -n-nonyl, and -n-decyl.
  • a branched alkyl means that one or more straight chain -(Ci-Cg)alkyl groups, such as methyl, ethyl or propyl, replace one or both hydrogens in a -CH 2 - group of a straight chain alkyl.
  • a branched non cyclic hydrocarbon means that one or more straight chain -(Ci-Cio)alkyl groups, such as methyl, ethyl or propyl, replace one or both hydrogens in a -CH 2 - group of a straight chain non cyclic hydrocarbon.
  • Representative branched - (Ci-Cio)alkyls include -iso-propyl, -sec-butyl, -iso-butyl, -tert-butyl, -iso-pentyl, -neopentyl, -1- methylbutyl, -2-methylbutyl, -3-methylbutyl, - 1 , 1 -dimethylpropyl, -1,2-dimethylpropyl, -1- methylpentyl, -2-methylpentyl, -3-methylpentyl, -4-methylpentyl, -1-ethylbutyl, -2-ethylbutyl, -3- ethylbutyl, -1,1-dimethylbutyl, -1,2-dimethylbutyl, -1,3-dimethylbutyl, -2,2-dimethylbutyl, -2,3-dimethylbutyl,
  • (Ci-C 6 )alkyl means a straight chain or branched non cyclic hydrocarbon having from 1 to 6 carbon atoms.
  • Representative straight chain -(Ci -Ce)alkyls include methyl, ethyl, -n propyl, -n butyl, -n pentyl, and -n-hexyl.
  • Representative branched (Ci-C6)alkyls include -iso-propyl, -sec-butyl, -iso- butyl, -tert-butyl, -iso-pentyl, -neopentyl, - 1 -methylbutyl, -2-methylbutyl, -3-methylbutyl, -1,1- dimethylpropyl, - 1 ,2-dimethylpropyl, - 1 -methylpentyl, -2-methylpentyl, -3-methylpentyl, A- methylpentyl, - 1 -ethylbutyl, -2-ethylbutyl, -3-ethylbutyl, -1,1-dimethtylbutyl, - 1 ,2-dimethylbutyl, -1,3-dimethylbutyl, -2,2-dimethylbutyl, -2,3-dimethylbutyl
  • (C 2 -C 6 )alkyl means a straight chain or branched non cyclic hydrocarbon having from 2 to 6 carbon atoms.
  • Representative straight chain -(C 2 -C6)alkyls include -ethyl, -n-propyl, -n butyl, -n pentyl, and -n hexyl.
  • Representative branched -(C 2 -C 6 )alkyls include -iso-propyl, -sec-butyl, -iso- butyl, -tert-butyl, -iso-pentyl, -neopentyl, - 1 -methylbutyl, -2-methylbutyl, -3-methylbutyl, -1,1- dimethylpropyl, - 1 ,2-dimethylpropyl, - 1 -methylpentyl, -2-methylpentyl, -3-methylpentyl, A- methylpentyl, - 1 -ethylbutyl, -2-ethylbutyl, -3-ethylbutyl, -1,1-dimethtylbutyl, - 1 ,2-dimethylbutyl, -1,3-dimethylbutyl, -2,2-dimethylbutyl, -2,3-d
  • (Ci-C 4 )alkyl means a straight chain or branched non cyclic hydrocarbon having from 1 to 4 carbon atoms.
  • Representative straight chain -(Q -C 4 )alkyls include methyl, ethyl, -n propyl, and -n butyl.
  • Representative branched -(Ci-C 4 )alkyls include -iso-propyl, -sec -butyl, -iso-butyl, and -tert- butyl.
  • (C 2 -Cz t )alkyl means a straight chain or branched non cyclic hydrocarbon having from 2 to 4 carbon atoms.
  • Representative straight chain -(C 2 -C 4 )alkyls include -ethyl, -n-propyl, and -n butyl.
  • Representative branched -(Ci-C 4 )alkyls include -iso-propyl, -sec-butyl, -iso-butyl, and -tert-butyl.
  • (Ci-C 3 )alkyl means a straight chain or branched non-cyclic hydrocarbon having from 1 to 3 carbon atoms.
  • Representative straight chain (Ci -C 3 )alkyls include -methyl, -ethyl, and -n-propyl.
  • Representative branched -(Ci-C 3 )alkyls include -iso-propyl.
  • (Ci-C 2 )alkyl means a straight chain non cyclic hydrocarbon having 1 or 2 carbon atoms.
  • Representative straight chain (Ci-C 2 )alkyls include methyl and ethyl
  • Cycloalkyl means a saturated monocyclic hydrocarbon.
  • the term “cycloalkyl” encompasses, inter alia, "(C 3 -Ci 2 )cycloalkyl,” “(C 4 -Ci 2 )cycloalkyl,” “(C 3 -C 8 )cycloalkyl,” “(C 4 - C 8 )cycloalkyl,” “(C 3 -C 6 )cycloalkyl,” and “(C 4 -C 6 )cycloalkyl.”
  • “(C 3 -C 7 )cycloalkyl” means a saturated monocyclic hydrocarbon having from 3 to 7 carbon atoms.
  • Representative (C 3 - C 7 )cycloalkyls include cyclopropyl, -cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • "-(3- to 7-membered)heterocycle” or “-(3- to 7-membered)heterocyclo” means a 3 to 7 membered monocyclic heterocyclic ring which is either saturated, unsaturated non-aromatic, or aromatic.
  • a 3 -membered heterocycle can contain up to 1 heteroatom
  • a 4-membered heterocycle can contain up to 2 heteroatoms
  • a 5-membered heterocycle can contain up to 4 heteroatoms
  • a 6- membered heterocycle can contain up to 4 heteroatoms
  • a 7-membered heterocycle can contain up to 5 heteroatoms.
  • Each heteroatom is independently selected from nitrogen, which can be quaternized; oxygen; and sulfur, including sulfoxide and sulfone.
  • the -(3- to 7- membered) heterocycle can be attached via a nitrogen or carbon atom.
  • Representative (3- to 7- membered)heterocycles include pyridyl, furyl, thiophenyl, pyrrolyl, oxazolyl, imidazolyl, thiazolidinyl, thiadiazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, triazinyl, morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, 2,3-dihydrofuranyl, dihydropyranyl, hydantoinyl, valerolactamyl, oxiran
  • "-(5- or 6-membered)heterocycle” or “-(5- or 6-membered)heterocyclo” means a 5 or 6 membered monocyclic heterocyclic ring which is either saturated, unsaturated non-aromatic, or aromatic.
  • a 5-membered heterocycle can contain up to 4 heteroatoms and a 6 membered heterocycle can contain up to 4 heteroatoms.
  • Each heteroatom is independently selected from nitrogen, which can be quaternized; oxygen; and sulfur, including sulfoxide and sulfone.
  • the -(5- or 6- membered)heterocycle can be attached via a nitrogen or carbon atom.
  • Representative (5- or 6- membered)heterocycles include pyridyl, furyl, thiophenyl, pyrrolyl, oxazolyl, imidazolyl, thiazolidinyl, thiadiazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, triazinyl, morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, 2,3-dihydrofuranyl, dihydropyranyl, hydantoinyl, valerolactamyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropyridinyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydr
  • "-(3- to 5-membered)heterocycle” or “-(3- to 5-membered)heterocyclo” means a 3 to 5 membered monocyclic heterocyclic ring which is either saturated, unsaturated non-aromatic, or aromatic.
  • a 3 -membered heterocycle can contain up to 1 heteroatom
  • a 4-membered heterocycle can contain up to 2 heteroatoms
  • a 5-membered heterocycle can contain up to 4 heteroatoms.
  • Each heteroatom is independently selected from nitrogen, which can be quaternized; oxygen; and sulfur, including sulfoxide and sulfone.
  • the -(3- to 5-membered)heterocycle can be attached via a nitrogen or carbon atom.
  • Representative -(3- to 5-membered)heterocycles include furyl, thiophenyl, pyrrolyl, oxazolyl, imidazolyl, thiazolidinyl, thiadiazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, triazinyl, pyrrolidinonyl, pyrrolidinyl, 2,3-dihydrofuranyl, hydantoinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl and the like.
  • -(7- to 10-membered)bicycloheterocycle or "-(7- to 10-membered)bicycloheterocyclo” means a 7 to 10 membered bicyclic, heterocyclic ring which is either saturated, unsaturated non- aromatic, or aromatic.
  • a -(I - to 10-membered)bicycloheterocycle contains from I to 4 heteroatoms independently selected from nitrogen, which can be quaternized; oxygen; and sulfur, including sulfoxide and sulfone.
  • the -(I - to 10-membered)bicycloneterocycle can be attached via a nitrogen or carbon atom.
  • Representative -(7- to 10-membered)bicycloheterocycles include quinolinyl, - isoquinolinyl, -chromonyl, -coumarinyl, -indolyl, -indolizinyl, benzo[b]furanyl, benzo[b]thiophenyl, -indazolyl, -purinyl, -4H-quinolizinyl, isoquinolyl, -quinolyl, phthalazinyl, -naphthyridinyl, carbazolyl, - ⁇ -carbolinyl, -indolinyl, -isoindolinyl, 1,2,3,4 tetrahydroquinolinyl, -1,2,3,4- tetrahydroisoquinolinyl, pyrrolopyrrolyl and the like.
  • alkenyl means a straight chain or branched non-cyclic unsaturated hydrocarbon having one or more carbon-carbon double bonds (e.g., derived from an alkene).
  • alkenyl encompasses, inter alia, "(d-Cio)alkenyl,” “(C r C 6 )alkenyl,” “(Ci-C 4 )alkenyl,” “(C r C 3 )alkenyl,” “(Ci-C 2 )alkenyl,” “(C 2 -C 4 )alkenyl,” and “(C 2 -C 6 )alkenyl,” and includes but is not limited to, vinyl and allyl functional groups.
  • Aryl means an aromatic carbocylic moiety such as phenyl, anthryl, or phenanthryl.
  • Heteroaryl means an aromatic heterocycle ring, including both monocyclic and bicyclic ring systems, where at least one carbon atom of one or both of the rings is replaced with a heteroatom independently selected from nitrogen, oxygen, and sulfur, or at least two carbon atoms of one or both of the rings are replaced with a heteroatom independently selected from nitrogen, oxygen, and sulfur.
  • heteroaryl encompasses, inter alia, (5 to 10-membered)heteroaryl,” and (5 or 6-membered)heteroaryl.”
  • -(5- to 10-membered) heteroaryl means an aromatic heterocycle ring of 5 to 10 members, including both monocyclic and bicyclic ring systems, where at least one carbon atom of one or both of the rings is replaced with a heteroatom independently selected from nitrogen, oxygen, and sulfur, or at least two carbon atoms of one or both of the rings are replaced with a heteroatom independently selected from nitrogen, oxygen, and sulfur.
  • one of the -(5- to 10- membered)heteroaryl's rings contain at least one carbon atom.
  • both of the - (5- to 10-membered)heteroaryl's rings contain at least one carbon atom.
  • Representative -(5- to 10- membered)heteroaryls include pyridyl, furyl, benzofuranyl, thiophenyl, benzothiophenyl, quinolinyl, isoquinolinyl, pyrrolyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl, oxadiazolinyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidyl, pyrimidinyl, pyrazinyl, thiadiazolyl, triazinyl, thienyl, cinnolinyl, phthalazinyl, and quinazolinyl.
  • 5-(5- or 6-membered)heteroaryl means a monocyclic aromatic heterocycle ring of 5 or 6 members where at least one carbon atom is replaced with a heteroatom independently selected from nitrogen, oxygen, and sulfur.
  • one of the (5- or 6-membered)heteroaryl's ring contains at least one carbon atom.
  • Representative -(5- or 6-membered)heteroaryls include pyridyl, furyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5- oxadiazolyl, 1,2,3-triazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidyl, pyrazinyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,5-triazinyl, and thiophenyl.
  • first group is "substituted with one or more" second groups
  • one or more hydrogen atoms of the first group is replaced with a corresponding number of second groups.
  • the number of second groups is two or greater, each second group can be the same or different.
  • Nitrogen protecting group means a substituent commonly employed to block or protect a nitrogen functionality while reacting other functional groups on a compound.
  • nitrogen-protecting groups include the following: formyl, trityl, methoxytrityl, tosyl, phthalimido, acetyl, trichloroacetyl, chloroacetyl, bromoacetyl, iodoacetyl, benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (FMOC), 2-trimethylsilylethoxycarbonyl (Teoc), 1 -methyl- 1 -(4- biphenylyl)ethoxycarbonyl (Bpoc), t-butoxycarbonyl (BOC), allyloxycarbonyl (Alloc), trihaloacetyl, benzyl, benzoyl, nitrophenylacetyl, and the like.
  • Ylide refers to a neutral compound that contains two adjacent atoms bearing formal positive and negative charges.
  • Sulfoxonium ylide refers to an ylide compound having a sulfur-oxygen bond e.g., compounds of Formula (V).
  • Keto ylide means a neutral compound comprising a keto group as well as two adjacent atoms bearing formal positive and negative charges; examples of keto ylides include the keto sulfoxonium ylide compounds of Formulas (VI), (X), and (XVIII), above.
  • Activated ester means an ester derivative that readily reacts with another chemical moiety including but not limited to, anhydrides (e.g., Formulas (IV), (IX), (XIII), (XVII), (XXIV), (XXV), (XXVI), (XXVII)), carboxylic acid-succinimides (e.g., Formula (XX)), carboxylic acid phosphoesters (e.g., Formulas (XXII), (XXIII), (XXX)), and carboxylic acid imidazolides (e.g., Formulas (XXVIII), (XXIX)).
  • anhydrides e.g., Formulas (IV), (IX), (XIII), (XVII), (XXIV), (XXV), (XXVI), (XXVII)
  • carboxylic acid-succinimides e.g., Formula (XX)
  • carboxylic acid phosphoesters e.g., Formulas (XX
  • Substrate encompasses a starting material that is used in, and transformed by, a chemical reaction.
  • Stepoisomer "stereoisomeric form,” and the like are general terms for all isomers of individual molecules that differ only in the orientation of their atoms in space. In includes enantiomers and isomers of compounds with more than one chiral center that are not mirror images of one another ("diastereomers").
  • “Chiral center” refers to a carbon atom to which four different groups are attached.
  • “Enantiomer” or “enantiomeric” refers to a molecule that is nonsuperimposable on its mirror image and hence optically active where the enantiomer rotates the plane of polarized light in one direction and its mirror image rotates the plane of polarized light in the opposite direction.
  • , where (F + ) + (F - ) 1
  • (ee) and (de) can expressed as a percent enantiomeric or diastereomeric excess.
  • racemic refers to a mixture of equal molar amounts of two enantiomers of a compound, which mixture is optically inactive.
  • a composition is "enriched" in a particular chiral compound, enantiomer, or diastereomer will typically comprise at least about 60%, 70%, 80%, 90%, or even more of that particular chiral compound, enantiomer, or diastereomer.
  • the amount of enrichment can be determined using conventional analytical methods routinely used by those of ordinary skill in the art, including but not limited to, NMR spectroscopy in the presence of chiral shift reagents, gas chromatographic analysis using chiral columns, and high pressure liquid chromatographic analysis using chiral columns.
  • a single chiral compound, enantiomer, or diastereomer will be substantially free of other corresponding chiral compound, enantiomer, or diastereomers.
  • the composition comprises less than about 10% of the specified undesired chiral compound, enantiomer, or diastereomer as established using conventional analytical methods routinely used by those of ordinary skill in the art, such as the methods noted above.
  • the amount of undesired chiral compound, enantiomer, or diastereomer may be less than about 10%, for example, less than about 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or even less.
  • compositions that contain at least about 99% of a specified chiral compound, enantiomer, or diastereomer are referred to herein as “chirally pure,” “enantiomerically pure,” and “diastereomerically pure,” respectively.
  • the present disclosure provides two alternative processes for the preparation of an ⁇ -chloroketone compound according to Formula (I). Both methods comprise contacting a compound of Formula (II) with an activating agent to form an activated ester intermediate compound.
  • the activating agent is a chloroformate compound of Formula (III)
  • the activating agent is an acyl chloride compound of Formula (XII) or an carboxylic acid anhydride compound of Formula (XXXI).
  • this activated ester intermediate compound is contacted with a sulfoxonium ylide of Formula (V) to provide a keto ylide intermediate compound of Formula (VI), and this keto ylide intermediate is contacted with anhydrous HCl to provide the ⁇ - chloroketone of Formula (I).
  • R 2 is selected from the group consisting of alkyl, alkenyl, and aryl, wherein the alkyl is selected from -(C r C 2 )alkyl, -(C r C 3 )alkyl, -(C r C 4 )alkyl, -(C r C 6 )alkyl, and -(d-Cio)alkyl, each alkyl being unsubstituted or substituted with at least one moiety selected from the group consisting of -(C 3 -C 7 )cycloalkyl, alkenyl, -phenyl, and -(5- to 10-membered)heteroaryl.
  • R 3 and R 4 are each independently selected from the group consisting of -(Ci-C 2 )alkyl, -(Ci- C 3 )alkyl, -(C r C 4 )alkyl, -(C r C 6 )alkyl, -(C r Ci 0 )alkyl, each alkyl being unsubstituted or substituted with at least one moiety selected from the group consisting of -(C 3 -Ci 0 )cycloalkyl, -(C 3 -C 6 )cycloalkyl, -phenyl, and -(5- to 10-membered)heteroaryl, each -(C 3 -Ci 0 )cycloalkyl, -(C 3 -C 6 )cycloalkyl , -phenyl, and -(5- to 10-membered)heteroaryl being unsubstituted or substituted with at least one moiety selected
  • R 6 is a nitrogen-protecting group.
  • Activation of the carboxyl group of the substrate compounds is provided by contact with a chloroformate reagent of Formula (III) (e.g., compound (2)), an acyl chloride reagent of Formula (XII) (e.g., compound (7)), or a carboxylic acid anhydride reagent of Formula (XXXI) (e.g., compound (27)), as depicted in reactions 1, 4, 7, and 10 of Schemes 1 -4, respectively.
  • a chloroformate reagent of Formula (III) e.g., compound (2)
  • an acyl chloride reagent of Formula (XII) e.g., compound (7)
  • a carboxylic acid anhydride reagent of Formula (XXXI) e.g., compound (27)
  • the reaction is mediated by a suitable base and provides an activated ester as the product, e.g., compounds of Formula (IV), and Formula (IX), e.g., compound (3), and Formula (XIII), as depicted in Schemes 1, 3, 4, and 2, respectively.
  • a suitable base e.g., compounds of Formula (IV), and Formula (IX), e.g., compound (3), and Formula (XIII), as depicted in Schemes 1, 3, 4, and 2, respectively.
  • the substrate may carry one or more protecting groups to mask a potentially reactive atom or group to preclude untoward chemical reactions.
  • the substrate is an amino acid in which the nitrogen atom carries a protecting group, e.g., the moiety identified as R 6 .
  • Suitable nitrogen protecting groups include formyl, trityl group, methoxytrityl, tosyl group, benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (FMOC), t-butoxycarbonyl (BOC), benzyl, benzoyl, and nitrophenylacetyl groups.
  • the nitrogen protecting group is a t- butoxycarbonyl (BOC) protecting group.
  • the substrate is a chiral compound which can be a substantially chirally pure compound or a chirally pure compound.
  • the substrate is a substantially chirally pure L-amino acid or a chirally pure L-amino acid.
  • the substrate is a substantially chirally pure N-protected-L- amino acid or a chirally N-protected-L-pure amino acid.
  • the substrate is a substantially chirally pure D-amino acid or a chirally pure D-amino acid.
  • the substrate is a substantially chirally pure N-protected-D-amino acid or a chirally N-protected-D-pure amino acid.
  • Activated ester formation is carried out in a suitable organic solvent, e.g., an aprotic solvent including but not limited to: tetrahydrofuran (THF), 2-methyl THF, toluene, benzotrifluoride (i.e.
  • a suitable organic solvent e.g., an aprotic solvent including but not limited to: tetrahydrofuran (THF), 2-methyl THF, toluene, benzotrifluoride (i.e.
  • the organic solvent is an anhydrous organic solvent.
  • the solvent is anhydrous THF.
  • the substrate i.e. a compound of Formula (II), Formula (XIV), or Formula (VIII) (e.g., compound (I)) is taken up in the solvent at a suitable temperature, generally at about 20 0 C.
  • the substrate may however, be taken up in the solvent at temperatures below room temperature (e.g., within the range of from about 0 0 C up to about 20 0 C) or above room temperature (e.g., within the range of from about 20 0 C up to about 100 0 C) if desired or necessary.
  • activated ester formation is carried out with an initial amount of substrate present within a range of from about 0.025 M to about 1.0 M, from about 0.05 M to about 0.75 M, from about 0.1 M to about 0.5 M, from about 0.15 M to about 0.4 M, from about 0.2 M to about 0.3 M. In certain embodiments, activated ester formation is carried out with an initial amount of substrate present at a concentration of about 0.25 M.
  • a suitable base may be added to the solvent before, after or simultaneously with the substrate.
  • a base is added to the solvent before, after or simultaneously with the substrate, and, in a particular embodiment, that base is an organic base.
  • Suitable organic bases include, but are not limited to, N-methylmorpholine, N-ethylmorpholine, N- methylpyrollidine, N-methylpiperidine, pyridine, lutidines, collidines, 2,6-di-tertbutylpyridine, DBU, DBN, tetramethylguanidine, diisopropylethylamine, dimethylaniline, triethylamine and N,N,N',N'-tetramethylethylenediamine and phosphazene bases.
  • the base is triethylamine.
  • the base added is an inorganic base, which may be selected from, but not limited to, lithium, sodium, potassium or cesium carbonate; and lithium, sodium or potassium phosphate.
  • the inorganic base is a Group II metal salt.
  • activated ester formation is carried out with an initial amount of base within a range of from about 4 equivalents to about 1 equivalent, on a molar basis, relative to the substrate (i.e., the compounds of Formula (II), Formula (XIV), or Formula (VIII), e.g., compound (I)).
  • activated ester formation is carried out with an initial amount of base within a range of from about 2 equivalents to about 1 equivalent, from about 2 equivalents to about 1 equivalent, from about 1.5 equivalents to about 1 equivalent, from about 1.25 equivalents to about 1 equivalent, or about 1 equivalent, on a molar basis, relative to the substrate.
  • activated ester formation is carried out with an initial amount of base representing about 1.1 equivalents, on a molar basis, relative to the substrate.
  • the activating reagent e.g., a chloroformate or an acyl chloride
  • the activating reagent is added to the reaction mixture either before, after or simultaneously with the substrate, and therefore, either before after or simultaneously with the base.
  • the activating reagent e.g., a chloroformate or an acyl chloride
  • Suitable chloroformate reagents include, but are not limited to, those compounds of Formula (III), in which R 2 is an alkyl, alkenyl, aryl, or heteroaryl group selected from the group consisting of phenyl, isobutyl, vinyl, -(C r C 2 )alkyl, -(C r C 3 )alkyl, -(C r C 4 )alkyl, -(C r C 6 )alkyl, and -(C r C 10 )alkyl, where each alkyl group may be unsubstituted or may be substituted with at least one moiety selected from the group consisting of -(C 3 -C 7 )cycloalkyl, -phenyl, and -(5- to 10-membered)heteroaryl.
  • R 2 is an alkyl, alkenyl, aryl, or heteroaryl group selected from the group consisting of phenyl, isobutyl
  • the chloroformate is benzyl chloroformate, phenyl chloroformate, vinyl chloroformate, methyl chloroformate, or isobutyl chloroformate. In particular embodiments, the chloroformate is isobutyl chloroformate.
  • activated ester formation is carried out with an initial amount of chloroformate (i.e. a compound of Formula (III), e.g., compound (2)) within a range of from about 4 equivalents to about 1 equivalent, on a molar basis, relative to the substrate (i.e. the compound of Formula (II), Formula (XIV), or Formula (VIII), e.g., compound (I)).
  • activated ester formation is carried out with an initial amount of chloroformate within a range of from about 2 equivalents to about 1 equivalent, from about 2 equivalents to about 1 equivalent, from about 1.5 equivalents to about 1 equivalent, from about 1.25 equivalents to about 1 equivalent, on a molar basis, relative to the substrate.
  • activated ester formation is carried out with an initial amount of chloroformate representing about 1 equivalent, on a molar basis, relative to the substrate.
  • activated ester formation is carried out with an initial amount of acyl chloride (i.e. a compound of Formula (XII), e.g., compound (7)) within a range of from about 4 equivalents to about 1 equivalent, on a molar basis, relative to the substrate (i.e. the compound of Formula (II), Formula (XIV), or Formula (VIII), e.g., compound (I)).
  • an initial amount of acyl chloride i.e. a compound of Formula (XII), e.g., compound (7)
  • activated ester formation is carried out with an initial amount of acyl chloride within a range of from about 2 equivalents to about 1 equivalent, from about 2 equivalents to about 1 equivalent, from about 1.5 equivalents to about 1 equivalent, from about 1.25 equivalents to about 1 equivalent, on a molar basis, relative to the substrate.
  • activated ester formation is carried out with an initial amount of acyl chloride representing about 1 equivalent, on a molar basis, relative to the substrate.
  • activated ester formation is carried out by reaction of a carboxylic acid anhydride (e.g., pivaloyl anhydride) with a substrate (i.e. the compound of Formula (II), Formula (XIV), or Formula (VIII), e.g., compound (I)). That is, the carboxylic acid anhydride of Formula (XXXI) is used in place of the acid chloride in the reaction of Scheme 2.
  • a carboxylic acid anhydride of Formula (XXXI) is used in place of the acid chloride in the reaction of Scheme 2.
  • pivaloyl anhydride (27) is used in place of pivaloyl chloride (7) in the reaction 4 of Scheme 2 to provide the activated ester of Formula (XIII).
  • activated ester formation is carried out at a temperature within the range of from about -30 0 C to about 30 0 C, from about -20 0 C to about 20 0 C, from about -10 0 C to about 10 0 C, or from about -5°C to about 5°C. In particular embodiments, activated ester formation is carried out at a temperature of about 0 0 C.
  • activated ester formation is carried out for a period of time sufficient to convert at least about 50%, 60%, 70%, 80%, 85%, 90%, 95%, 97%, or 99% of the substrate of Formula (II), Formula (VIII), e.g., compound (1) to the activated ester product of Formula (IV and XIII), Formula (IX), and compound (3), respectively.
  • activated ester formation is carried out for a period of time with the range of from about 5 minutes to 10 hours, from about 10 minutes to about 5 hours, from about 15 minutes to about 2 hours, or from about 20 minutes to about 1 hour. In a particular embodiment, activated ester formation is carried out for about 30 minutes.
  • a precipitate may form during the reaction providing the activated ester product.
  • the precipitate may be collected (e.g., by filtration) and washed with a solvent, e.g., that used for the reaction forming the activated ester product, and the washings obtained combined with the filtered reaction mixture.
  • the activated ester product i.e. the compound of Formula (IV), Formula (XIII), or Formula (IX) (e.g., compound (3)), formed in reaction 1, 4, 7, or 10 of reaction Schemes 1 -4, respectively, may be isolated and purified using methods, reagents, and equipment known in the art.
  • the reaction mixture can be evaporated, optionally washed, and then resuspended in a suitable solvent (e.g., anhydrous THF), and used directly for preparation of the keto sulfoxonium ylides of Formula (VI) and Formula (X) (e.g., compound (5), according to reactions 2, 5, 8, and 11 of reaction Schemes 1-4, respectively.
  • a suitable solvent e.g., anhydrous THF
  • the chloroformate reagent of Formula (III) is selected from among phenyl chloroformate (compound (10)), benzyl chloroformate (compound (12)), vinyl chloroformate (compound 14)), and methyl chloroformate (compound (16)), each of which is depicted below:
  • the chloroformates are used to provide N-protected activated ester derivatives of L-amino acids (where R 5 and R 6 are as described above), according to the reactions depicted in Scheme 1 and Scheme 3, above, resulting in compounds (11), (13), (15) and (17), respectively, shown below:
  • R 5 is a phenyl moiety and R 6 is a Boc protecting group
  • the activated esters are, respectively, compounds (18)-(21), depicted below:
  • activation of the carboxyl group of a substrate compound of Formula (II), Formula (XIV), or Formula (VIII) is provided by contact with a dialkyl halophosphate reagent of compound (8) as depicted in reaction 21 of Scheme 10 below:
  • diaryl- or dialkyl halophosphate reactions may be mediated by a suitable base and provide an activated ester as the product, e.g., compounds of Formula (XXII), and Formula (XXIII) as depicted in Schemes 7, and 10, respectively.
  • the substrate may carry one or more protecting groups to mask a potentially reactive atom or group to preclude untoward chemical reactions.
  • the nitrogen atom carries a protecting group, e.g., the moiety identified as R 6 .
  • Suitable nitrogen protecting groups include formyl, trityl group, methoxytrityl, tosyl group, benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (FMOC), t-butoxycarbonyl (BOC), benzyl, benzoyl, and nitrophenylacetyl groups.
  • the nitrogen protecting group is a t-butoxycarbonyl (BOC) protecting group.
  • the substrate is a chiral compound which can be a substantially chirally pure compound or a chirally pure compound.
  • the substrate is a substantially chirally pure L-amino acid or a chirally pure L-amino acid.
  • the substrate is a substantially chirally pure N-protected-L- amino acid or a chirally N-protected-L-pure amino acid.
  • the substrate is a substantially chirally pure D-amino acid or a chirally pure D-amino acid.
  • the substrate is a substantially chirally pure N-protected-D-amino acid or a chirally N-protected-D-pure amino acid.
  • Activated ester formation is carried out in a suitable organic solvent, e.g., an aprotic solvent such as, but not limited to, include (but not limited to): tetrahydrofuran (THF), 2-methyl THF, toluene, benzotrifluoride (i.e.
  • the organic solvent is an anhydrous organic solvent.
  • the solvent is anhydrous THF.
  • the substrate i.e. a compound of Formula (II), Formula (XIV), or Formula (VIII) (e.g., compound (I)) is taken up in the solvent at a suitable temperature, generally at about 20 0 C.
  • the substrate may however, be taken up in the solvent at temperatures below room temperature (e.g., within the range of from about 0 0 C up to about 20 0 C) or above room temperature (e.g., within the range of from about 20 0 C up to about 100 0 C) if desired or necessary.
  • activated ester formation is carried out with an initial amount of substrate present within a range of from about 0.025 M to about 1.0 M, from about 0.05 M to about 0.75 M, from about 0.1 M to about 0.5 M, from about 0.15 M to about 0.4 M, from about 0.2 M to about 0.3 M.
  • anhydride formation is carried out with an initial amount of substrate present at a concentration of about 0.25 M.
  • a suitable base may be added to the solvent before, after or simultaneously with the substrate.
  • a base is added to the solvent before, after or simultaneously with the substrate, and, in a particular embodiment, that base is an organic base.
  • Suitable organic bases include, but are not limited to, N-methylmorpholine, N-ethylmorpholine, N- methylpyrollidine, N-methylpiperidine, pyridine, lutidines, collidines, 2,6-di-tertbutylpyridine, DBU, DBN, tetramethylguanidine, diisopropylethylamine, dimethylaniline, triethylamine and N,N,N',N'-tetramethylethylenediamine and phosphazene bases.
  • the base is triethylamine.
  • the base added is an inorganic base, which may be selected from, but not limited to, lithium, sodium, potassium or cesium carbonate; and lithium, sodium or potassium phosphate.
  • the inorganic base is a Group II metal salt.
  • activated ester formation is carried out with an initial amount of base within a range of from about 4 equivalents to about 1 equivalent, on a molar basis, relative to the substrate (i.e. the compound of Formula (II), Formula (XIV), or Formula (VIII), e.g., compound (I)).
  • activated ester formation is carried out with an initial amount of base within a range of from about 2 equivalents to about 1 equivalent, from about 2 equivalents to about 1 equivalent, from about 1.5 equivalents to about 1 equivalent, from about 1.25 equivalents to about 1 equivalent, or about 1 equivalent, on a molar basis, relative to the substrate.
  • activated ester formation is carried out with an initial amount of base representing about 1.1 equivalents, on a molar basis, relative to the substrate.
  • the activating reagent e.g., a diaryl or diaryl halophosphate or dialkyl halophosphate, (e.g., diethyl chlorophosphate, compound (9))
  • the activating reagent e.g., a diaryl or diaryl halophosphate or dialkyl halophosphate, (e.g., diethyl chlorophosphate, compound (9))
  • the activating reagent e.g., a diaryl halophosphate or a dialkyl halophosphate (e.g., diethyl chlorophosphate, compound (9))
  • aliquots e.g., dropwise, to the reaction mixture containing both the substrate and the base.
  • Suitable halophosphate reagents include, but are not limited to, those compounds of Formula
  • XXI in which X is Cl, Br, or I and R 7 and R 8 are each independently selected from the group consisting of -methyl, -ethyl, -propyl, -isopropyl, -butyl, -iso-butyl, -?-butyl, and phenyl.
  • X is Cl.
  • R 7 and R 8 are both ethyl.
  • activated ester formation is carried out with an initial amount of a diaryl halophosphate or a dialkyl halophosphate (i.e. a compound of Formula (XXI), e.g., compound (9)) within a range of from about 4 equivalents to about 1 equivalent, on a molar basis, relative to the substrate (i.e. the compound of Formula (II), Formula (XIV), or Formula (VIII), e.g., compound (I)).
  • a diaryl halophosphate or a dialkyl halophosphate i.e. a compound of Formula (XXI), e.g., compound (9)
  • activated ester formation is carried out with an initial amount of a diaryl halophosphate or a dialkyl halophosphate within a range of from about 2 equivalents to about 1 equivalent, from about 2 equivalents to about 1 equivalent, from about 1.5 equivalents to about 1 equivalent, from about 1.25 equivalents to about 1 equivalent, on a molar basis, relative to the substrate.
  • activated ester formation is carried out with an initial amount of diaryl or dialkyl halophosphate representing about 1 equivalent, on a molar basis, relative to the substrate.
  • activated ester formation is carried out by reaction of a carboxylic acid with N-hydroxysuccinimide generally according to methods known in the art.
  • the N-hydroxysuccinimide activated ester is a commercially-available
  • activated ester formation is carried out at a temperature within the range of from about -30 0 C to about 30 0 C, from about -20 0 C to about 20 0 C, from about -10 0 C to about
  • activated ester formation is carried out at a temperature of about 0 0 C.
  • activated ester formation is carried out for a period of time sufficient to convert at least about 50%, 60%, 70%, 80%, 85%, 90%, 95%, 97%, or 99% of the substrate of
  • activated ester formation is carried out for a period of time with the range of from about 5 minutes to 10 hours, from about 10 minutes to about 5 hours, from about 15 minutes to about
  • activated ester formation is carried out for about 30 minutes.
  • a precipitate may form during the reaction providing the activated ester product.
  • the precipitate may be collected (e.g., by filtration) and washed with a solvent, e.g., that used for the reaction forming the activated ester product, and the washings obtained combined with the filtered reaction mixture.
  • the activated ester product i.e. the compound of Formula (XXII), or
  • Formula (XXIII), formed in reaction 16, 19, or 22 of reaction Schemes 6, 7, and 10, respectively, may be isolated and purified using methods, reagents, and equipment known in the art.
  • the reaction mixture can be evaporated, optionally washed, and then resuspended in a suitable solvent (e.g., anhydrous THF), and used directly for preparation of the keto sulfoxonium ylides of Formula (VI) according to reactions 19, and 22 and 11 of reaction Schemes 7, and 10, respectively.
  • a suitable solvent e.g., anhydrous THF
  • keto ylides and ⁇ -chloroketones in accordance with the present disclosure including but not limited to: carbonyl ditriazole, dialkyldicarbonates (e.g., EtOC(O)OC(O)OEt), diaryl or dialkylphosphinic halides (e.g., Ph 2 P(O)Cl), alkyl and aryl cyanoformates (e.g., MeOC(O)CN), carbodiimides (e.g., DCC), chlorothiophosphates, halo-l,3,5-triazines (e.g., 2,4,6-trichlorotriazine, 2- chloro-4,6-dimethoxytriazine), N-alkyl-2-halopyridinium salts (e.g., N-methyl-2-fluoropyridinium salts).
  • dialkyldicarbonates e.g., EtOC(O)OC(O)OEt
  • an activated ester is mediated by reaction of a carboxylic acid with N,N-carbonyl diimidazole (CDI) generally according to the method of Example 2(G), below, to provide activated esters, e.g. , the corresponding carboxylic acid imidazolides of Formula (XXVIII), and Formula (XXIX), depicted below:
  • CDI N,N-carbonyl diimidazole
  • reaction of a carboxylic acid with N,N-carbonyl diimidazole (CDI) can provide compounds (22), and (23), respectively
  • R 5 is a phenyl moiety and R 6 is a Boc protecting group
  • the activated esters are, respectively, compound (24) and compound (25), depicted below:
  • the sulfoxonium methylide reagent of Formula V is prepared, e.g., as described below, and isolated before use as a reagent in reactions 2, 5, 8, and 11, of reaction Schemes 1-4, respectively, converting intermediates of Formula (IV), Formula (XIII), and Formula (IX) (e.g., compound (3)) to the corresponding keto sulfoxonium ylides of Formula (VI), and Formula (X) (e.g., compound (5)).
  • an appropriate sulfoxide i.e. (R 3 )(R 4 )S(O)
  • a sulfoxide i.e. (R 3 )(R 4 )S(O)
  • methyl iodide e.g., dimethylsulfoxide
  • dialkyl methyl sulfoxonium salt i.e. the product of the reaction depicted in Scheme 8, can be isolated or purified using methods, reagents, and equipment known to one of ordinary skill in the art.
  • Other methods for preparation of compounds according to Formula (XVII) are found in the art, see, e.g., Smith et al, Tetrahedron 1958, p317, Lampman, G.M. ; Koops, R. W. ; Olden, CC; J. Chem. Educ, 1985, 62: 267, and Ng, J. S.; Liu, C; McGarrigle, E. M.; Aggarwal, V.
  • the methylating agent is methyl bromide.
  • the ylide precursor is selected from, but not limited to, trimethylsulfoxonium chloride, methanesulfonate, tosylate, triflate, and tetrafluoroborate.
  • dialkyl methylsulfoxonium iodide salt is contacted with a strong base in an organic solvent to provide the dialkyl sulfoxonium methylide of Formula (V), as depicted in Scheme 9, below:
  • dialkyl sulfoxonium methylide of Formula (V) (e.g., the product of the reaction depicted in Scheme 9, can be isolated or purified using methods, reagents, and equipment known to one of ordinary skill in the art.
  • the dialkyl methylsulfoxonium salt of Formula (XVII), which may be prepared as depicted in reaction Scheme 8, is contacted with a strong base in an organic solvent to provide the dialkyl sulfoxonium methylide of Formula (V), as depicted in Scheme 9, above.
  • the dialkyl sulfoxonium methylide of Formula (V) e.g., compound (4)
  • can be used directly by contacting with activated esters for formation of the keto sulfoxonium ylides of Formula (VI) and Formula (X) e.g., compound (5), as depicted in reactions 2, 5, 8, and 11 of Schemes 1-4, respectively.
  • the dialkyl methylsulfoxonium salt of Formula (XVII) is taken up in a suitable organic solvent, e.g., an aprotic solvent such as but not limited to DMSO, DMF, dimethylacetamide, N-methylpyrollidinone, dioxane, THF, methyl-THF, acetonitrile, toluene and mixtures thereof.
  • a suitable organic solvent e.g., an aprotic solvent such as but not limited to DMSO, DMF, dimethylacetamide, N-methylpyrollidinone, dioxane, THF, methyl-THF, acetonitrile, toluene and mixtures thereof.
  • the solvent is a polar aprotic solvent.
  • the organic solvent is an anhydrous organic solvent.
  • the solvent is anhydrous THF.
  • the substrate, dialkyl methylsulfoxonium salt of Formula (XVII), is taken up in the solvent at a suitable temperature, generally at about 20 0 C.
  • the substrate sulfoxonium methylide of Formula (V) may however, be taken up in the solvent at temperatures below room temperature (e.g., within the range of from about 0 0 C up to about 20 0 C) or above room temperature (e.g., within the range of from about 20 0 C up to about 100 0 C) if desired or necessary.
  • formation of the dialkyl sulfoxonium methylide of Formula (V) is carried out with an initial amount of substrate dialkyl methylsulfoxonium salt of Formula (XVII) present within a range of from about 0.025 M to about 1.0 M, from about 0.05 M to about 0.8 M, from about 0.1 M to about 0.5 M, from about 0.15 M to about 0.6 M, from about 0.25 M to about 0.5 M, or from about 0.35 M to about 0.4 M.
  • dialkyl sulfoxonium methylide formation is carried out with an initial amount of substrate dialkyl methylsulfoxonium salt present at a concentration of about 0.38 M.
  • the base is added to the reaction mixture before, after or simultaneously with the dialkyl methylsulfoxonium salt of Formula (XVII).
  • the base is selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium hydride, potassium hydride, lithium/sodium/potassium alkoxides (e.g., lithium tert-butoxide, potassium tert-butoxide, and sodium tert-butoxide; lithium tert- amylate, potassium tert-amylate, and sodium tert-amylate), lithium diisopropylamide (LDA), lithium hexamethyldisilazane, sodium hexamethyldisilazane, potassium hexamethyldisilazane (i.e., Li/Na/K HMDS), butyl lithium (BuLi), phosphazene bases, diaza(l,3)bicy
  • dialkyl sulfoxonium methylide of Formula (V) is carried out with an initial amount of base within a range of from about 1 equivalent to about 2 equivalents, from about 1 equivalent to about 1.5 equivalents, from about 1 equivalent to about 1.25 equivalents, or from about 1 equivalent to about 1.1 equivalents on a molar basis relative to the dialkyl methylsulfoxonium salt starting material.
  • dialkyl sulfoxonium methylide formation is carried out with an initial amount of base of about 1 equivalent, on a molar basis relative to the dialkyl methylsulfoxonium salt starting material.
  • formation of the dialkyl sulfoxonium methylide of Formula (V) is carried out at a temperature within the range of from about 40 0 C to about 120 0 C, or from about 60 0 C to about 100 0 C. In certain embodiments, dialkyl sulfoxonium methylide formation is carried out at a temperature of about 90 0 C. In certain embodiments, dialkyl sulfoxonium methylide formation is carried out at a temperature of about 65°C, e.g., the approximate reflux temperature of THF.
  • dialkyl sulfoxonium methylide of Formula (V) formation of the dialkyl sulfoxonium methylide of Formula (V) is carried out for a period of time sufficient to convert at least about 50%, 60%, 70%, 80%, 85%, 90%, 95%, 97%, or 99% of the dialkyl methylsulfoxonium salt starting material to the dialkyl sulfoxonium methylide of Formula (V).
  • dialkyl sulfoxonium methylide formation is carried out for a period of time with the range of from about 15 minutes to 8 hours, from about 30 minutes to about 6 hours, from about 1 hour to about 4 hours, or from about 1.5 hours to about 3 hours.
  • dialkyl sulfoxonium methylide formation is carried out for about two hours.
  • the reaction mixture is cooled to a temperature suitable for formation of the keto sulfoxonium ylide according to reactions 2, 5, 8, and 11 of reaction Schemes 1-4, respectively.
  • the reaction mixture comprising the dialkyl sulfoxonium methylide of Formula (V) is cooled to a temperature within the range of from about -30 0 C to about 30 0 C, from about -20 0 C to about 20 0 C, from about -10 0 C to about 10 0 C, or from about -5°C to about 5°C.
  • the reaction mixture comprising the dialkyl sulfoxonium methylide of Formula (V) is cooled to a temperature of about 0 0 C or cooler, about -10 0 C or cooler, or about -20 0 C or cooler.
  • the initial amount of dialkyl methylsulfoxonium salt of Formula (XVII) present in the reaction mixture is within a range of from about 1 equivalent to about 10 equivalents, from about 1 equivalent to about 8 equivalents, from about 1 equivalent to about 4 equivalents, or from about 1 equivalent to about 2 equivalents on a molar basis relative to the total amount of activated ester compound of Formula (II) or Formula (VIII), Formula (XV), or Formula (IX) (e.g. , compound (2)) ultimately added to the reaction mixture.
  • the initial amount of dialkyl methylsulfoxonium salt of Formula (XVII) in the reaction mixture corresponds to about 1.5 equivalents on a molar basis relative to the total amount of activated ester compound of Formula (II) or Formula (VIII), Formula (XV), or Formula (IX) (e.g., compound (2)) ultimately added to the reaction mixture.
  • the initial amount of dialkyl sulfoxonium methylide of Formula (V) in the reaction mixture is within a range of from about 1 equivalent to about 10 equivalents, from about 1 equivalent to about 8 equivalents, from about 1 equivalent to about 4 equivalents, or from about 1 equivalent to about 2 equivalents on a molar basis relative to the total amount of activated ester compound of Formula (II) or Formula (VIII), Formula (XV), or Formula (IX) (e.g., compound (2)) added to the reaction mixture.
  • the initial amount of dialkyl sulfoxonium methylide of Formula (V) in the reaction mixture corresponds to about 1.5 equivalents on a molar basis relative to the total amount of activated ester compound of Formula (II) or Formula (VIII), Formula (XV), or Formula (IX) (e.g. , compound (2)) added to the reaction mixture.
  • preparation of the keto sulfoxonium ylide i.e.
  • a compound of Formula (VI), or Formula (X) (e.g., compound (5)) is initiated by addition of an activated ester compound as disclosed herein (e.g., compounds of Formula (IV), Formula (IX), Formula (XIII), Formula (XVII), Formula (XX), Formula (XXII), Formula (XXIII), Formula (XXIV), Formula (XXV), Formula (XXVI), Formula (XXVII), Formula (XXVIII), Formula (XXIX), or Formula (XXX), or compounds having the specific structures of compound (3), compound (11), compound (13), compound (15), compound (17), compound (18), compound (19), compound (20), compound (21), compound (24), compound (25), or compound (26)) to the reaction mixture in which the dialkyl sulfoxonium methylide of Formula (V) is prepared.
  • an activated ester compound as disclosed herein (e.g., compounds of Formula (IV), Formula (IX), Formula (XIII), Formula (XVII), Formula (XX), Formula (
  • the activated ester is added in aliquots ("dropwise") over an extended period of time ranging from about 10 minutes to 2 hours, from about 20 minutes to 90 minutes, from abut 30 minutes to an hour. In a specific embodiment, the activated ester is added over about a 45 minute period. In certain embodiments, the above additions are made in a drop-wise fashion.
  • keto sulfoxonium ylide i.e. a compound of Formula (VI), or Formula (X) (e.g., compound (5))
  • formation of the keto sulfoxonium ylide is carried out for a period of time sufficient to convert at least about 50%, 60%, 70%, 80%, 85%, 90%, 95%, 97%, or 99% of the activated ester compound as disclosed herein (see above) starting material to the corresponding keto sulfoxonium ylide of Formula (VI), or Formula (X) (e.g., compound (5)).
  • keto sulfoxonium ylide formation is continued (i.e., after completion of addition of the activated ester starting material) for an additional period of time with the range of from about 15 minutes to 8 hours, from about 30 minutes to about 6 hours, from about 1 hour to about 4 hours, or from about 1.5 hours to about 3 hours. In a particular embodiment, keto sulfoxonium ylide formation is carried out for at least about 2 additional hours, at least about 3 additional hours, or at least about 4 additional hours, or more.
  • formation of the keto sulfoxonium ylide is quenched with water (e.g., using a volume of water within a range of from about 10 to about 50%, from about 15% to about 40%, or from about 20% to about 30% of the total reaction volume).
  • the organic layer is separated and washed (e.g., with brine), dried (e.g., over sodium sulfate) and evaporated under reduced pressure.
  • the residue obtained may be washed (azeotroped) with an appropriate solvent (e.g., toluene) and again evaporated under reduced pressure to provide a residue comprising the keto sulfoxonium ylide Formula (VI) or Formula (X).
  • keto sulfoxonium ylide compounds of Formula (VI), or Formula (X) can be isolated and further purified using methods, reagents, and equipment known in the art including but not limited to gas chromatographic methods using chiral columns, and high pressure liquid chromatographic analysis using chiral columns.
  • methods, reagents, and equipment known in the art including but not limited to gas chromatographic methods using chiral columns, and high pressure liquid chromatographic analysis using chiral columns.
  • Illustrative examples showing the use of activated esters to synthesize keto sulfoxonium ylide compounds useful for preparing ⁇ -chloroketones are provided in Examples l.B. and 2.A through 2.G.
  • keto sulfoxonium ylide of Formula (VI), or Formula (X) (e.g., compound (5)) is taken up in a suitable organic solvent and contacted with an appropriate source of anhydrous HCl at a suitable temperature and for an appropriate period of time to provide an ⁇ -chloroketone product of Formula (I), or Formula (VII) (e.g., compound (6)).
  • the keto sulfoxonium ylide is taken up in a suitable organic solvent, e.g., an aprotic solvent such as but not limited to DMSO, DMF, dimethylacetamide, N- methylpyrollidinone, dioxane, THF, methyl-THF, acetonitrile, toluene, acetic acid in DMF, and mixtures thereof.
  • a suitable organic solvent e.g., an aprotic solvent such as but not limited to DMSO, DMF, dimethylacetamide, N- methylpyrollidinone, dioxane, THF, methyl-THF, acetonitrile, toluene, acetic acid in DMF, and mixtures thereof.
  • the solvent is a polar aprotic solvent.
  • the organic solvent is an anhydrous organic solvent.
  • the solvent is an anhydrous solvent.
  • the solvent is THF or anhydrous THF.
  • anhydrous HCl is added as a gas, as solution in an inert solvent (e.g., 4 M HCl in dioxane) or it may prepared in situ.
  • an inert solvent e.g. 4 M HCl in dioxane
  • a chloride salt is contacted with a strong acid.
  • such chloride salts include, but are not limited to LiCl and tetrabutylammonium chloride.
  • the chloride salt is NaCl or KCl.
  • the organic acids is selected from, but not limited to, methanesulfonic, ethanesulfonic, trifluoromethansulfonic, and nonafluorobutanesulfonic acids.
  • the acid is a mineral acid, such as but not limited to concentrated sulfuric acid.
  • anhydrous HCl is prepared in situ by treatment of an acid chloride, such as but not limited to a carboxylic acid chloride (e.g., acetyl chloride), thionyl chloride, phosphorus(III) or (V) chloride, phosphorus oxychloride, chlorosulfonic acid) with a nucleophile, e.g., an alcohol such as but not limited to methanol.
  • anhydrous HCl is prepared in situ by contacting LiCl with methanesulfonic acid.
  • the chloride salt and/or the organic acid are added to the reaction before, after or simultaneously with the keto sulfoxonium ylide starting material of Formula (VI), or Formula (X).
  • formation of ⁇ -chloroketone of Formula (VI), or Formula (X) according to reaction 3, 6, 9, or 12 of Schemes 1-4, respectively is carried out at an initial temperature within the range of from about -30 0 C to about 30 0 C, from about -20 0 C to about 20 0 C, from about -10 0 C to about 10 0 C, or from about -5°C to about 5°C.
  • ⁇ -chloroketone formation is carried out at an initial temperature of about 0 0 C.
  • the temperature of the reaction mixture comprising the keto sulfoxonium ylide, chloride salt, and organic acid may be raised from the initial temperature to a final temperature within the range of from about 20 0 C to about 120 0 C, from about 30 0 C to about 110 0 C, from about 40 0 C to about 100 0 C, from about 50 0 C to about 90 0 C, or from about 60 0 C to about 80 0 C.
  • the final temperature is about 70 0 C.
  • the reaction temperature is raised gradually from the initial temperature to the final temperature.
  • the reaction may be maintained at the final temperature, with stirring, for a period of from about 30 minutes to about 8 hours, from about 60 minutes to about 4 hours, from about 90 minutes to about 2.5 hours. In a particular embodiment, the reaction may be maintained at the final temperature for about 2 hours.
  • formation of an ⁇ -chloroketone of Formula (VI), or Formula (X) according to reaction 3, 6, 9, or 12 of Schemes 1-4, respectively, is carried out for a total period of time sufficient for conversion of at least about 50%, 60%, 70%, 80%, 85%, 90%, 95%, 97%, or 99% of the substrate keto sulfoxonium ylide of Formula (VI) or Formula (X) to the ⁇ -chloroketone product of Formula (I) or Formula (VII).
  • ⁇ -chloroketone formation is carried out for a total period of time with the range of from about 30 minutes to 10 hours, from about 45 minutes to about 6 hours, from about 1 hour to about 4 hours, or from about 1.5 hours to about 3 hours.
  • formation of the ⁇ -chloroketone of Formula (VI), or Formula (X) according to reaction 3, 6, 9, or 12 of Schemes 1-4, respectively is carried out for a total of about 2 hours.
  • formation of the ⁇ -chloroketone of Formula (VI), or Formula (X) according to reaction 3, 6, 9, or 12 of Schemes 1-4, respectively is carried out for a total of about three hours.
  • ⁇ -chloroketone formation is carried out with an initial concentration an initial amount of the keto sulfoxonium ylide of Formula (VI) or Formula (X) substrate present within a range of from about 0.01 M to about 1.0 M, from about 0.025 M to about 0.75 M, from about 0.05 M to about 0.5 M, from about 0.1 M to about 0.4 M, from about 0.15 M to about 0.3 M.
  • activated ester formation is carried out with an initial amount of substrate present at a concentration of about 0.2 M.
  • ⁇ -chloroketone formation is carried out with an initial amount of chloride salt within a range of from about 4 equivalents to about 1 equivalent, on a molar basis, relative to the keto sulfoxonium ylide substrate of Formula (VI) or Formula (X).
  • ⁇ -chloroketone formation is carried out with an initial amount of chloride salt within a range of from about 2 equivalents to about 1 equivalent, from about 2 equivalents to about 1 equivalent, from about 1.5 equivalents to about 1 equivalent, from about 1.25 equivalents to about 1 equivalent, or about 1 equivalent, on a molar basis, relative to the keto sulfoxonium ylide substrate.
  • activated ester formation is carried out with an initial amount of chloride salt representing about 1.1 equivalents, on a molar basis, relative to the keto sulfoxonium ylide substrate.
  • ⁇ -chloroketone formation is carried out with an initial amount of organic acid within a range of from about 4 equivalents to about 1 equivalent, on a molar basis, relative to the keto sulfoxonium ylide substrate of Formula (VI) or Formula (X).
  • ⁇ -chloroketone formation is carried out with an initial amount of organic acid within a range of from about 2 equivalents to about 1 equivalent, from about 2 equivalents to about 1 equivalent, from about 1.5 equivalents to about 1 equivalent, from about 1.25 equivalents to about 1 equivalent, or about 1 equivalent, on a molar basis, relative to the keto sulfoxonium ylide substrate.
  • activated ester formation is carried out with an initial amount of organic acid representing about 1.1 equivalents, on a molar basis, relative to the keto sulfoxonium ylide substrate.
  • ⁇ -chloroketone formation is quenched with water (e.g., using a volume of water within a range of from about 25 to about 200%, from about 50% to about 200%, or from about 80% to about 150% of the total reaction volume).
  • the reaction is quenched with an approximately equal volume of water.
  • the temperature of the reaction is lowered, e.g., to about 20 0 C (room temperature) before it is quenched.
  • the organic layer is separated and washed (e.g., with brine), dried (e.g., over sodium sulfate) and evaporated under reduced pressure.
  • the residue obtained which comprises the ⁇ -chloroketone, may be taken up in an appropriate solvent or solvent mixture and crystallized.
  • the residue is taken up with hot heptane/ethyl acetate (5: 1), and, upon cooling, crystallized therefrom.
  • the ⁇ -chloroketone compounds of Formula (I), Formula (XV), or Formula (VII) (e.g., compound (6)) can be isolated and further purified using methods, reagents, and equipment known in the art including but not limited to gas chromatographic methods using chiral columns, and high pressure liquid chromatographic analysis using chiral columns. 5.
  • This example illustrates a typical experimental procedure for stereoselective synthesis of an ⁇ -chloroketone compound of Formula (I), specifically compound (6) (i.e., the ⁇ -chloroketone derivative of N-boc-L-phenylalanine) via an activated ester intermediate compound of Formula (IV), specifically compound (3), and a sulfoxonium ylide intermediate compound of Formula (VI), specifically compound (5), as depicted in Scheme 4.
  • compound (6) i.e., the ⁇ -chloroketone derivative of N-boc-L-phenylalanine
  • HPLC was used to determine the e.e. of the sulfoxonium ylide intermediate as follows: Column: Chiral pak AD-H column; 4.6 mm x 25 cm; Temperature: 25 0 C; Flow Rate: 0.8 mL/min; Mobile Phase: Isocratic mobile phase 80:20 ethanol:heptane; Duration: 12 min. The retention times observed were as follows: L-ylide: 6.4 min., and D-ylide: 10.9 min.
  • Example 2 Formation of Various Activated Ester and Chiral Sulfoxonium Ylide Intermediates Useful for Syntheses of Compounds of Formula (I) Using Various Activating Agents
  • Example 2 illustrates how a chiral keto sulfoxonium ylide intermediate compound of Formula (VI), specifically compound (5), which are useful for making ⁇ -chloroketone compounds of Formula (I) can be synthesized using a variety of activating agents, such as compounds of Formula (III) or Formula (XII), specifically including phenyl chloroformate, benzyl chloroformate, N-Boc-D- Phe-O-succinimide, pivaloyl chloride, diethyl chlorophosphate, carbonyl diimidazole, and isobutyl chloroformate.
  • Example 2.F. further illustrates the conversion of the chiral keto sulfoxonium ylide of compound (5) to the ⁇ -chloroketone derivative of N-Boc-L-phenylalanine, compound (6).
  • Keto sulfoxonium ylide of compound (5) formation In a separate 3-neck RB flask, potassium tert-butoxide (7.50 mmol, 0.84 g) was dissolved in 15 mL anhydrous THF and trimethylsulfoxonium chloride (3.75 mmol, 0.48 g) was added. The resulting slurry was heated at 90 0 C for 2 h. The reaction mixture was then cooled to room temperature and subsequently to about -20 0 C. The filtered activated ester solution from above was then added dropwise maintaining the temperature at about - 20 0 C. The reaction was stirred at the same temperature for 4 h.
  • reaction mixture was quenched by adding 10 mL water, the organic layer was separated and washed with brine (2 x 15 mL), dried over Na 2 SO 4 and concentrated under reduced pressure to obtain the desired product of compound (5) as a light yellow sticky solid (0.76 g, 95% yield, 76% ee).
  • reaction mixture was then cooled to room temperature and subsequently to about -20 0 C.
  • the filtered activated ester solution from above was then added dropwise maintaining the temperature at about -20 0 C.
  • the reaction was stirred at the same temperature for 4 h.
  • the reaction mixture was quenched by adding 10 mL water, the organic layer was separated and washed with brine (2 x 15 mL), dried over Na 2 SO 4 and concentrated under reduced pressure to obtain the desired product of compound (5) as a light yellow sticky solid (0.78 g, 98% yield, 20% ee).
  • reaction mixture was quenched by adding 7 mL water, the organic layer was separated and washed with brine (2 x 10 mL), dried over Na 2 SO 4 and concentrated under reduced pressure to obtain the desired product as a light yellow solid (0.40 g, 87% yield, 99% ee).
  • reaction mixture was quenched by adding 10 mL water, the organic layer was separated and washed with brine (2 x 15 mL), dried over Na 2 S ⁇ 4 and concentrated under reduced pressure to obtain the desired product of compound (5) as a light yellow solid (0.79 g, 98% yield, 96% ee).
  • Activated ester of compound (26) formation To a 3-neck RB flask was added 0.66 g (2.5 mmol) of N-Boc-L-Phe and 3 mL of anhydrous THF. The solution was cooled to -15 0 C and triethylamine (5.0 mmol, 0.70 mL) was added dropwise. After stirring for 10 minutes at -10 0 C, this solution was added dropwise to a precooled solution of diethyl chlorophosphate (2.5 mmol, 0.36 mL) in 10 mL of anhydrous THF at -15 0 C. A white precipitate was observed. The reaction mixture was stirred between -10 0 C and -15 0 C for 30 minutes and then the precipitate was filtered and washed with 10 mL THF. The filtrate thus obtained was used directly for ylide formation.
  • reaction mixture was quenched by adding 10 mL water, the organic layer was separated and washed with brine (2 x 15 mL), dried over Na 2 SO 4 and concentrated under reduced pressure to obtain desired product of compound (5) as light yellow solid (0.68 g, 85% yield, 87% ee).
  • Keto sulfoxonium ylide compound (5) formation In a separate 3-neck RB flask, potassium tert-butoxide (4.12 mmol, 0.46 g) was dissolved in 15 mL anhydrous THF and trimethylsulfoxonium iodide (3.75 mmol, 0.82 g) was added. The resulting slurry was heated at 90 0 C for 2 h. The reaction mixture was then cooled to room temperature and subsequently to about -20 0 C. The filtered activated ester solution from above was then added dropwise maintaining the temperature at about -20 0 C. The reaction was stirred at the same temperature for 2 h.
  • reaction mixture was quenched by adding 15 mL water, the organic layer was separated and washed with brine (2 x 120 mL), dried over Na 2 SO 4 and concentrated under reduced pressure to obtain desired product of compound (5) as light yellow sticky solid (0.55 g, 65% yield, 99% ee).
  • ⁇ -Chloroketone of compound (6) formation The keto sulfoxonium ylide of compound (5) (6.18 mmol, 2.0 g) from above was dissolved in 30 mL anhydrous THF and the solution was cooled to 0 0 C. Lithium chloride (6.80 mmol, 0.29 g) and methanesulfonic acid (6.80 mmol, 0.44 mL) were added. The temperature was slowly raised to room temperature and subsequently to 80 0 C. The reaction mixture was stirred at 80 0 C for 2 h. After cooling to room temperature, the reaction was quenched by adding 30 mL water.
  • N-Boc-L-Phe-imidazolide which includes the intermediates compound (24) and compound (25), or N-Boc-D-Phe-imidazolide, which includes the intermediates corresponding to the opposing D-enantiomers of compound (24) and compound (25).
  • Keto sulfoxonium ylide formation A 3-neck 250-mL RB flask equipped with a thermocouple, a magnetic stirrer, a magnetic stir bar and a reflux condenser was charged with trimethylsulfoxonium chloride (5.77 g, 45 mmol), potassium tert-butoxi ⁇ e (45 mL, 45 mmol, 1 M in THF) and 30 mL anhydrous THF. The solution was refluxed for 2 h, cooled to room temperature and then split into 2 x 37.5 mL aliquots.
  • the reaction can be carried out as above, except that trimethylsulfoxonium iodide is substituted for the trimethylsulfoxonium chloride, and the concentrated solution of either Boc-L-Phe-imidazolide or Boc-D-Phe-imidazolide (approx 2.69 g, 7.5 mmol) is added dropwise to a solution cooled to and maintained at -20 0 C.
  • Boc-L-Phe-imidazolide or Boc-D-Phe-imidazolide approximately 2.69 g, 7.5 mmol

Abstract

The present disclosure provides compositions and methods for the preparation of ? chloroketones from carboxylic acids. In particular embodiments, the present disclosure provides procedures for the preparation of chiral ? chloroketone derivatives of amino acids.

Description

PROCESSES FOR THE PREPARATION OF ALPHA-CHLOROKETONES FROM CARBOXYLIC ACIDS
1. TECHNICAL FIELD
[0001] The present disclosure provides compositions and methods for the preparation of α-chloroketones from carboxylic acids.
2. BACKGROUND
[0002] Alpha-chloroketones have intrinsic activity as enzyme inhibitors and are also useful as intermediates for the preparation of a number of clinically and commercially important compounds. In particular, chiral alpha-chloroketones derived from amino acids are useful for the preparation of chirally pure therapeutic agents, including, for example, inhibitors of renin, angiotensin converting enzyme (ACE), and HIV proteases, see e.g., Wang et al. (2004) J. Org. Chem. 69: 1629-1633. Among the therapeutic agents for which chiral α-chloroketones can be used as synthetic intermediates are: Atazanavir, Nelfmavir, Cefovecin, Indacaterol, Ziprasidone, Lumefantrine, Mauladrine, and numerous antifungals (including e.g., Itraconazole, Bromuconazole, Chlorfenvinphos, Econazole, Enilconazole, Fenticonazole, Hexaconazole, Itraconazole, Ketoconazole, Sulconazole, Terconazole. In view of their importance and synthetic utility, a number of methods have been described for the preparation of α-chloroketones, including Nugent et al. (2007) Org. Synth. 84j 58-67, U.S. Patent No. 6,399,793 Bl to Kronenthal et. al, and U.S. Patent No. 6,924,397 B2 to Nugent et. al However, those methods involve the use of dangerous reagents (e.g., diazomethane) that are not suitable for commercial production, or they do not provide the requisite level of chiral purity in the α-chloroketone product. (See e.g., Wang et al (2004) J. Org. Chem. 69: 1629-1633.) Accordingly, there is a need for additional methods for the preparation of α-chloroketones from carboxylic acids, particularly for the preparation of substantially chirally pure α-chloroketones from amino acids.
3. SUMMARY
[0003] The present disclosure is directed to processes for the preparation of α-chloroketones from carboxylic acids, and, more particularly, to processes for the preparation of substantially chirally pure and chirally pure α-chloroketones derivatives of amino acids.
[0004] In certain embodiments, the present disclosure describes a method for the preparation of compounds of Formula (I), which method is depicted in Scheme 1 below:
Scheme 1
Figure imgf000003_0001
("I) (IV) (Vl) (I)
[0005] According to the process disclosed in Scheme 1 , the carboxyl group of a compound of Formula (II) is activated by contact with a chloroformate reagent, of Formula (III) to provide an activated ester intermediate of Formula (IV). The activated ester intermediate of Formula (IV) is contacted with a sulfoxonium ylide of Formula (V) to provide the keto ylide intermediate of Formula (VI), which, in turn, is contacted with anhydrous HCl to provide the α-chloroketone of Formula (I).
[0006] With respect to the compounds depicted in Scheme 1 , R1 is selected from the group consisting Of-CH(R5)NH(R6), -(CrC2)alkyl, -(CrC3)alkyl, -(CrC4)alkyl, -(C1-C6)alkyl,-(C1-C10)alkyl, alkenyl, aryl, and heteroaryl in which each alkyl, aryl, and heteroaryl can be unsubstituted or substituted with at least one moiety selected from the group consisting of -OH, -SH, -SHCH3, -COOH, -C(O)NH2, -NHCH(NH2)(=NH), -(C3-Ci0)cycloalkyl, -(C3-C6)cycloalkyl, -phenyl, and -(5- to 10-membered)heteroaryl. Moreover, each of the -(C3-C6)CyC loalkyl, -phenyl, and -(5- to 10-membered)heteroaryl may also be unsubstituted or may be substituted with at least one moiety selected from the group consisting of hydrogen, -OH, -CH2OH, -CH2CH2OH -NH2, -halo, -CN, -NO2, -C(O)NH2,-(Ci-C6)alkyl, -C(O)NH(Ci -C4))alkyl, -C(O)N((Ci-C4)alkyl)2, and -(Ci-C4)alkyl.
[0007] With respect to the compounds depicted in Scheme 1, R2 is an alkyl, alkenyl, aryl, or heteroaryl group selected from the group consisting of phenyl, benzyl, vinyl, -(Ci-C2)alkyl, -(Ci- C3)alkyl, -(Ci-C4)alkyl, -(Ci-C6)alkyl, and -(Ci-Cio)alkyl, where each alkyl group may be unsubstituted or may be substituted with at least one moiety selected from the group consisting of -(C3-C7)cycloalkyl, -phenyl, and -(5- to 10-membered)heteroaryl.
[0008] In particular embodiments, R2 is selected from the group consisting of phenyl, benzyl, vinyl, methyl, and isobutyl. In particular embodiments, R is isobutyl.
[0009] With respect to the compounds depicted in Scheme 1 , R3 and R4 are each independently selected from the group consisting of -(CrC2)alkyl, -(CrC3)alkyl, -(CrC4)alkyl, -(CrC6)alkyl, -(C r Cio)alkyl, where each alkyl group may be unsubstituted or may be substituted with at least one moiety selected from the group consisting of -(C3-Ci0)cycloalkyl, -(C3-C6)cycloalkyl, -phenyl, and -(5- to 10-membered)heteroaryl. Moreover, each -(C3-Ci0)cycloalkyl, -(C3-C6)cyc loalkyl , -phenyl, and -(5- to 10-membered)heteroaryl may also be unsubstituted or may be substituted with at least one moiety selected from the group consisting of -(Ci-C2)alkyl, -(Ci-C3)alkyl, and -(Ci-C4)alkyl. [0010] In particular embodiments, R3 and R4 are both methyl.
[0011] In those embodiments in which R1 is -CH(R5)NH(R6), R5 is selected from the group consisting of-(d-C2)alkyl, -(CrC3)alkyl, -(CrC4)alkyl, -(Ci-C6)alkyl, and -(Ci-Cio)alkyl, and each alkyl may be unsubstituted or it may be substituted with at least one moiety selected from the group consisting of -OH, -SH, -SHCH3, -COOH, -C(O)NH2, -NHCH(NH2)(=NH), -(C3-C10)cycloalkyl, -(C3-C6)cycloalkyl, -phenyl, and -(5- to 10-membered)heteroaryl. Moreover, each -(C3- Cio)cycloalkyl, -(C3-C6)cycloalkyl , -phenyl, and -(5- to 10-membered)heteroaryl may also be unsubstituted or it may be substituted with at least one moiety selected from the group consisting of hydrogen, -OH, -CH2OH, -CH2CH2OH -NH2, -halo, -CN, -NO2, -C(O)NH2,-(Ci-C6)alkyl, -C(O)NH(Ci -C4))alkyl, -C(O)N((Ci-C4)alkyl)2, and -(Ci-C4)alkyl.
[0012] In those embodiments in which R1 is -CH(R5)NH(R6), R6 is a nitrogen protecting group. In certain embodiments, R6 is selected from the group consisting of benzyloxycarbonyl (Cbz), 9- fluorenylmethoxycarbonyl (FMOC), and t-butoxycarbonyl (BOC). In particular embodiments, R6 is t- butoxycarbonyl (BOC).
[0013] In certain embodiments, the sulfoxonium methylide reagent of Formula V is prepared and isolated before use as a reagent in reaction 2 of Scheme 1 above (as well as in reactions 5, 8, 11, 14, 17, 20, and 22 of Schemes 2-7, and 10 below). In one embodiment, an appropriate sulfoxide (i.e. (R3)(R4)S(O)), e.g., dimethylsulfoxide, is contacted with methyl iodide to provide the corresponding dialkyl methylsulfoxonium iodide salt, which, in turn, may be contacted with a strong base in an organic solvent to provide the dialkyl sulfoxonium methylide of Formula (V).
[0014] In certain embodiments, the activated ester product of Formula (IV), formed in Reaction 1 and the reaction mixture in which the sulfoxonium ylide reagent of Formula (V) is formed are directly combined, i.e., without purification of either product. In certain embodiments, the activated ester product of Formula (IV) is collected, resuspended, and added directly to the reaction mixture in which the sulfoxonium ylide reagent of Formula (V) is formed. In a particular embodiment, the activated ester product of Formula (IV) is collected, resuspended, and added in multiple aliquots directly to the reaction mixture in which the sulfoxonium ylide reagent of Formula (V) is formed.
[0015] The HCl used in reaction 1 for conversion of keto ylide compounds of Formula (VI) to compounds of Formula (I) is anhydrous HCl. In certain embodiments, the anhydrous HCl is provided in situ by contacting a chloride salt and an organic acid in an organic solvent. In certain embodiments, the chloride salt is LiCl. In certain embodiments, the organic acid is methanesulfonic acid. In certain embodiments the organic solvent is anhydrous.
[0016] In another embodiment, the general process of Scheme 1 can be carried out wherein rather than using a chloro formate compound of Formula (III), the compound of Formula (II) is activated by contact with an acyl chloride reagent of Formula (XII) or a carboxylic acid anhydride reagent of Formula (XXXI) to provide an activated intermediate of Formula (XIII).
Figure imgf000005_0001
(XIl) (XXXl)
[0017] This alternative process using an acyl chloride reagent of Formula (XII) or a carboxylic acid anhydride reagent of Formula (XXXI) is disclosed in Scheme 2 below. The carboxyl group of a compound of Formula (II) is activated by contact with an acyl chloride reagent of Formula (XII) to provide the activated intermediate of Formula (XIII). As in the general process of Scheme 1, the activated intermediate of Formula (XIII) then is contacted with a sulfoxonium ylide of Formula (V) to provide the keto ylide intermediate of Formula (VI), which in turn, is contacted with anhydrous HCl to provide the α-chloroketone of Formula (I).
Scheme 2
Figure imgf000005_0002
(") (XIIi) (Vi) (I)
[0018] With respect to the compounds of Scheme 2, R1 to R6 are as described above regarding Scheme 1. In certain embodiments, R is tert-butyl and, therefore the compound of Formula (XII) is compound (7) (pivaloyl chloride):
Figure imgf000005_0003
(7)
[0019] In one embodiment, the carboxylic acid anhydride compound of Formula (XXXI) is compound (27), pivaloyl anhydride, is used in reaction 4 of Scheme 2 (in place of pivaloyl chloride (7)) to provide the activated ester of Formula (XIII).
Figure imgf000006_0001
[0020] In one embodiment of the process of Scheme 1, the present disclosure also provides methods for the preparation of compounds of Formula (VII) according to the process depicted in Scheme 3, below:
Scheme 3
Figure imgf000006_0002
(VIII) (IX) (X) (VM)
[0021] According to the process disclosed in Scheme 3, the carboxyl group of a compound of Formula (VIII) is activated by contact with a chloroformate reagent of Formula (III) to provide an activated intermediate of Formula (IX). The activated intermediate of Formula (IX) is contacted with a sulfoxonium ylide of Formula (V) to provide the keto ylide intermediate of Formula (X), which, in turn is contacted with anhydrous HCl (e.g., produced by LiCl and methanesulfonic mixture) to provide the α-chloroketone of Formula (VII).
[0022] With respect to the compounds of Scheme 3, R2 to R6 are as described above in connection with Scheme 1.
[0023] In certain embodiments, the product of Scheme 3 is a substantially chirally pure compound of Formula (VII). In certain embodiments, the product of Scheme 3 is a chirally pure compound of Formula (VII).
[0024] In certain embodiments, the process of Scheme 3 (i.e. reactions 7, 8, and 9) can be carried out using, as starting material, a substantially chirally pure or chirally pure L-amino acid compound of Formula (XIVa), or a substantially chirally pure or chirally pure D-amino acid compound of Formula (XIVb).
Figure imgf000006_0003
[0025] In this instance, the process of Scheme 3 will provide the α-chloroketone derivative of an L- amino acid compound of Formula (XVa) or the α-chloroketone derivative of a D-amino acid compound of Formula (XVb) as the product.
Figure imgf000007_0001
(XVa) (XVb)
[0026] In such embodiments, therefore, the product of Scheme 3 is a substantially chirally pure compound of Formula (XVa) or compound of Formula (XVb). In certain embodiments, the product of Scheme 3 is a chirally pure compound of Formula (XVa) or compound of Formula (XVb).
[0027] In one embodiment of the process Scheme 3, the present disclosure also provides methods for the preparation of an α-chloroketone derivative of N-protected amino acid compounds of Formula (VII) (e.g., compound (6)) according to the process depicted in Scheme 4, below:
Scheme 4
Figure imgf000007_0002
(6) (5)
[0028] According to the processes disclosed in Scheme 4, the carboxyl group of compound (1) is activated by contact with the chloroformate reagent isobutyl chloroformate, compound (2), to provide the activated ester intermediate, compound (3). The activated ester intermediate, compound (3), is contacted with a sulfoxonium ylide, compound (4), to provide the keto ylide intermediate, compound (5), which, in turn, is contacted with anhydrous HCl to provide the α-chloroketone, compound (6).
[0029] In certain embodiments, the product of Scheme 4 is substantially chirally pure compound (6). In certain embodiments, the product of Scheme 4 is chirally pure compound (6).
[0030] In other embodiments, the starting material is not a chirally pure compound; e.g., where the starting material is mixture (e.g., a racemic mixture) comprising both an N-protected-D-amino acid and an N-protected-L-amino acid. Examples of each are, respectively, compounds of Formula (XVI) and (VIII). In such embodiments, the chemical processes described herein can be depicted as in Scheme 5 below:
Scheme 5
Figure imgf000008_0001
(XVI) (XVII) (XVIII) (XIX) where R2-R6 are as described above in connection with Scheme 1 and the starting material of Formula (XVI) may encompass a mixture comprising a compound of Formula (VIII) and a compound of Formula (XIV) and the product of Formula (XIX) may encompass a mixture comprising a compound of Formula (XVa) and a compound of Formula (XVb).
[0031] In another embodiment, the commercially available activated ester of Formula (XX) (derived from N-hydroxysuccinimide) is contacted with a sulfoxonium ylide of Formula (V) to provide the keto ylide intermediate of Formula (VI), which in turn, is contacted with anhydrous HCl to provide the α-chloroketone of Formula (I), as depicted in Scheme 6, below:
Scheme 6
Figure imgf000008_0002
(XX) (Vl) (I)
[0032] In another embodiment, the general process of Scheme 1 can be carried out wherein rather than using a chloro formate compound of Formula (III), the carboxyl group of a compound of Formula (II) is activated by contact with a dialkyl or diaryl halophosphate of Formula (XXI) to provide the activated ester intermediate of Formula (XXII), as depicted in the process disclosed in Scheme 7 below.
Scheme 7
Figure imgf000009_0001
CO (XXII) (Vl) (I)
[0033] The activated ester intermediate of Formula (XXII) is contacted with a sulfoxonium ylide of Formula (V) to provide the keto ylide intermediate of Formula (VI), which as in the general process of Scheme 1, then is contacted with anhydrous HCl to provide the α-chloroketones of Formula (I).
[0034] With respect to the compounds of Scheme 7, R1 to R6 are as described above in connection with Scheme 1, and R7 and R8 are each independently selected from the group consisting Of (Ci-C6) alkyl and aryl and X is Br, Cl, or I. In particular embodiments, R7 and R8 are each independently selected from the group consisting of -methyl, -ethyl, -propyl, -isopropyl, -butyl, -iso-butyl, -?-butyl, and phenyl. In a specific embodiment, R7 and R8 are both ethyl. In another specific embodiment, X is Cl.
[0035] In another alternative embodiment of the general process of Scheme 1 for preparing an α- chloroketone compound of Formula (I) provided by the present disclosure, rather than using a chloro formate compound of Formula (III), the carboxyl group of a compound of Formula (II) is activated by contact with N,N-carbonyl diimidazole (CDI) reagent to provide the activated esters of Formula(XXVIII), and Formula (XXIX), depicted below:
R
Figure imgf000009_0002
(XXVlIl) (XXIX)
[0036] The activated ester intermediates of Formula (XXVIII) or Formula (XXIX), alone or as a mixture, then is contacted with a sulfoxonium ylide of Formula (V) to provide the keto ylide intermediate of Formula (VI). As in the general process of Scheme 1, the keto ylide intermediate of Formula (VI) then is contacted with anhydrous HCl to provide the α-chloroketones of Formula.
[0037] In further embodiments, a compound of Formula (II) is activated with CDI to provide compounds (22), and (23) shown below:
Figure imgf000010_0001
[0038] In certain embodiments, the activated ester compounds prepared using CDI, R5 is a phenyl moiety and R6 is a Boc protecting group, thereby providing compound (24) and compound (25), depicted below:
Figure imgf000010_0002
[0039] With respect to the process using CDI reagent, R1 to R6 of the compounds are as described above in connection with Scheme 1.
[0040] In certain embodiments, the disclosure provides an activated ester compound useful for preparing an α-chloroketone compound of Formula (I), with R!-R6 defined as in connection with Scheme 1 , wherein the compound is selected from the compounds having the following structural formulas depicted herein: Formula (IV), Formula (IX), Formula (XIII), Formula (XVII), Formula (XX), Formula (XXII), Formula (XXIII), Formula (XXIV), Formula (XXV), Formula (XXVI), Formula (XXVII), Formula (XXVIII), Formula (XXIX), and Formula (XXX).
[0041] In particular embodiments, the disclosure provides an activated ester compound useful for preparing an α-chloroketone of Formula (I), wherein the compound is selected from the list of compounds having the following numbered structures disclosed herein: compound (3), compound (11), compound (13), compound (15), compound (17), compound (18), compound (19), compound (20), compound (21), compound (24), compound (25), and compound (26).
[0042] In certain embodiments, the disclosure provides a keto sulfoxonium ylide compound useful for preparing an α-chloroketone of Formula (I), wherein the compound is selected from the compounds having the following structural formulas depicted herein: Formula (VI), Formula (X), and Formula (XVIII). In a particular embodiment, the disclosure provides a keto sulfoxonium ylide compound useful for preparing an α-chloroketone of Formula (I), wherein the compound has the structure of compound (5) as disclosed herein.
4. DETAILED DESCRIPTION
[0043] The present disclosure concerns processes for the preparation of α-chloroketones from carboxylic acids, particularly for the preparation of substantially chirally pure α-chloroketone derivatives of amino acids and chirally pure α-chloroketone derivatives of amino acids. Included herein is disclosure of the condensation reaction of a carboxylic acid with a chloro formate reagent which provides an activated ester intermediate that can be readily converted to a keto sulfoxonium ylide by reaction with an appropriate sulfoxonium ylide. Also included herein is the condensation reaction of a carboxylic acid with an acyl chloride, a dialkyl or diaryl halophosphate, a carboxylic acid anhydride, N-hydroxysuccinimide, or N,N-carbonyl diimidazole to provide an activated ester intermediate that can be converted by reaction with an appropriate sulfoxonium ylide to a keto sulfoxonium ylide. The keto sulfoxonium ylide can be converted to a desired α-chloroketone by contact with chloride in the presence of a suitable organic acid, e.g., anhydrous HCl provided by LiCl in the presence of methanesulfonic acid.
4.1. Definitions
[0044] As used herein, the following terms are intended to have the following meanings: [0045] "Alkyl" means a straight chain or branched non cyclic hydrocarbon. The term alkyl encompasses, inter alia, "(CrC10)alkyl," "(CrC6)alkyl," "(CrC4)alkyl," "(CrC3)alkyl," "(CrC2)alkyl," "(C2-C4)alkyl," and "(C2-C6)alkyl."
[0046] "(Ci-Cio)alkyl," means a straight chain or branched non-cyclic hydrocarbon having from 1 to 10 carbon atoms. Representative straight chain -(Ci-Cio)alkyls include -methyl, ethyl, -n propyl, -n- butyl, -n-pentyl, -n-hexyl, -n-heptyl, -n-octyl, -n-nonyl, and -n-decyl. A branched alkyl means that one or more straight chain -(Ci-Cg)alkyl groups, such as methyl, ethyl or propyl, replace one or both hydrogens in a -CH2- group of a straight chain alkyl. A branched non cyclic hydrocarbon means that one or more straight chain -(Ci-Cio)alkyl groups, such as methyl, ethyl or propyl, replace one or both hydrogens in a -CH2- group of a straight chain non cyclic hydrocarbon. Representative branched - (Ci-Cio)alkyls include -iso-propyl, -sec-butyl, -iso-butyl, -tert-butyl, -iso-pentyl, -neopentyl, -1- methylbutyl, -2-methylbutyl, -3-methylbutyl, - 1 , 1 -dimethylpropyl, -1,2-dimethylpropyl, -1- methylpentyl, -2-methylpentyl, -3-methylpentyl, -4-methylpentyl, -1-ethylbutyl, -2-ethylbutyl, -3- ethylbutyl, -1,1-dimethylbutyl, -1,2-dimethylbutyl, -1,3-dimethylbutyl, -2,2-dimethylbutyl, -2,3-dimethylbutyl, -3,3-dimethylbutyl, - 1 -methylhexyl, -2-methylhexyl, -3-methylhexyl, A- methylhexyl, -5-methylhexyl, -1,2-dimethylpentyl, -1,3-dimethylpentyl, - 1 ,2-dimethylhexyl, -1,3- dimethylhexyl, -3,3-dimethylhexyl, - 1 ,2-dimethylheptyl, -1,3-dimethylheptyl, and -3,3- dimethylheptyl. [0047] "(Ci-C6)alkyl," means a straight chain or branched non cyclic hydrocarbon having from 1 to 6 carbon atoms. Representative straight chain -(Ci -Ce)alkyls include methyl, ethyl, -n propyl, -n butyl, -n pentyl, and -n-hexyl. Representative branched (Ci-C6)alkyls include -iso-propyl, -sec-butyl, -iso- butyl, -tert-butyl, -iso-pentyl, -neopentyl, - 1 -methylbutyl, -2-methylbutyl, -3-methylbutyl, -1,1- dimethylpropyl, - 1 ,2-dimethylpropyl, - 1 -methylpentyl, -2-methylpentyl, -3-methylpentyl, A- methylpentyl, - 1 -ethylbutyl, -2-ethylbutyl, -3-ethylbutyl, -1,1-dimethtylbutyl, - 1 ,2-dimethylbutyl, -1,3-dimethylbutyl, -2,2-dimethylbutyl, -2,3-dimethylbutyl, and -3,3-dimethylbutyl.
[0048] "(C2-C6)alkyl," means a straight chain or branched non cyclic hydrocarbon having from 2 to 6 carbon atoms. Representative straight chain -(C2-C6)alkyls include -ethyl, -n-propyl, -n butyl, -n pentyl, and -n hexyl. Representative branched -(C2-C6)alkyls include -iso-propyl, -sec-butyl, -iso- butyl, -tert-butyl, -iso-pentyl, -neopentyl, - 1 -methylbutyl, -2-methylbutyl, -3-methylbutyl, -1,1- dimethylpropyl, - 1 ,2-dimethylpropyl, - 1 -methylpentyl, -2-methylpentyl, -3-methylpentyl, A- methylpentyl, - 1 -ethylbutyl, -2-ethylbutyl, -3-ethylbutyl, -1,1-dimethtylbutyl, - 1 ,2-dimethylbutyl, -1,3-dimethylbutyl, -2,2-dimethylbutyl, -2,3-dimethylbutyl, and -3,3-dimethylbutyl.
[0049] "(Ci-C4)alkyl," means a straight chain or branched non cyclic hydrocarbon having from 1 to 4 carbon atoms. Representative straight chain -(Q -C4)alkyls include methyl, ethyl, -n propyl, and -n butyl. Representative branched -(Ci-C4)alkyls include -iso-propyl, -sec -butyl, -iso-butyl, and -tert- butyl.
[0050] "(C2-Czt)alkyl," means a straight chain or branched non cyclic hydrocarbon having from 2 to 4 carbon atoms. Representative straight chain -(C2-C4)alkyls include -ethyl, -n-propyl, and -n butyl. Representative branched -(Ci-C4)alkyls include -iso-propyl, -sec-butyl, -iso-butyl, and -tert-butyl.
[0051] "(Ci-C3)alkyl," means a straight chain or branched non-cyclic hydrocarbon having from 1 to 3 carbon atoms. Representative straight chain (Ci -C3)alkyls include -methyl, -ethyl, and -n-propyl. Representative branched -(Ci-C3)alkyls include -iso-propyl.
[0052] "(Ci-C2)alkyl" means a straight chain non cyclic hydrocarbon having 1 or 2 carbon atoms. Representative straight chain (Ci-C2)alkyls include methyl and ethyl
[0053] "Cycloalkyl" means a saturated monocyclic hydrocarbon. The term "cycloalkyl" encompasses, inter alia, "(C3-Ci2)cycloalkyl," "(C4-Ci2)cycloalkyl," "(C3-C8)cycloalkyl," "(C4- C8)cycloalkyl," "(C3-C6)cycloalkyl," and "(C4-C6)cycloalkyl." For example, "(C3-C7)cycloalkyl," means a saturated monocyclic hydrocarbon having from 3 to 7 carbon atoms. Representative (C3- C7)cycloalkyls include cyclopropyl, -cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
[0054] "-(3- to 7-membered)heterocycle" or "-(3- to 7-membered)heterocyclo" means a 3 to 7 membered monocyclic heterocyclic ring which is either saturated, unsaturated non-aromatic, or aromatic. A 3 -membered heterocycle can contain up to 1 heteroatom, a 4-membered heterocycle can contain up to 2 heteroatoms, a 5-membered heterocycle can contain up to 4 heteroatoms, a 6- membered heterocycle can contain up to 4 heteroatoms, and a 7-membered heterocycle can contain up to 5 heteroatoms. Each heteroatom is independently selected from nitrogen, which can be quaternized; oxygen; and sulfur, including sulfoxide and sulfone. The -(3- to 7- membered) heterocycle can be attached via a nitrogen or carbon atom. Representative (3- to 7- membered)heterocycles include pyridyl, furyl, thiophenyl, pyrrolyl, oxazolyl, imidazolyl, thiazolidinyl, thiadiazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, triazinyl, morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, 2,3-dihydrofuranyl, dihydropyranyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropyridinyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.
[0055] "-(5- or 6-membered)heterocycle" or "-(5- or 6-membered)heterocyclo" means a 5 or 6 membered monocyclic heterocyclic ring which is either saturated, unsaturated non-aromatic, or aromatic. A 5-membered heterocycle can contain up to 4 heteroatoms and a 6 membered heterocycle can contain up to 4 heteroatoms. Each heteroatom is independently selected from nitrogen, which can be quaternized; oxygen; and sulfur, including sulfoxide and sulfone. The -(5- or 6- membered)heterocycle can be attached via a nitrogen or carbon atom. Representative (5- or 6- membered)heterocycles include pyridyl, furyl, thiophenyl, pyrrolyl, oxazolyl, imidazolyl, thiazolidinyl, thiadiazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, triazinyl, morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, 2,3-dihydrofuranyl, dihydropyranyl, hydantoinyl, valerolactamyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropyridinyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.
[0056] "-(3- to 5-membered)heterocycle" or "-(3- to 5-membered)heterocyclo" means a 3 to 5 membered monocyclic heterocyclic ring which is either saturated, unsaturated non-aromatic, or aromatic. A 3 -membered heterocycle can contain up to 1 heteroatom, a 4-membered heterocycle can contain up to 2 heteroatoms, and a 5-membered heterocycle can contain up to 4 heteroatoms. Each heteroatom is independently selected from nitrogen, which can be quaternized; oxygen; and sulfur, including sulfoxide and sulfone. The -(3- to 5-membered)heterocycle can be attached via a nitrogen or carbon atom. Representative -(3- to 5-membered)heterocycles include furyl, thiophenyl, pyrrolyl, oxazolyl, imidazolyl, thiazolidinyl, thiadiazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, triazinyl, pyrrolidinonyl, pyrrolidinyl, 2,3-dihydrofuranyl, hydantoinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl and the like.
[0057] "-(7- to 10-membered)bicycloheterocycle" or "-(7- to 10-membered)bicycloheterocyclo" means a 7 to 10 membered bicyclic, heterocyclic ring which is either saturated, unsaturated non- aromatic, or aromatic. A -(I - to 10-membered)bicycloheterocycle contains from I to 4 heteroatoms independently selected from nitrogen, which can be quaternized; oxygen; and sulfur, including sulfoxide and sulfone. The -(I - to 10-membered)bicycloneterocycle can be attached via a nitrogen or carbon atom. Representative -(7- to 10-membered)bicycloheterocycles include quinolinyl, - isoquinolinyl, -chromonyl, -coumarinyl, -indolyl, -indolizinyl, benzo[b]furanyl, benzo[b]thiophenyl, -indazolyl, -purinyl, -4H-quinolizinyl, isoquinolyl, -quinolyl, phthalazinyl, -naphthyridinyl, carbazolyl, -β-carbolinyl, -indolinyl, -isoindolinyl, 1,2,3,4 tetrahydroquinolinyl, -1,2,3,4- tetrahydroisoquinolinyl, pyrrolopyrrolyl and the like.
[0058] "Alkenyl" means a straight chain or branched non-cyclic unsaturated hydrocarbon having one or more carbon-carbon double bonds (e.g., derived from an alkene). The term alkenyl encompasses, inter alia, "(d-Cio)alkenyl," "(CrC6)alkenyl," "(Ci-C4)alkenyl," "(CrC3)alkenyl," "(Ci-C2)alkenyl," "(C2-C4)alkenyl," and "(C2-C6)alkenyl," and includes but is not limited to, vinyl and allyl functional groups.
[0059] "Aryl" means an aromatic carbocylic moiety such as phenyl, anthryl, or phenanthryl.
[0060] "Heteroaryl" means an aromatic heterocycle ring, including both monocyclic and bicyclic ring systems, where at least one carbon atom of one or both of the rings is replaced with a heteroatom independently selected from nitrogen, oxygen, and sulfur, or at least two carbon atoms of one or both of the rings are replaced with a heteroatom independently selected from nitrogen, oxygen, and sulfur. The term "heteroaryl" encompasses, inter alia, (5 to 10-membered)heteroaryl," and (5 or 6-membered)heteroaryl."
[0061] "-(5- to 10-membered) heteroaryl" means an aromatic heterocycle ring of 5 to 10 members, including both monocyclic and bicyclic ring systems, where at least one carbon atom of one or both of the rings is replaced with a heteroatom independently selected from nitrogen, oxygen, and sulfur, or at least two carbon atoms of one or both of the rings are replaced with a heteroatom independently selected from nitrogen, oxygen, and sulfur. In one embodiment, one of the -(5- to 10- membered)heteroaryl's rings contain at least one carbon atom. In another embodiment, both of the - (5- to 10-membered)heteroaryl's rings contain at least one carbon atom. Representative -(5- to 10- membered)heteroaryls include pyridyl, furyl, benzofuranyl, thiophenyl, benzothiophenyl, quinolinyl, isoquinolinyl, pyrrolyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl, oxadiazolinyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidyl, pyrimidinyl, pyrazinyl, thiadiazolyl, triazinyl, thienyl, cinnolinyl, phthalazinyl, and quinazolinyl.
[0062] "-(5- or 6-membered)heteroaryl" means a monocyclic aromatic heterocycle ring of 5 or 6 members where at least one carbon atom is replaced with a heteroatom independently selected from nitrogen, oxygen, and sulfur. In one embodiment, one of the (5- or 6-membered)heteroaryl's ring contains at least one carbon atom. Representative -(5- or 6-membered)heteroaryls include pyridyl, furyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5- oxadiazolyl, 1,2,3-triazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidyl, pyrazinyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,5-triazinyl, and thiophenyl.
[0063] When a first group is "substituted with one or more" second groups, one or more hydrogen atoms of the first group is replaced with a corresponding number of second groups. When the number of second groups is two or greater, each second group can be the same or different.
[0064] "Nitrogen protecting group" means a substituent commonly employed to block or protect a nitrogen functionality while reacting other functional groups on a compound. Examples of such nitrogen-protecting groups include the following: formyl, trityl, methoxytrityl, tosyl, phthalimido, acetyl, trichloroacetyl, chloroacetyl, bromoacetyl, iodoacetyl, benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (FMOC), 2-trimethylsilylethoxycarbonyl (Teoc), 1 -methyl- 1 -(4- biphenylyl)ethoxycarbonyl (Bpoc), t-butoxycarbonyl (BOC), allyloxycarbonyl (Alloc), trihaloacetyl, benzyl, benzoyl, nitrophenylacetyl, and the like. Further examples of nitrogen protecting groups are described by P.G.M. Wuts and T. W. Greene, "Greene's Protective Groups in Organic Synthesis - Fourth Edition," John Wiley and Sons, New York, N.Y., 2007, Chapter 7 ("Greene") which chapter is hereby incorporated by reference in its entirety.
[0065] "Ylide" as used herein refers to a neutral compound that contains two adjacent atoms bearing formal positive and negative charges.
[0066] "Sulfoxonium ylide" as used herein refers to an ylide compound having a sulfur-oxygen bond e.g., compounds of Formula (V).
[0067] "Keto ylide" means a neutral compound comprising a keto group as well as two adjacent atoms bearing formal positive and negative charges; examples of keto ylides include the keto sulfoxonium ylide compounds of Formulas (VI), (X), and (XVIII), above.
[0068] "Activated ester" means an ester derivative that readily reacts with another chemical moiety including but not limited to, anhydrides (e.g., Formulas (IV), (IX), (XIII), (XVII), (XXIV), (XXV), (XXVI), (XXVII)), carboxylic acid-succinimides (e.g., Formula (XX)), carboxylic acid phosphoesters (e.g., Formulas (XXII), (XXIII), (XXX)), and carboxylic acid imidazolides (e.g., Formulas (XXVIII), (XXIX)).
[0069] "Substrate" encompasses a starting material that is used in, and transformed by, a chemical reaction.
[0070] "Stereoisomer," "stereoisomeric form," and the like are general terms for all isomers of individual molecules that differ only in the orientation of their atoms in space. In includes enantiomers and isomers of compounds with more than one chiral center that are not mirror images of one another ("diastereomers").
[0071] "Chiral center" refers to a carbon atom to which four different groups are attached. [0072] "Enantiomer" or "enantiomeric" refers to a molecule that is nonsuperimposable on its mirror image and hence optically active where the enantiomer rotates the plane of polarized light in one direction and its mirror image rotates the plane of polarized light in the opposite direction.
[0073] "Enantiomeric excess" "(ee)" and "diastereomeric excess" "(de)" are terms used to describe a mixture in which one enantiomer or diastereomer is present at a level greater than that of the other in a chemical substance. This difference is defined as the absolute value of the difference between the mole fractions of each enantiomer in the mixture of enantiomers: ee = I (F + ) - (F - )|, where (F + ) + (F - ) = 1 Thus, (ee) and (de) can expressed as a percent enantiomeric or diastereomeric excess.
[0074] The term "racemic" refers to a mixture of equal molar amounts of two enantiomers of a compound, which mixture is optically inactive.
[0075] As used herein, a composition is "enriched" in a particular chiral compound, enantiomer, or diastereomer will typically comprise at least about 60%, 70%, 80%, 90%, or even more of that particular chiral compound, enantiomer, or diastereomer. The amount of enrichment can be determined using conventional analytical methods routinely used by those of ordinary skill in the art, including but not limited to, NMR spectroscopy in the presence of chiral shift reagents, gas chromatographic analysis using chiral columns, and high pressure liquid chromatographic analysis using chiral columns. In some embodiments a single chiral compound, enantiomer, or diastereomer will be substantially free of other corresponding chiral compound, enantiomer, or diastereomers.
[0076] By "substantially free" is meant that the composition comprises less than about 10% of the specified undesired chiral compound, enantiomer, or diastereomer as established using conventional analytical methods routinely used by those of ordinary skill in the art, such as the methods noted above. In some embodiments, the amount of undesired chiral compound, enantiomer, or diastereomer may be less than about 10%, for example, less than about 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or even less.
[0077] Chirally enantiomerically, or diastereomerically enriched compositions that contain at least about 95% of a specified chiral compound, enantiomer, or diastereomer are referred to herein as "substantially chirally pure," "substantially enantiomerically pure" and "substantially diastereomerically pure," respectively.
[0078] Compositions that contain at least about 99% of a specified chiral compound, enantiomer, or diastereomer are referred to herein as "chirally pure," "enantiomerically pure," and "diastereomerically pure," respectively. 4.2. Processes for the Preparation of α-Chloroketones.
4.2.1. Activated Ester Formation: Chloroformate,
Acyl Halide, and Carboxylic Acid Anhydride Activation
[0079] As depicted above in Schemes 1 and 3, the present disclosure provides two alternative processes for the preparation of an α-chloroketone compound according to Formula (I). Both methods comprise contacting a compound of Formula (II) with an activating agent to form an activated ester intermediate compound. However, in the process of Scheme 1 , the activating agent is a chloroformate compound of Formula (III), whereas in the process of Scheme 3, the activating agent is an acyl chloride compound of Formula (XII) or an carboxylic acid anhydride compound of Formula (XXXI). Then in both of the two alternative embodiments, this activated ester intermediate compound is contacted with a sulfoxonium ylide of Formula (V) to provide a keto ylide intermediate compound of Formula (VI), and this keto ylide intermediate is contacted with anhydrous HCl to provide the α- chloroketone of Formula (I).
[0080] Accordingly, the two alternative process embodiments for preparing an α-chloroketone compound of Formula (I) can be summarized as a process comprising the following steps:
O
(I)
(a) contacting a compound of Formula (II):
Figure imgf000017_0001
(II) with a compound of Formula (III), Formula (XII), or Formula (XXXI)
Figure imgf000017_0002
(III) (XII) (XXXI) to provide a compound of Formula (IV), or Formula (XIII), respectively;
Figure imgf000017_0003
(IV) (XIII)
(b) contacting the compound of Formula (IV), or Formula (XIII), with a compound of Formula (V) O
, Il , R3-S— R4 Il CH2
(V) to provide a compound of Formula (VI)
Figure imgf000018_0001
(c) contacting the compound of Formula (VI) with anhydrous HCl to provide the compound of Formula (I).
[0081] In the processes of Scheme 1 and Scheme 2, the groups R!-R6 can be selected from those described in connection with Scheme 1. Accordingly, the possible selections for R!-R6 as follows:
[0082] R1 is selected from the group consisting Of-CH(R5)NH(R6), -(d-C2)alkyl, -(Ci-C3)alkyl, -(Ci-C4)alkyl, -(Ci-C6)alkyl, and -(Ci-Cio)alkyl, aryl, heteroaryl, each alkyl, aryl, and heteroaryl being unsubstituted or substituted with at least one moiety selected from the group consisting of -OH, -SH, -SHCH3, -COOH, -C(O)NH2, -NHCH(NH2)(=NH), -(C3-Ci0)cycloalkyl, -(C3-C6)cycloalkyl, -phenyl, and -(5- to 10-membered)heteroaryl, each -(C3-Cio)cycloalkyl, -(C3-C6)cycloalkyl , -phenyl, and -(5- to 10-membered)heteroaryl being unsubstituted or substituted with at least one moiety selected from the group consisting of hydrogen, -OH, -CH2OH, -CH2CH2OH -NH2, -halo, -CN, -NO2, -C(O)NH2,-(Ci-C6)alkyl, -C(O)NH(Ci -C4))alkyl, -C(O)N((Ci-C4)alkyl)2, and -(Ci-C4)alkyl.
[0083] R2 is selected from the group consisting of alkyl, alkenyl, and aryl, wherein the alkyl is selected from -(CrC2)alkyl, -(CrC3)alkyl, -(CrC4)alkyl, -(CrC6)alkyl, and -(d-Cio)alkyl, each alkyl being unsubstituted or substituted with at least one moiety selected from the group consisting of -(C3-C7)cycloalkyl, alkenyl, -phenyl, and -(5- to 10-membered)heteroaryl.
[0084] R3 and R4 are each independently selected from the group consisting of -(Ci-C2)alkyl, -(Ci- C3)alkyl, -(CrC4)alkyl, -(CrC6)alkyl, -(CrCi0)alkyl, each alkyl being unsubstituted or substituted with at least one moiety selected from the group consisting of -(C3-Ci0)cycloalkyl, -(C3-C6)cycloalkyl, -phenyl, and -(5- to 10-membered)heteroaryl, each -(C3-Ci0)cycloalkyl, -(C3-C6)cycloalkyl , -phenyl, and -(5- to 10-membered)heteroaryl being unsubstituted or substituted with at least one moiety selected from the group consisting of -(Ci-C2)alkyl, -(Ci-C3)alkyl, and -(Cr C4)alkyl.
[0085] R5 is selected from the group consisting of -(CrC2)alkyl, -(CrC3)alkyl, -(CrC4)alkyl, -(Cr C6)alkyl, and -(Ci-Cio)alkyl, each alkyl being unsubstituted or substituted with at least one moiety selected from the group consisting of -OH, -SH, -SHCH3, -COOH, -C(O)NH2, -NHCH(NH2)(=NH), -(C3-Cio)cycloalkyl, -(C3-C6)cycloalkyl, -phenyl, and -(5- to 10-membered)heteroaryl, each -(C3- Cio)cycloalkyl, -(C3-C6)cycloalkyl , -phenyl, and -(5- to 10-membered)heteroaryl being unsubstituted or substituted with at least one moiety selected from the group consisting of hydrogen, -OH, -CH2OH, -CH2CH2OH -NH2, -halo, -CN, -NO2, -C(O)NH2,-(CrC6)alkyl, -C(O)NH(Ci-C4))alkyl, -C(O)N((Ci-C4)alkyl)2, and -(Ci-C4)alkyl.
[0086] R6 is a nitrogen-protecting group.
[0087] Activation of the carboxyl group of the substrate compounds (i.e. those of Formula (II), Formula (XIV), Formula (VIII); e.g., compound (I)) is provided by contact with a chloroformate reagent of Formula (III) (e.g., compound (2)), an acyl chloride reagent of Formula (XII) (e.g., compound (7)), or a carboxylic acid anhydride reagent of Formula (XXXI) (e.g., compound (27)), as depicted in reactions 1, 4, 7, and 10 of Schemes 1 -4, respectively. The reaction is mediated by a suitable base and provides an activated ester as the product, e.g., compounds of Formula (IV), and Formula (IX), e.g., compound (3), and Formula (XIII), as depicted in Schemes 1, 3, 4, and 2, respectively.
[0088] In certain embodiments, the substrate may carry one or more protecting groups to mask a potentially reactive atom or group to preclude untoward chemical reactions. In particular embodiments, e.g., those explicitly illustrated in Schemes 3 and 4, the substrate is an amino acid in which the nitrogen atom carries a protecting group, e.g., the moiety identified as R6. Suitable nitrogen protecting groups include formyl, trityl group, methoxytrityl, tosyl group, benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (FMOC), t-butoxycarbonyl (BOC), benzyl, benzoyl, and nitrophenylacetyl groups. In particular embodiments, the nitrogen protecting group is a t- butoxycarbonyl (BOC) protecting group.
[0089] In certain embodiments, the substrate is a chiral compound which can be a substantially chirally pure compound or a chirally pure compound. In particular embodiments, the substrate is a substantially chirally pure L-amino acid or a chirally pure L-amino acid. In certain embodiments, the substrate is a substantially chirally pure N-protected-L- amino acid or a chirally N-protected-L-pure amino acid. In other embodiments, the substrate is a substantially chirally pure D-amino acid or a chirally pure D-amino acid. In certain embodiments, the substrate is a substantially chirally pure N-protected-D-amino acid or a chirally N-protected-D-pure amino acid.
[0090] Activated ester formation is carried out in a suitable organic solvent, e.g., an aprotic solvent including but not limited to: tetrahydrofuran (THF), 2-methyl THF, toluene, benzotrifluoride (i.e. α,α,α-trifluorotoluene or α,α,α-trifluoromethylbenzene), hexane, heptane, acetone, methyl isobutylketone, acetonitrile, dioxane, diethoxymethane, dimethoxyethane, dichloromethane, chloroform, alkyl acetates, e.g., methyl, ethyl, isopropyl, and butyl acetate. In certain embodiments, the organic solvent is an anhydrous organic solvent. In particular embodiments, the solvent is anhydrous THF.
[0091] In certain embodiments, the substrate, i.e. a compound of Formula (II), Formula (XIV), or Formula (VIII) (e.g., compound (I)) is taken up in the solvent at a suitable temperature, generally at about 200C. The substrate may however, be taken up in the solvent at temperatures below room temperature (e.g., within the range of from about 00C up to about 200C) or above room temperature (e.g., within the range of from about 200C up to about 1000C) if desired or necessary.
[0092] In certain embodiments, activated ester formation is carried out with an initial amount of substrate present within a range of from about 0.025 M to about 1.0 M, from about 0.05 M to about 0.75 M, from about 0.1 M to about 0.5 M, from about 0.15 M to about 0.4 M, from about 0.2 M to about 0.3 M. In certain embodiments, activated ester formation is carried out with an initial amount of substrate present at a concentration of about 0.25 M.
[0093] In some embodiments, a suitable base may be added to the solvent before, after or simultaneously with the substrate. In certain embodiments, a base is added to the solvent before, after or simultaneously with the substrate, and, in a particular embodiment, that base is an organic base. Suitable organic bases include, but are not limited to, N-methylmorpholine, N-ethylmorpholine, N- methylpyrollidine, N-methylpiperidine, pyridine, lutidines, collidines, 2,6-di-tertbutylpyridine, DBU, DBN, tetramethylguanidine, diisopropylethylamine, dimethylaniline, triethylamine and N,N,N',N'-tetramethylethylenediamine and phosphazene bases. In particular embodiments, the base is triethylamine. In other embodiments, the base added is an inorganic base, which may be selected from, but not limited to, lithium, sodium, potassium or cesium carbonate; and lithium, sodium or potassium phosphate. In another aspect of this embodiment, the inorganic base is a Group II metal salt.
[0094] In certain embodiments, activated ester formation is carried out with an initial amount of base within a range of from about 4 equivalents to about 1 equivalent, on a molar basis, relative to the substrate (i.e., the compounds of Formula (II), Formula (XIV), or Formula (VIII), e.g., compound (I)). In certain embodiments, activated ester formation is carried out with an initial amount of base within a range of from about 2 equivalents to about 1 equivalent, from about 2 equivalents to about 1 equivalent, from about 1.5 equivalents to about 1 equivalent, from about 1.25 equivalents to about 1 equivalent, or about 1 equivalent, on a molar basis, relative to the substrate. In particular embodiments, activated ester formation is carried out with an initial amount of base representing about 1.1 equivalents, on a molar basis, relative to the substrate.
[0095] In certain embodiments, the activating reagent, e.g., a chloroformate or an acyl chloride, is added to the reaction mixture either before, after or simultaneously with the substrate, and therefore, either before after or simultaneously with the base. In particular embodiments, the activating reagent, e.g., a chloroformate or an acyl chloride, is added in aliquots, e.g., dropwise, to the reaction mixture containing both the substrate and the base.
[0096] Suitable chloroformate reagents include, but are not limited to, those compounds of Formula (III), in which R2 is an alkyl, alkenyl, aryl, or heteroaryl group selected from the group consisting of phenyl, isobutyl, vinyl, -(CrC2)alkyl, -(CrC3)alkyl, -(CrC4)alkyl, -(CrC6)alkyl, and -(CrC10)alkyl, where each alkyl group may be unsubstituted or may be substituted with at least one moiety selected from the group consisting of -(C3-C7)cycloalkyl, -phenyl, and -(5- to 10-membered)heteroaryl. In certain embodiments, the chloroformate is benzyl chloroformate, phenyl chloroformate, vinyl chloroformate, methyl chloroformate, or isobutyl chloroformate. In particular embodiments, the chloroformate is isobutyl chloroformate.
[0097] In certain embodiments, activated ester formation is carried out with an initial amount of chloroformate (i.e. a compound of Formula (III), e.g., compound (2)) within a range of from about 4 equivalents to about 1 equivalent, on a molar basis, relative to the substrate (i.e. the compound of Formula (II), Formula (XIV), or Formula (VIII), e.g., compound (I)). In certain embodiments, activated ester formation is carried out with an initial amount of chloroformate within a range of from about 2 equivalents to about 1 equivalent, from about 2 equivalents to about 1 equivalent, from about 1.5 equivalents to about 1 equivalent, from about 1.25 equivalents to about 1 equivalent, on a molar basis, relative to the substrate. In particular embodiments, activated ester formation is carried out with an initial amount of chloroformate representing about 1 equivalent, on a molar basis, relative to the substrate.
[0098] In certain embodiments, activated ester formation is carried out with an initial amount of acyl chloride (i.e. a compound of Formula (XII), e.g., compound (7)) within a range of from about 4 equivalents to about 1 equivalent, on a molar basis, relative to the substrate (i.e. the compound of Formula (II), Formula (XIV), or Formula (VIII), e.g., compound (I)). In certain embodiments, activated ester formation is carried out with an initial amount of acyl chloride within a range of from about 2 equivalents to about 1 equivalent, from about 2 equivalents to about 1 equivalent, from about 1.5 equivalents to about 1 equivalent, from about 1.25 equivalents to about 1 equivalent, on a molar basis, relative to the substrate. In particular embodiments, activated ester formation is carried out with an initial amount of acyl chloride representing about 1 equivalent, on a molar basis, relative to the substrate.
[0099] In certain embodiments, activated ester formation is carried out by reaction of a carboxylic acid anhydride (e.g., pivaloyl anhydride) with a substrate (i.e. the compound of Formula (II), Formula (XIV), or Formula (VIII), e.g., compound (I)). That is, the carboxylic acid anhydride of Formula (XXXI) is used in place of the acid chloride in the reaction of Scheme 2. Thus, in one embodiment, pivaloyl anhydride (27) is used in place of pivaloyl chloride (7) in the reaction 4 of Scheme 2 to provide the activated ester of Formula (XIII).
[0100] In certain embodiments, activated ester formation is carried out at a temperature within the range of from about -300C to about 300C, from about -200C to about 200C, from about -100C to about 100C, or from about -5°C to about 5°C. In particular embodiments, activated ester formation is carried out at a temperature of about 00C.
[0101] In certain embodiments, activated ester formation is carried out for a period of time sufficient to convert at least about 50%, 60%, 70%, 80%, 85%, 90%, 95%, 97%, or 99% of the substrate of Formula (II), Formula (VIII), e.g., compound (1) to the activated ester product of Formula (IV and XIII), Formula (IX), and compound (3), respectively. In certain embodiments, activated ester formation is carried out for a period of time with the range of from about 5 minutes to 10 hours, from about 10 minutes to about 5 hours, from about 15 minutes to about 2 hours, or from about 20 minutes to about 1 hour. In a particular embodiment, activated ester formation is carried out for about 30 minutes.
[0102] In certain embodiments, a precipitate may form during the reaction providing the activated ester product. The precipitate may be collected (e.g., by filtration) and washed with a solvent, e.g., that used for the reaction forming the activated ester product, and the washings obtained combined with the filtered reaction mixture.
[0103] In certain embodiments, the activated ester product, i.e. the compound of Formula (IV), Formula (XIII), or Formula (IX) (e.g., compound (3)), formed in reaction 1, 4, 7, or 10 of reaction Schemes 1 -4, respectively, may be isolated and purified using methods, reagents, and equipment known in the art. In other embodiments, the reaction mixture can be evaporated, optionally washed, and then resuspended in a suitable solvent (e.g., anhydrous THF), and used directly for preparation of the keto sulfoxonium ylides of Formula (VI) and Formula (X) (e.g., compound (5), according to reactions 2, 5, 8, and 11 of reaction Schemes 1-4, respectively.
[0104] In certain embodiments the chloroformate reagent of Formula (III) is selected from among phenyl chloroformate (compound (10)), benzyl chloroformate (compound (12)), vinyl chloroformate (compound 14)), and methyl chloroformate (compound (16)), each of which is depicted below:
Figure imgf000022_0001
(10) (12) (14) (16)
[0105] These chloroformates are used in accordance with the disclosed methods to provide the corresponding activated esters of Formula (XXIV), Formula (XXV), Formula (XXVI), and Formula (XXVII), each of which is depicted below:
Figure imgf000023_0001
o o
^CH3
"O' ^O^^ R1^^O'
(XXVI) (XXVII)
[0106] In particular embodiments, the chloroformates are used to provide N-protected activated ester derivatives of L-amino acids (where R5 and R6 are as described above), according to the reactions depicted in Scheme 1 and Scheme 3, above, resulting in compounds (11), (13), (15) and (17), respectively, shown below:
Figure imgf000023_0002
(H) (13)
Figure imgf000023_0003
(15) (17)
[0107] In a particular aspect of each of these embodiments, R5 is a phenyl moiety and R6 is a Boc protecting group, and the activated esters are, respectively, compounds (18)-(21), depicted below:
Figure imgf000023_0004
4.2.2. Diaryl halophosphate, Dialkylhalophosphate and N-hydroxysuccinimide Mediated Formation of Activated Esters
[0108] In another alternative embodiment, the general process of Scheme 1 can be modified wherein rather than using a chloroformate compound of Formula (III), the carboxyl group of a compound of Formula (II) is activated by contact with a dialkyl or diaryl halophosphate of Formula (XXI) to provide the activated ester intermediate of Formula (XXII), as depicted in the process disclosed in Scheme 7 (above).
[0109] In one embodiment, activation of the carboxyl group of a substrate compound of Formula (II), Formula (XIV), or Formula (VIII) (e.g., compound (I)) is provided by contact with a dialkyl halophosphate reagent of compound (8) as depicted in reaction 21 of Scheme 10 below:
Scheme 10
Figure imgf000024_0001
(II) (XXIII) (Vl) (I)
[0110] The diaryl- or dialkyl halophosphate reactions may be mediated by a suitable base and provide an activated ester as the product, e.g., compounds of Formula (XXII), and Formula (XXIII) as depicted in Schemes 7, and 10, respectively.
[0111] In certain embodiments, the substrate may carry one or more protecting groups to mask a potentially reactive atom or group to preclude untoward chemical reactions. In particular embodiments, e.g., those in which the substrate is an amino acid, the nitrogen atom carries a protecting group, e.g., the moiety identified as R6. Suitable nitrogen protecting groups include formyl, trityl group, methoxytrityl, tosyl group, benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (FMOC), t-butoxycarbonyl (BOC), benzyl, benzoyl, and nitrophenylacetyl groups. In particular embodiments, the nitrogen protecting group is a t-butoxycarbonyl (BOC) protecting group.
[0112] In certain embodiments, the substrate is a chiral compound which can be a substantially chirally pure compound or a chirally pure compound. In particular embodiments, the substrate is a substantially chirally pure L-amino acid or a chirally pure L-amino acid. In certain embodiments, the substrate is a substantially chirally pure N-protected-L- amino acid or a chirally N-protected-L-pure amino acid. In other embodiments, the substrate is a substantially chirally pure D-amino acid or a chirally pure D-amino acid. In certain embodiments, the substrate is a substantially chirally pure N-protected-D-amino acid or a chirally N-protected-D-pure amino acid. [0113] Activated ester formation is carried out in a suitable organic solvent, e.g., an aprotic solvent such as, but not limited to, include (but not limited to): tetrahydrofuran (THF), 2-methyl THF, toluene, benzotrifluoride (i.e. α, α, α - trifluorotoluene or α, α, α -trifluoromethylbenzene), hexane, heptane, acetone, methyl isobutylketone, acetonitrile, dioxane, diethoxymethane, dimethoxyethane, dichloromethane, chloroform, alkyl acetates, e.g., methyl, ethyl, isopropyl, and butyl acetate. In certain embodiments, the organic solvent is an anhydrous organic solvent. In particular embodiments, the solvent is anhydrous THF.
[0114] In certain embodiments, the substrate, i.e. a compound of Formula (II), Formula (XIV), or Formula (VIII) (e.g., compound (I)) is taken up in the solvent at a suitable temperature, generally at about 200C. The substrate may however, be taken up in the solvent at temperatures below room temperature (e.g., within the range of from about 00C up to about 200C) or above room temperature (e.g., within the range of from about 200C up to about 1000C) if desired or necessary.
[0115] In certain embodiments, activated ester formation is carried out with an initial amount of substrate present within a range of from about 0.025 M to about 1.0 M, from about 0.05 M to about 0.75 M, from about 0.1 M to about 0.5 M, from about 0.15 M to about 0.4 M, from about 0.2 M to about 0.3 M. In certain embodiments, anhydride formation is carried out with an initial amount of substrate present at a concentration of about 0.25 M.
[0116] In some embodiments, a suitable base may be added to the solvent before, after or simultaneously with the substrate. In certain embodiments, a base is added to the solvent before, after or simultaneously with the substrate, and, in a particular embodiment, that base is an organic base. Suitable organic bases include, but are not limited to, N-methylmorpholine, N-ethylmorpholine, N- methylpyrollidine, N-methylpiperidine, pyridine, lutidines, collidines, 2,6-di-tertbutylpyridine, DBU, DBN, tetramethylguanidine, diisopropylethylamine, dimethylaniline, triethylamine and N,N,N',N'-tetramethylethylenediamine and phosphazene bases. In particular embodiments, the base is triethylamine. In other embodiments, the base added is an inorganic base, which may be selected from, but not limited to, lithium, sodium, potassium or cesium carbonate; and lithium, sodium or potassium phosphate. In another aspect of this embodiment, the inorganic base is a Group II metal salt.
[0117] In certain embodiments, activated ester formation is carried out with an initial amount of base within a range of from about 4 equivalents to about 1 equivalent, on a molar basis, relative to the substrate (i.e. the compound of Formula (II), Formula (XIV), or Formula (VIII), e.g., compound (I)). In certain embodiments, activated ester formation is carried out with an initial amount of base within a range of from about 2 equivalents to about 1 equivalent, from about 2 equivalents to about 1 equivalent, from about 1.5 equivalents to about 1 equivalent, from about 1.25 equivalents to about 1 equivalent, or about 1 equivalent, on a molar basis, relative to the substrate. In particular embodiments, activated ester formation is carried out with an initial amount of base representing about 1.1 equivalents, on a molar basis, relative to the substrate.
[0118] In certain embodiments, the activating reagent, e.g., a diaryl or diaryl halophosphate or dialkyl halophosphate, (e.g., diethyl chlorophosphate, compound (9)), is added to the reaction mixture either before, after or simultaneously with the substrate, and therefore, either before after or simultaneously with the base. In particular embodiments, the activating reagent, e.g., a diaryl halophosphate or a dialkyl halophosphate (e.g., diethyl chlorophosphate, compound (9)), is added in aliquots, e.g., dropwise, to the reaction mixture containing both the substrate and the base.
[0119] Suitable halophosphate reagents include, but are not limited to, those compounds of Formula
(XXI), in which X is Cl, Br, or I and R7 and R8 are each independently selected from the group consisting of -methyl, -ethyl, -propyl, -isopropyl, -butyl, -iso-butyl, -?-butyl, and phenyl. In a particular embodiment, X is Cl. In another embodiment, R7 and R8 are both ethyl.
[0120] In particular embodiments, e.g., where the activated ester is formed by contacting diethyl chlorophosphate of compound (8) with a carboxylic acid of Formula (VIII), a compound of Formula
(XXX) is produced
Figure imgf000026_0001
(XXX)
[0121] As in the case of the process of Scheme 4 above, where R5 is phenyl and R6 is a Boc protecting group, the activated ester, compound (26) is provided:
Figure imgf000026_0002
[0122] In certain embodiments, activated ester formation is carried out with an initial amount of a diaryl halophosphate or a dialkyl halophosphate (i.e. a compound of Formula (XXI), e.g., compound (9)) within a range of from about 4 equivalents to about 1 equivalent, on a molar basis, relative to the substrate (i.e. the compound of Formula (II), Formula (XIV), or Formula (VIII), e.g., compound (I)). In certain embodiments, activated ester formation is carried out with an initial amount of a diaryl halophosphate or a dialkyl halophosphate within a range of from about 2 equivalents to about 1 equivalent, from about 2 equivalents to about 1 equivalent, from about 1.5 equivalents to about 1 equivalent, from about 1.25 equivalents to about 1 equivalent, on a molar basis, relative to the substrate. In particular embodiments, activated ester formation is carried out with an initial amount of diaryl or dialkyl halophosphate representing about 1 equivalent, on a molar basis, relative to the substrate.
[0123] In certain embodiments, activated ester formation is carried out by reaction of a carboxylic acid with N-hydroxysuccinimide generally according to methods known in the art. In certain embodiments, the N-hydroxysuccinimide activated ester is a commercially-available
N-hydroxysuccinimide derivative of an N-protected amino acid.
[0124] In certain embodiments, activated ester formation is carried out at a temperature within the range of from about -300C to about 300C, from about -200C to about 200C, from about -100C to about
100C, or from about -5°C to about 5°C. In particular embodiments, activated ester formation is carried out at a temperature of about 00C.
[0125] In certain embodiments, activated ester formation is carried out for a period of time sufficient to convert at least about 50%, 60%, 70%, 80%, 85%, 90%, 95%, 97%, or 99% of the substrate of
Formula (II) to the activated ester product of Formula (XXII), or Formula (XXIII). In certain embodiments, activated ester formation is carried out for a period of time with the range of from about 5 minutes to 10 hours, from about 10 minutes to about 5 hours, from about 15 minutes to about
2 hours, or from about 20 minutes to about 1 hour. In a particular embodiment, activated ester formation is carried out for about 30 minutes.
[0126] In certain embodiments, a precipitate may form during the reaction providing the activated ester product. The precipitate may be collected (e.g., by filtration) and washed with a solvent, e.g., that used for the reaction forming the activated ester product, and the washings obtained combined with the filtered reaction mixture.
[0127] In certain embodiments, the activated ester product, i.e. the compound of Formula (XXII), or
Formula (XXIII), formed in reaction 16, 19, or 22 of reaction Schemes 6, 7, and 10, respectively, may be isolated and purified using methods, reagents, and equipment known in the art. In other embodiments, the reaction mixture can be evaporated, optionally washed, and then resuspended in a suitable solvent (e.g., anhydrous THF), and used directly for preparation of the keto sulfoxonium ylides of Formula (VI) according to reactions 19, and 22 and 11 of reaction Schemes 7, and 10, respectively.
[0128] One of ordinary skill will recognize that a broad range of activating agents can be used to prepare the keto ylides and α-chloroketones in accordance with the present disclosure including but not limited to: carbonyl ditriazole, dialkyldicarbonates (e.g., EtOC(O)OC(O)OEt), diaryl or dialkylphosphinic halides (e.g., Ph2P(O)Cl), alkyl and aryl cyanoformates (e.g., MeOC(O)CN), carbodiimides (e.g., DCC), chlorothiophosphates, halo-l,3,5-triazines (e.g., 2,4,6-trichlorotriazine, 2- chloro-4,6-dimethoxytriazine), N-alkyl-2-halopyridinium salts (e.g., N-methyl-2-fluoropyridinium salts). [0129] Additionally, one of ordinary skill will recognize that a range of additional activated intermediates may be used in accordance with the methods disclosed herein, including but not limited to: S-alkyl and S-aryl thiolesters, cyanoesters, acid chlorides, N-hydroxybenzotriazolyl esters, N- hydroxyphthalimido esters, esters derived from 2-hydroxypyridine-N-oxide, and sulfonate esters (e.g., derived from MsCl).
4.2.3. ΛyV-Carbonyl Diimidazole Mediated Formation of Activated Esters [0130] In other embodiments of the disclosure formation of an activated ester is mediated by reaction of a carboxylic acid with N,N-carbonyl diimidazole (CDI) generally according to the method of Example 2(G), below, to provide activated esters, e.g. , the corresponding carboxylic acid imidazolides of Formula (XXVIII), and Formula (XXIX), depicted below:
Figure imgf000028_0001
(XXVIII) (XXIX)
[0131] In particular embodiments, reaction of a carboxylic acid with N,N-carbonyl diimidazole (CDI) can provide compounds (22), and (23), respectively
Figure imgf000028_0002
(22) (23)
which are carboxylic acid imidazolide activated ester derivatives of L-amino acids (where R5 and R6 are as described above).
[0132] In a particular aspect of each of these embodiments, R5 is a phenyl moiety and R6 is a Boc protecting group, and the activated esters are, respectively, compound (24) and compound (25), depicted below:
Figure imgf000028_0003
4.2.4. Sulfoxonium Methylide Formation
[0133] In certain embodiments, the sulfoxonium methylide reagent of Formula V is prepared, e.g., as described below, and isolated before use as a reagent in reactions 2, 5, 8, and 11, of reaction Schemes 1-4, respectively, converting intermediates of Formula (IV), Formula (XIII), and Formula (IX) (e.g., compound (3)) to the corresponding keto sulfoxonium ylides of Formula (VI), and Formula (X) (e.g., compound (5)).
[0134] In certain embodiments, an appropriate sulfoxide (i.e. (R3)(R4)S(O)), e.g., dimethylsulfoxide, is contacted with, e.g. , methyl iodide to provide the corresponding dialkyl methylsulfoxonium iodide salt using methods known in the art and commercially-available reagents, as depicted in Scheme 8 below.
Scheme 8
Figure imgf000029_0001
XVI XVII
[0135] The dialkyl methyl sulfoxonium salt, i.e. the product of the reaction depicted in Scheme 8, can be isolated or purified using methods, reagents, and equipment known to one of ordinary skill in the art. Other methods for preparation of compounds according to Formula (XVII) are found in the art, see, e.g., Smith et al, Tetrahedron 1958, p317, Lampman, G.M. ; Koops, R. W. ; Olden, CC; J. Chem. Educ, 1985, 62: 267, and Ng, J. S.; Liu, C; McGarrigle, E. M.; Aggarwal, V. K., Encyclopedia of Reagents for Organic Synthesis ( DOI: 10.1002/047084289X.rt351.pub2 ). [0136] In other embodiments, the methylating agent is methyl bromide. In still further embodiments, the ylide precursor, is selected from, but not limited to, trimethylsulfoxonium chloride, methanesulfonate, tosylate, triflate, and tetrafluoroborate.
[0137] In certain embodiments, the dialkyl methylsulfoxonium iodide salt is contacted with a strong base in an organic solvent to provide the dialkyl sulfoxonium methylide of Formula (V), as depicted in Scheme 9, below:
Scheme 9
O lϋ o
R4-S-R3 Basθ , R4-S-R3
CH3 CH2
XVII V [0138] The dialkyl sulfoxonium methylide of Formula (V) (e.g., the product of the reaction depicted in Scheme 9, can be isolated or purified using methods, reagents, and equipment known to one of ordinary skill in the art.
4.2.5. Keto Sulfoxonium Ylide Formation
[0139] In certain embodiments, the dialkyl methylsulfoxonium salt of Formula (XVII), which may be prepared as depicted in reaction Scheme 8, is contacted with a strong base in an organic solvent to provide the dialkyl sulfoxonium methylide of Formula (V), as depicted in Scheme 9, above. The dialkyl sulfoxonium methylide of Formula (V) (e.g., compound (4)) can be used directly by contacting with activated esters for formation of the keto sulfoxonium ylides of Formula (VI) and Formula (X) (e.g., compound (5), as depicted in reactions 2, 5, 8, and 11 of Schemes 1-4, respectively.
[0140] In certain embodiments, the dialkyl methylsulfoxonium salt of Formula (XVII), is taken up in a suitable organic solvent, e.g., an aprotic solvent such as but not limited to DMSO, DMF, dimethylacetamide, N-methylpyrollidinone, dioxane, THF, methyl-THF, acetonitrile, toluene and mixtures thereof. In particular embodiments, the solvent is a polar aprotic solvent. In certain embodiments, the organic solvent is an anhydrous organic solvent. In particular embodiments, the solvent is anhydrous THF.
[0141] In certain embodiments, the substrate, dialkyl methylsulfoxonium salt of Formula (XVII), is taken up in the solvent at a suitable temperature, generally at about 200C. The substrate sulfoxonium methylide of Formula (V) may however, be taken up in the solvent at temperatures below room temperature (e.g., within the range of from about 00C up to about 200C) or above room temperature (e.g., within the range of from about 200C up to about 1000C) if desired or necessary. [0142] In certain embodiments, formation of the dialkyl sulfoxonium methylide of Formula (V) is carried out with an initial amount of substrate dialkyl methylsulfoxonium salt of Formula (XVII) present within a range of from about 0.025 M to about 1.0 M, from about 0.05 M to about 0.8 M, from about 0.1 M to about 0.5 M, from about 0.15 M to about 0.6 M, from about 0.25 M to about 0.5 M, or from about 0.35 M to about 0.4 M. In certain embodiments, dialkyl sulfoxonium methylide formation is carried out with an initial amount of substrate dialkyl methylsulfoxonium salt present at a concentration of about 0.38 M.
[0143] In certain embodiments, the base is added to the reaction mixture before, after or simultaneously with the dialkyl methylsulfoxonium salt of Formula (XVII). In certain embodiments, the base is selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium hydride, potassium hydride, lithium/sodium/potassium alkoxides (e.g., lithium tert-butoxide, potassium tert-butoxide, and sodium tert-butoxide; lithium tert- amylate, potassium tert-amylate, and sodium tert-amylate), lithium diisopropylamide (LDA), lithium hexamethyldisilazane, sodium hexamethyldisilazane, potassium hexamethyldisilazane (i.e., Li/Na/K HMDS), butyl lithium (BuLi), phosphazene bases, diaza(l,3)bicyclo[5.4.0]undecane (DBU), diaza(l,5)bicyclo[4.3.0]non-5-ene (DBN), and tetramethylguanidine. In instances in which the inorganic base is insoluble, phase transfer conditions may be applied using catalysts, including, as but one example, tetrabutylammonium hydroxide. In a particular embodiment, the base is potassium tert-butoxide.
[0144] In certain embodiments, formation of the dialkyl sulfoxonium methylide of Formula (V) is carried out with an initial amount of base within a range of from about 1 equivalent to about 2 equivalents, from about 1 equivalent to about 1.5 equivalents, from about 1 equivalent to about 1.25 equivalents, or from about 1 equivalent to about 1.1 equivalents on a molar basis relative to the dialkyl methylsulfoxonium salt starting material. In certain embodiments, dialkyl sulfoxonium methylide formation is carried out with an initial amount of base of about 1 equivalent, on a molar basis relative to the dialkyl methylsulfoxonium salt starting material.
[0145] In certain embodiments, formation of the dialkyl sulfoxonium methylide of Formula (V) is carried out at a temperature within the range of from about 400C to about 1200C, or from about 600C to about 1000C. In certain embodiments, dialkyl sulfoxonium methylide formation is carried out at a temperature of about 900C. In certain embodiments, dialkyl sulfoxonium methylide formation is carried out at a temperature of about 65°C, e.g., the approximate reflux temperature of THF.
[0146] In certain embodiments, formation of the dialkyl sulfoxonium methylide of Formula (V) is carried out for a period of time sufficient to convert at least about 50%, 60%, 70%, 80%, 85%, 90%, 95%, 97%, or 99% of the dialkyl methylsulfoxonium salt starting material to the dialkyl sulfoxonium methylide of Formula (V). In certain embodiments, dialkyl sulfoxonium methylide formation is carried out for a period of time with the range of from about 15 minutes to 8 hours, from about 30 minutes to about 6 hours, from about 1 hour to about 4 hours, or from about 1.5 hours to about 3 hours. In a particular embodiment, dialkyl sulfoxonium methylide formation is carried out for about two hours.
[0147] In those embodiments in which the dialkyl sulfoxonium methylide of Formula (V) is to be used directly, the reaction mixture is cooled to a temperature suitable for formation of the keto sulfoxonium ylide according to reactions 2, 5, 8, and 11 of reaction Schemes 1-4, respectively. In particular embodiments the reaction mixture comprising the dialkyl sulfoxonium methylide of Formula (V) is cooled to a temperature within the range of from about -300C to about 300C, from about -200C to about 200C, from about -100C to about 100C, or from about -5°C to about 5°C. In particular embodiments, the reaction mixture comprising the dialkyl sulfoxonium methylide of Formula (V) is cooled to a temperature of about 00C or cooler, about -100C or cooler, or about -200C or cooler.
[0148] In certain embodiments, e.g., where the in situ formed dialkyl sulfoxonium methylide of Formula (V) is to be used directly, the initial amount of dialkyl methylsulfoxonium salt of Formula (XVII) present in the reaction mixture is within a range of from about 1 equivalent to about 10 equivalents, from about 1 equivalent to about 8 equivalents, from about 1 equivalent to about 4 equivalents, or from about 1 equivalent to about 2 equivalents on a molar basis relative to the total amount of activated ester compound of Formula (II) or Formula (VIII), Formula (XV), or Formula (IX) (e.g. , compound (2)) ultimately added to the reaction mixture. In certain embodiments, the initial amount of dialkyl methylsulfoxonium salt of Formula (XVII) in the reaction mixture corresponds to about 1.5 equivalents on a molar basis relative to the total amount of activated ester compound of Formula (II) or Formula (VIII), Formula (XV), or Formula (IX) (e.g., compound (2)) ultimately added to the reaction mixture.
[0149] In certain embodiments, the initial amount of dialkyl sulfoxonium methylide of Formula (V) in the reaction mixture is within a range of from about 1 equivalent to about 10 equivalents, from about 1 equivalent to about 8 equivalents, from about 1 equivalent to about 4 equivalents, or from about 1 equivalent to about 2 equivalents on a molar basis relative to the total amount of activated ester compound of Formula (II) or Formula (VIII), Formula (XV), or Formula (IX) (e.g., compound (2)) added to the reaction mixture. In certain embodiments, the initial amount of dialkyl sulfoxonium methylide of Formula (V) in the reaction mixture corresponds to about 1.5 equivalents on a molar basis relative to the total amount of activated ester compound of Formula (II) or Formula (VIII), Formula (XV), or Formula (IX) (e.g. , compound (2)) added to the reaction mixture. [0150] In certain embodiments, preparation of the keto sulfoxonium ylide (i.e. a compound of Formula (VI), or Formula (X) (e.g., compound (5)), is initiated by addition of an activated ester compound as disclosed herein (e.g., compounds of Formula (IV), Formula (IX), Formula (XIII), Formula (XVII), Formula (XX), Formula (XXII), Formula (XXIII), Formula (XXIV), Formula (XXV), Formula (XXVI), Formula (XXVII), Formula (XXVIII), Formula (XXIX), or Formula (XXX), or compounds having the specific structures of compound (3), compound (11), compound (13), compound (15), compound (17), compound (18), compound (19), compound (20), compound (21), compound (24), compound (25), or compound (26)) to the reaction mixture in which the dialkyl sulfoxonium methylide of Formula (V) is prepared. In certain embodiments, the activated ester is added in aliquots ("dropwise") over an extended period of time ranging from about 10 minutes to 2 hours, from about 20 minutes to 90 minutes, from abut 30 minutes to an hour. In a specific embodiment, the activated ester is added over about a 45 minute period. In certain embodiments, the above additions are made in a drop-wise fashion.
[0151] In certain embodiments, formation of the keto sulfoxonium ylide (i.e. a compound of Formula (VI), or Formula (X) (e.g., compound (5)), is carried out for a period of time sufficient to convert at least about 50%, 60%, 70%, 80%, 85%, 90%, 95%, 97%, or 99% of the activated ester compound as disclosed herein (see above) starting material to the corresponding keto sulfoxonium ylide of Formula (VI), or Formula (X) (e.g., compound (5)). In certain embodiments, keto sulfoxonium ylide formation is continued (i.e., after completion of addition of the activated ester starting material) for an additional period of time with the range of from about 15 minutes to 8 hours, from about 30 minutes to about 6 hours, from about 1 hour to about 4 hours, or from about 1.5 hours to about 3 hours. In a particular embodiment, keto sulfoxonium ylide formation is carried out for at least about 2 additional hours, at least about 3 additional hours, or at least about 4 additional hours, or more.
[0152] In one embodiment, formation of the keto sulfoxonium ylide is quenched with water (e.g., using a volume of water within a range of from about 10 to about 50%, from about 15% to about 40%, or from about 20% to about 30% of the total reaction volume). The organic layer is separated and washed (e.g., with brine), dried (e.g., over sodium sulfate) and evaporated under reduced pressure. Where desired the residue obtained may be washed (azeotroped) with an appropriate solvent (e.g., toluene) and again evaporated under reduced pressure to provide a residue comprising the keto sulfoxonium ylide Formula (VI) or Formula (X).
[0153] The keto sulfoxonium ylide compounds of Formula (VI), or Formula (X) (e.g., compound (5)) can be isolated and further purified using methods, reagents, and equipment known in the art including but not limited to gas chromatographic methods using chiral columns, and high pressure liquid chromatographic analysis using chiral columns. Illustrative examples showing the use of activated esters to synthesize keto sulfoxonium ylide compounds useful for preparing α-chloroketones are provided in Examples l.B. and 2.A through 2.G.
4.2.6. α-Chloroketone Formation
[0154] The keto sulfoxonium ylide of Formula (VI), or Formula (X) (e.g., compound (5)) is taken up in a suitable organic solvent and contacted with an appropriate source of anhydrous HCl at a suitable temperature and for an appropriate period of time to provide an α-chloroketone product of Formula (I), or Formula (VII) (e.g., compound (6)).
[0155] In certain embodiments, the keto sulfoxonium ylide is taken up in a suitable organic solvent, e.g., an aprotic solvent such as but not limited to DMSO, DMF, dimethylacetamide, N- methylpyrollidinone, dioxane, THF, methyl-THF, acetonitrile, toluene, acetic acid in DMF, and mixtures thereof. In particular embodiments, the solvent is a polar aprotic solvent. In certain embodiments, the organic solvent is an anhydrous organic solvent. In certain embodiments the solvent is an anhydrous solvent. In certain embodiments, the solvent is THF or anhydrous THF. [0156] In various embodiments of the present disclosure, anhydrous HCl is added as a gas, as solution in an inert solvent (e.g., 4 M HCl in dioxane) or it may prepared in situ. For in situ preparation of anhydrous HCl, a chloride salt is contacted with a strong acid. In certain embodiments, such chloride salts include, but are not limited to LiCl and tetrabutylammonium chloride. In other embodiments, the chloride salt is NaCl or KCl. In particular embodiments, the organic acids is selected from, but not limited to, methanesulfonic, ethanesulfonic, trifluoromethansulfonic, and nonafluorobutanesulfonic acids. In another embodiment, the acid is a mineral acid, such as but not limited to concentrated sulfuric acid. In other embodiments, anhydrous HCl is prepared in situ by treatment of an acid chloride, such as but not limited to a carboxylic acid chloride (e.g., acetyl chloride), thionyl chloride, phosphorus(III) or (V) chloride, phosphorus oxychloride, chlorosulfonic acid) with a nucleophile, e.g., an alcohol such as but not limited to methanol. In a particular embodiment, anhydrous HCl is prepared in situ by contacting LiCl with methanesulfonic acid. In certain embodiments, the chloride salt and/or the organic acid are added to the reaction before, after or simultaneously with the keto sulfoxonium ylide starting material of Formula (VI), or Formula (X). [0157] In certain embodiments, formation of α-chloroketone of Formula (VI), or Formula (X) according to reaction 3, 6, 9, or 12 of Schemes 1-4, respectively, is carried out at an initial temperature within the range of from about -300C to about 300C, from about -200C to about 200C, from about -100C to about 100C, or from about -5°C to about 5°C. In particular embodiments, α-chloroketone formation is carried out at an initial temperature of about 00C. The temperature of the reaction mixture comprising the keto sulfoxonium ylide, chloride salt, and organic acid may be raised from the initial temperature to a final temperature within the range of from about 200C to about 1200C, from about 300C to about 1100C, from about 400C to about 1000C, from about 500C to about 900C, or from about 600C to about 800C. In a particular embodiment the final temperature is about 700C. In particular embodiments, the reaction temperature is raised gradually from the initial temperature to the final temperature. The reaction may be maintained at the final temperature, with stirring, for a period of from about 30 minutes to about 8 hours, from about 60 minutes to about 4 hours, from about 90 minutes to about 2.5 hours. In a particular embodiment, the reaction may be maintained at the final temperature for about 2 hours.
[0158] In particular embodiments, formation of an α-chloroketone of Formula (VI), or Formula (X) according to reaction 3, 6, 9, or 12 of Schemes 1-4, respectively, is carried out for a total period of time sufficient for conversion of at least about 50%, 60%, 70%, 80%, 85%, 90%, 95%, 97%, or 99% of the substrate keto sulfoxonium ylide of Formula (VI) or Formula (X) to the α-chloroketone product of Formula (I) or Formula (VII). In certain embodiments, α-chloroketone formation is carried out for a total period of time with the range of from about 30 minutes to 10 hours, from about 45 minutes to about 6 hours, from about 1 hour to about 4 hours, or from about 1.5 hours to about 3 hours. In a particular embodiment, formation of the α-chloroketone of Formula (VI), or Formula (X) according to reaction 3, 6, 9, or 12 of Schemes 1-4, respectively, is carried out for a total of about 2 hours. In other embodiments, formation of the α-chloroketone of Formula (VI), or Formula (X) according to reaction 3, 6, 9, or 12 of Schemes 1-4, respectively, is carried out for a total of about three hours. [0159] In certain embodiments, α-chloroketone formation is carried out with an initial concentration an initial amount of the keto sulfoxonium ylide of Formula (VI) or Formula (X) substrate present within a range of from about 0.01 M to about 1.0 M, from about 0.025 M to about 0.75 M, from about 0.05 M to about 0.5 M, from about 0.1 M to about 0.4 M, from about 0.15 M to about 0.3 M. In certain embodiments, activated ester formation is carried out with an initial amount of substrate present at a concentration of about 0.2 M.
[0160] In certain embodiments, α-chloroketone formation is carried out with an initial amount of chloride salt within a range of from about 4 equivalents to about 1 equivalent, on a molar basis, relative to the keto sulfoxonium ylide substrate of Formula (VI) or Formula (X). In certain embodiments, α-chloroketone formation is carried out with an initial amount of chloride salt within a range of from about 2 equivalents to about 1 equivalent, from about 2 equivalents to about 1 equivalent, from about 1.5 equivalents to about 1 equivalent, from about 1.25 equivalents to about 1 equivalent, or about 1 equivalent, on a molar basis, relative to the keto sulfoxonium ylide substrate. In particular embodiments, activated ester formation is carried out with an initial amount of chloride salt representing about 1.1 equivalents, on a molar basis, relative to the keto sulfoxonium ylide substrate.
[0161] In certain embodiments, α-chloroketone formation is carried out with an initial amount of organic acid within a range of from about 4 equivalents to about 1 equivalent, on a molar basis, relative to the keto sulfoxonium ylide substrate of Formula (VI) or Formula (X). In certain embodiments, α-chloroketone formation is carried out with an initial amount of organic acid within a range of from about 2 equivalents to about 1 equivalent, from about 2 equivalents to about 1 equivalent, from about 1.5 equivalents to about 1 equivalent, from about 1.25 equivalents to about 1 equivalent, or about 1 equivalent, on a molar basis, relative to the keto sulfoxonium ylide substrate. In particular embodiments, activated ester formation is carried out with an initial amount of organic acid representing about 1.1 equivalents, on a molar basis, relative to the keto sulfoxonium ylide substrate.
[0162] In certain embodiments, α-chloroketone formation is quenched with water (e.g., using a volume of water within a range of from about 25 to about 200%, from about 50% to about 200%, or from about 80% to about 150% of the total reaction volume). In particular embodiments, the reaction is quenched with an approximately equal volume of water. In particular embodiments, the temperature of the reaction is lowered, e.g., to about 200C (room temperature) before it is quenched. The organic layer is separated and washed (e.g., with brine), dried (e.g., over sodium sulfate) and evaporated under reduced pressure. The residue obtained, which comprises the α-chloroketone, may be taken up in an appropriate solvent or solvent mixture and crystallized. In particular embodiments, the residue is taken up with hot heptane/ethyl acetate (5: 1), and, upon cooling, crystallized therefrom. [0163] The α-chloroketone compounds of Formula (I), Formula (XV), or Formula (VII) (e.g., compound (6)) can be isolated and further purified using methods, reagents, and equipment known in the art including but not limited to gas chromatographic methods using chiral columns, and high pressure liquid chromatographic analysis using chiral columns. 5. EXAMPLES
[0164] Various features and embodiments of the disclosure are illustrated by the following representative Examples which are intended to be illustrative but not limiting.
Example 1: Formation of α-Chloroketone Via Sulfoxonium Ylide
[0165] This example illustrates a typical experimental procedure for stereoselective synthesis of an α-chloroketone compound of Formula (I), specifically compound (6) (i.e., the α-chloroketone derivative of N-boc-L-phenylalanine) via an activated ester intermediate compound of Formula (IV), specifically compound (3), and a sulfoxonium ylide intermediate compound of Formula (VI), specifically compound (5), as depicted in Scheme 4.
A. Formation of activated ester using isobutyl chloroformate
[0166] To a 250 mL 3-neck round-bottom flask, was added 5.0 g (18.8 mmol) of N-Boc-L- Phenylalanine (compound (I)) and 75 mL of anhydrous tetrahydrofuran (THF). The solution was then cooled to 00C and triethylamine (20.7 mmol, 2.9 mL) was added dropwise for 10 minutes. After stirring for 15 minutes at 0 0C, isobutylchloroformate (compound (2)) (18.8 mmol, 2.4 mL) was added to the same solution dropwise maintaining the temperature at 00C. Formation of the activated ester compound (compound (3) as a white precipitate was observed. The reaction mixture was stirred at 00C for 30 minutes and the precipitate was then filtered and washed with 15 mL THF.
B. Sulfoxonium ylide formation
[0167] In a separate 250 mL 3-neck round bottom flask, potassium tert-butoxide (28.2mmol, 3.16 g) was taken up in 75 mL anhydrous THF to which trimethylsulfoxonium iodide (28.2 mmol, 6.20 g) was added. The resultant slurry was heated at 900C for 2 hours. The reaction mixture was then cooled to room temperature and subsequently to 00C.
[0168] The filtered activated ester solution from above step A was added dropwise at 00C over a period of 45 minutes. The reaction was stirred at 0 0C for 2 hours, after which the reaction was quenched by adding 35 mL water, separated organic layers and washed with brine (3 x 25 mL), dried over Na2Sθ4 and concentrated under reduced pressure. The semisolid obtained was then azeotroped with toluene to obtain desired sulfoxonium ylide intermediate of compound (5) as light yellow solid (4.75 g, 79% yield, 99% ee).
[0169] HPLC was used to determine the e.e. of the sulfoxonium ylide intermediate as follows: Column: Chiral pak AD-H column; 4.6 mm x 25 cm; Temperature: 25 0C; Flow Rate: 0.8 mL/min; Mobile Phase: Isocratic mobile phase 80:20 ethanol:heptane; Duration: 12 min. The retention times observed were as follows: L-ylide: 6.4 min., and D-ylide: 10.9 min.
C. a-Chloroketone formation [0170] The procedure for formation of the α-chloroketone of compound (6) was similar to that described in the literature (see e.g., J. Org. Chem. 2004, 69, 1629). The sulfoxonium ylide intermediate (14.6 mmol) from above was taken up in 75 mL anhydrous THF and the solution was cooled to 00C. Lithium chloride (16.1 mmol, 0.685 g) and methanesulfonic acid (16.1 mmol, 1.05 mL) were added. The temperature was slowly raised to about 200C (room temperature) and subsequently to 700C. The reaction mixture was stirred at 700C for 2 hour. After cooling to room temperature, the reaction was quenched by adding 75 mL water. Phases were separated and the aqueous layer was extracted with 75 mL of 2: 1 heptane/ethyl acetate mixtures. The organic layers were combined and washed with saturated NaHCθ3 (2 x 50 mL), water (1 x 50 mL) and brine (1 x 50 mL) and dried over Na2SOzI. Concentration under reduced pressure afforded crude α-chloroketone product (2.0 g, 45% yield). Crystallization of product from hot 5: 1 heptane/ethyl acetate mixtures yielded 0.56 g of white solid. However, purity of crystallized α-chloroketone derivative ofN-boc-L- phenylalanine (compound (6)) could not improve beyond 50% by HPLC. No further crystallization or purification was carried out.
Example 2: Formation of Various Activated Ester and Chiral Sulfoxonium Ylide Intermediates Useful for Syntheses of Compounds of Formula (I) Using Various Activating Agents
[0171] This Example illustrates how a chiral keto sulfoxonium ylide intermediate compound of Formula (VI), specifically compound (5), which are useful for making α-chloroketone compounds of Formula (I) can be synthesized using a variety of activating agents, such as compounds of Formula (III) or Formula (XII), specifically including phenyl chloroformate, benzyl chloroformate, N-Boc-D- Phe-O-succinimide, pivaloyl chloride, diethyl chlorophosphate, carbonyl diimidazole, and isobutyl chloroformate. Example 2.F. further illustrates the conversion of the chiral keto sulfoxonium ylide of compound (5) to the α-chloroketone derivative of N-Boc-L-phenylalanine, compound (6).
A. Synthesis of keto sulfoxonium ylide of compound (5) using phenyl chloroformate. [0172] Anhydride of compound (19) formation: To a 3-neck RB flask was added 0.66 g (2.5 mmol) of N-Boc-L-Phe and 3 mL of anhydrous THF. The solution was cooled to -15 0C and triethylamine (5.0 mmol, 0.70 mL) was added dropwise. After stirring for 10 minutes at -10 0C, this solution was added dropwise to a precooled solution of phenyl chloroformate (2.5 mmol, 0.31 mL) in 10 mL of anhydrous THF at -15 0C. A white precipitate was observed. The reaction mixture was stirred between -10 0C and -15 0C for 30 minutes and then the precipitate was filtered and washed with 10 mL THF. The filtrate thus obtained was used directly for ylide formation.
[0173] Keto sulfoxonium ylide of compound (5) formation: In a separate 3-neck RB flask, potassium tert-butoxide (7.50 mmol, 0.84 g) was dissolved in 15 mL anhydrous THF and trimethylsulfoxonium chloride (3.75 mmol, 0.48 g) was added. The resulting slurry was heated at 90 0C for 2 h. The reaction mixture was then cooled to room temperature and subsequently to about -20 0C. The filtered activated ester solution from above was then added dropwise maintaining the temperature at about - 20 0C. The reaction was stirred at the same temperature for 4 h. The reaction mixture was quenched by adding 10 mL water, the organic layer was separated and washed with brine (2 x 15 mL), dried over Na2SO4 and concentrated under reduced pressure to obtain the desired product of compound (5) as a light yellow sticky solid (0.76 g, 95% yield, 76% ee).
B. Synthesis of a keto sulfoxonium ylide of compound (5) using benzyl chloroformate [0174] Activated ester of compound (18) formation: To a 3-neck RB flask was added 0.66 g (2.5 mmol) of N-Boc-L-Phe and 3 mL of anhydrous THF. The solution was cooled to -15 0C and triethylamine (5.0 mmol, 0.70 mL) was added dropwise. After stirring for 10 minutes at -10 0C, this solution was added dropwise to a precooled solution of benzyl chloroformate (2.5mmol, 0.31 mL) in 10 mL of anhydrous THF at -15 0C. A white precipitate was observed. The reaction mixture was stirred between -10 0C and -15 0C for 30 minutes and then the precipitate was filtered and washed with 10 mL THF. The filtrate thus obtained was used directly for ylide formation. [0175] Keto sulfoxonium ylide of compound (5) formation: In a separate 3-neck RB flask, potassium tert-butoxide (7.50 mmol, 0.84 g) was dissolved in 15 mL anhydrous THF and trimethylsulfoxonium chloride (3.75 mmol, 0.48 g) was added. The resulting slurry was heated at 90 0C for 2 h. The reaction mixture was then cooled to room temperature and subsequently to about -20 0C. The filtered activated ester solution from above was then added dropwise maintaining the temperature at about -20 0C. The reaction was stirred at the same temperature for 4 h. The reaction mixture was quenched by adding 10 mL water, the organic layer was separated and washed with brine (2 x 15 mL), dried over Na2SO4 and concentrated under reduced pressure to obtain the desired product of compound (5) as a light yellow sticky solid (0.78 g, 98% yield, 20% ee).
C. Synthesis of a keto sulfoxonium ylide of compound (5) using a commercial succinimide ester
[0176] To a 3-neck RB flask potassium tert-butoxide (4.14 mmol, 0.47 g) was dissolved in 15 mL anhydrous THF and trimethylsulfoxonium chloride (2.07 mmol, 0.27 g) was added. The resulting slurry was heated at 90 0C for 2 h. The reaction mixture was then cooled to room temperature and subsequently to about -20 C. A solution of N-Boc-D-Phe-O-succinimide (1.38 mmol, 0.5 g) dissolved in 10 mL anhydrous THF was then added dropwise maintaining the temperature at about -20 0C. The reaction was stirred at the same temperature for 4 h. The reaction mixture was quenched by adding 7 mL water, the organic layer was separated and washed with brine (2 x 10 mL), dried over Na2SO4 and concentrated under reduced pressure to obtain the desired product as a light yellow solid (0.40 g, 87% yield, 99% ee).
D. Synthesis of a keto sulfoxonium ylide of compound (5) using pivaloyl chloride
[0177] Activated ester formation: To a 3-neck RB flask was added 0.66 g (2.5 mmol) of N-Boc-L-
Phe and 3 mL of anhydrous THF. The solution was cooled to -15 0C and triethylamine (5.0 mmol, 0.70 mL) was added dropwise. After stirring for 10 minutes at -10 °C, this solution was added dropwise to a precooled solution of pivaloyl chloride (2.5 mmol, 0.31 mL) in 10 mL of anhydrous THF at -15 0C. A white precipitate was observed. The reaction mixture was stirred between -10 0C and -15 0C for 30 minutes and then the precipitate was filtered and washed with 10 mL THF. The filtrate thus obtained was used directly for ylide formation.
[0178] Sulfoxonium ylide of compound (5) formation: In a separate 3-neck RB flask, potassium tert- butoxide (7.50 mmol, 0.84 g) was dissolved in 15 mL anhydrous THF and trimethylsulfoxonium iodide (3.75 mmol, 0.82 g) was added. The resulting slurry was heated at 90 0C for 2 h. The reaction mixture was then cooled to room temperature and subsequently to about -20 0C. The filtered anhydride solution from above was then added dropwise maintaining the temperature at about -20 0C. The reaction was stirred at the same temperature for 4 h. The reaction mixture was quenched by adding 10 mL water, the organic layer was separated and washed with brine (2 x 15 mL), dried over Na2Sθ4 and concentrated under reduced pressure to obtain the desired product of compound (5) as a light yellow solid (0.79 g, 98% yield, 96% ee).
E. Synthesis of a keto sulfoxonium ylide of compound (5) using diethyl chlorophosphate
[0179] Activated ester of compound (26) formation: To a 3-neck RB flask was added 0.66 g (2.5 mmol) of N-Boc-L-Phe and 3 mL of anhydrous THF. The solution was cooled to -15 0C and triethylamine (5.0 mmol, 0.70 mL) was added dropwise. After stirring for 10 minutes at -10 0C, this solution was added dropwise to a precooled solution of diethyl chlorophosphate (2.5 mmol, 0.36 mL) in 10 mL of anhydrous THF at -15 0C. A white precipitate was observed. The reaction mixture was stirred between -10 0C and -15 0C for 30 minutes and then the precipitate was filtered and washed with 10 mL THF. The filtrate thus obtained was used directly for ylide formation.
[0180] Sulfoxonium ylide of compound (5) formation: In a separate 3-neck RB flask, potassium tert- butoxide (7.50 mmol, 0.84 g) was dissolved in 15 mL anhydrous THF and trimethylsulfoxonium iodide (3.75 mmol, 0.82 g) was added. The resulting slurry was heated at 90 0C for 2 h. The reaction mixture was then cooled to room temperature and subsequently to about -20 0C. The filtered activated ester solution from above was then added dropwise maintaining the temperature at about -20 0C. The reaction was stirred at the same temperature for 3 h. The reaction mixture was quenched by adding 10 mL water, the organic layer was separated and washed with brine (2 x 15 mL), dried over Na2SO4 and concentrated under reduced pressure to obtain desired product of compound (5) as light yellow solid (0.68 g, 85% yield, 87% ee).
F. Synthesis of a keto sulfoxonium ylide of compound (5) and formation of an a- chloroketone compound of Formula (I) (compound (6)) using isobutyl chloroformate
[0181] Activated ester of compound (3) formation: To a 3-neck RB flask was added 0.66 g (2.5 mmol) of N-Boc-L-Phe (compound (I)) and 3 mL of anhydrous THF. The solution was cooled to -10 0C and triethylamine (2.75 mmol, 0.38 mL) was added dropwise. After stirring for 10 minutes at -10 0C, this solution was added dropwise to a precooled solution of isobutyl chloroformate (compound (2)) (2.5 mmol, 0.32 mL) in 7.5 mL of anhydrous THF at -15 0C. A white precipitate was observed. The reaction mixture was stirred between -10 0C and -15 0C for 30 minutes and then the precipitate was filtered and washed with 10 mL THF. The filtrate thus obtained was used directly for ylide formation.
[0182] Keto sulfoxonium ylide compound (5) formation: In a separate 3-neck RB flask, potassium tert-butoxide (4.12 mmol, 0.46 g) was dissolved in 15 mL anhydrous THF and trimethylsulfoxonium iodide (3.75 mmol, 0.82 g) was added. The resulting slurry was heated at 90 0C for 2 h. The reaction mixture was then cooled to room temperature and subsequently to about -20 0C. The filtered activated ester solution from above was then added dropwise maintaining the temperature at about -20 0C. The reaction was stirred at the same temperature for 2 h. The reaction mixture was quenched by adding 15 mL water, the organic layer was separated and washed with brine (2 x 120 mL), dried over Na2SO4 and concentrated under reduced pressure to obtain desired product of compound (5) as light yellow sticky solid (0.55 g, 65% yield, 99% ee).
[0183] α-Chloroketone of compound (6) formation: The keto sulfoxonium ylide of compound (5) (6.18 mmol, 2.0 g) from above was dissolved in 30 mL anhydrous THF and the solution was cooled to 0 0C. Lithium chloride (6.80 mmol, 0.29 g) and methanesulfonic acid (6.80 mmol, 0.44 mL) were added. The temperature was slowly raised to room temperature and subsequently to 80 0C. The reaction mixture was stirred at 80 0C for 2 h. After cooling to room temperature, the reaction was quenched by adding 30 mL water. The phases were separated and the aqueous layer was extracted with 30 mL of 2:1 heptane/ethyl acetate. The organic layers were combined and washed with saturated NaHCO3 (2 x 30 mL), water (2 x 25 mL) and brine (2 x 15 mL) and dried over Na2SO4. Concentration under reduced pressure afforded crude α-chloroketone of compound (6) (1.5 g, 81% yield) as a yellow semi solid. Crystallization of product from hot 5: 1 heptane/ethyl acetate mixtures yielded 0.30 g of white solid of compound (6) with a purity of 96.8% (by HPLC) and a chiral purity of 99% ee.
G. Synthesis of a keto sulfoxonium ylide using carbonyl diimidazole (CDI) [0184] Activated ester formation: To a RB flask was added N-Boc-L-Phe or N-Boc-D-Phe (1.99 g,
7.5 mmol), N,N'-carbonyldiimidazole (CDI) (1.46 g, 9.0 mmol), and THF (25 mL). The solutions were stirred at 45 0C for 72 hours and then concentrated to -4-5 mL resulting in a concentrated solution of N-Boc-L-Phe-imidazolide, which includes the intermediates compound (24) and compound (25), or N-Boc-D-Phe-imidazolide, which includes the intermediates corresponding to the opposing D-enantiomers of compound (24) and compound (25).
[0185] Keto sulfoxonium ylide formation: A 3-neck 250-mL RB flask equipped with a thermocouple, a magnetic stirrer, a magnetic stir bar and a reflux condenser was charged with trimethylsulfoxonium chloride (5.77 g, 45 mmol), potassium tert-butoxiάe (45 mL, 45 mmol, 1 M in THF) and 30 mL anhydrous THF. The solution was refluxed for 2 h, cooled to room temperature and then split into 2 x 37.5 mL aliquots. The aliquots were cooled to 0 0C followed by addition of the concentrated solution of either N-Boc-L-Phe-imidazolide or N-Boc-D-Phe-imidazolide (approx 2.69 g, 7.5 mmol). The addition took place over 10 min while maintaining the temperature at 0 0C. The solutions were allowed to stir at the same temperature for 4 h. 10 mL water was added to quench the reaction. The organic layer was separated and washed with brine (2 x 10 mL), dried with Na2SO4, filtered, and concentrated under reduced pressure. This gave L-Phe-sulfoxonium ylide of compound (5) (2.73 g, 80% pure, <1% ee) as a sticky white solid, or D-Phe-sulfoxonium ylide, the opposing D- enantiomer of compound (5),(2.92 g, 87% pure, <1% ee) as a white flaky solid respectively. [0186] Alternatively, the reaction can be carried out as above, except that trimethylsulfoxonium iodide is substituted for the trimethylsulfoxonium chloride, and the concentrated solution of either Boc-L-Phe-imidazolide or Boc-D-Phe-imidazolide (approx 2.69 g, 7.5 mmol) is added dropwise to a solution cooled to and maintained at -20 0C. The resulting D- or L-amino acid keto sulfoxonium ylides are expected to form in substantially greater enantiomeric excess than the reaction carried out at 00C.
[0187] All publications, patents, patent applications and other documents cited in this application are hereby incorporated by reference in their entireties for all purposes to the same extent as if each individual publication, patent, patent application or other document were individually indicated to be incorporated by reference for all purposes.
[0188] While various specific embodiments have been illustrated and described, it will be appreciated that various changes can be made without departing from the spirit and scope of the invention(s).

Claims

CLAIMSWhat is claimed is:
1. A process for the preparation of a compound according to Formula (I):
O
(I) comprising contacting a compound of Formula (II)
Figure imgf000042_0001
(II) with a compound of Formula (III), Formula (XII), or Formula (XXXI)
Figure imgf000042_0002
(XXXI) to provide a compound of Formula (IV) or Formula (XIII)
Figure imgf000042_0003
(IV) (XIII)
contacting the compound of Formula (IV) or Formula (XIII) with a compound of Formula (V)
O
R3 ,-S I'— R A4
Il CH2
(V) to provide a compound of Formula (VI)
Figure imgf000042_0004
contacting the compound of Formula (VI) with anhydrous HCl to provide the compound of Formula (I); wherein: R1 is selected from the group consisting Of-CH(R5)NH(R6), -(d-C2)alkyl, -(Cr C3)alkyl, -(d-C4)alkyl, -(Ci-C6)alkyl, and -(d-Cio)alkyl, aryl, heteroaryl, each alkyl, aryl, and heteroaryl being unsubstituted or substituted with at least one moiety selected from the group consisting of -OH, -SH, -SHCH3, -COOH, -C(O)NH2, -NHCH(NH2X=NH), -(C3-C10)cycloalkyl, -(C3-C6)cycloalkyl, -phenyl, and -(5- to 10-membered)heteroaryl, each -(C3-Ci0)cycloalkyl, -(C3-C6)cycloalkyl , -phenyl, and -(5- to 10-membered)heteroaryl being unsubstituted or substituted with at least one moiety selected from the group consisting of hydrogen, -OH, -CH2OH, - CH2CH2OH -NH2, -halo, -CN, -NO2, -C(O)NH2,-(Ci-C6)alkyl, -C(O)NH(Ci- C4))alkyl, -C(O)N((Ci-C4)alkyl)2, and -(d-C4)alkyl;
R2 is selected from the group consisting of alkyl, alkenyl, and aryl, wherein the alkyl is selected from -(CrC2)alkyl, -(CrC3)alkyl, -(d-C4)alkyl, -(Ci-C6)alkyl, and -(Ci- Cio)alkyl, each alkyl being unsubstituted or substituted with at least one moiety selected from the group consisting of -(C3-C7)cycloalkyl, alkenyl, -phenyl, and -(5- to 10-membered)heteroaryl;
R3 and R4 are each independently selected from the group consisting of -(Ci-C2)alkyl, -(Ci-d)alkyl, -(CrC4)alkyl, -(CrC6)alkyl, -(Ci-Cio)alkyl, each alkyl being unsubstituted or substituted with at least one moiety selected from the group consisting of -(C3-Cio)cycloalkyl, -(C3-C6)cycloalkyl, -phenyl, and -(5- to 10-membered)heteroaryl, each -(C3-Ci0)cycloalkyl, -(C3-C6)cycloalkyl , -phenyl, and -(5- to 10-membered)heteroaryl being unsubstituted or substituted with at least one moiety selected from the group consisting of -(Ci-C2)alkyl, -(Ci-C3)alkyl, and -(d-C4)alkyl;
R5 is selected from the group consisting of -(CrC2)alkyl, -(CrC3)alkyl, -(Ci- C4)alkyl, -(d-C6)alkyl, and -(CrCio)alkyl, each alkyl being unsubstituted or substituted with at least one moiety selected from the group consisting of -OH, -SH, - SHCH3, -COOH, -C(O)NH2, -NHCH(NH2)(=NH), -(C3-Cio)cycloalkyl, -(C3- C6)cycloalkyl, -phenyl, and -(5- to 10-membered)heteroaryl, each -(C3- Cio)cycloalkyl, -(C3-C6)cycloalkyl , -phenyl, and -(5- to 10-membered)heteroaryl being unsubstituted or substituted with at least one moiety selected from the group consisting of hydrogen, -OH, -CH2OH, -CH2CH2OH -NH2, -halo, -CN, -NO2, -C(O)NH2,-(Ci-C6)alkyl, -C(O)NH(Ci -C4))alkyl, -C(O)N((CrC4)alkyl)2, and -(Ci- C4) alkyl; and
R6 is a nitrogen-protecting group.
2. The process of claim 1, wherein the method comprises
contacting a compound of Formula (II)
Figure imgf000044_0001
(II) with a compound of Formula (III)
2.O Cl
R2'
O (III) to provide a compound of Formula (IV)
Figure imgf000044_0002
(IV)
3. The process of claim 2, wherein R is selected from the group consisting of phenyl, benzyl, isobutyl, methyl, and vinyl.
4. The process of claim 3, wherein R is isobutyl.
5. The process of claim 1 , wherein the method comprises contacting a compound of Formula (II)
Figure imgf000044_0003
(II) with a compound of Formula (XII)
Figure imgf000044_0004
(XII) to provide a compound of Formula (XIII)
Figure imgf000045_0001
(XIII)
6. The process of claim 5, wherein the compound of Formula (XII) is compound (7):
Figure imgf000045_0002
(7)
7. The process of claim 1, wherein the method comprises contacting a compound of Formula (II)
Figure imgf000045_0003
(II) with a compound of Formula (XXXI)
Figure imgf000045_0004
(XXXI) to provide a compound of Formula (XIII)
Figure imgf000045_0005
(XIII)
8. The process of claim 7, herein the compound of Formula (XXXI) is compound (27):
Figure imgf000045_0006
(27)
9. The process of any one of claims 1-8, wherein R1 is -CH(R5)NH(R6).
10. The process of claim 9, wherein R6 is selected from the group consisting of benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (FMOC), and t-butoxycarbonyl (BOC).
11. The process of claim 10, wherein R6 is t-butoxycarbonyl (Boc).
12. The process of claim 9, wherein R5 is selected from the group consisting of -(Ci- C6)alkyl, unsubstituted or substituted with a moiety selected from the group consisting of -OH, -SH, - SHCH3, -COOH, -C(O)NH2, -NHCH(NH2)(=NH), -phenyl, -4-OH-phenyl, and
-(5- to 10-membered)heteroaryl.
13. The process of claim 12, wherein R5 is -CH2-phenyl.
14. The process of claim 13, wherein the compound of Formula (I) is a substantially chirally pure compound of structure:
Figure imgf000046_0001
15. The process of any one of claims 1-14, wherein R3 and R4 are both methyl.
16. The process of any one of claims 1-15, wherein the compound of Formula (V) is prepared by contacting a compound of Formula (XI), wherein X is halo,
Figure imgf000046_0002
(Xl)
with a base to provide the compound of Formula (V).
17. The process of claim 16, wherein the base is selected from the group consisting of sodium hydride, potassium tert-amylate, and potassium tert-butoxide.
18. The process of claim 17, wherein the base is potassium tert-butoxide.
19. The process of claim 16, wherein X is iodide.
20. The process of any one of claims 1-19, wherein the anhydrous HCl is generated by contacting a chloride salt with an organic acid under anhydrous conditions.
21. The process of claim 20, wherein the organic acid is methanesulfonic acid and the chloride salt is LiCl.
22. The process of any one of claims 1-21, wherein the compound of Formula (I) is substantially chirally pure.
23. A process for the preparation of a compound according to Formula (I):
Figure imgf000047_0001
comprising contacting a compound of Formula (IV)
Figure imgf000047_0002
with a compound of Formula (V)
Figure imgf000047_0003
to provide a compound of Formula (VI)
Figure imgf000047_0004
converting the compound of Formula (VI) to the compound of Formula (I); wherein:
R1 is selected from the group consisting Of-CH(R5)NH(R6), -(d-C2)alkyl, -(C r C3)alkyl, -(Ci-C4)alkyl, -(CrC6)alkyl, and -(d-Cio)alkyl, each alkyl being unsubstituted or substituted with at least one moiety selected from the group consisting of -OH, -SH, -SHCH3, -COOH, -C(O)NH2, -NHCH(NH2)(=NH), -(C3- Cio)cycloalkyl, -(C3-C6)cycloalkyl, -phenyl, and -(5- to 10-membered)heteroaryl, each -(C3-Cio)cycloalkyl, -(C3-C6)cycloalkyl , -phenyl, and -(5- to 10-membered)heteroaryl being unsubstituted or substituted with at least one moiety selected from the group consisting of hydrogen, -OH, -CH2OH, -CH2CH2OH -NH2, ■ halo, -CN, -NO2, -C(O)NH2,-(CrC6)alkyl, -C(O)NH(Ci-C4))alkyl, -C(O)N((Cr C4)alkyl)2, and -(CrC4)alkyl; R is selected from the group consisting of alkyl, alkenyl, and aryl, wherein alkyl is selected from -(d-C2)alkyl, -(CrC3)alkyl, -(CrC4)alkyl, -(CrC6)alkyl, and -(C1- Cio)alkyl, each alkyl being unsubstituted or substituted with at least one moiety selected from the group consisting of -(C3-C7)cycloalkyl, -phenyl, and -(5- to 10-membered)heteroaryl;
R3 and R4 are each independently selected from the group consisting of -(Ci-C2)alkyl, -(CrC3)alkyl, -(Ci-C4)alkyl, -(CrC6)alkyl, -(CrC10)alkyl, each alkyl being unsubstituted or substituted with at least one moiety selected from the group consisting of -(C3-Cio)cycloalkyl, -(C3-C6)cycloalkyl, -phenyl, and -(5- to 10-membered)heteroaryl, each -(C3-Ci0)cycloalkyl, -(C3-C6)cycloalkyl , -phenyl, and -(5- to 10-membered)heteroaryl being unsubstituted or substituted with at least one moiety selected from the group consisting of -(Ci-C2)alkyl, -(Ci-C3)alkyl, and -(Ci-C4)alkyl;
R5 is selected from the group consisting of -(Ci-C2)alkyl, -(Ci-C3)alkyl, -(C1- C4)alkyl, -(Ci-C6)alkyl, and -(Ci-Cio)alkyl, each alkyl being unsubstituted or substituted with at least one moiety selected from the group consisting of -OH, -SH, - SHCH3, -COOH, -C(O)NH2, -NHCH(NH2)(=NH), -(C3-Ci0)cycloalkyl, -(C3- C6)cycloalkyl, -phenyl, and -(5- to 10-membered)heteroaryl, each -(C3- Cio)cycloalkyl, -(C3-C6)cycloalkyl , -phenyl, and -(5- to 10-membered)heteroaryl being unsubstituted or substituted with at least one moiety selected from the group consisting of hydrogen, -OH, -CH2OH, -CH2CH2OH -NH2, -halo, -CN, -NO2, -C(O)NH2,-(CrC6)alkyl, -C(O)NH(C1 -C4))alkyl, -C(O)N((CrC4)alkyl)2, and -(C1- C4) alkyl; and
R6 is a nitrogen-protecting group.
24. The process of claim 23, wherein R1 is -CH(R5)NH(R6).
25. The process of claim 24, wherein R6 is selected from the group consisting of benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (FMOC), and t-butoxycarbonyl (BOC).
26. The process of claim 25, wherein R6 is t-butoxycarbonyl (Boc).
27. The process of claim 24, wherein R5 is selected from the group consisting of -(C1- C6)alkyl, unsubstituted or substituted with a moiety selected from the group consisting of -OH, -SH, - SHCH3, -COOH, -C(O)NH2, -NHCH(NH2)(=NH), -phenyl, -4-OH-phenyl, and
-(5- to 10-membered)heteroaryl.
28. The process of claim 27, wherein R5 is -CH2-phenyl.
29. The process of claim any one of claims 23-28, wherein R3 and R4 are both methyl.
30. A process for the preparation of a compound according to Formula (I):
O
I R1' comprising contacting a compound of Formula (II)
Figure imgf000049_0001
with a compound of Formula (XXI)
Figure imgf000049_0002
XXI to provide a compound of Formula (XXII)
Figure imgf000049_0003
contacting the compound of Formula (XXII) with a compound of Formula (V)
O R3-S— R4
V C Ii H2 to provide a compound of Formula (VI)
Figure imgf000049_0004
contacting the compound of Formula (VI) with anhydrous HCl to provide the compound of Formula (I); wherein:
R1 is selected from the group consisting Of-CH(R5)NH(R6), -(d-C2)alkyl, -(C r C3)alkyl, -(Q-C^alkyl, -(CrC6)alkyl, and -(CrC10)alkyl, each alkyl being unsubstituted or substituted with at least one moiety selected from the group consisting of -OH, -SH, -SHCH3, -COOH, -C(O)NH2, -NHCH(NH2)(=NH), -(C3- Cio)cycloalkyl, -(C3-C6)cycloalkyl, -phenyl, and -(5- to 10-membered)heteroaryl, each -(C3-Cio)cycloalkyl, -(C3-C6)cycloalkyl , -phenyl, and -(5- to 10-membered)heteroaryl being unsubstituted or substituted with at least one moiety selected from the group consisting of hydrogen, -OH, -CH2OH, -CH2CH2OH -NH2, - halo, -CN, -NO2, -C(O)NH2,-(CrC6)alkyl, -C(O)NH(CrC4))alkyl, -C(0)N((Cr C4)alkyl)2, and -(CrC4)alkyl;
R3 and R4 are each independently selected from the group consisting of -(CrC2)alkyl, -(CrC3)alkyl, -(CrC4)alkyl, -(CrC6)alkyl, -(CrC10)alkyl, each alkyl being unsubstituted or substituted with at least one moiety selected from the group consisting of -(C3-Cio)cycloalkyl, -(C3-C6)cycloalkyl, -phenyl, and -(5- to 10-membered)heteroaryl, each -(C3-Cio)cycloalkyl, -(C3-C6)cycloalkyl , -phenyl, and -(5- to 10-membered)heteroaryl being unsubstituted or substituted with at least one moiety selected from the group consisting of -(Ci-C2)alkyl, -(Ci-C3)alkyl, and -(Ci-C4)alkyl;
R5 is selected from the group consisting of -(Ci-C2)alkyl, -(Ci-C3)alkyl, -(C1- C4)alkyl, -(Ci-C6)alkyl, and -(Ci-Cio)alkyl, each alkyl being unsubstituted or substituted with at least one moiety selected from the group consisting of -OH, -SH, - SHCH3, -COOH, -C(O)NH2, -NHCH(NH2)(=NH), -(C3-Ci0)cycloalkyl, -(C3- C6)cycloalkyl, -phenyl, and -(5- to 10-membered)heteroaryl, each -(C3- Cio)cycloalkyl, -(C3-C6)cycloalkyl , -phenyl, and -(5- to 10-membered)heteroaryl being unsubstituted or substituted with at least one moiety selected from the group consisting of hydrogen, -OH, -CH2OH, -CH2CH2OH -NH2, -halo, -CN, -NO2, -C(O)NH2,-(CrC6)alkyl, -C(O)NH(C1 -C4))alkyl, -C(O)N((CrC4)alkyl)2, and -(C1- C4)alkyl;
R6 is a nitrogen-protecting group; and
R7 and R8 are each independently selected from the group consisting of (C1-C6) alkyl and aryl.
31. A process for the preparation of a compound according to Formula (I):
O
I R1' comprising contacting a compound of Formula (XX)
Figure imgf000051_0001
with a compound of Formula (V)
R3-S— R4 V CH2 to provide a compound of Formula (VI)
Figure imgf000051_0002
contacting the compound of Formula (VI) with anhydrous HCl to provide the compound of Formula (I); wherein:
R1 is selected from the group consisting of -CH(R5)NH(R6), -(d-C2)alkyl, -(C r C3)alkyl, -(Ci-C4)alkyl, -(CrC6)alkyl, and -(d-Cio)alkyl, each alkyl being unsubstituted or substituted with at least one moiety selected from the group consisting of -OH, -SH, -SHCH3, -COOH, -C(O)NH2, -NHCH(NH2)(=NH), -(C3- Cio)cycloalkyl, -(C3-C6)cycloalkyl, -phenyl, and -(5- to 10-membered)heteroaryl, each -(C3-Cio)cycloalkyl, -(C3-C6)cycloalkyl , -phenyl, and -(5- to 10-membered)heteroaryl being unsubstituted or substituted with at least one moiety selected from the group consisting of hydrogen, -OH, -CH2OH, -CH2CH2OH -NH2, - halo, -CN, -NO2, -C(O)NH2,-(CrC6)alkyl, -C(O)NH(Ci-C4))alkyl, -C(0)N((Cr C4)alkyl)2, and -(CrC4)alkyl;
R3 and R4 are each independently selected from the group consisting of -(Ci-C2)alkyl, -(Ci-C3)alkyl, -(Ci-C4)alkyl, -(CrC6)alkyl, -(d-Cio)alkyl, each alkyl being unsubstituted or substituted with at least one moiety selected from the group consisting of -(C3-Cio)cycloalkyl, -(C3-C6)cycloalkyl, -phenyl, and -(5- to 10-membered)heteroaryl, each -(C3-Cio)cycloalkyl, -(C3-C6)cycloalkyl , -phenyl, and -(5- to 10-membered)heteroaryl being unsubstituted or substituted with at least one moiety selected from the group consisting of -(Ci-C2)alkyl, -(Ci-C3)alkyl, and -(Ci-C4)alkyl; R5 is selected from the group consisting of -(Ci-C2)alkyl, -(Ci-C3)alkyl, -(Ci- C4)alkyl, -(Ci-C6)alkyl, and -(Ci-Cio)alkyl, each alkyl being unsubstituted or substituted with at least one moiety selected from the group consisting of -OH, -SH, SHCH3, -COOH, -C(O)NH2, -NHCH(NH2)(=NH), -(C3-C10)cycloalkyl, -(C3- C6)cycloalkyl, -phenyl, and -(5- to 10-membered)heteroaryl, each -(C3- Cio)cycloalkyl, -(C3-C6)cycloalkyl , -phenyl, and -(5- to 10-membered)heteroaryl being unsubstituted or substituted with at least one moiety selected from the group consisting of hydrogen, -OH, -CH2OH, -CH2CH2OH -NH2, -halo, -CN, -NO2, -C(O)NH2,-(Ci-C6)alkyl, -C(O)NH(Ci -C4))alkyl, -C(O)N((Ci-C4)alkyl)2, and -(Ci- C4)alkyl; and
R6 is a nitrogen-protecting group.
32. A compound selected from the group consisting of
Figure imgf000052_0001
Figure imgf000053_0001
33. The compound of claim 32 having the structure:
Figure imgf000053_0002
34. The compound of claim 32 having the structure:
Figure imgf000053_0003
35. The compound of claim 32 having the structure:
Figure imgf000053_0004
36. The compound of claim 32 having the structure:
Figure imgf000054_0001
37. The compound of claim 32 having the structure:
Figure imgf000054_0002
38. The compound of claim 32 having the structure:
Figure imgf000054_0003
39. The compound of claim 32 having the structure:
Figure imgf000054_0004
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