WO2012075277A2 - Procédés de synthèse - Google Patents

Procédés de synthèse Download PDF

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Publication number
WO2012075277A2
WO2012075277A2 PCT/US2011/062878 US2011062878W WO2012075277A2 WO 2012075277 A2 WO2012075277 A2 WO 2012075277A2 US 2011062878 W US2011062878 W US 2011062878W WO 2012075277 A2 WO2012075277 A2 WO 2012075277A2
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group
optionally substituted
compound
aliphatic
groups
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PCT/US2011/062878
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WO2012075277A3 (fr
Inventor
Alexei Gridnev
Christopher A. Simoneau
Scott D. Allen
Jay J. Farmer
Stephen Godleski
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Novomer, Inc.
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Publication of WO2012075277A2 publication Critical patent/WO2012075277A2/fr
Publication of WO2012075277A3 publication Critical patent/WO2012075277A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • One strategy to reduce the cost contribution of the catalyst is to increase the rate and productivity of the catalysts. For example, in the field of epoxide-CC ⁇
  • the present invention provides new strategies for the efficient synthesis of salicylaldehyde derivatives having utility in the production of catalytic metal complexes.
  • the methods disclosed herein may also find utility in the synthesis of biologically active organic molecules in the pharmaceutical industry and elsewhere. Summary of the Invention
  • the present invention encompasses a method for the synthesis of a compound having formula I:
  • Z is selected from the group consisting of neutral nitrogen-containing groups, neutral phosphorous containing groups and cationic groups,
  • R a represents one or more optionally present moieties selected from the group
  • R b is selected from the group consisting of Ci-6 acyl, and -C(OR 13 ) 2 ,
  • R 10 at each occurrence is independently selected from the group consisting of:
  • R 11 and R 12 at each occurrence are independently selected from the group consisting of: -H; optionally substituted Ci to C 12 aliphatic; an optionally substituted 3- to 14-membered carbocycle; an optionally substituted 3- to 14-membered heterocycle; where two or more R 11 or R 12 groups can optionally be taken together with intervening atoms to form an optionally substituted 3- to 10- membered ring, and
  • R 13 at each occurrence is independently selected from the group consisting of:
  • R 15 at each occurrence is independently selected from the group consisting of:
  • Ci to C 12 aliphatic
  • 3- to 14-membered carbocycle optionally substituted Ci to C 12 aliphatic
  • Z is of any one of the formulae described and/or depicted in
  • Certain compounds of the present invention can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and/or diastereomers.
  • inventive compounds and compositions thereof may be in the form of an individual enantiomer, diastereomer or geometric isomer, or may be in the form of a mixture of stereoisomers.
  • the compounds of the invention are enantiopure compounds.
  • mixtures of enantiomers or diastereomers are provided.
  • certain compounds, as described herein may have one or more double bonds that can exist as either a Z or E isomer, unless otherwise indicated.
  • the invention additionally encompasses the compounds as individual isomers substantially free of other isomers and alternatively, as mixtures of various isomers, e.g., racemic mixtures of enantiomers.
  • this invention also encompasses compositions comprising one or more compounds.
  • isomers includes any and all geometric isomers and stereoisomers.
  • isomers include cis- and iraws-isomers, E- and Z- isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention.
  • a compound may, in some embodiments, be provided substantially free of one or more corresponding stereoisomers, and may also be referred to as "stereochemically enriched.” Where a particular enantiomer is preferred, it may, in some embodiments be provided substantially free of the opposite enantiomer, and may also be referred to as “optically enriched.” “Optically enriched,” as used herein, means that the compound is made up of a significantly greater proportion of one enantiomer. In certain embodiments the compound is made up of at least about 90% by weight of an enantiomer.
  • the compound is made up of at least about 95%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, or 99.9% by weight of an enantiomer.
  • the enantiomeric excess of provided compounds is at least about 90%, 95%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, or 99.9%.
  • enantiomers may be isolated from racemic mixtures by any method known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts or prepared by asymmetric syntheses.
  • halo and halogen refer to an atom selected from fluorine (fluoro, -F), chlorine (chloro, -CI), bromine (bromo, -Br), and iodine (iodo, -I).
  • aliphatic or "aliphatic group”, as used herein, denotes a hydrocarbon moiety that may be straight-chain (i.e., unbranched), branched, or cyclic (including fused, bridging, and spiro-fused polycyclic) and may be completely saturated or may contain one or more units of unsaturation, but which is not aromatic. Unless otherwise specified, aliphatic groups contain 1-30 carbon atoms.
  • aliphatic groups contain 1-12 carbon atoms. In certain embodiments, aliphatic groups contain 1-8 carbon atoms. In certain embodiments, aliphatic groups contain 1-6 carbon atoms. In some embodiments, aliphatic groups contain 1-5 carbon atoms, in some embodiments, aliphatic groups contain 1-4 carbon atoms, in yet other embodiments aliphatic groups contain 1-3 carbon atoms, and in yet other embodiments aliphatic groups contain 1-2 carbon atoms.
  • Suitable aliphatic groups include, but are not limited to, linear or branched, alkyl, alkenyl, and alkynyl groups, and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
  • the term aliphatic group encompasses aliphatic groups wherein one or more hydrogen atoms are replaced with a halogen atom.
  • the term aliphatic group encompasses chlorinated or fluorinated aliphatic groups including perfluorinated compounds.
  • epoxide refers to a substituted or unsubstituted oxirane.
  • Such substituted oxiranes include monosubstituted oxiranes, disubstituted oxiranes, trisubstituted oxiranes, and tetrasubstituted oxiranes.
  • Such epoxides may be further optionally substituted as defined herein.
  • epoxides comprise a single oxirane moiety.
  • epoxides comprise two or more oxirane moieties.
  • polymer refers to a molecule of high relative molecular mass, the structure of which comprises the multiple repetition of units derived, actually or conceptually, from molecules of low relative molecular mass.
  • a polymer is comprised of only one monomer species (e.g., polyethylene oxide).
  • a polymer of the present invention is a copolymer, terpolymer, heteropolymer, block copolymer, or tapered heteropolymer of one or more epoxides.
  • cycloaliphatic used alone or as part of a larger moiety, refer to a saturated or partially unsaturated cyclic aliphatic
  • Cycloaliphatic groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, and cyclooctadienyl.
  • the cycloalkyl has 3-6 carbons.
  • cycloaliphatic also include aliphatic rings that are fused to one or more aromatic or nonaromatic rings, such as decahydronaphthyl or tetrahydronaphthyl, where the radical or point of attachment is on the aliphatic ring.
  • a carbocyclic groups is bicyclic.
  • a carbocyclic group is tricyclic.
  • a carbocyclic group is polycyclic.
  • alkyl refers to saturated, straight- or branched-chain hydrocarbon radicals derived by removal of a single hydrogen atom from an aliphatic moiety.
  • alkyl groups contain 1-12 carbon atoms. In certain embodiments, alkyl groups contain 1-8 carbon atoms. In certain embodiments, alkyl groups contain 1-6 carbon atoms. In some embodiments, alkyl groups contain 1-5 carbon atoms, in some embodiments, alkyl groups contain 1-4 carbon atoms, in yet other embodiments alkyl groups contain 1-3 carbon atoms, and in yet other embodiments alkyl groups contain 1-2 carbon atoms.
  • alkyl radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec -butyl, sec-pentyl, iso-pentyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, sec-hexyl, n-heptyl, n-octyl, n-decyl, n-undecyl, dodecyl, and the like.
  • alkenyl denotes a monovalent group derived by the removal of a single hydrogen atom from a straight- or branched-chain aliphatic moiety having at least one carbon-carbon double bond. Unless otherwise specified, alkenyl groups contain 2-12 carbon atoms. In certain embodiments, alkenyl groups contain 2-8 carbon atoms. In certain embodiments, alkenyl groups contain 2-6 carbon atoms. In some embodiments, alkenyl groups contain 2-5 carbon atoms, in some embodiments, alkenyl groups contain 2-4 carbon atoms, in yet other embodiments alkenyl groups contain 2-3 carbon atoms, and in yet other embodiments alkenyl groups contain 2 carbon atoms.
  • Alkenyl groups include, for example, ethenyl, propenyl, allyl, 1,3-butadienyl, butenyl, l-methyl-2-buten-l-yl, allyl, 1,3-butadienyl, allenyl, and the like.
  • alkynyl refers to a monovalent group derived by the removal of a single hydrogen atom from a straight- or branched-chain aliphatic moiety having at least one carbon-carbon triple bond. Unless otherwise specified, alkynyl groups contain 2-12 carbon atoms. In certain embodiments, alkynyl groups contain 2-8 carbon atoms. In certain embodiments, alkynyl groups contain 2-6 carbon atoms.
  • alkynyl groups contain 2-5 carbon atoms, in some embodiments, alkynyl groups contain 2-4 carbon atoms, in yet other embodiments alkynyl groups contain 2-3 carbon atoms, and in yet other embodiments alkynyl groups contain 2 carbon atoms.
  • Representative alkynyl groups include, but are not limited to, ethynyl, 2-propynyl (propargyl), 1-propynyl, and the like.
  • Carbocycle and "carbocyclic ring” as used herein, refer to monocyclic and polycyclic moieties wherein the rings contain only carbon atoms. Unless otherwise specified, carbocycles may be saturated, partially unsaturated or aromatic, and contain 3 to 20 carbon atoms.
  • Representative carbocyles include cyclopropane, cyclobutane, cyclopentane, cyclohexane, bicyclo[2,2, l]heptane, norbornene, phenyl, cyclohexene, naphthalene, and spiro[4.5]decane, to name but a few.
  • aryloxy refers to monocyclic and polycyclic ring systems having a total of six to 20 ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to twelve ring members.
  • aryl may be used interchangeably with the term “aryl ring”.
  • aryl refers to an aromatic ring system which includes, but is not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents.
  • aryl is a group in which an aromatic ring is fused to one or more additional rings, such as benzofuranyl, indanyl, phthalimidyl, naphthimidyl, phenantriidinyl, or
  • heteroaliphatic refers to aliphatic groups wherein one or more carbon atoms are independently replaced by one or more atoms selected from the group consisting of oxygen, sulfur, nitrogen, phosphorus, or boron. In certain embodiments, one to six carbon atoms are independently replaced by one or more of oxygen, sulfur, nitrogen, or phosphorus. Heteroaliphatic groups may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and include saturated, unsaturated or partially unsaturated groups.
  • heteroaryl and “heteroar-”, used alone or as part of a larger moiety e.g., “heteroaralkyl”, or “heteroaralkoxy” refer to groups having 5 to 14 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 ⁇ electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms.
  • heteroatom refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.
  • Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, benzofuranyl and pteridinyl.
  • heteroaryl and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring.
  • Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl,
  • heteroaryl group may be mono- or polycyclic.
  • heteroaryl may be used interchangeably with the terms “heteroaryl ring”, “heteroaryl group”, or “heteroaromatic”, any of which terms include rings that are optionally substituted.
  • heterooaralkyl refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.
  • heterocycle As used herein, the terms “heterocycle”, “heterocyclyl”, “heterocyclic radical”, and “heterocyclic ring” are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7-14-membered bicyclic heterocyclic moiety that is saturated, partially unsaturated, or aromatic and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above.
  • nitrogen includes a substituted nitrogen.
  • the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), ⁇ (as in pyrrolidinyl), or + NR (as in N-substituted pyrrolidinyl).
  • a heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted.
  • saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl.
  • heterocycle refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.
  • acyl refers to a group having a formula -C(0)R where R is hydrogen or an optionally substituted aliphatic, aryl, or heterocyclic group.
  • partially unsaturated refers to a ring moiety that includes at least one double or triple bond.
  • the term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.
  • protecting group it is meant that a particular functional moiety, e.g., O, S, or N, is masked or blocked, permitting, if desired, a reaction to be carried out selectively at another reactive site in a multifunctional compound.
  • a protecting group reacts selectively in good yield to give a protected substrate that is stable to the projected reactions; the protecting group is preferably selectively removable by readily available, preferably non-toxic reagents that do not attack the other functional groups; the protecting group forms a separable derivative (more preferably without the generation of new stereogenic centers); and the protecting group will preferably have a minimum of additional functionality to avoid further sites of reaction.
  • oxygen, sulfur, nitrogen, and carbon protecting groups may be utilized.
  • hydroxyl protecting groups include methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), ?-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), -methoxybenzyloxymethyl (PMBM), (4- methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), ?-butoxymethyl, 4- pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM),
  • 2,2,2-trichloroethoxymethyl bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4- methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxide,
  • CTMP 1- [(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP), l,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl,
  • TDMS i-butyldiphenylsilyl
  • TDPS i-butyldiphenylsilyl
  • tribenzylsilyl tri- -xylylsilyl
  • triphenylsilyl diphenylmethylsilyl
  • DPMS diphenylmethylsilyl
  • TMPS ?-butylmethoxyphenylsilyl
  • the protecting groups include methylene acetal, ethylidene acetal,
  • Amino-protecting groups include methyl carbamate, ethyl carbamante, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-?-butyl-[9-(10,10-dioxo-10, 10,10, 10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ),
  • N-dithiasuccinimide Dts
  • N-2,3-diphenylmaleimide N-2,5-dimethylpyrrole
  • N- 1, 1, 4,4- tetramethyldisilylazacyclopentane adduct STABASE
  • 5-substituted l,3-dimethyl-l,3,5- triazacyclohexan-2-one 5-substituted l,3-dibenzyl-l,3,5-triazacyclohexan-2-one
  • 1- substituted 3,5-dinitro-4-pyridone N-methylamine, N-allylamine
  • Mpt dimethylthiophosphinamide
  • Ppt diphenylthiophosphinamide
  • dialkyl phosphoramidates dibenzyl phosphoramidate, diphenyl phosphoramidate
  • benzenesulfenamide o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide,
  • triphenylmethylsulfenamide 3-nitropyridinesulfenamide (Npys), -toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6,-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6- trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4- methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6- dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7, 8-pentamethylchroman-6- sulfonamide (Pmc), methanesulfonamide (Ms), ⁇ -trimethylsilylethane
  • NMBS benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.
  • exemplary protecting groups are detailed herein, however, it will be appreciated that the present invention is not intended to be limited to these protecting groups; rather, a variety of additional equivalent protecting groups can be readily identified using the above criteria and utilized in the method of the present invention. Additionally, a variety of protecting groups are described in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, the entirety of which is incorporated herein by reference.
  • radical or “optionally substituted radical” is sometimes used.
  • radical means a moiety or functional group having an available position for attachment to the structure on which the substituent is bound. In general the point of attachment would bear a hydrogen atom if the substituent were an independent neutral molecule rather than a substituent.
  • radical or “optionally-substituted radical” in this context are thus interchangeable with “group” or “optionally-substituted group”.
  • compounds of the invention may contain “optionally substituted” moieties.
  • substituted whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent.
  • an "optionally substituted group'Or “optionally substituted radical” may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds.
  • stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.
  • substituents are shown attached to a bond that crosses a bond in a ring of the depicted molecule. This convention indicates that one or more of the substituents may be attached to the ring at any available position (usually in place of a hydrogen atom of the parent structure). In cases where an atom of a ring so substituted has two substitutable positions, two groups may be present on the same ring atom. Unless otherwise indicated, when more than one substituent is present, each is defined independently of the others, and each may have a different structure. In cases where the substituent shown crossing a bond of the ring is -R, this has the same meaning as if the ring were said to be "optionally substituted" as described in the preceding paragraph.
  • Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are independently halogen; -(CH 2 V 4 R 0 ; -(CH 2 )o-40R°;
  • -CH CHPh, which may be substituted with R°; -N0 2 ; -CN; -N 3 ; -(CH 2 ) 0 - 4 N(R o ) 2 ;
  • R° may be substituted as defined below and is independently hydrogen, Ci-s aliphatic, -CH 2 Ph, -O(CH 2 ) 0 -iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with intervening atom(s), form a 3-12- membered saturated, partially unsaturated, or aryl mono- or polycyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.
  • Suitable monovalent substituents on R° are independently halogen, -(CH 2 ) 0 - 2 R e , -(haloR*), -(CH 2 ) 0 - 2 OH, -(CH 2 ) 0 - 2 OR e , -(CH 2 ) 0 - 2 CH(OR e ) 2 ;
  • Suitable divalent substituents that are bound to vicinal substitutable carbons of an "optionally substituted” group include: -0(CR 2 ) 2- 3 ⁇ -, wherein each independent occurrence of R is selected from hydrogen, Ci_6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on the aliphatic group of R * include halogen, -R", -(haloR"), -OH, -OR", -O(haloR'), -CN, -C(0)OH, -C(0)OR e , -NH 2 , -NHR", -NR' 2 , or -N0 2 , wherein each R* is unsubstituted or where preceded by "halo" is substituted only with one or more halogens, and is independently C1-4 aliphatic, -CH 2 Ph, -O(CH 2 ) 0 -iPh, or a 5- 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include -R ⁇ , -NR ⁇ 2 , -C(0)R ⁇ , -C(0)OR ⁇ , -C(0)C(0)R ⁇ , -C(0)CH 2 C(0)R ⁇ , -S(0) 2 R ⁇ , -S(0) 2 NR ⁇ 2 , -C(S)NR ⁇ 2 , -C(NH)NR ⁇ 2 , or -N(R ⁇ )S(0) 2 R ⁇ ; wherein each R ⁇ is independently hydrogen, Ci_6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R ⁇ , taken together with intervening atom(s) form
  • a substitutable nitrogen may be substituted with three R ⁇ substituents to provide a charged ammonium moiety -N + (R ⁇ )3, wherein the ammonium moiety is further complexed with a suitable counterion.
  • Suitable substituents on the aliphatic group of R ⁇ are independently halogen, -R", -(haloR*), -OH, -OR", -0(haloR e ), -CN, -C(0)OH, -C(0)OR e , -NH 2 , -NHR", -NR' 2 , or
  • each R' is unsubstituted or where preceded by "halo" is substituted only with one or more halogens, and is independently C1-4 aliphatic, -CH 2 Ph, -0(CH 2 )o-iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • catalyst refers to a substance the presence of which increases the rate and/or extent of a chemical reaction, while not being consumed or undergoing a permanent chemical change itself.
  • leaving group refers to a group bonded to a carbon atom of a molecule that, when reacted with a nucleophilic reagent, will be displaced from the carbon atom with formation of a new bond between that carbon atom and the nucleophile.
  • leaving groups are known in the art, the most common being halogen atoms and sulfonate esters, though other groups can also play this role including, but not limited to: hydroxyl groups, certain acyloxy groups, phosphorous groups, and the like.
  • the present invention encompasses methods for the synthesis of a compound having formula I:
  • Z is selected from the group consisting of neutral nitrogen-containing groups, neutral phosphorous-containing groups and cationic groups,
  • R a represents one or more optionally present moieties selected from the group
  • R 10 at each occurrence is independently selected from the group consisting of: -H; optionally substituted Ci-i 2 aliphatic; an optionally substituted 3- to 14-membered carbocycle; an optionally substituted 3- to 14-membered heterocycle -S(0) 2 R 13 ; -Si(R 15 ) 3 ; -C(0)R 13 ; and a hydroxyl protecting group,
  • R 11 and R 12 at each occurrence are independently selected from the group
  • R 13 at each occurrence is independently selected from the group consisting of:
  • R 15 at each occurrence is independently selected from the group consisting of: optionally substituted Ci to C 12 aliphatic; and an optionally substituted 3- to 14-membered carbocycle.
  • the present invention encompasses a method comprising steps of: a) Providing a compound of formula S-I
  • methods of the present invention comprise one or more additional steps selected from the group consisting of: replacing the aliphatic hydroxyl group with a Z group; converting the aliphatic hydroxyl group of P-I to a leaving group; displacing the leaving group with a Z group; acylating the aromatic ring at an unsubstituted position ortho to the phenol; protecting the phenolic hydroxyl group; removing a hydroxyl protecting group from the phenol; and alkylating, nitrating, or halogenating a position on the aromatic ring.
  • the present invention encompasses a method comprising the steps of: a) Providing a compound of formula S-I
  • methods of the present invention comprise a step of converting the aliphatic hydroxyl group to a leaving group such as a halogen, a sulfonate ester and the like.
  • the step of converting the compound of formula P-I to P-III comprises the substeps of: i) Reacting the compound of formula P-I to in one or more steps to provide a compound of formula P-II:
  • methods of the present invention comprise a further step of masking the phenolic hydroxyl group with a suitable hydroxy -protecting group.
  • suitable hydroxyl protecting groups are known in the art and can be selected by the skilled artisan based on the disclosure and treachings herein, for example suitable phenol protecting groups are disclosed in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, the entirety of which is incorporated herein by reference.
  • the phenolic hydroxyl group is protected prior to conversion of the aliphatic hydroxyl group into a leaving group.
  • the aliphatic hydroxyl group is first converted to a leaving group, then the phenolic hydroxyl group is masked with a protecting group.
  • the steps of protecting the phenolic hydroxyl group and converting the aliphatic hydroxyl group to a leaving group are performed concomitantly and the same moiety is introduced at each position.
  • the step of converting the compound of formula P-I to P-III comprises the substeps of: i) Reacting the compound of formula P-I in one or more steps to provide a compound of formula P-I':
  • the methods comprise a substep of converting a compound of formula P-II to a compound of formula P-II":
  • methods comprising this step further comprise displacing the aliphatic sulfonate ester with a Z group and then hydrolyzing the phenolic sulfonate ester to provide a compound of formula P-III.
  • methods of the present invention comprise the step of performing one or more chemical reactions to convert a compound of formula P-III to a ompound of formula I:
  • such embodiments include a step of introducing a substituent at the position ortho to the phenol (e.g. R b in formula I). In certain embodiments, this includes a step of manipulating a group attached to the position ortho to the phenol.
  • R b in the product I is selected from the group consisting of -H, R a , Ci_6 acyl, and -C(OR 13 ) 2 , where R a and R 13 are as defined above.
  • R b in the product I is Ci_6 acyl or a protected analog of a Ci_6 acyl group.
  • R b in the product I is a formyl group or a protected version of a formyl group.
  • methods of the present invention comprise a step of introducing an acyl group ortho to the phenolic position in any of the compounds P-I, P-I', P-II, ⁇ - ⁇ , P-II", P-III, or P-III'.
  • methods of the present invention comprise a step of introducing a formyl group ortho to the phenolic position in any of the compounds P-I, P-I', P-II, P-II', P-II", P-III, or P-III'.
  • methods of the present invention comprise the step of acylating a compound of formula P-III in one or more steps to provide a compound of formula la:
  • methods of the present invention comprise acylating compound P-I to provide a compound of formula P-Ia:
  • methods of the present invention include a step of acylating a compou rovide a compound of formula P-Ia':
  • methods of the present invention include a step of acylating a compound rovide a compound of formula P-IIa':
  • methods of the present invention include a step of acylating a compound of formula ⁇ - ⁇ to provide a compound of formula P-IIIa':
  • methods of the present invention include a step of acylating a compou provide a compound of formula P-IIa:
  • the methods above further include a step of protecting the carbonyl group in compound P-Ia, P-Ia', P-IIa, or P-IIa'.
  • the carbonyl protecting group is selected from the group consisting of acetals, ketals, hydrozones, and imines.
  • suitable carbonyl protecting groups are known in the art and can be selected by the skilled artisan, examples of suitable groups are disclosed in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, the entirety of which is incorporated herein by reference.
  • the method above further includes the step of protecting both the carbonyl group and the phenolic hydroxyl group of compounds P-Ia or P-IIa.
  • these two moieties are protected simultaneously by forming a group comprising an acetal or ketal incorporating the oxygen atom of the phenolic hydroxyl group and the carbon atom of the carbonyl moiety.
  • such derivatives comprise intramolecular derivatives.
  • the phenol of one molecule may participate in acetal or ketal formation with a second molecule of P-IIa.
  • the methods further comprise a step of removing the carbonyl protecting group.
  • the step of removing the carbonyl protecting group provides a compound of formual P-III or la
  • a starting material is a coumarin or dihydrocoumarin having the structure S-II:
  • R a is -H or an optionally substituted aliphatic group.
  • R a is -H, a Ci-s aliphatic group, a Ci_6 aliphatic group, or a C 1-4 aliphatic group.
  • R a is a Ci-6 aliphatic group.
  • R a is a C 1-4 aliphatic group.
  • a starting material for the synthesis is a dihydrocoumarin having the structure S-III:
  • the method is characterized in that a starting material for the synthesis is a dihydrocoumarin having the structure S-IV:
  • the method is characterized in that a starting material for the synthesis is a coumarin having the structure S-V:
  • the method is characterized in that a starting material for the synthesis is a coumarin having the structure S-VI:
  • the method is characterized in that a starting material for the sy n having the structure S-VII:
  • the method is characterized in that a starting material for the synthesis is a dihydrocoumarin having the structure S-VIII:
  • a reducing agent used in the reduction step comprises a metal hydride compound.
  • the reducing agent comprises hydrogen gas in the presence of a transition metal catalyst.
  • the metal hydride compound comprises a Group Ilia metal.
  • the metal hydride compound comprises a boron or aluminum compound.
  • a hydroxyl protecting group used to protect the phenol is selected from the group consisting of esters, ethers, silyl ethers, ketals, hemiketals, acetals, hemiacetals, and sulfonate esters.
  • the phenolic protecting group is an ether, an ester, or a sulfonate ester.
  • the hydroxy protecting group used in the protection step is selected from the group consisting of alkyl groups, acyl groups, silyl groups, alkyl sulphonate groups, boron groups, and acetal groups.
  • the protecting group comprises an allylic or benzylic ether.
  • the protecting group is selected from the group consisting of: allyl, benzyl, / methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, -nitrobenzyl, -halobenzyl, 2,6-dichlorobenzyl, p- cyanobenzyl, and -phenylbenzyl.
  • the step of removing the hydroxy protecting group comprises hydrogenolysis.
  • the hydroxy protecting group used in the protection step comprises a silyl ether.
  • the silyl ether is selected from the group consisting of: trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t- butyldimethylsilyl (TBDMS), i-butyldiphenylsilyl (TBDPS), tribenzylsilyl, ⁇ - ⁇ - xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), and ?-butylmethoxyphenylsilyl (TBMPS).
  • TMS trimethylsilyl
  • TES triethylsilyl
  • TIPS triisoprop
  • the hydroxy protecting group used in the protection step comprises an acyl group.
  • the acyl protecting group is selected from the group consisting of: formate, benzoylformate, acetate, chloroacetate,
  • the methods of the present invention include a further step of removing the phenolic hydroxyl group after performing one or more chemical reactions on other reactive sites in the molecule.
  • the step of removing the hydroxy protecting group comprises a reaction selected from the group consisting of:
  • the step of removing the hydroxy protecting group comprises hydrogenolysis.
  • the hydroxyl protecting group is an allyl or benzyl ether and the step of removing the hydroxy protecting group comprises hydrogenolysis.
  • the step of removing the hydroxy protecting group comprises a reaction selected from the group consisting of treatment with acid, and treatment with fluoride.
  • the hydroxy protecting group comprises a silyl ether and the step of removing the hydroxy protecting group comprises a reaction selected from the group consisting of treatment with acid, and treatment with fluoride.
  • the step of removing the hydroxy protecting group comprises a reaction selected from the group consisting of treatment with acid, treatment and treatment with base.
  • the hydroxy protecting group comprises an ester or a sulfonate ester and the step of removing the hydroxy protecting group comprises treatment with base.
  • the step of protecting the phenolic OH group with a protecting group is performed in the same reaction vessel as the reduction without workup and isolation of compound P-I.
  • the step of protecting the phenolic OH group comprises treating a product of the reduction step with a reagent selected from the group consisting of: an acid chloride, an acid anhydride, an alkyl halide, a chlorosilane, a sulfonyl halide, and a sulfonic anhydride.
  • the step of converting the aliphatic hydroxyl group to a leaving group comprises converting the aliphatic hydroxyl group to a halogen.
  • the step of converting the aliphatic hydroxyl to a halogen comprises replacing the hydroxyl group with a chlorine atom.
  • the step of converting the aliphatic hydroxyl to a halogen comprises replacing the hydroxyl group with a bromine atom.
  • the step of replacing the aliphatic hydroxyl to a halogen comprises replacing the hydroxyl group with an iodine atom.
  • the step of converting the aliphatic hydroxyl group to a leaving group comprises converting the aliphatic hydroxyl to a sulfonate ester.
  • the phenolic protecting group and the leaving group are both sulfonate esters.
  • the step of protecting the phenolic OH group and converting the aliphatic OH group to a leaving group are the same step.
  • the step of protecting the phenolic OH group and converting the aliphatic OH group to a leaving group comprises the step of treating compound P-I with at least two equivalents of a reagent selected from the group consisting of a sulfonyl halide, and a sulfonic anhydride.
  • the sulfonate ester is selected from the group consisting of: methane sulfonate, ethane sulfonate, -toluene sulfonate, benzene sulfonate, trifluoromethane sulfonate, pentafluorophenyl sulfonate, -bromophenylsulfonate, and p- nitrophenylsulfonate.
  • Z is selected from the group consisting of neutral nitrogen containing groups, neutral phosphorous containing groups and cationic groups. In certain embodiments, Z is any of the groups further described in Appendix A included herewith.
  • the step of displacing the leaving group comprises reacting the compound with a reactant having the formula -H. In certain embodiments,
  • the reactant Z-H is selected from the group consisting of: wherein R 1 , R 1 , R 2 , R 2 , and R 3 are independently selected from the group consisting of: optionally substituted, Ci-20 aliphatic, optionally substituted 6- to 14- membered aryl, optionally substituted 3- to 14-membered heterocyclic, optionally substituted Ci-12 acyl, and a polymer, where any two or more of the R groups can optionally be taken together with intervening atoms to form one or more optionally substituted rings optionally containing one or more additional heteroatoms.
  • Z-H is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the reactant Z-H is: r2 , wherein R 1 and R 2 are independently selected from the group consisting of: optionally substituted, Ci-20 aliphatic, optionally substituted 6- to 14-membered aryl, optionally substituted 3- to 14-membered heterocyclic, where R 1 and R 2 can optionally be taken together to form one or more optionally substituted rings optionally containing one or more additional heteroatoms.
  • the step of displacing the leaving group comprises reacting the compound with a reactant having the formula Z(R)3, where Z is a neutral nitrogen atom, R is not -H, and the product I comprises a salt.
  • Z(R) 3 has the formula: , and compound I comprises a guanidinium salt, wherein R 1 , R 1 , R 2 , R 2 , and R 3 are independently selected from the group consisting of: optionally substituted, C 1-20 aliphatic, optionally substituted 6- to 14- membered aryl, optionally substituted 3- to 14-membered heterocyclic, optionally substituted C 1-12 acyl, and a polymer, where any two or more of the R groups can optionally be taken together with intervening atoms to form one or more optionally substituted rings optionally containing one or more additional heteroatoms.
  • Z(R)3 is N-(R)3
  • Z(R)3 has the formula:
  • R 1 , R 2 , and R 3 are independently selected from the group consisting of: optionally substituted, C 1-20 aliphatic, optionally substituted 6- to 14- membered aryl, optionally substituted 3- to 14-membered heterocyclic, where any two or more of the R groups can optionally be taken together with intervening atoms to form one or more optionally substituted rings optionally containing one or more additional heteroatoms, and
  • compound I comprises ammonium salt.
  • the step of displacing the leaving group comprises reacting the compound with a reactant comprising a nitrogen-containing heterocycle wherein a nitrogen atom of the heterocycle displaces the leaving group.
  • the nitrogen-containing heterocycle is aromatic, and the product comprises a salt.
  • the present invention comprises the steps of contacting the compound of formula S-I with a reducing agent to provide a product having a formula selected from the group consisting of Q-II, Q-IIa, and a mixture of Q-II and Q-IIa
  • the present invention comprises the steps of contacting the first layer of the first layer of the first layer of the first layer of the first layer of the first layer of the first layer of the first layer of the first layer of the first layer of the first layer of the first layer of the first layer of the first layer of the second layer of the second layer of the second layer of the second layer of the second layer of the second layer of the third layer of the third layer of the third layer of the third layer of the third layer of the third layer of contacting
  • the present invention comprises a step of reducing a compound of structure S-Ia to rovide a compound of structure S-Ib:
  • the step of reducing S-Ia to S-Ib comprises catalytic hydrogenation.
  • methods of the present invention comprise the step of contacting the compound of formula S-I with a reducing agent in the presence of a compound of formula Z-H to produce the compound of formula I.
  • methods of the present invention comprise the steps of: contacting a compound of formula S-I with a compound having the formula
  • the compound of formula Z-Si(R 13 )3 is selected from the group consisting of:
  • the present invention encompasses methods for converting a comp
  • the present invention encompasses methods for converting
  • the present invention encompasses methods for converting a
  • the present invention encompasses methods for converting a
  • the present invention encompasses methods for converting a compound of formula S-VIII into the analogs shown
  • Step 2 protection of phenolic hydroxy 1 group
  • Step 3 activation of aliphatic hydroxyl group
  • the tosylate and MeTBD are combined and heated in an appropriate solvent to provide the charged guanidinium product.
  • 6-methyl-dihydrocoumarin can be reduced to 2-(3-hydroxypropyl)-4-methylphenol using the same procedure shown for dihydrocoumarin in Example 1.
  • the group "Z" in compounds described hereinabove is selected from those described below in this appendix.
  • a Z group is selected from the group consisting of neutral nitrogen-containing groups, cationic groups, phosphorous- containing groups, and combinations of two or more of these.
  • one or more tethered groups on provided compounds of formula I are neutral nitrogen-containing groups.
  • such groups include one or more of the structures in Table Z-l :
  • each R 1 and R 2 is independently hydrogen or an optionally substituted radical selected from the group consisting of C 1-20 aliphatic; C 1-20 heteroaliphatic; a 3- to 8- membered saturated or partially unsaturated monocyclic carbocycle; a 7- to 14- membered saturated or partially unsaturated polycyclic carbocycle; a 5- to 6- membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; an 8- to 14-membered polycyclic heteroaryl ring having 1 -5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; a 3- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; a 6- to 14-membered saturated or partially unsaturated polycyclic heterocycle having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; phenyl; or an 8- to 14-membered polycyclic
  • each R 1 group is the same. In other embodiments, R 1 groups are different. In certain embodiments, R 1 is hydrogen. In some embodiments, R 1 is an optionally substituted radical selected from the group consisting of C 1-20 aliphatic; C 1-20 heteroaliphatic, 5- to 14-membered heteroaryl, phenyl, 8- to 10-membered aryl and 3- to 7-membered heterocyclic.
  • R 1 is an optionally substituted radical selected from the group consisting of a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle; a 7- to 14-membered saturated or partially unsaturated polycyclic carbocycle; a 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; an 8- to 14-membered polycyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; a 3- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; a 6- to 14-membered saturated or partially unsaturated polycyclic heterocycle having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; phenyl; or an 8- to 14-membered polycyclic aryl ring.
  • R 1 is an optionally substituted radical selected from the group consisting of C 1-12 aliphatic and C 1-12 heteroaliphatic. In some embodiments, R 1 is optionally substituted C 1-20 aliphatic. In some embodiments, R 1 is optionally substituted Ci-12 aliphatic. In some embodiments, R 1 is optionally substituted Ci_6 aliphatic. In some embodiments, R 1 is optionally substituted C 1-20 heteroaliphatic. In some embodiments, R 1 is optionally substituted C 1-12 heteroaliphatic. In some embodiments, R 1 is optionally substituted phenyl. In some embodiments, R 1 is optionally substituted 8- to 10-membered aryl.
  • R 1 is an optionally substituted 5- to 6-membered heteroaryl group. In some embodiments, R 1 is an optionally substituted 8- to 14-membered polycyclic heteroaryl group. In some embodiments, R 1 is optionally substituted 3- to 8- membered heterocyclic. In certain embodiments, each R 1 is indepedendently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, optionally substituted phenyl, or optionally substituted benzyl.
  • R 1 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, phenyl or benzyl. In some embodiments, R 1 is butyl. In some embodiments, R 1 is isopropyl. In some embodiments, R 1 is neopentyl. In some embodiments, R 1 is perfluoro. In some embodiments, R 1 is -CF 2 CF 3 . In some
  • R 1 is phenyl. In some embodiments, R 1 is benzyl.
  • each R 2 group is the same. In other embodiments, R 2 groups are different. In certain embodiments, R 2 is hydrogen. In some embodiments, R 2 is an optionally substituted radical selected from the group consisting of C 1-20 aliphatic; C 1-20 heteroaliphatic, 5- to 14-membered heteroaryl, phenyl, 8- to 10-membered aryl and 3- to 7-membered heterocyclic.
  • R 2 is an optionally substituted radical selected from the group consisting of a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle; a 7- to 14-membered saturated or partially unsaturated polycyclic carbocycle; a 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; an 8- to 14-membered polycyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; a 3- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; a 6- to 14-membered saturated or partially unsaturated polycyclic heterocycle having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; phenyl; or an 8- to 14-membered poly cyclic aryl ring.
  • R 2 is an optionally substituted radical selected from the group consisting of C 1-12 aliphatic and C 1-12 heteroaliphatic. In some embodiments, R 2 is optionally substituted C 1-20 aliphatic. In some embodiments, R 2 is optionally substituted Ci-12 aliphatic. In some embodiments, R 2 is optionally substituted Ci-6 aliphatic. In some embodiments, R 2 is optionally substituted C 1-20 heteroaliphatic. In some embodiments, R 2 is optionally substituted C 1-12 heteroaliphatic. In some embodiments, R 2 is optionally substituted phenyl. In some embodiments, R 2 is optionally substituted 8- to 10-membered aryl.
  • R 2 is an optionally substituted 5- to 6-membered heteroaryl group. In some embodiments, R 2 is an optionally substituted 8- to 14-membered polycyclic heteroaryl group. In some embodiments, R 2 is optionally substituted 3- to 8- membered heterocyclic.
  • each R 2 is indepedendently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, optionally substituted phenyl, or optionally substituted benzyl.
  • R 2 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, phenyl or benzyl.
  • R 2 is butyl.
  • R 2 is isopropyl.
  • R 2 is neopentyl.
  • R 2 is perfluoro.
  • R 2 is -CF 2 CF 3 .
  • R 2 is phenyl. In some embodiments, R 2 is benzyl.
  • each R 1 and R 2 are hydrogen. In some embodiments, each R 1 is hydrogen each and each R 2 is other than hydrogen. In some embodiments, each R 2 is hydrogen each and each R 1 is other than hydrogen.
  • R 1 and R 2 are both methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, phenyl or benzyl. In some embodiments, R 1 and R 2 are each butyl. In some embodiments, R 1 and R 2 are each isopropyl. In some embodiments, R 1 and R 2 are each perfluoro. In some embodiments, R 1 and R 2 are -CF2CF3. In some embodiments, R 1 and R 2 are each phenyl. In some embodiments, R 1 and R 2 are each benzyl.
  • R 1 and R 2 are taken together with intervening atoms to form one or more optionally substituted carbocyclic, heterocyclic, aryl, or heteroaryl rings.
  • R 1 and R 2 are taken together to form a ring fragment selected from the group consisting of: -C(R y ) 2 -, -C(R y ) 2 C(R y ) 2 -, -C(R y ) 2 C(R y ) 2 C(R y ) 2 -, -C(R y ) 2 OC(R y ) 2 -, and -C(R y ) 2 NR y C(R y ) 2 -, wherein R y is as defined above.
  • R 1 and R 2 are taken together to form a ring fragment selected from the group consisting of: -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 OCH 2 -, and -CH 2 NR y CH 2 -.
  • R 1 and R 2 are taken together to form an unsaturated linker moiety optionally containing one or more additional heteroatoms.
  • the resulting nitrogen-containing ring is partially unsaturated.
  • the resulting nitrogen-containing ring comprises a fused polycyclic heterocycle.
  • R 3 is H. In certain embodiments, R 3 is optionally C 1-20 aliphatic; C 1-20 heteroaliphatic, 5- to 14-membered heteroaryl, phenyl, 8- to 10-membered aryl or 3- to 7-membered heterocyclic.
  • R 3 is an optionally substituted radical selected from the group consisting of a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle; a 7- to 14-membered saturated or partially unsaturated polycyclic carbocycle; a 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; an 8- to 14- membered polycyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; a 3- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; a 6- to 14-membered saturated or partially unsaturated polycyclic heterocycle having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; phenyl; or an 8- to 14-membered polycyclic aryl ring.
  • R 3 is optionally substituted C 1-12 aliphatic.
  • R 3 is optionally substituted C 1-12
  • R 3 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, phenyl or benzyl. In some embodiments, R 3 is butyl. In some embodiments, R 3 is isopropyl. In some embodiments, R 3 is perfluoro. In some embodiments, R 3 is -CF 2 CF 3 . In some embodiments, one or more R 1 or R 2 groups are taken together with R 3 and intervening atoms to form an optionally substituted heterocyclic or heteroaryl ring. In certain embodiments, R 1 and R 3 are taken together to form an optionally substituted 5- or 6-membered ring.
  • R 2 and R 3 are taken together to form an optionally substituted 5- or 6-membered ring optionally containing one or more additional heteroatoms.
  • R 1 , R 2 and R 3 are taken together to form an optionally substituted fused ring system.
  • such rings formed by combinations of any of R 1 , R 2 and R 3 are partially unsaturated or aromatic.
  • R 4 is hydrogen. In some embodiments, R 4 is an optionally substituted radical selected from the group consisting of C 1-12 aliphatic, phenyl, 8- to 10-membered aryl, and 3- to 8-membered heterocyclic. In certain embodiments, R 4 is a Ci-12 aliphatic. In certain embodiments, R 4 is a Ci_6 aliphatic. In some embodiments, R 4 is an optionally substituted 8- to 10-membered aryl group. In certain embodiments, R 4 is optionally substituted C 1-12 acyl or in some embodiments, optionally substituted Ci_6 acyl. In certain embodiments, R 4 is optionally substituted phenyl.
  • R 4 is a hydroxyl protecting group. In some embodiments, R 4 is a silyl protecting group. In some embodiments, R 4 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, allyl, phenyl or benzyl.
  • R 1 and R 4 are taken together with intervening atoms to form one or more optionally substituted heterocyclic or heteroaryl rings optionally containing one or more additional heteroatoms.
  • a Z group is an N-linked amino group: , wherein R 1 and R 2 are as defined above and described in classes and subclasses herein.
  • an N-linked amino group is selected from the group consisting of:
  • one or more Z groups is an N-linked hydroxyl amine R
  • N-linked hydroxyl amine Z groups selected from the group consisting of:
  • a Z group in a provided compound of formula I is an amidine.
  • such amidine groups are selected from:
  • an Z group is an N-linked amidine: R wherein each of R 1 , R 2 , and R 3 is as defined above and described in classes and subclasses herein.
  • N-linked amidine groups are selected from the group consisting of:
  • Z groups are amidine groups linked through a carbon
  • one or more Z groups is a carbamate.
  • a carbamate is N-linked: , wherein each of R 1 and R 2 defined above and described in classes and subclasses herein.
  • a carbamate is N-linked: , wherein each of R 1 and R 2 defined above and described in classes and subclasses herein.
  • R 2 is selected from the group consisting of: methyl, ?-butyl, ?-amyl, benzyl, adamantyl, allyl, 4-methoxycarbonylphenyl, 2-(methylsulfonyl)ethyl, 2-(4-biphenylyl)-prop-2-yl, 2-(trimethylsilyl)ethyl, 2-bromoethyl, and 9-fluorenylmethyl.
  • a Z group is a guanidine or bis-guanidine group:
  • each R 1 and R 2 is as defined above and described in classes and subclasses herein.
  • any two or more R 1 or R 2 groups are taken together with intervening atoms to form one or more optionally substituted carbocyclic, heterocyclic, aryl, or heteroaryl rings.
  • R 1 and R 2 groups are taken together to form an optionally substituted 5- or 6-membered ring.
  • three or more R 1 and/or R 2 groups are taken together to form an optionally substituted fused ring system.
  • a Z group is a guanidine or bis guanidine moiety, it ed from the group consisting of:
  • Z groups are oxime or hydrazone groups:
  • R 1 , R 2 , R 3 , and R 4 is as defined above and described in classes and subclasses herein.
  • a Z group is an N-oxide derivative: ; wherein each of R 1 and R 2 is as defined above and described in classes and subclasses herein.
  • an N-oxide Z group is selected from the group consisting of
  • a Z groups on provided compounds of formula I comprise a cationic group.
  • a cationic group is selected from a structure in Table Z-2:
  • each of R 1 , R 2 , and R 3 is independently as defined above and described in classes and subclasses herein;
  • R 5 is R 2 or hydroxyl; wherein R 1 and R 5 can be taken together with intervening atoms to form one or more optionally substituted carbocyclic, heterocyclic, aryl, or heteroaryl rings; each R 6 and R 7 is independently hydrogen or an optionally substituted radical selected from the group consisting of C 1-20 aliphatic; C 1-20 heteroaliphatic; a 3- to 8- membered saturated or partially unsaturated monocyclic carbocycle; a 7- to 14- membered saturated or partially unsaturated polycyclic carbocycle; a 5- to 6- membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; an 8- to 14-membered polycyclic heteroaryl ring having 1 -5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; a 3- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; a 6- to 14-membered saturated
  • X " is any anion
  • Ring A is an optionally substituted, 5- to 10-membered heteroaryl group
  • Ring B is an optionally substituted, 3- to 8-membered saturated or partially
  • unsaturated monocyclic heterocyclic ring having 0-2 heteroatoms in addition to the depicted ring nitrogen atom independently selected from nitrogen, oxygen, or sulfur.
  • a cationic group is a protonated amine: ⁇ , where each of R 1 and R 2 is as defined above and described in classes and subclasses
  • a protonated amine Z group is selected from the group consisting of:
  • a Z group is a guanidinium group:
  • each R 1 and R 2 is independently as defined above and described in classes and subclasses herein.
  • each R 1 and R 2 is independently hydrogen or Ci-20 aliphatic.
  • each R 1 and R 2 is independently hydrogen or C 1-12 aliphatic.
  • each R 1 and R 2 is independently hydrogen or C 1-20 heteroaliphatic.
  • each R 1 and R 2 is independently hydrogen or phenyl.
  • each R 1 and R 2 is independently hydrogen or 8- to 10- membered aryl.
  • each R 1 and R 2 is independently hydrogen or 5- to 10-membered heteroaryl.
  • each R 1 and R 2 is independently hydrogen or 3- to 7-membered heterocyclic.
  • one or more of R 1 and R 2 is optionally substituted C 1-12 aliphatic.
  • any two or more R 1 or R 2 groups are taken together with intervening atoms to form one or more optionally substituted carbocyclic, heterocyclic, aryl, or heteroaryl rings.
  • R 1 and R 2 groups are taken together to form an optionally substituted 5- or 6-membered ring.
  • three or more R 1 and/or R 2 groups are taken together to form an optionally substituted fused ring system.
  • a R 1 and R 2 group are taken together with intervening
  • Ring G is an optionally substituted 5- to 7-membered saturated or partially unsaturated heterocyclic ring.
  • guanidinium Z group is selected from the group consisting of:
  • a Z group is a sulfonium group or an arsonium group: -S -As-R 3
  • an arsonium Z group is selected from the group consisting of:
  • a Z group is an optionally substituted nitrogen-containing heterocycle.
  • the nitrogen-containing heterocycle is an aromatic heterocycle.
  • the optionally substituted nitrogen-containing heterocycle is selected from the group consisting of: pyridine, imidazole, pyrrolidine, pyrazole, quinoline, thiazole, dithiazole, oxazole, triazole, pyrazolem, isoxazole, isothiazole, tetrazole, pyrazine, thiazine, and triazine.
  • a nitrogen-containing heterocycle includes a quaternarized nitrogen atom.
  • certai en-containing heterocycle includes an
  • the optionally substituted nitrogen-containing heterocycle is selected from the group consisting of pyridinium, imidazolium, pyrrolidinium, pyrazolium, quinolinium, thiazolium, dithiazolium, oxazolium, triazolium, isoxazolium, isothiazolium, tetrazolium, pyrazinium, thiazinium, and triazinium.
  • a nitrogen-containing heterocycle is linked to a compound of formula I via a ring nitrogen atom.
  • a ring nitrogen to which the attachment is made is thereby quaternized, and in some embodiments, linkage to a compound of formula I takes the place of an N-H bond and the nitrogen atom thereby remains neutral.
  • an optionally substituted N-linked nitrogen- containing heterocycle is a pyridinium derivative.
  • optionally substituted N-linked nitrogen-containing heterocycle is an imidazolium derivative.
  • optionally substituted N-linked nitrogen-containing heterocycle is a thiazolium derivative.
  • optionally substituted N-linked nitrogen- containing heterocycle is a pyridinium derivative.
  • a Z group is .
  • ring A is an optionally substituted, 5- to 10-membered heteroaryl group.
  • Ring A is an optionally substituted, 6-membered heteroaryl group.
  • Ring A is a ring of a fused heterocycle. In some embodiments, Ring A is an optionally substituted pyridyl group.
  • a nitrogen-containing heterocycle Z group is selected from the group consisting of:
  • Ring B is a 5-membered saturated or partially unsaturated monocyclic heterocyclic ring. In certain embodiments, Ring B is a 6-membered saturated or partially unsaturated heterocycle. In certain embodiments, Ring B is a 7-membered saturated or partially unsaturated heterocycle.
  • Ring B is tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl.
  • Ring B is piperidinyl.
  • a Z group is where each R 1 , R 2 , and R 3 is independently as defined above and described in classes and subclasses herein.
  • a Z group is , wherein each R 1 and R 2 is independently as defined above and described in classes and subclasses herein.
  • a Z group is wherein each R , R , and R is independently as defined above and described in classes and subclasses herein.
  • a Z group is , wherein each of R 1 , R 2 , R 6 , and R 7 is as defined above and described in classes and subclasses herein.
  • R 6 and R 7 are each independently an optionally substituted group selected from the group consisting of C 1-20 aliphatic; C 1-20
  • R 6 and R 7 are each independently an optionally substituted C 1-20 aliphatic. In some embodiments, R 6 and R 7 are each independently an optionally substituted C 1-20 heteroaliphatic having. In some embodiments, R 6 and R 7 are each independently an optionally substituted phenyl or 8-10-membered aryl. In some embodiments, R 6 and R 7 are each independently an optionally substituted 5- tolO-membered heteroaryl.
  • R 6 and R 7 can be taken together with intervening atoms to form one or more rings selected from the group consisting of: optionally substituted C3-C14 carbocycle, optionally substituted C3- Ci4 heterocycle, optionally substituted C6-C1 0 aryl, and optionally substituted 5- to 10- membered heteroaryl.
  • R 6 and R 7 are each independently an optionally substituted Ci-6 aliphatic.
  • each occurrence of R 6 and R 7 is independently methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, or benzyl.
  • each occurrence of R 6 and R 7 is independently perfluoro.
  • each occurrence of R 6 and R 7 is independently -CF 2 CF 3 .
  • a Z group is is independently as defined above and described in classes and subclasses herein.
  • a Z group is wherein each R 1 , R 2 , and R 3 independently as defined above and described in classes and subclasses herein.
  • a Z group is
  • each R 1 and R 2 independently as defined above and described in classes and subclasses herein.
  • a Z group is R R wherein each R 1 and R 2 is independently as defined above and described in classes and subclasses herein.
  • a Z group is wherein each R , R , and R independently as defined above and described in classes and subclasses herein.
  • a Z group is , wherein each R and R 2 is independently as defined above and described in classes and subclasses herein.

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Abstract

Nouvelles stratégies pour la synthèse de dérivés salicylaldéhydes utiles pour la production de complexes métalliques catalytiques.
PCT/US2011/062878 2010-12-01 2011-12-01 Procédés de synthèse WO2012075277A2 (fr)

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WO2010022388A2 (fr) * 2008-08-22 2010-02-25 Novomer, Inc. Catalyseurs et procédés de synthèse de polymère

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WO2010022388A2 (fr) * 2008-08-22 2010-02-25 Novomer, Inc. Catalyseurs et procédés de synthèse de polymère

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