WO2006030208A1 - Amino acid - Google Patents

Amino acid

Info

Publication number
WO2006030208A1
WO2006030208A1 PCT/GB2005/003546 GB2005003546W WO2006030208A1 WO 2006030208 A1 WO2006030208 A1 WO 2006030208A1 GB 2005003546 W GB2005003546 W GB 2005003546W WO 2006030208 A1 WO2006030208 A1 WO 2006030208A1
Authority
WO
WIPO (PCT)
Prior art keywords
pent
methyl
ethyl
propane
amino
Prior art date
Application number
PCT/GB2005/003546
Other languages
French (fr)
Inventor
Ronald Grigg
Shaun Mccaffrey
Original Assignee
University Of Leeds
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by University Of Leeds filed Critical University Of Leeds
Publication of WO2006030208A1 publication Critical patent/WO2006030208A1/en

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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N41/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a sulfur atom bound to a hetero atom
    • A01N41/02—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a sulfur atom bound to a hetero atom containing a sulfur-to-oxygen double bond
    • A01N41/04—Sulfonic acids; Derivatives thereof
    • A01N41/08—Sulfonic acid halides; alpha-Hydroxy-sulfonic acids; Amino-sulfonic acids; Thiosulfonic acids; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
    • A01N37/44—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing at least one carboxylic group or a thio analogue, or a derivative thereof, and a nitrogen atom attached to the same carbon skeleton by a single or double bond, this nitrogen atom not being a member of a derivative or of a thio analogue of a carboxylic group, e.g. amino-carboxylic acids
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/02—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms
    • A01N43/04—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom
    • A01N43/06—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom five-membered rings
    • A01N43/12—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom five-membered rings condensed with a carbocyclic ring
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/02—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms
    • A01N43/04—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom
    • A01N43/14—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom six-membered rings
    • A01N43/16—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom six-membered rings with oxygen as the ring hetero atom
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
    • A01N43/36—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom five-membered rings
    • A01N43/38—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom five-membered rings condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
    • A01N43/40—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
    • A01N43/40—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings
    • A01N43/42—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
    • A01N43/54—1,3-Diazines; Hydrogenated 1,3-diazines
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
    • A01N43/60—1,4-Diazines; Hydrogenated 1,4-diazines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C229/36—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C313/00—Sulfinic acids; Sulfenic acids; Halides, esters or anhydrides thereof; Amides of sulfinic or sulfenic acids, i.e. compounds having singly-bound oxygen atoms of sulfinic or sulfenic groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C313/02—Sulfinic acids; Derivatives thereof
    • C07C313/06—Sulfinamides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/22—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an aralkyl radical attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/61—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 carbon atoms of the nitrogen-containing ring
    • C07D217/24—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/12—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/81—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/76—Benzo[c]pyrans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom 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
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/36—Nitrogen atoms

Definitions

  • the present invention relates to enantiopure, non-proteinogenic ⁇ -amino acids and a method for the preparation thereof.
  • Biological systems are enantiodiscriminatory. In the vast majority of cases most or all of the desired biological activity of a drug resides in one enantiomer, the other enantiomer is therefore an impurity which at best lowers the potency of the drug, at worst it may be potentially fatal. Administration of a racemic mixture of a drug compound is therefore wasteful and potentially dangerous.
  • Enantiomerically pure drugs are available via resolution of racemic mixtures or asymmetric synthesis. Asymmetric synthesis of drug and other compounds is preferable as resolution is often a difficult and time-consuming procedure, particularly on a large scale.
  • Asymmetric synthesis of enantiopure non-proteinogenic ⁇ -amino acids is of great interest to the pharmaceutical industry and has been achieved via a number of different synthetic routes.
  • the inventors have provided further ⁇ -amino acids that are useful as, or in the synthesis of, inter alia, pharmaceutical, nutraceutical or agricultural products.
  • R is an optionally substituted alkenyl, alkynyl or a cyclic group
  • R 1 is optionally substituted NR 7 2 , NR 7 COR 7 , NR 7 CONR 7 2 , NR 7 COOR 7 , NR 7 SOR 7 , NR 7 SOOR 7 or NR 7 CSNR 7 2 wherein R 7 is H or optionally substituted C 1-6 alkyl or Cl-6 haloalkyl;
  • R 2 is optionally substituted CO 2 R 8 or CONR 9 R 10 wherein R 8 , R 9 and R 10 are H, alkyl (e.g. C 1-6 alkyl), aryl or heteroaryl; and wherein R 1 and R 2 , which are from the same compound, or from two different compounds, of formula I, are optionally joined together to form a cyclic compound of ring size C3-C8 of formula II or IE;
  • R 11 and R 12 are H or optionally substituted alkyl, alkylaryl, aryl, alkylheteroaryl, heteroaryl wherein each substitutable carbon atom in R and R 2 may be optionally and independently substituted with one or more of OR 13 , SR 13 , CO 2 R 13 , or NR 13 2 wherein R 13 is H, optionally substituted Cl-6 alkyl, Cl-6 haloalkyl, aryl or heteroaryl; and wherein R 12 and R 7 are optionally joined together to form a cyclic compound of ring size C3-C8 (e.g C5-C6);
  • R 3 which may be absent, is H or optionally substituted alkyl (C 1-8), alkylaryl, aryl, alkylheteroaryl or heteroaryl;
  • R 4 and R 5 are H, alkyl (C 1-8), aryl, heteroaryl, vinyl, amide, ester, alkyl (C1-C8) amide or alkyl (C1-C8) ester and wherein R 4 and/or R 5 are optionally joined together or to R to form an optionally substituted cyclic group (for example a heterocyclic group), for example of ring size C3-C8 (e.g C5 or C6 optionally fused to one or more 5 or 6 membered hydrocarbon rings);
  • R 6 which may be absent, is H, optionally substituted alkyl, aryl or heteroaryl;
  • radicals R 7 may be the same or different.
  • alkyl relates to both straight chain and branched alkyl radicals, for example, of 1 to 12 carbon atoms, e.g. I 5 2, 3, 4, 5, 6, 7, 8 carbon atoms including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert- butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, preferably methyl or ethyl.
  • alkyl also encompasses cycloalkyl radicals including but not limited to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • the alkyl group may be a "haloalkyl” group i.e. an alkyl group, preferably C 1-8, substituted with one or more fluorine atoms.
  • alkenyl means a straight or branched alkenyl radical of, for example, 2 to 12 carbon atoms, such as 2, 3, 4, 5 or 6 carbon atoms, and containing one or more carbon-carbon double bonds and includes but is not limited to ethenyl, n-propyl-1- ene, n-propyl-2-ene, isopropylene etc.
  • Heteroalkenyl relates to an alkenyl group containing one or more heteroatoms selected from N, O or S.
  • Alkynyl relates to a straight or branched alkynyl radical of, for example, 2 to 12 carbon atoms, such as 2, 3, 4, 5 or 6 carbon atoms, and containing one or more triple bonds.
  • the alkynyl group may be -C ⁇ CR wherein R is alkyl (C 1-8), aryl, heteroaryl or cycloalkyl.
  • Cyclic group means a hydrocarbon ring or ring system, which may be unsaturated or partially unsaturated but is usually saturated, typically containing 5 to 13 ring- forming atoms, for example a 5- or 6- membered ring.
  • a cyclic group includes cyclohydrocarbyl and heterocyclyl.
  • Cyclohydrocarbyl relates to a saturated, partly unsaturated or unsaturated 3 - 10, for example, 5, 6, 7, 8, 9 or 10, membered hydrocarbon ring, including cycloalkenyl, cycloheteroalkenyl or aryl.
  • Aryl means an aromatic, for example, C6 to 10 membered hydrocarbon containing one ring or being fused to one or more saturated or unsaturated hydrocarbon.
  • Aryl may include phenyl, indenyl, naphthyl, tetrahydronaphthyl, anthracenyl, phenanthracenyl.
  • Heterocyclyl means, for example, a C3-10, for example 5 or 6, membered membered ring system containing one or more heteroatoms selected from N, O or S and includes heteroaryl.
  • the heterocyclyl system may contain one ring or may be fused to one or more saturated or unsaturated rings; the heterocyclyl may be fully saturated, partially saturated or unsaturated.
  • Heteroaryl means an aromatic, for example, 5-10 membered aromatic ring containing one or more heteroatoms selected from N, O or S such as indole, and containing one ring which is optionally fused to one or more saturated or unsaturated rings.
  • cyclohydrocarbyl or heterocyclyl groups include but are not limited to phenyl, acridine, benzimidazole, benzofuran, benzothiophene, benzoxazole, benzothiazole, carbazole, cinnoline, dioxane, dioxolane, dithiazine, dithiazole, dithiolane, furan, imidazole, imidazoline, imidazolidine, indole, indoline, indolizine, indazole, isoindole, isoquinoline, isooxazole, isothiazole, morpholine, napthyridine, oxazole, oxadiazole, oxathiazole, oxathiazolidine, oxazine, oxadiazine, phenazine, phenothiazine, phenoxazine, phthalazine, piperazine,
  • Halogen means F, Cl, Br, or I.
  • the halogen is F.
  • R is optionally substituted cyclohydrocarbyl or heterocyclyl.
  • R is a five or six membered cyclohydrocarbyl or heterocyclyl group wherein the cyclohydrocarbyl or heterocyclyl group is optionally fused to one or more 5 or 6 membered hydrocarbon rings.
  • the 5 or 6 membered hydrocarbon ring to which R is attached may be an optionally substituted cyclohydrocarbyl or heterocyclyl group, for example, a phenyl ring including biphenyl, naphthyl or anthracenyl.
  • Each substitutable carbon atom in R may be optionally and independently substituted with one or more of halogen (typically Cl or F) 5 alkyl (Cl-12 e.g. Cl-8 e.g Cl, C2 C3 or C4), Cl-6 fluoroalkyl (e.g.
  • R is optionally substituted alkenyl, cycloalkenyl or cycloheteroalkenyl.
  • Each substitutable carbon atom in R may be optionally and independently substituted with one or more of halogen (typically F), alkyl (Cl-12 e.g. Cl-8 e.g Cl, C2 C3 or C4), Cl-6 fluoroalkyl (e.g.
  • cycloalkenyl cycloheteroalkenyl, cycloalkynyl, heterocyclyl (which in turn may be optionally and independently substituted, for example with one or more halogen or aryl group), aryl, alkylOR 14 , CN, COOR 14 , COR 14 , NO 2 , OR 14 , SR 14 , NR 14 2 , CONR 14 2 , SOOR 14 , SONR 14 , SOR 14 , SOONR 14 , NR 14 COR 14 , NR 14 CONR 14 2 , NR 14 COR 14 , NR 14 COOR 14 , NR 14 SOOR 14 wherein R 14 is H, Cl-6 alkyl, Cl-6 fluoroalkyl.
  • R is an optionally substituted aryl or heteroaryl group.
  • the optionally substituted aryl or heteroaryl group may be fused to a saturated or unsaturated 5 or 6 membered hydrocarbon ring.
  • the 5 or 6 membered hydrocarbon ring (to which the optionally substituted aryl is fused) may include between one and three heteroatoms.
  • the 5 or 6 membered hydrocarbon ring to which the optionally substituted aryl is fused or attached may be a phenyl ring, for example, R may be a biphenyl, naphthyl or anthracenyl.
  • the aryl group, or the ring to which it may be fused is substituted with one or more of halogen (typically F), Cl-6 alkyl or Cl-6 fluoroalkyl (e.g. CF 3 ).
  • R is a substituted phenyl group wherein each substitutable carbon atom in R may be optionally and independently substituted with one or more alkyl (e.g. C1-C6) group as described herein.
  • R may be optionally substituted phenyl, acridine, benzimidazole, benzofuran, benzothiophene, benzoxazole, benzothiazole, carbazole, cinnoline, dithiazine, dithiazole, furan, imidazole, imidazoline, imidazolidine, indole, indoline, indolizine, indazole, isoindole, isoquinoline, isooxazole, isothiazole, napthyridine, naphthyl, nucleoside, oxazole, oxadiazole, oxathiazole, oxathiazolidine, oxazine, oxadiazine, phenazine, phenothiazine, phenoxazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, carbazole, c
  • R can be optionally substituted at any position. Substitution can occur at the ortho, meta or para positions relative to the cyclic ring.
  • R, R 3 , R 4 , R 5 , R 6 . R 7 , R 11 and R 12 are as defined herein.
  • Compounds of formula II may be prepared as described herein or by reacting a compound of formula I with a compound of formula IV wherein R 12 may be H and wherein R and R may be joined together to form a cyclic compound of ring size C3-C8 (e.g C5-C6) to form a dipeptide followed by cyclisation of the dipeptide to provide a compound of formula II. This may be achieved thermally or in the presence of a catalyst.
  • Some compounds of the formula (I) may have chiral centres and/or geometric isomeric centres (E- and Z- isomers), and it is to be understood that the invention encompasses all such optical (R- and S-), diastereomers and geometric isomers.
  • the present invention further provides a compound according to the invention which comprises the racemate, the S or the R enantiomer or a mixture thereof, of a compound according to the invention.
  • the compound is the S-enantiomer or the R-enantiomer.
  • a compound according to the invention may be selected from the group consisting of Ethyl 2S,4S-(2-methyl-propane-2-sulfinylamino)-4-phenyl-pent-4-enoate, Ethyl 2R,4R-(2-methyl-propane-2-sulfinylamino)-4-phenyl-pent-4-enoate,
  • the compounds of the first aspect may be provided as a salt, preferably as a pharmaceutically acceptable salt of compounds of formula I.
  • pharmaceutically acceptable salts of these compounds include those derived from organic acids such as acetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, phosphoric, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, mandelic acid, methanesulphonic acid, benzenesulphonic acid and p-toluenesulphonic acid, mineral acids such as hydrochloric, hydrobromic, and sulphuric acid and the like, giving methanesulphonate, benzenesulphonate, p-toluenesulphonate, hydrochloride and sulphate, and the like, respectively or those derived from bases such as organic and inorganic bases.
  • suitable inorganic bases for the formulation of salts of compounds for this invention include the hydroxides, carbonates, and bicarbonates of ammonia, lithium, sodium, calcium, potassium, aluminium, iron, magnesium, zinc and the like. Salts can also be formed with suitable organic bases.
  • bases suitable for the formation of pharmaceutically acceptable base addition salts with compounds of the present invention include organic bases which are non-toxic and strong enough to form salts.
  • Such organic bases are already well-known in the art and may include amino acids such as arginine and lysine, mono-, di-, or trihydroxyalkylamines such as mono-, di-, and triethanolamine, choline, mono-, di-, and trialkylamines, such as methylamine, dimethylamine, and trimethylamine, guanidine; piperidine, N-methylglucosamine; N-methylpiperazine; morpholine; ethylenediamine; N-benzylphenethylamine; tris(hydroxymethyl) aminomethane; and the like.
  • amino acids such as arginine and lysine, mono-, di-, or trihydroxyalkylamines such as mono-, di-, and triethanolamine, choline, mono-, di-, and trialkylamines, such as methylamine, dimethylamine, and trimethylamine, guanidine; piperidine, N-methylglucosamine; N-methylpiperazine; morpholine;
  • Salts may be prepared in a conventional manner using methods well known in the art. Acid addition salts of said basic compounds may be prepared by dissolving the free base compounds according to the first or second aspects of the invention in aqueous or aqueous alcohol solution or other suitable solvents containing the required acid.
  • a base salt of said compound may be prepared by reacting said compound with a suitable base.
  • the acid or base salt may separate directly or can be obtained by concentrating the solution e.g. by evaporation.
  • the compounds of this invention may also exist in solvated or hydrated forms.
  • the invention also extends to a prodrug of the aforementioned compounds such as an ester or amide thereof.
  • a prodrug is any compound that may be converted under physiological conditions or by solvolysis to any of the compounds of the invention or to a pharmaceutically acceptable salt of the compounds of the invention.
  • a prodrug may be inactive when administered to a subject but is converted in vivo to an active compound of the invention.
  • the present invention also provides derivatives including esters, amides, carbamates, carbonates, ureides, ureas, thioureas, hydantoins, thiohydantoins, diketopiperazines, solvates, hydrates, affinity reagents, peptides or prodrugs thereof
  • a hydrolysable ester of a compound of the formula (I) containing a hydroxy group includes inorganic esters such as phosphate esters and acyloxyalkyl ethers and related compounds which as a result of in vivo hydrolysis of the ester break down to give the parent hydroxy group.
  • examples of acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxy-methoxy.
  • a selection of in vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters).
  • Dialkylcarbamoyl and N-(N ⁇ N-diall ⁇ ylaminoethyl)-iV-alkylcarbamoyl (to give carbamates), N 1 N- diaUcylaminoacetyl and carboxyacetyl.
  • substituents on benzoyl include morpholino and piperazino.
  • a suitable example of a hydrolysable amide of a compound of the formula (I) containing a carboxy group is, for example, iV-C 1-6 alkyl amide or iV,7V-di-C 1-6 alkyl amide such as iV-methyl, N-ethyl, iV-propyl, ⁇ N-dimethyl, iV-ethyl-JV-methyl or N 1 N- diethyl amide.
  • a further aspect of the invention provides a process for the manufacture of a compound of formula I which comprises reacting the following compounds in the presence of a catalyst:
  • R 16 and R 17 are H, alkyl (C 1-8), aryl, heteroaryl, cycloalkenyl, cycloheteralkenyl and wherein R and R are optionally joined together to form an optionally substituted cyclic compound of ring size C3-C8 including aryl, heteroaryl, cycloalkenyl or cycloheteroalkenyl;
  • R 18 and R 19 are O, S, CO, CS 5 NR 23 , CR 23 R 23 , NNR 23 2 , NOR 23 , R 23 NNCOR 23 , R 23 NNCO 2 R 23 or NNSO 2 R 23 wherein R 23 is H or optionally substituted Cl-8 alkyl, halogen, Cl -6 haloalkyl, carbocyclyl or heterocyclyl and wherein n is on an integer between 0 and 6 (e.g 1, 2, 3, 4 or 5); R is optionally
  • R 16 and R 17 are H, alkyl (C 1-8), aryl, heteroaryl, cycloalkenyl or cycloheteralkenyl and wherein R 16 and R 17 are optionally joined together to form an optionally substituted cyclic compound of ring size C3-C8 including an aryl, heteroaryl, cycloalkenyl or cycloheteroalkenyl cyclic group;
  • R 18 and R 19 are O, S, CO 5 CS, NR 23 , CR 23 R 23 , NNR 23 2 , NOR 23 , R 23 NNCOR 23 , R 23 NNCO 2 R 23 , NNSO 2 R 23 wherein R 23 is H or optionally substituted C 1-8 alkyl, halogen, C 1-6 haloalkyl, carbocyclyl or heterocyclyl and wherein n is an integer between 0 and 6 (e.g 1, 2,
  • R is as defined herein; and wherein when R 5 is a chiral auxiliary group, Y is a protecting group; wherein when R 15 is H or optionally substituted alkyl (C 1-8), aryl, heteroaryl, cycloalkyl (i.e. Rl 5 is not a chiral auxiliary group), Y is a chiral auxiliary group; iv.) optionally removing R 15 and/or Y to obtain a compound of Formula I.
  • the process comprises reacting a compound of formula R-X (as in (a) above) with allene gas or a substituted allene and an ⁇ - iminoester derivative of formula (V) in the presence of a catalyst.
  • the catalytic asymmetric alkylation of ⁇ -iminoesters according to the process of the invention is particularly attractive since it offers a simple, versatile route to both enantiomers of a chiral product.
  • the process of the invention provides for enantiospecific synthesis of non-proteogenic ⁇ -amino acids which allows access to both the R and S enantiomers. Representative examples of R and S enantiomers according to the invention are shown in Table 1.
  • a chiral auxiliary group is a temporary chiral component included to induce asymmetry and which is removed as in step (iv) above.
  • the chiral auxiliary group R 15 is menthyl or ⁇ -methylbenzyl or when Y is the chiral auxiliary group, preferably sulphinylimino, R 15 is a non-chiral group (for example Ph2P(O) or Tosyl).
  • the ⁇ -iminoester is a sulphinylimino ester.
  • the catalyst is a palladium catalyst combined with indium.
  • R 3 , R 4 , R 5 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 and R 21 are as described herein.
  • a further aspect of the invention provides a compound of formula (V) since such a compound is useful in the synthesis of a compound according to the first aspect of the invention.
  • a further aspect of the invention provides an agent, for example, a pharmaceutical, nutraceutical or agrochemical agent comprising one or more compounds according to the invention.
  • the agent may, for example, be a small molecule.
  • small molecules include, but are not limited to, peptides, peptidomimetics (e.g., peptoids), amino acids and amino acid analogs.
  • a further aspect of the invention provides a peptide or protein comprising a residue of a compound according to the invention wherein the residue is of formula (X)
  • R, R 3 , R 4 , R 5 and R 6 are as defined herein.
  • the present invention further provides a method for the synthesis of a peptide or protein, the method comprising providing a peptide which includes at least one compound, or salt thereof, according to the invention.
  • peptides and proteins may be in whole or in part machine-aided, for example using an automated peptide synthesiser.
  • the methods of this invention can also be readily adapted and applied to the synthesis of peptidomimetics, such as those formed from N-alkyl amino acids (e.g peptoids).
  • Solid phase peptide synthesis generally proceeds by initial attachment of a first (alpha)-amino protected amino acid to a solid support (typically a resin) at its carboxylic end via a linker. Resins with certain protected amino acids already attached are available from commercial sources or can be synthesised by known methods.
  • the (alpha) protecting group is removed from the resin linked amino acid and a second (alpha) amino acid protected amino acid is coupled to the first amino acid using a coupling agent. Cycles of deprotection and coupling of protected amino acids continue until the desired peptide sequence is prepared.
  • reaction conditions reagent, solvent, concentration, temperature, time etc
  • deprotection of the alpha amino protecting group selected for synthesis preferably do not cleave a substantial amount of the growing peptide from the resin selected for synthesis.
  • Potentially reactive groups on the side chains of protected amino acid synthetic peptide building blocks may also be protected, typically with protecting groups that are not that are not substantially removed by the reaction conditions selected for removal of the (alpha) amino protecting group.
  • a variety of protecting groups, reaction conditions for deprotection, coupling agents, reaction conditions for coupling linkers, resins and conditions for cleavage of the peptide from the resin are known in the art.
  • the compounds, salts and agents (e.g. peptides, proteins etc) of the invention can be incorporated into pharmaceutical, nutraceutical or agricultural/agrochemical compositions.
  • compositions typically include the compound, salt or agent along with a pharmaceutically or nutraceutically acceptable carrier.
  • pharmaceutically acceptable carrier includes solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Supplementary active compounds can also be incorporated into the compositions.
  • a pharmaceutical or nutraceutical composition is formulated to be compatible with its intended route of administration.
  • routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), transmucosal, and rectal administration.
  • Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.
  • the parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
  • compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
  • suitable carriers include physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, NJ) or phosphate buffered saline (PBS).
  • the composition must be sterile and should be fluid to the extent that easy syringability exists. It should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars, polyalcohols such as manitol, sorbitol, sodium chloride in the composition.
  • Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminium monostearate and gelatin.
  • Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • Oral compositions generally include an inert diluent or an edible carrier.
  • the active compound can be incorporated with excipients and used in the form of tablets, troche or capsules, e.g., gelatin capsules.
  • Oral compositions can also be prepared using a fluid carrier for use as a mouthwash.
  • compositions can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch
  • a lubricant such as magnesium stearate or Sterotes
  • a glidant such as colloidal silicon dioxide
  • a sweetening agent such as sucrose or saccharin
  • Systemic administration can also be by transmucosal or transdermal means.
  • penetrants appropriate to the barrier to be permeated are used in the formulation.
  • penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives.
  • Transmucosal administration can be accomplished through the use of nasal sprays or suppositories.
  • the compounds are formulated into ointments, salves, gels, or creams as generally known in the art.
  • the compounds may be prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • a controlled release formulation including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art.
  • the materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc.
  • Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • Exemplary doses include milligram or microgram amounts of the compound per kilogram of subject or sample weight (e.g., about 1 microgram per kilogram to about
  • a compound 500 milligrams per kilogram, about 100 micrograms per kilogram to about 5 milligrams per kilogram, or about 1 microgram per kilogram to about 50 micrograms per kilogram. It is furthermore understood that appropriate doses of a compound depend upon the potency of the compound with respect to the expression or activity to be modulated. When one or more of these compounds is to be administered to an animal (e.g., a human), a physician, veterinarian, or researcher may, for example, prescribe a relatively low dose at first, subsequently increasing the dose until an appropriate response is obtained.
  • an animal e.g., a human
  • the specific dose level for any particular animal subject will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, gender, and diet of the subject, the time of administration, the route of administration, the rate of excretion, any drug combination, and the degree of expression or activity to be modulated.
  • Mass spectra were recorded using a micromass ZMD 2000 spectrometer employing the electrospray (ES+) ionisation technique.
  • Infra-red spectra were recorded using a Perkin-Elmer FT-IR spectrometer. TR. spectra of liquids were recorded as thin films on sodium chloride plates. IR spectra of solids were recorded using the "golden gate” apparatus.
  • Microanalysis was performed using a Carlo-Erber 1108 elemental analyser and by titration against barium perchlorate.
  • the oxygen flask combustion technique was used in preparation for the titration.
  • Aryl, alkynyl, vinyl iodide, bromide or triflate (0.75 mmol) was added to a suspension of chiral ⁇ -iminoester (0.5 mmol), indium metal powder (0.088 g, 0.75 mmol), Pd(OAc) 2 (0.01 Ig, 0.05 mmol), tri-2-furyl phosphine (0.024 g, 0.1 mmol), CuI (0.019 g, 0.1 mmol) and piperidine (0.05 ml, 0.5 mmol) in DMF (10 ml) in a Schlenk tube.
  • Ethyl 2S,4S,5R (3-methylene-2,3-dihydro-benzofuran-2-yl)-(2-methyl-propane- 2-sulfmylamino)-acetate Obtained as a pale orange oil (0.108g, 64 %); ⁇ c (75 MHz, CDCl 3 ); 170.45 (CO), 163.13 (Ar), 144.48 (Ar), 131.14 (Ar), 126.52 (Ar), 124.27 (Ar), 121.39 (Ar), 121.11 (Ar), 110.67 (Ar), 102.69 (-CH 2 ), 85.78 (OCH), 62.99 (OCH 2 ), 62.65 (NC), 56.73 (C(CH 3 ) 3 ), 22.57 (C(CH 3 ) 3 ), 14.50 (CO 2 CH 2 CH 3 ).

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Abstract

The present invention relates to enantiopure, non-proteinogenic α-amino acids, and methods for the synthesis thereof, that are useful as, or in the synthesis of, pharmaceutical, nutraceutical or agricultural products.

Description

Amino Acid
The present invention relates to enantiopure, non-proteinogenic α-amino acids and a method for the preparation thereof.
Biological systems are enantiodiscriminatory. In the vast majority of cases most or all of the desired biological activity of a drug resides in one enantiomer, the other enantiomer is therefore an impurity which at best lowers the potency of the drug, at worst it may be potentially fatal. Administration of a racemic mixture of a drug compound is therefore wasteful and potentially dangerous. Enantiomerically pure drugs are available via resolution of racemic mixtures or asymmetric synthesis. Asymmetric synthesis of drug and other compounds is preferable as resolution is often a difficult and time-consuming procedure, particularly on a large scale.
Asymmetric synthesis of enantiopure non-proteinogenic α-amino acids is of great interest to the pharmaceutical industry and has been achieved via a number of different synthetic routes.
A palladium-catalysed synthesis of an α-amino acid from the reaction of an allene with isopropenyl bromide gave a racemic and stereoisomeric mixture, E/Z = 75/25, of the α-iminoester intermediate (Kopola et al., Tetrahedron Letters, 30 (30): 3963- 3966 (1989)). Resolution of the racemic mixture is required to obtain the enantiopure α-amino acid(s).
The inventors have provided further α-amino acids that are useful as, or in the synthesis of, inter alia, pharmaceutical, nutraceutical or agricultural products.
According to a first aspect of the present invention there is provided a compound, or derivative thereof, of formula I
Figure imgf000003_0001
wherein R is an optionally substituted alkenyl, alkynyl or a cyclic group;
R1 is optionally substituted NR7 2, NR7COR7, NR7CONR7 2, NR7COOR7, NR7SOR7, NR7SOOR7 or NR7CSNR7 2 wherein R7 is H or optionally substituted C 1-6 alkyl or Cl-6 haloalkyl;
R2 is optionally substituted CO2R8 or CONR9R10 wherein R8, R9 and R10 are H, alkyl (e.g. C 1-6 alkyl), aryl or heteroaryl; and wherein R1 and R2, which are from the same compound, or from two different compounds, of formula I, are optionally joined together to form a cyclic compound of ring size C3-C8 of formula II or IE;
Figure imgf000003_0002
wherein R11 and R12 are H or optionally substituted alkyl, alkylaryl, aryl, alkylheteroaryl, heteroaryl wherein each substitutable carbon atom in R and R 2 may be optionally and independently substituted with one or more of OR13, SR13, CO2R13, or NR13 2 wherein R13 is H, optionally substituted Cl-6 alkyl, Cl-6 haloalkyl, aryl or heteroaryl; and wherein R12 and R7 are optionally joined together to form a cyclic compound of ring size C3-C8 (e.g C5-C6);
R3, which may be absent, is H or optionally substituted alkyl (C 1-8), alkylaryl, aryl, alkylheteroaryl or heteroaryl;
R4 and R5 are H, alkyl (C 1-8), aryl, heteroaryl, vinyl, amide, ester, alkyl (C1-C8) amide or alkyl (C1-C8) ester and wherein R4 and/or R5 are optionally joined together or to R to form an optionally substituted cyclic group (for example a heterocyclic group), for example of ring size C3-C8 (e.g C5 or C6 optionally fused to one or more 5 or 6 membered hydrocarbon rings);
R6 ; which may be absent, is H, optionally substituted alkyl, aryl or heteroaryl;
or a pharmaceutically acceptable salt, and other pharmaceutically acceptable biohydrolysable derivatives thereof, and including the proviso that the compound is not 2-Amino-4-methylene-hex-5-enoic acid, 2-Amino-5-methyl-4-methylene-hex-5- enoic acid or 2-Amino-4-phenyl-pent-4-enoic acid.
For the avoidance of doubt when a group as defined above contains two or more radicals, e.g the radical R7 as for example NR7SOOR7, the radicals R7 may be the same or different.
As used herein "alkyl" relates to both straight chain and branched alkyl radicals, for example, of 1 to 12 carbon atoms, e.g. I5 2, 3, 4, 5, 6, 7, 8 carbon atoms including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert- butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, preferably methyl or ethyl. The term alkyl also encompasses cycloalkyl radicals including but not limited to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. The alkyl group may be a "haloalkyl" group i.e. an alkyl group, preferably C 1-8, substituted with one or more fluorine atoms.
The term "alkenyl" means a straight or branched alkenyl radical of, for example, 2 to 12 carbon atoms, such as 2, 3, 4, 5 or 6 carbon atoms, and containing one or more carbon-carbon double bonds and includes but is not limited to ethenyl, n-propyl-1- ene, n-propyl-2-ene, isopropylene etc.
"Heteroalkenyl" relates to an alkenyl group containing one or more heteroatoms selected from N, O or S.
"Alkynyl" relates to a straight or branched alkynyl radical of, for example, 2 to 12 carbon atoms, such as 2, 3, 4, 5 or 6 carbon atoms, and containing one or more triple bonds. The alkynyl group may be -C≡ CR wherein R is alkyl (C 1-8), aryl, heteroaryl or cycloalkyl.
"Cyclic group" means a hydrocarbon ring or ring system, which may be unsaturated or partially unsaturated but is usually saturated, typically containing 5 to 13 ring- forming atoms, for example a 5- or 6- membered ring. A cyclic group includes cyclohydrocarbyl and heterocyclyl.
"Cyclohydrocarbyl" relates to a saturated, partly unsaturated or unsaturated 3 - 10, for example, 5, 6, 7, 8, 9 or 10, membered hydrocarbon ring, including cycloalkenyl, cycloheteroalkenyl or aryl.
"Aryl" means an aromatic, for example, C6 to 10 membered hydrocarbon containing one ring or being fused to one or more saturated or unsaturated hydrocarbon. Aryl may include phenyl, indenyl, naphthyl, tetrahydronaphthyl, anthracenyl, phenanthracenyl. "Heterocyclyl" means, for example, a C3-10, for example 5 or 6, membered membered ring system containing one or more heteroatoms selected from N, O or S and includes heteroaryl. The heterocyclyl system may contain one ring or may be fused to one or more saturated or unsaturated rings; the heterocyclyl may be fully saturated, partially saturated or unsaturated.
"Heteroaryl" means an aromatic, for example, 5-10 membered aromatic ring containing one or more heteroatoms selected from N, O or S such as indole, and containing one ring which is optionally fused to one or more saturated or unsaturated rings.
Examples of cyclohydrocarbyl or heterocyclyl groups include but are not limited to phenyl, acridine, benzimidazole, benzofuran, benzothiophene, benzoxazole, benzothiazole, carbazole, cinnoline, dioxane, dioxolane, dithiazine, dithiazole, dithiolane, furan, imidazole, imidazoline, imidazolidine, indole, indoline, indolizine, indazole, isoindole, isoquinoline, isooxazole, isothiazole, morpholine, napthyridine, oxazole, oxadiazole, oxathiazole, oxathiazolidine, oxazine, oxadiazine, phenazine, phenothiazine, phenoxazine, phthalazine, piperazine, piperidine, pteridine, purine, pyran, pyrazine, pyrazole, pyrazoline, pyridazine, pyridine, pyridone, pyrimidhie, pyrrolidine, pyrolidinone, pyrrole, pyrroline, quinoline, quinoxalήie, quinazoline, quinolizine, quinolizidine, tetrahydrofuran, tetrazine, tetrazole, thiophene, thiopyran, thiadiazine, thiadiazole, thiatriazole, thiazine, thiazole, thiomorpholine, thianaphthalene, thiopyran, triazine, triazole, trithiane, tropine.
Halogen means F, Cl, Br, or I. Preferably, the halogen is F.
In a preferred aspect of the invention R is optionally substituted cyclohydrocarbyl or heterocyclyl. Preferably, R is a five or six membered cyclohydrocarbyl or heterocyclyl group wherein the cyclohydrocarbyl or heterocyclyl group is optionally fused to one or more 5 or 6 membered hydrocarbon rings. The 5 or 6 membered hydrocarbon ring to which R is attached may be an optionally substituted cyclohydrocarbyl or heterocyclyl group, for example, a phenyl ring including biphenyl, naphthyl or anthracenyl. Each substitutable carbon atom in R may be optionally and independently substituted with one or more of halogen (typically Cl or F)5 alkyl (Cl-12 e.g. Cl-8 e.g Cl, C2 C3 or C4), Cl-6 fluoroalkyl (e.g. CF3), cycloalkenyl, cycloheteroalkenyl, heterocyclyl, aryl, alkylOR14, CN, COOR14, COR14, NO2, OR14, SR14, NR142, CONR14 2, SOOR14, SONR14, SOR14, SOONR14, NR14COR14, NR14CONR142, NR14COR14, NR14COOR14, NR14SOOR14 wherein R14 is H, Cl-6 alkyl or Cl-6 fluroalkyl.
In a further preferred aspect of the invention, R is optionally substituted alkenyl, cycloalkenyl or cycloheteroalkenyl. Each substitutable carbon atom in R may be optionally and independently substituted with one or more of halogen (typically F), alkyl (Cl-12 e.g. Cl-8 e.g Cl, C2 C3 or C4), Cl-6 fluoroalkyl (e.g. CF3), cycloalkenyl, cycloheteroalkenyl, cycloalkynyl, heterocyclyl (which in turn may be optionally and independently substituted, for example with one or more halogen or aryl group), aryl, alkylOR14, CN, COOR14, COR14, NO2, OR14, SR14, NR14 2, CONR14 2, SOOR14, SONR14, SOR14, SOONR14, NR14COR14, NR14CONR14 2, NR14COR14, NR14COOR14, NR14SOOR14 wherein R14 is H, Cl-6 alkyl, Cl-6 fluoroalkyl.
hi a further preferred aspect of the invention, R is an optionally substituted aryl or heteroaryl group. The optionally substituted aryl or heteroaryl group may be fused to a saturated or unsaturated 5 or 6 membered hydrocarbon ring. The 5 or 6 membered hydrocarbon ring (to which the optionally substituted aryl is fused) may include between one and three heteroatoms. The 5 or 6 membered hydrocarbon ring to which the optionally substituted aryl is fused or attached may be a phenyl ring, for example, R may be a biphenyl, naphthyl or anthracenyl. In a further preferred aspect of the invention, the aryl group, or the ring to which it may be fused, is substituted with one or more of halogen (typically F), Cl-6 alkyl or Cl-6 fluoroalkyl (e.g. CF3). In a further preferred aspect of the invention, R is a substituted phenyl group wherein each substitutable carbon atom in R may be optionally and independently substituted with one or more alkyl (e.g. C1-C6) group as described herein.
In a compound according to the invention R may be optionally substituted phenyl, acridine, benzimidazole, benzofuran, benzothiophene, benzoxazole, benzothiazole, carbazole, cinnoline, dithiazine, dithiazole, furan, imidazole, imidazoline, imidazolidine, indole, indoline, indolizine, indazole, isoindole, isoquinoline, isooxazole, isothiazole, napthyridine, naphthyl, nucleoside, oxazole, oxadiazole, oxathiazole, oxathiazolidine, oxazine, oxadiazine, phenazine, phenothiazine, phenoxazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyrazoline, pyridazine, pyridine, pyridone, pyrimidine, pyrrole, pyrroline, quinoline, quinoxaline, quinazoline, quinolizine, quinolizidine, tetrazine, tetrazole, thiophene, thiadiazine, thiadiazole, thiatriazole, thiazine, thiazole, thianaphthalene, thiopyran, triazine, triazole wherein each substitutable carbon atom in R may be optionally and independently substituted with one or more of halogen (typically Cl or F), alkyl (Cl- 12 e.g. C 1-8 e.g Cl, C2 C3 or C4), C 1-6 fluoroalkyl (e.g. CF3), cycloalkenyl, cycloheteroalkenyl, heterocyclyl, aryl, alkylOR14, CN, COOR14, COR14, NO2, OR14, SR14, NR14 2, CONR14 2, SOOR14, SONR14, SOR14, SOONR14, NR14COR14, NR14CONR14 2, NR14COR14, NR14COOR14, NR14SOOR14 wherein R14 is H, Cl-6 alkyl or C 1-6 fluroalkyl. .
As discussed above, R can be optionally substituted at any position. Substitution can occur at the ortho, meta or para positions relative to the cyclic ring.
In a further preferred aspect of the invention there is provided a compound, or derivative thereof, of formula II
Figure imgf000009_0001
wherein R, R3, R4, R5, R6. R7, R11 and R12 are as defined herein.
Compounds of formula II may be prepared as described herein or by reacting a compound of formula I with a compound of formula IV wherein R12 may be H and wherein R and R may be joined together to form a cyclic compound of ring size C3-C8 (e.g C5-C6) to form a dipeptide followed by cyclisation of the dipeptide to provide a compound of formula II. This may be achieved thermally or in the presence of a catalyst.
Figure imgf000009_0002
Some compounds of the formula (I) may have chiral centres and/or geometric isomeric centres (E- and Z- isomers), and it is to be understood that the invention encompasses all such optical (R- and S-), diastereomers and geometric isomers.
Thus, the present invention further provides a compound according to the invention which comprises the racemate, the S or the R enantiomer or a mixture thereof, of a compound according to the invention. Preferably, the compound is the S-enantiomer or the R-enantiomer.
A compound according to the invention may be selected from the group consisting of Ethyl 2S,4S-(2-methyl-propane-2-sulfinylamino)-4-phenyl-pent-4-enoate, Ethyl 2R,4R-(2-methyl-propane-2-sulfinylamino)-4-phenyl-pent-4-enoate,
Ethyl 2S,4S-(2-methyl-propane-2-sulfinylamino)-4-thiophen-2-yl-pent-4-enoate,
Ethyl 2R,4R-(2-methyl-propane-2-sulfmylamino)-4-thiophen-2-yl-pent-4-enoate,
Ethyl 2S,4S-(3-niethoxy-phenyl)-2-(2-methyl-propane-2-sulfinylamino)-pent- 4-enoate,
Ethyl 2R,4R-(3 -methoxy-phenyl)-2-(2-methyl-propane-2-sulfinylamino)-pent- 4-enoate,
Ethyl 2S,4S-(2-methyl-propane-2-sulfmylamino)-4-pyrazin-2-yl-pent-4-enoate,
Ethyl 2R,4R-(2-methyl-propane-2-sulfinylamino)-4-pyrazin-2-yl-pent-4-enoate,
Ethyl 2S,4S-(3,4-dicUoro-phenyl)-2-(2-methyl-propane-2-sulfmylamino)-pent- 4-enoate,
Ethyl 2R,4R-(3 ,4-dichloro-phenyl)-2-(2-methyl-propane-2-sulfmylammo)-pent- 4-enoate,
Ethyl 2S,4S-(6-chloro-pyridin-2-yl)-2-(2-methyl-propane-2-sulfinylamino)-pent- 4-enoate,
Ethyl 2R,4R-(6-chloro-pyridin-2-yl)-2-(2-methyl-propane-2-sulfinylamino)-pent- 4-enoate,
Ethyl 2S,4S-(3,5-bis-trifluoromethyl-phenyl)-2-(2-methyl-propane-2-sulfinylamino) -pent-4-enoate, Ethyl 2R,4R-(3,5-bis-trifluoromethyl-phenyl)-2-(2-methyl-propane-2-sulfinylamino) -pent-4-enoate,
Ethyl 2S,4S-(2-methyl-propane-2-sulfϊnylamino)-4-p-tolyl-pent-4-enoate,
Ethyl 2R54R-(2-methyl-propane-2-sulfϊnylamino)-4-p-tolyl-pent-4-enoate,
Ethyl 2S,4S-(2-methyl-propane-2-sulfinylamino)- 4-(4-trifluoromethyl-phenyl)-pent- 4-enoate,
Ethyl 2R,4R-(2-methyl-propane-2-sulfinylamino)- 4-(4-trifluoromethyl-phenyl)-pent- 4-enoate,
Ethyl 2S,4S-(2-methyl-propane-2-sulfinylamino)-4-(4-pyrrol- 1 -yl-phenyl)-pent- 4-enoate,
Ethyl 2R,4R-(2-methyl-propane-2-sulfmylamino)- 4-(4-pyrrol-l -yl-phenyl)-pent- 4-enoate,
Ethyl 2R,4R,5S (l-benzenesulfonyl-3-methylene-2,3-dihydro-lH-indol-2-yl)-(2- methyl-propane-2-sulfinylamino)-acetate,
Ethyl 2S54S,5R (l-benzenesulfonyl-3-methylene-2,3-dihydro-lH-indol-2-yl)-(2- metliyl-propane-2-sulfinylamino)-acetate:)
Ethyl 2S,4S55R (3-methylene-2,3-dihydro-benzofuran-2-yl)-(2-methyl-propane-2- sulfϊnylamino)-acetate,
Ethyl 2R,4R,5S (3-methylene-2,3-dihydro-benzofuran-2-yl)-(2-methyl-propane-2- sulfinylamino)-acetate, 2-(S)-2-Amino-4-phenyl-pent-4-enoic acid,
2-(R)-2-Amino-4-phenyl-pent-4-enoic acid,
2-(S)-2-Amino-4-p-tolyl-pent-4-enoic acid,
2-(R)-2-Amino-4-p-tolyl-pent-4-enoic acid,
2-(S)-2-Amino-4-(3 ,4-dichloro-phenyl)-pent-4-enoic acid,
2-(R)-2- Amino-4-(3 ,4-dichloro-phenyl)-pent-4-enoic acid,
2-(S)-2-Amino-4-(4-trifluoromethyl-phenyl)-pent-4-enoic acid,
2-(R)-2-Amino-4-(4-trifluoromethyl-phenyl)-pent-4-enoic acid,
2-(S)-2- Amino-4-(3 -methoxy-phenyl)-pent-4-enoic acid,
2-(R)-2- Amino-4-(3 -methoxy-phenyl)-pent-4-enoic acid,
2-(S)-2-Amino-4-(3,5-bis-trifluoromethyl-phenyl)-pent-4-enoic acid5
2-(R)-2-Amino-4-(3,5-bis-trifluoromethyl-phenyl)-pent-4-enoic acid,
2-(S)-2-Amino-4-(6-chloro-pyridin-2-yl)-pent-4-enoic acid,
2-(R)-2-Amino-4-(6-chloro-pyridin-2-yl)-pent-4-enoic acid,
Ethyl 2S,4S-(2-methyl-propane-2-sulfinylamino)-4-pyrazin-2-yl-pent-4-enoate,
Ethyl 2R,4R-(2-methyl-propane-2-sulfinylamino)-4-pyrazin-2-yl-pent-4-enoate, 2S-2-Amino-4-pyrazin-2-yl-pent-4-enoic acid,
2R-2-Amino-4-pyrazin-2-yl-pent-4-enoic acid,
Ethyl 2S,4S-biphenyl-4-yl-2-(2-methyl-propane-2-sulfinylamino)-pent-4-enoate,
Ethyl 2R,4R-biphenyl-4-yl-2-(2-methyl-propane-2-sulfinylamino)-pent-4-enoate,
2S-Amino-4-biphenyl-4-yl-pent-4-enoic acid,
2R-Amino-4-biphenyl-4-yl-pent-4-enoic acid,
Ethyl 2S,4S-(1 ,3-dimethyl-2,4-dioxo-l ,2,3,4-tetrahydro-pyrimidin-5-yl)-2-(2-methyl- propane-2-sulfinylamino)-pent-4-enoate,
Ethyl 2R,4R-(l,3-dimethyl-254-dioxo-l,2,3,4-tetrahydro-pyrimidin-5-yl)-2-(2- methyl-propane-2-sulfinylamino)-pent-4-enoate,
2S-Amino-4-(l ,3 -dimethyl-2,4-dioxo- 1 ,2,3 ,4-tetrahydro-pyrimidin-5-yl)-pent-4- enoic acid,
2R-Amino-4-(l,3-dimethyl-254-dioxo-l,2,3,4-tetrahydro-pyrimidin-5-yl)-pent-4- enoic acid,
Ethyl 2S,4S-methyl-2-(2-methyl-propane-2-sulfinylamino)-4-phenyl-pent-4-enoate5
Ethyl 2R,4R-metih^yl-2-(2-me1hyl-propane-2-sulfinylamino)-4-phenyl-pent-4-enoate,
2S-Amino-2-methyl-4-phenyl-pent-4-enoic acid,
2R-Amino-2-methyl-4-phenyl-pent-4-enoic acid, Ethyl 2S,4S-3,3-dimethyl-2-(2-methyl-propane-2-sulfinylaniino)-4-phenyl-pent-4- enoate,
Ethyl 2R,4R-353-dimethyl-2-(2-methyl-propane-2-sulfinylamino)-4-phenyl-pent-4- enoate,
2S-Amino-3,3-dimethyl-4-phenyl-pent-4-enoic acid,
2R- Amino-3 ,3 -dimethyl-4-phenyl-pent-4-enoic acid,
Ethyl 2S,4S-3-cyclohexyl-2-(2-methyl-propane-2-sulfinylamino)-4-phenyl-pent-4- enoate,
Ethyl 2R,4R-3-cyclohexyl-2-(2-methyl-propane-2-sulfinylamino)-4-phenyl-pent-4- enoate,
2S-Amino-3-cyclohexyl-4-phenyl-pent-4-enoic acid and
2R- Amino-3 -cyclohexyl-4-phenyl-pent-4-enoic acid
2S,3R-2-Amino-(3-methylene-2,3-dihydro-benzofuran-2-yl)-acetic acid
2R,3S-2-Amino-(3-methylene-2,3-dihydro-benzofuran-2-yl)-acetic acid
2S ,3 R-2- Amino-( 1 -benzenesulfonyl-3 -methylene-2,3 -dihydro- 1 H-indol-2-yl)-acetic acid
2R53S-2-Amino-(l-benzenesulfonyl-3-methylene-2,3-dihydro-lH-indol-2-yl)-acetic acid Ethyl (S)-((R)-3-methylene-253-dihydro-benzofuran-2-yl)-((S)-2-methyl-propane-2- sulfϊnylatnino) acetate
Ethyl (R)-((S)-3 -methylene-2,3 -dihydro-benzofuran-2-yl)-((R)-2-methyl-propane-2- sulfinylamino) acetate
Ethyl (S)-((R)-l-benzenesulfonyl-3-methylene-2,3-dihydro-lH-indol-2-yl)-((S)-2- methyl-propane-2-sulfinylamino) acetate
Ethyl (R)-((S)-l-benzenesulfonyl-3-methylene-2,3-dihydro-lH-indol-2-yl)-((R)-2- methyl-propane-2-sulfinylamino) acetate
Ethyl (S)-((R)-4-methylene-isochroman-3-yl)-((S)-2-methyl-propane-2-sulfinyl amino) acetate
Ethyl (R)-((S)-4-methylene-isochroman-3-yl)-((R)-2-methyl-propane-2-sulfinyl amino) acetate
Ethyl (S)-((R)-2-methyl-4-methylene- 1 -oxo- 1 ,2,3 ,4-tetrahydro-isoquinolin-3 -yl)-((S)- 2-methyl-propane-2-sulfinylamino) acetate
Ethyl (R)-((S)-2-methyl-4-methylene-l-oxo-l,2,3,4-tetrahydro-isoquinolin-3-yl)-((R) -2-methyl-propane-2-sulfinylamino) acetate
Ethyl (S)-4-benzofuran-(3E)-ylidenemethyl-2-((S)-2-methyl-propane-2-sulfinyl amino)-pent-4-enoate
Ethyl (R)-4-benzofuran-(3E)-ylidenemethyl-2-((R)-2-methyl-propane-2-sulfinyl amino)-pent-4-enoate Ethyl (R)-4-[l-benzenesulfonyl-l,2-dihydro-indol-(3E)-ylidenemethyl]-2-((R)-2-met hyl-propane-2-sulfinylatnino) ρent-4-enoate
Ethyl (R)-4-isochroman-(4E)-ylidenemethyl-2-((R)-2-methyl-propane-2-sulfinyl amino)-pent-4-enoate
Ethyl 2R,4R-4-[2-Methyl-l-oxo-2,3-dihydro-lH-isoquinolin-(4E)-ylidenemethyl]-2- (2-methyl-propane-2-sulfinylaniino)-pent-4-enoate
Ethyl (R)-amhio-((S)-4-methylene-isochroman-3-yl)-acetic acetate
(R)- Amino-((S)-4-methylene-isochroman-3 -yl)-acetic acid
Ethyl methyl-2-((R)-2-methyl-propane-2-sulfinylamino)-4-phenyl-pent-4-enoate
The compounds of the first aspect may be provided as a salt, preferably as a pharmaceutically acceptable salt of compounds of formula I. Examples of pharmaceutically acceptable salts of these compounds include those derived from organic acids such as acetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, phosphoric, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, mandelic acid, methanesulphonic acid, benzenesulphonic acid and p-toluenesulphonic acid, mineral acids such as hydrochloric, hydrobromic, and sulphuric acid and the like, giving methanesulphonate, benzenesulphonate, p-toluenesulphonate, hydrochloride and sulphate, and the like, respectively or those derived from bases such as organic and inorganic bases. Examples of suitable inorganic bases for the formulation of salts of compounds for this invention include the hydroxides, carbonates, and bicarbonates of ammonia, lithium, sodium, calcium, potassium, aluminium, iron, magnesium, zinc and the like. Salts can also be formed with suitable organic bases. Such bases suitable for the formation of pharmaceutically acceptable base addition salts with compounds of the present invention include organic bases which are non-toxic and strong enough to form salts. Such organic bases are already well-known in the art and may include amino acids such as arginine and lysine, mono-, di-, or trihydroxyalkylamines such as mono-, di-, and triethanolamine, choline, mono-, di-, and trialkylamines, such as methylamine, dimethylamine, and trimethylamine, guanidine; piperidine, N-methylglucosamine; N-methylpiperazine; morpholine; ethylenediamine; N-benzylphenethylamine; tris(hydroxymethyl) aminomethane; and the like.
Salts may be prepared in a conventional manner using methods well known in the art. Acid addition salts of said basic compounds may be prepared by dissolving the free base compounds according to the first or second aspects of the invention in aqueous or aqueous alcohol solution or other suitable solvents containing the required acid.
Where a compound of the invention contains an acidic function, a base salt of said compound may be prepared by reacting said compound with a suitable base. The acid or base salt may separate directly or can be obtained by concentrating the solution e.g. by evaporation. The compounds of this invention may also exist in solvated or hydrated forms.
The invention also extends to a prodrug of the aforementioned compounds such as an ester or amide thereof. A prodrug is any compound that may be converted under physiological conditions or by solvolysis to any of the compounds of the invention or to a pharmaceutically acceptable salt of the compounds of the invention. A prodrug may be inactive when administered to a subject but is converted in vivo to an active compound of the invention.
The present invention also provides derivatives including esters, amides, carbamates, carbonates, ureides, ureas, thioureas, hydantoins, thiohydantoins, diketopiperazines, solvates, hydrates, affinity reagents, peptides or prodrugs thereof
A hydrolysable ester of a compound of the formula (I) containing a hydroxy group includes inorganic esters such as phosphate esters and acyloxyalkyl ethers and related compounds which as a result of in vivo hydrolysis of the ester break down to give the parent hydroxy group. Examples of acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxy-methoxy. A selection of in vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters). Dialkylcarbamoyl and N-(N^N-diall<ylaminoethyl)-iV-alkylcarbamoyl (to give carbamates), N1N- diaUcylaminoacetyl and carboxyacetyl. Examples of substituents on benzoyl include morpholino and piperazino.
A suitable example of a hydrolysable amide of a compound of the formula (I) containing a carboxy group is, for example, iV-C1-6alkyl amide or iV,7V-di-C1-6alkyl amide such as iV-methyl, N-ethyl, iV-propyl, ΛζN-dimethyl, iV-ethyl-JV-methyl or N1N- diethyl amide.
A further aspect of the invention provides a process for the manufacture of a compound of formula I which comprises reacting the following compounds in the presence of a catalyst:
i) a compound selected from a) a compound of formula R-X wherein R is as defined herein and X is halide or trifiate;
b) a compound of formula (VI) wherein R16 and R17, one or both of which may be absent, are H, alkyl (C 1-8), aryl, heteroaryl, cycloalkenyl, cycloheteralkenyl and wherein R and R are optionally joined together to form an optionally substituted cyclic compound of ring size C3-C8 including aryl, heteroaryl, cycloalkenyl or cycloheteroalkenyl; R18 and R19 are O, S, CO, CS5 NR23, CR23R23, NNR23 2, NOR23, R23NNCOR23, R23NNCO2R23 or NNSO2R23 wherein R23 is H or optionally substituted Cl-8 alkyl, halogen, Cl -6 haloalkyl, carbocyclyl or heterocyclyl and wherein n is on an integer between 0 and 6 (e.g 1, 2, 3, 4 or 5); R is optionally substituted alkenyl or alkynyl wherein each substitutable carbon atom in R20 may be optionally and independently substituted with one or more of H, alkyl, alkylaryl, alkylheteroaryl, aryl, heteroaryl or CR24R24 wherein R24, which may be absent, is H, aryl or heteroaryl; or
Figure imgf000019_0001
c) a compound of formula (VII) wherein R16 and R17 , one or both of which may be absent, are H, alkyl (C 1-8), aryl, heteroaryl, cycloalkenyl or cycloheteralkenyl and wherein R16 and R17 are optionally joined together to form an optionally substituted cyclic compound of ring size C3-C8 including an aryl, heteroaryl, cycloalkenyl or cycloheteroalkenyl cyclic group; R18 and R19 are O, S, CO5 CS, NR23, CR23R23, NNR23 2, NOR23, R23NNCOR23, R23NNCO2R23, NNSO2R23 wherein R23 is H or optionally substituted C 1-8 alkyl, halogen, C 1-6 haloalkyl, carbocyclyl or heterocyclyl and wherein n is an integer between 0 and 6 (e.g 1, 2, 3, 4 or 5); R2 is C; R21 is CR24R24 wherein R24 is H, aryl or heteroaryl;
R21
Figure imgf000019_0002
ii) where compound (i) above is (a) or (b) only, allene gas or a substituted allene; and iii) an α-iminoester derivative of formula (V)
Figure imgf000020_0001
wherein R is as defined herein; and wherein when R 5 is a chiral auxiliary group, Y is a protecting group; wherein when R15 is H or optionally substituted alkyl (C 1-8), aryl, heteroaryl, cycloalkyl (i.e. Rl 5 is not a chiral auxiliary group), Y is a chiral auxiliary group; iv.) optionally removing R15 and/or Y to obtain a compound of Formula I.
Compounds of formulae (VI) and (VII) may be prepared as described in Grigg et al., Tetrahedron, 1997, 53, 11803-11826; Grigg et al., Tetrahedron, 2001, 57, 7729- 7735; Grigg and Savic Tetrahedron Letters, 1996, 37, 6565-6568 and Grigg and Sridharan Tetrahedron Letters, 1992, 33, 7965-8.
In a preferred aspect of the invention, the process comprises reacting a compound of formula R-X (as in (a) above) with allene gas or a substituted allene and an α- iminoester derivative of formula (V) in the presence of a catalyst.
The catalytic asymmetric alkylation of α-iminoesters according to the process of the invention is particularly attractive since it offers a simple, versatile route to both enantiomers of a chiral product. The process of the invention provides for enantiospecific synthesis of non-proteogenic α-amino acids which allows access to both the R and S enantiomers. Representative examples of R and S enantiomers according to the invention are shown in Table 1.
As used herein "a chiral auxiliary group" is a temporary chiral component included to induce asymmetry and which is removed as in step (iv) above. Preferably, when Y is a non-chiral group, the chiral auxiliary group R15 is menthyl or α-methylbenzyl or when Y is the chiral auxiliary group, preferably sulphinylimino, R15 is a non-chiral group (for example Ph2P(O) or Tosyl).
In a preferred process according to the invention the α-iminoester is a sulphinylimino ester.
In a further preferred process according to the invention, the catalyst is a palladium catalyst combined with indium.
Compounds of formula (VIII) and (IX) may be manufactured using the general process
Figure imgf000021_0001
wherein R3, R4, R5, R15, R16, R17, R18, R19, R20 and R21 are as described herein.
The invention provides examples of compounds of formula VIII and IX as shown below that are prepared as follows:
Figure imgf000022_0001
A further aspect of the invention provides a compound of formula (V) since such a compound is useful in the synthesis of a compound according to the first aspect of the invention.
A further aspect of the invention provides an agent, for example, a pharmaceutical, nutraceutical or agrochemical agent comprising one or more compounds according to the invention. The agent may, for example, be a small molecule. Examples of small molecules include, but are not limited to, peptides, peptidomimetics (e.g., peptoids), amino acids and amino acid analogs.
A further aspect of the invention provides a peptide or protein comprising a residue of a compound according to the invention wherein the residue is of formula (X)
Figure imgf000023_0001
wherein R, R3, R4, R5 and R6 are as defined herein.
The present invention further provides a method for the synthesis of a peptide or protein, the method comprising providing a peptide which includes at least one compound, or salt thereof, according to the invention.
The synthesis of peptides and proteins may be in whole or in part machine-aided, for example using an automated peptide synthesiser.
The methods of this invention can also be readily adapted and applied to the synthesis of peptidomimetics, such as those formed from N-alkyl amino acids (e.g peptoids).
The synthesis of peptides is well known in the art. Solid phase peptide synthesis generally proceeds by initial attachment of a first (alpha)-amino protected amino acid to a solid support (typically a resin) at its carboxylic end via a linker. Resins with certain protected amino acids already attached are available from commercial sources or can be synthesised by known methods. The (alpha) protecting group is removed from the resin linked amino acid and a second (alpha) amino acid protected amino acid is coupled to the first amino acid using a coupling agent. Cycles of deprotection and coupling of protected amino acids continue until the desired peptide sequence is prepared. The reaction conditions (reagent, solvent, concentration, temperature, time etc) of deprotection of the alpha amino protecting group selected for synthesis preferably do not cleave a substantial amount of the growing peptide from the resin selected for synthesis. Potentially reactive groups on the side chains of protected amino acid synthetic peptide building blocks may also be protected, typically with protecting groups that are not that are not substantially removed by the reaction conditions selected for removal of the (alpha) amino protecting group. A variety of protecting groups, reaction conditions for deprotection, coupling agents, reaction conditions for coupling linkers, resins and conditions for cleavage of the peptide from the resin are known in the art.
Details of solid phase peptide synthesis are given, for example, in Greene and Wut, protecting groups in Organic synthesis, Wiley Science (1984) and later editions; Atherton and Sheppard (1989) in solid-phase peptide synthesis, A Practical Approach, IRL Press at Oxford University Press; Barany et al., (1987) hit. J. Peptide Protein Res 30: 705-739.
The compounds, salts and agents (e.g. peptides, proteins etc) of the invention can be incorporated into pharmaceutical, nutraceutical or agricultural/agrochemical compositions.
Pharmaceutical or nutraceutical compositions typically include the compound, salt or agent along with a pharmaceutically or nutraceutically acceptable carrier. As used herein the language "pharmaceutically acceptable carrier" includes solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Supplementary active compounds can also be incorporated into the compositions.
A pharmaceutical or nutraceutical composition is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), transmucosal, and rectal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, NJ) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringability exists. It should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as manitol, sorbitol, sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminium monostearate and gelatin. Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
Oral compositions generally include an inert diluent or an edible carrier. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troche or capsules, e.g., gelatin capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash.
Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, troches, capsules and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the compounds are formulated into ointments, salves, gels, or creams as generally known in the art.
In one embodiment, the compounds may be prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811.
It is advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
Exemplary doses include milligram or microgram amounts of the compound per kilogram of subject or sample weight (e.g., about 1 microgram per kilogram to about
500 milligrams per kilogram, about 100 micrograms per kilogram to about 5 milligrams per kilogram, or about 1 microgram per kilogram to about 50 micrograms per kilogram. It is furthermore understood that appropriate doses of a compound depend upon the potency of the compound with respect to the expression or activity to be modulated. When one or more of these compounds is to be administered to an animal (e.g., a human), a physician, veterinarian, or researcher may, for example, prescribe a relatively low dose at first, subsequently increasing the dose until an appropriate response is obtained. In addition, it is understood that the specific dose level for any particular animal subject will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, gender, and diet of the subject, the time of administration, the route of administration, the rate of excretion, any drug combination, and the degree of expression or activity to be modulated.
The invention will now be described by way of reference to the following non- limiting examples.
EXAMPLES
Materials and Methods
General procedures
Unless otherwise noted all reagents were obtained from commercial suppliers and used without further purification. All solvents were dried or purified by literature procedures ( W.L.F Aramerago, D.D Perrin, Purification of Laboratory Chemicals, (TV), Pergamon Press, 1997). Unless otherwise noted reactions were carried out using oven dried glassware under an inert N2 atmosphere. Reaction progress was monitored with thin layer chromatography using Merck 60 F254 plastic coated silica plates. Chromatography columns were prepared using Fisher chemicals 6OA 35 - 70 micron silica gel.
Nuclear magnetic resonance spectra were recorded using Bruker DPX300 and DRX500 MHz spectrometers. Chemical shifts are reported in parts per million (δ) downfield relative to the internal reference tetramethylsilane. Unless otherwise specified NMR spectra were recorded in deuterochloroform at room temperature. Abbreviations used; Ar = aromatic, d = doublet, dd = doublet of doublets, dq = doublet of quartets, dt = doublet of triplets, m = multiplet, q = quartet, s = singlet, t = triplet.
Mass spectra were recorded using a micromass ZMD 2000 spectrometer employing the electrospray (ES+) ionisation technique.
Infra-red spectra were recorded using a Perkin-Elmer FT-IR spectrometer. TR. spectra of liquids were recorded as thin films on sodium chloride plates. IR spectra of solids were recorded using the "golden gate" apparatus.
Optical rotations were measured on an Optical Activity AA- 1000 polarimeter. Rotations are quoted in 10"1 deg cm2 g"1. Unless otherwise stated chloroform was the solvent used.
Microanalysis was performed using a Carlo-Erber 1108 elemental analyser and by titration against barium perchlorate. The oxygen flask combustion technique was used in preparation for the titration.
General procedure for the synthesis of iV-suIfϊnylamino esters
Figure imgf000029_0001
Aryl, alkynyl, vinyl iodide, bromide or triflate (0.75 mmol), was added to a suspension of chiral α-iminoester (0.5 mmol), indium metal powder (0.088 g, 0.75 mmol), Pd(OAc)2 (0.01 Ig, 0.05 mmol), tri-2-furyl phosphine (0.024 g, 0.1 mmol), CuI (0.019 g, 0.1 mmol) and piperidine (0.05 ml, 0.5 mmol) in DMF (10 ml) in a Schlenk tube. In the case of allene the mixture was subjected to two freeze, pump, thaw cycles and then charged, using standard Schlenk techniques, with allene gas (ca. 1 bar). For substituted allenes/alkenes /alkynes the freeze, pump, thaw cycles were omitted. The mixture was stirred and heated to 40 0C (oil bath temperature) for 24 h, left to cool and vented. Ethyl acetate (20 ml) and 5 % HCl solution (10 ml) added and the mixture stirred for 20 mins. The phases were separated and the aqueous layer extracted with ethyl acetate (20 ml). The organic extracts were combined and washed with water (3 x 100 ml), dried over magnesium sulphate, filtered and the filtrate concentrated in vacuo. The residue was purified by flash chromatography to give the N-sulfinylamino esters.
Deprotection of iV-suIfinylamino esters
4M HCI/Dioxan NaOH/H,O
Figure imgf000030_0001
Figure imgf000030_0003
Figure imgf000030_0002
4M HCl in dioxane (5 eqv) was added to a 0.1 M solution of the sulfinamine in EtOH. The solution was stirred at room temperature for 2 h and the solvent removed in vacuo. IM NaOH solution (2 eqv) was added to a 0.1 M solution of the ester in a 1:1 v/v H2O : EtOH solvent system and the mixture stirred and heated to reflux (80 0C oil bath temperature) for 4 h. The solution was left to cool to room temperature, the solvent removed in vacuo, the residue was dissolved in water and applied to the top of an amberlyst H+ ion exchange column and eluted with distilled water followed by a 1 % NH3 solution in distilled water. The ammonia fractions were concentrated in vacuo to give the products as pale yellow to colourless solids.
Figure imgf000031_0001
Ethyl 2S,4S-(2-methyl-propane-2-suIfinylamino)-4-phenyl-pent-4-enoate
Obtained as a pale yellow oil (0.117 g, 78 %) after flash chromatography (9:1 v/v diethyl ether : hexane); [a]™ ; + 81.4; RF 0.43 (diethyl ether); Found, C, 62.9; H, 7.8; N3 4.35; S5 9.9 %, C17H25NO3S requires C, 63.1; H, 7.8; N, 4.3; S, 9.9 %; vmjcm l 3294, 2983, 2253, 1794, 1732, 1630; δH (500 MHz, CDCl3); 7.37 - 7.34 (3H, m, Ph)5 7.29 - 7.27 (2H, m, Ph), 5.34 (IH, s, G=GFT2), 5.12 (IH, s, C=CiT2), 4.10 - 4.01 (3H5 m, CO2CH2CH3, NH, NCH,), 3.04 (1Η, dd, H2C=CCH2, J, l.O, 2.9 Hz5), 2.85 (1 Η, dd, H2C=CCH2, J, 1.0, 3.2 Hz), 1.26 (3Η, t, CO2CH2CH35 J, 7.1 Hz5), 1.16 (9H5 s, C(CH3)3; δc (75 MHz5 CDCl3) 173.3 (CO2Et)5 144.1(H2C=C)5 140.5 (Ar), 128.9 (Ar), 128.2 (Ar)5 126.6 (Ar), 117.0 (H2C=C), 62.1 (CO2CH2CH3), 57.3 (EtO2CQ5 56.5(SOQ5 40.8 (ArC(=CH2)Q, 23.0 SOC(CH3)35 14.5 (CO2CH2CH3); m/z (ES) 324 (MH+).
Figure imgf000031_0002
Ethyl 2R,4R-(2-methyl-propane-2-suIfinylamino)-4-phenyl-pent-4-enoate
Obtained as a pale yellow oil (0.117 g, 78 %) after flash chromatography (9:1 v/v diethyl ether : hexane); [af° ; -66.5; RF 0.43 (diethyl ether); Found, C5 63.0; H5 7.8; N5 4.4; S, 9.9 %, C17H25NO3S requires C5 63.1; H5 7.8; N, 4.3; S5 9.9 %; vmjcm l 3294, 2983, 2253, 1794, 1732, 1630; δH (500 MHz, CDCl3); 7.37 - 7.34 (3H, m, Ph), 7.29 - 7.27 (2H, m, Ph)5 5.34 (IH, s, C=CH2), 5.12 (IH5 s, C=CH2), 4.10 - 4.01 (3H5 m, CO2CH2CH3, NH, NCH5), 3.04 (m, dd5 H2C=CCH2, J5 l.O, 2.9 Hz,), 2.85 (1 H5 dd, H2C=CCH2, J3 1.0, 3.2 Hz), 1.26 (3H, t, CO2CH2CH33 J, 7.1 Hz,), 1.16 (9H, s, C(CH3)3; δc (75 MHz3 CDCl3) 173.3 (CO2Et)5 144.1(H2C=Q3 140.5 (Ar)3 128.9 (Ar)3 128.2 (Ar), 126.6 (Ar)3 117.0 (H2C=C)3 62.1 (CO2CH2CH3), 57.3 (EtO2CQ3 56.5(SOQ, 40.8 (ArC(=CH2)Q, 23.0 SOC(CHs)3, 14.5 (CO2CH2CH3); m/z (ES) 324 (MH+).
Figure imgf000032_0001
Ethyl 2S,4S-(2-methyl-propane-2-sulfinylamino)-4-thiophen-2-yl-pent-4-enoate
Obtained as a pale yellow oil (0.100 g, 61 %) after flash chromatography (4:1 v/v diethyl ether : hexane); [a]™ + 53.8; RF 0.18 (4:1 v/v diethyl ether : hexane) vmax/cm" \ 3583, 3428 (NH), 3291, 2982, 2962, 2870, 1735 (C=O) 1659, 1621, δH (500 MHz, CDCl3); 7.12 (IH, d, ArH, J, 5.1 Hz), 6.97 (IH3 d, ArH, J, 3.4 Hz), 6.92 (IH, dd, ArH, J, 5.1, 3.4 Hz), 5.39 (IH, s, C=CH), 4.95 (IH, s, C=CH), 4.12 - 4.03(4H, m,
NH, NCH3 Co2CH2), 2.95 (m3 dd3 C(=CΗ2)CH, J3 5.3, 14.3 Hz)3 2.71 (IH,
C(=CH2)CH, J, 8.4, 14.3 Hz)3 1.20 (3H3 t, CO2CH2CH3, J, 6.2 Hz), 1.12, (9H3 s, SC(CH3X); δc (75 MHz3 CDCl3) 171.9 (CO2Et), 142.9 (C=CH2), 135.7 (Ar), 126.5 (Ar), 124.5 (Ar), 123.8 (Ar), 113.8 (C=CH2), 60.8 (CO2CH2), 55.23 (OSC), 39.59 (CC=CH2)C), 29.29 (NC), 21.58 (C(CH3)S, 13.07 (CO2CH2CH3); m/z (ES) 330 (MH+)
Figure imgf000032_0002
Ethyl 2R,4R-(2-methyl-propane-2-sulfinylamino)-4-thiophen-2-yl-pent-4-enoate Obtained as a pale yellow oil (0.112 g, 68 %) after flash chromatography (3:1 v/v ethyl acetate : hexane); [af° ; - 24.2; RF 0.25 (3:1 v/v ethyl acetate : hexane); Found: C5 53.1; H, 7.1; N, 3.9; C15H23NO3S2.0.25 M H2O requires C, 53.2; H, 7.2; N5 4.2 %; Vmax/cm"1; 3428, 2981, 1738, 1659, 1519, 1367, 1203; δH (500 MHz5 CDCl3); 7.12 (IH5 d, ArH, J, 5.1 Hz), 6.97 (IH, d, ArH, J, 3.4 Hz), 6.92 (IH5 dd, ArH, J, 5.1, 3.4 Hz), 5.39 (IH, s, C=CH), 4.95 (IH, s, C=CH)5 4.12 - 4.04 (4H, m, NH5 NCH", CO- 2CH2), 2.95 (1Η, dd, C(=CΗ2)CH, J, 5.3, 14.3 Hz), 2.71 (IH, C(=CH2)CH, J, 8.4, 14.3 Hz), 1.20 (3H5 1, CO2CH2CH3, J, 6.2 Hz), 1.12, (9H, s, SC(CH3)3); δc (75 MHz, CDCl3) 171.87 (CO2Et), 142.90 (C=CH2), 135.73 (Ar), 126.46 (Ar), 123.79 (Ar), 122.86 (Ar)5 113.83 (C=CH2), 60.77 (CO2CH2), 56.01 (EtO2CC), 55.22 (SC)5 37.12 (C(=CH2)C), 21.57 (C(CH3)3), 13.06 (CO2CH2CH3); m/z (ES) 330 (MH+)
Figure imgf000033_0001
Ethyl 2S,4S-(3-methoxy-phenyl)-2-(2-methyl-propane-2-sulfinylamino)-pent-4- enoate
Obtained as a pale yellow oil (0.130 g, 72 %) after flash chromatography (9:1 v/v diethyl ether : hexane); [a]™ ; + 64.5; RF 0.47 (3:1 v/v ethyl acetate : hexane); Found: C, 60.4; H5 7.8; N, 3.7 C18H27NO4S. 0.5 H2O requires C, 60.4, H, 7.7, N5 3.9 %; Vmax/cm"1; 3583, 3453 (NH)5 3283, 2978, 2836, 1736 (C=O), 1628, δH (500 MHz, CDCl3); 7.19 (1 H, t, ArH, J, 7.7 Hz), 6.87 (IH5 s, ArH)5 6.82 (IH5 d, J5 7.7 Hz)5 6.75 (IH5 d5 ArH5 J, 7.7 Hz), 5.27 (IH, s, C=CH)5 5.04 (IH, s, C=CH), 4.07 - 4.03 (2H, m, CO2CH2,), 3.97 - 3.92 (2H, m, NHCH ), 3.74 (3Η, s, OMe)5 2.93 (IH5 dd5 CO=CH2)CH5 J5 5.3, 14.0 Hz) 2.74 (m, dd, C(=CΗ2)CH, J, 7.5 Hz, I4.O Hz), 1.35 (IH5 s, NH)5 1.17 (3H, t, CO2CH2CH3, J, 4.8 Hz)5 1.09 (9H5 s, SC(CH3)3); δc (75 MHz5 CDCl3) 171.85 (C=O)5 158.60 (H2C=Q, 150.48 (Ar), 142.52 (Ar), 140.55 (Ar), 134.76 (Ar)5 117.83 (Ar), 115.61 (H2C=C)5 111.91 (Ar), 60.72 (H2C=CC)5 55.85 (ArOC)5 55.09 NC), 54.19 (SC), 21.61 (C(CH3)S, 13.15 (CO2CH2CH3); m/z (ES) 354
Figure imgf000034_0001
Ethyl 2R,4R-(3-methoxy-phenyl)-2-(2-methyl-propane-2-sulfinylamino)-pent-4- enoate
Obtained as a pale yellow oil (0.088 g, 46 %) after flash chromatography (9:1 v/v diethyl ether : hexane); [α]β ; -77.1; RF 0.47 (3:1 v/v ethyl acetate : hexane); Found: C5 61.3; H5 7.8; N5 4.0, 9.2 % C18H27NO4S requires C5 61.2; H5 7.7; N5 4.0; S5 9.1 %; δH (500 MHz5 CDCl3); 7.18 (IH5 15 ArH, J5 7.9 Hz)5 6.87 (IH, d, ArH5 7.9 Hz)5 6.82 (IH5 s, ArH)5 6.76 (IH, d5 ArH5 J5 7.9 Hz), 5.27 (IH5 S5 C=CH)5 5.04 (IH, S5 C=CH), 4.07 - 4.03 (2H5 m, CO2CH25), 3.97 - 3.92 (2H5 m, NHCH), 3.74 (3H, S5 OMe)5 2.93 (IH5 dd, C(=CH2)CH, J5 5.3, 14.0 Hz) 2.74 (IH5 dd, C(=CH2)CH, J5 7.5 Hz5 14.0 Hz), 1.17 (3H, t, CO2CH2CH3, J, 7.1 Hz)5 1.09 (9H, s, SC(CH3)3); δc (75 MHz, CDCl3) 171.85 (CO)5 158.61 (H2C=Q, 142.22 (Ar), 140.55 (Ar)5 128.44 (Ar)5 117.43 (Ar)5 115.61 (C=CH2), 111.92 (Ar), 111.42 (Ar)5 60.62 (CO2Q5 55.87 (OCH3), 55.10 (SC), 54.19 (NC)5 (H2C=CCH2), 21.55 (SC(CH3)3), 13.05 (CO2CH2CH3); m/z (ES) 354 (MH+),
Figure imgf000034_0002
Ethyl 2S,4S-(2-methyl-propane-2-suIfinylamino)-4-pyrazin-2-yl-pent-4-enoate Obtained as a pale yellow oil (0.112 g, 69 %) after flash chromatography (ethyl acetate); [af°+ 63.5; RF 0.37; (ethyl acetate); VnJCm 1; 3584, 3436 (NH), 3289, 2982, 2963, 2240, 1734 (C=O), 1468, 1367, 1067; δH (500 MHz, CDCl3); 8.74 (IH, s, ArH); 8.47 (IH, s, ArH); 8.39 (IH, s, ArH); 5.81 (IH, s, C=CH); 5.42 (IH, s, C=CH); 4.14 - 4.04 (4H, m, br, CO2CH2, NHCH); 3.05 (IH, dd, NHCHCH, J, 5.3, 14.3 Hz); 2.93 (IH, dd, NHCHCH, J, 8.2, 14.3 Hz); 1.18 (3H, t, CO2CH2CH5, J, 7.2 Hz) 1.08 (9H, s, SC(CHj)3); δc (75 MHz, CDCl3) 172.00 (C=O), 152.02 (H2C=Q, 142.29 (Ar), 141.91 (Ar), 141.22 (Ar), 140.08 (Ar), 119.35 (H2OC), 60.69 (CO2CH2), 55.82 (EtO2CQ, 55.13 (SC), 37.13 (H2C=CQ, 21.54 (C(CH3)3, 13.08 (CO2CH2CH3); m/z (ES) 326 (MH*)
Figure imgf000035_0001
Ethyl 2R,4R-(2-methyl-propane-2-sulfinylamino)-4-pyrazin-2-yl-pent-4-enoate
Prepared on a 1.5 mmol scale. Obtained as a pale yellow oil (0.169 g, 35 %) after flash chromatography (ethyl acetate); [a]™ - 63.6; RF 0.37; (ethyl acetate); vmax/cm l; 3447, 2981, 1734, 1633, 1519, 1469; δH (500 MHz, CDCl3); 8.75 (IH, s, ArH); 8.46 (IH, s, ArH); 8.39 (IH, s, ArH); 5.81 (IH, s, C=CH); 5.42 (IH, s, C=CH); 4.17 - 4.04 (4H, m, br, CO2CH2, NHCH); 3.05 (IH5 dd, NHCHCH, J, 5.3 Hz, 14.3 Hz); 2.93 (IH, dd, NHCHCH, J, 8.2 Hz, 14.3 Hz); 1.18 (3H, t, CO2CH2CH5, J, 7.2 Hz) 1.08 (9H, s, SC(CH3)3); δc (75 MHz, CDCl3) 171.95 (C=O), 152.02 (H2C=Q, 142.32 (Ar), 141.89 (Ar), 141.19 (Ar), 140.57 (Ar), 119.35 (H2C=C), 60.63 (CO2CH2), 55.85 (EtO2CQ, 55.19 (SC), 37.09 (H2C=CQ, 21.76 (C(CHb)3, 13.08 (CO2CH2CH3); m/z (ES) 326 (MH+)
Figure imgf000036_0001
Ethyl 2S,4S-(3,4-dichloro-phenyl)-2-(2-methyl-propane-2-suIfinylamino)-pent-4- enoate
Obtained as a pale yellow oil (0.144 g, 73%) after flash chromatography (9:1 v/v diethyl ether : hexane); [af£ + 65.2; RF 0.48; (3:1 v/v ethyl acetate : hexane); Found; C, 52.2; H, 6.1; Cl, 17.8; N5 3.6, S5 7.9 % C17 H23 Cl2 NO3 S requires; C, 52.0; H5 5.9; Cl5 18.1; N5 3.6; S5 8.2 %; V1nJCm 1; 3583, 3450 (NH)5 3282, 298I5 2960, 1736, 1474, 1367, 1074; δH (500 MHz5 CDCl3); 7.37 (IH5 s, ArH)5 7.33 (IH5 d, ArH, J, 8.3 Hz)5 7.12 (IH5 d5 ArH, J5 8.3 Hz)5 5.29 (IH, s, C=CH), 5.11 (IH, s, C=CH)5 4.06 (2H, dq, CO2CH2, J, 7.2, 13.1 Hz) 3.89 IH, dd, NCH5 7.7, 6.2 Hz) 2.90 (IH5 dd, NCHCH, J, 6.2, 14.5 Hz), 2.75 (IH5 dd, NCHCH5 J, 7.75 14.5 Hz), 1.18 (3H5 15 CO2CH2CH3, J, 7.2 Hz), I.IO (9H5 S, SC(CHj)3; δc (75 MHz, CDCl3) 171.51 (C=O), 140.68 (C^CH2), 131.57 (Ar)5 130.73 (Ar)5 129.87 (Ar)5 128.87 (Ar), 127.77 (Ar), 124.67 (Ar), 117.79 (C=CH2), 60.58 (CO2CH2), 55.55 EtO2CC), 55.14 (SC), 38.96 (H2C-CQ, 21.62 (C(CH3)3), 13.05 (CO2CH2CH3); m/z (ES) 393 (MH+), 395 (MH+), 397 (MH+)
Figure imgf000036_0002
Ethyl 2R,4R-(3,4-dichloro-phenyl)-2-(2-methyl-propane-2-sulfinylamino)-pent- 4-enoate Obtained as a pale yellow oil (0.146 g, 74%) after flash chromatography (9:1 v/v diethyl ether : hexane); [af° - 70.8; RF 0.48; (3:1 v/v ethyl acetate : hexane); Found; C3 52.0; H, 6.2; Cl3 17.8; N3 3.6; S3 7.9 % C17 H23 Cl2 NO3 S requires; C3 52.0; H, 5.9; Cl3 18.1; N3 3.6; S3 8.2 %; vmjcm l; 3583, 3450 (NH)3 3274, 2978, 2956, 1736, 1473, 1366, 1070 δH (500 MHz3 CDCl3); 7.37 (IH3 d, ArH, J3 2 Hz)3 7.33 (IH3 d3 ArH, J, 8.3 Hz), 7.13 (IH, dd, ArH3 J3 23 8.3 Hz)3 5.29 (IH, S3 C=CH), 5.11 (IH3 s, C=CH)3 4.06 (2H3 dq3 CO2CH2, J3 7.6, 10.7 Hz), 3.89 (IH, dd, EtO2CCH3 J3 1.7, 7.4 Hz), 2.90 (IH3 dd, NCHCH, J, 5.5, 14.5 Hz), 2.73 (IH, dd, NCHCH, J, 7.5, 14.5 Hz), 1.19 (3H, t, CO2CH2CH3, J, 7.2 Hz), 1.10 (9H, s, SC(CH3)3; δc (75 MHz3 CDCl3) 171.50 (C=O), 140.68 (C=CH2), 131.55 (Ar)3 130.71 (Ar), 129.39 (Ar), 128.87 (Ar), 127.35 (Ar)3 124.68 (Ar)3 117.02 (C=CH2), 60.82 (CO2CH2), 55.55 EtO2CC), 55.13 (SC), 38.95 (H2C=CQ, 21.51 (C(CH3)3), 13.05 (CO2CH2CH3); m/z (ES) 393 (MH+), 395 (MH+), 397 (MH+)
Figure imgf000037_0001
Ethyl 2S,4S-(6-chloro-pyridin-2-yl)-2-(2-methyl-propane-2-sulfinylamino)-pent- 4-enoate
Prepared on a 1 mmol scale. Obtained as a pale yellow oil (0.187g, 52 %) after flash chromatography (6:1 v/v ethyl acetate : hexane); [a]™ + 86.7; Rp 0.41; (6:1 v/v ethyl acetate : hexane); Found; C, 53.3; H, 6.5; N, 7.8; S, 9.0 %; C16H23ClN2O3S requires; C, 53.6; H, 6.9; Cl, 9.9; N, 7.8; S, 8.9 %; Warn 1; 3417, 3209, 2981, 2961, 1737; δH (500 MHz, CDCl3); 8.40 (IH, s, ArH)3 7.63 (IH, d, ArH, J, 8.4 Hz), 7.32 (IH, dd, ArH, J3 8.4 Hz), 5.41 (IH, s, C=CH), 5.27 (IH3 s, C=CH)3 4.17 - 4.09 (3H3 m, br3 NH, CO2CH2), 3.96 (1Η, m, NHCH)3 3.00 (IH3 dd, H2C=CCH, J1 ), 2.86 (1Η, dd, H2C=CCH, J ), 1.26 (3Η, t, CO2CH2CH3, J, 7.2 Hz), l.l 8 (9Η, S, C(CΗ3)3; δc (75 MHz, CDCl3); 172.82 (CO), 151.06 (H2C=C), 147.96 (Ar), 140.11 (Ar), 136.86 (Ar), 135.10 (Ar)3 124.36 (Ar), 119.32 (C=CH2), 62.36 (CO2CH2), 56.74 (NC)5 56.61 (SC)5 22.95 (SC(CHs)3), 14.48 (CO2CH2CH3); m/z (ES) 359 (MH+), 361 (MH+)
Figure imgf000038_0001
Ethyl 2R,4R-(6-chloro-pyridin-2-yl)-2-(2-methyl-propane-2-sulfinylamino)- pent-4-enoate
Obtained as a pale yellow oil (0.088 g, 49%) after flash chromatography (6:1 v/v ethyl acetate : hexane); [a]™ - 59 A; RF 0.41; (6:1 v/v ethyl acetate : hexane); Found; C5 53.5; H5 7.0; Cl5 9.7; N5 7.7; S5 8.8 %; C16H23ClN2O3S requires; C, 53.6; H, 6.9; Cl5 9.9; N, 7.8; S, 8.9 %; vmax/cm4; 3448, 2983, 1737, 1461, 1366; δH (500 MHz5 CDCl3); 8.32 (IH5 d, ArH, J, 2.5 Hz) 7.57 (IH, dd, J, 2.5, 8.3 Hz) 7.25 (IH5 d, ArH, J5 8.3 Hz)5 5.34 (IH5 S5 C=CH), 5.19 (IH, s, C=CH), 4.06 - 4.01 (2H5 m5 CO2CH2, J5 7.2 Hz), 3.89 (IH, dd, EtO2CCHJ, 5.0, 7.7 Hz)5 2.92 (IH, dd, NCHCH, J, 0.6, 5.0 Hz)5 2.78 (IH, dd, NCHCH5 J5 0.6, 7.7Ηz), 1.19 (3H, t, CO2CH2CH3, J, 7.2 Hz)5 1.10 (9H5 s, SC(CH3)3); δc (75 MHz, CDCl3); 171.39 (C=O), 149.61 (H2C=C), 146.53 (Ar), 138.68 (Ar)5 135.47 (Ar)5 133.69 (Ar), 117.92 (H2C=C), 60.72 (CO2CH2), 55.35 (EtO2CCH)5 38.81 (EtO2CCHCH2), 21.61 (C(CH3)3), 13.06 (CO2CH2CH3); 359 (MH+), 361 (MH+)
Figure imgf000038_0002
Ethyl 2S,4S-(3,5-bis-trifluoromethyl-phenyl)-2-(2-methyl-propane-2- sulfinyIamino)-pent-4-enoate
Obtained as a pale yellow oil (0.159 g, 69%) after flash chromatography (3:1 v/v ethyl acetate : hexane to 6:1 v/v ethyl acetate : hexane ); [a]™+ 59.8; RF 0.58; (3:1 v/v ethyl acetate : hexane); v^/cm"1; 3583, 3454(NH)5 2983, 2963, 1739 (C=O), 1632, 1378, 1279, 1180, 1136, 1078; δH (500 MHz, CDCl3); 7.72 (3H, s, ArH), 5.41 (IH, s, C-CH), 5.28 (IH, s, C=CH), 4.13 - 4.01 (3H5 m, br, CO2CH2, NH), 3.91 - 3.88 (1Η, m, EtO2CCH), 3.07 (1Η, dd, NCΗCH, J, 5.1, 14.5 Hz), 2.93 (IH, dd, NCHCH, J, 7.3, 14.5 Hz), 1.18 (3H, t, CO2CH2CH3, J, 7.2 Hz), 1.07 (9H, s, SC(CH3)3; δc (75 MHz, CDCl3); 171.35 (C=O), 141.74 (H2C=Q, 140.72 (Ar), 13.90 (q, Ar, J, 33.3 Hz), 125.86 (Ar), 122.2 (q, CF3, J, 272.8 Hz), 119.94 (Ax), 118.75 (H2C=C), 60.98 (CO2CH2), 55.93 (NC), 55.12 (SC), 38.76 (H2C=CCH2), 21.43 (SC(CH3)3), 12.93 (CO2CH2CH3); m/z (ES) 460 (MH+)
Figure imgf000039_0001
Ethyl 2R,4R-(3,5-bis-trifluoromethyl-phenyl)-2-(2-methyl-propane-2- sulfmylammo)-pent-4-enoate
Obtained as a pale yellow oil (0.151 g, 66%) after flash chromatography (3:1 v/v ethyl acetate : hexane to 6:1 v/v ethyl acetate : hexane ); [a]™ - 53.0; RF 0.58; (3:1 v/v ethyl acetate : hexane); Found; C, 49.6; H, 5.1; N, 3.1; S, 6.8 % C19H23F6NO3S requires; C, 49.7; H, 5.1; F5 24.8; N, 3.1; S, 7.0 %; v^/cm"1; 3450, 2978, 1739, 1629, 1374, 1278; δH (500 MHz, CDCl3); 7.72 (3H, s, ArH), 5.41 (IH, s, C=CH), 5.28 (1Η, s, C=CH), 4.13 - 4.02 (3Η, m, br, CO2CH2, NH), 3.91 - 3.88 (1Η, m, EtO2CCH), 3.07 (1Η, dd, NCΗCH, J, 5.1, 14.5 Hz), 2.93 (IH, dd, NCHCH, J, 7.3, 14.5 Hz), 1.18 (3H, t, CO2CH2CH3, J, 7.2 Hz), 1. 07 (9H, s, SC(CH3)3; δc (75 MHz, CDCl3); 171.34 (C=O), 141.75 (H2C=Q, 140.72 (Ar), 130.90 (q, Ar, J, 33.3 Hz), 125.54 (Ar), 122.23 (q, CF3, J, 272.8 Hz), 119.94 (Ar), 118.75 (H2OC), 60.98 (CO2CH2), 55.93 (NC), 55.12 (SC)3 38.76 (H2C=CCH2), 21.43 (SC(CHa)3), 12.93(CO2CH2CH3);m/z;(ES)460(MH+),
Figure imgf000040_0001
Ethyl 2S,4S-(2-methyl-propane-2-sulfιnylainino)-4-p-tolyl-peiit-4-enoate
Obtained as a colourless oil (0.230 g, 68 %) after flash chromatography (8:1 v/v Et2O : hexane); [a]2°+ 87.2; i?F 0.53; (8:1 v/v Et2O : hexane); Found; C, 63.9; H, 8.4; N, 3.9; S, 9.4 %; C18H27NO3S requires; C, 64.1; H, 8.1; N, 4.2; S, 9.5 %; δH (500 MHz, CDCl3); 7.25 (2H, d, ArH, J, 7.9 Hz), 7.14 (2H, d, ArH, J, 7.9 Hz), 5.31 (IH, s, C=CH), 5.07 (1Η, s, C=CH), 4.14 - 4.10 (2Η, q, CO2CH2, J5 7.1 Hz), 3.00 (IH, dd, 5.4, 14.3 Hz); 2.80 (IH, dd, J5 7.6, 14.3 Hz); 2.35 (3H, S5 ArMe); 1.25 (3H, t, CO2CH2CH3, J5 7.1 Hz); 1.17 (9Η, s, C(CH3)3); δc (75 MHz, CDCl3); 171.29 (C=O), 142.42 (H2C=O, 136.50 (Ar), 136.05 (Ar), 128.11 (Ar), 125.21 (Ar), 114.65 (C=CH2), 60.54 (CO2CH2), 55.87 (NC), 55.08 (SC), 39.41 (H2C=CCH2), 21.52 (C(CHa)3), 20.05 (CO2CH2CH3), 13.05 (ArCH3); m/z; (ES) 338 (MH+)
Figure imgf000040_0002
Ethyl 2R,4R-(2-methyl-propane-2-sulfinylamino)-4-Jp-tolyl-pent-4-enoate
Obtained as a colourless oil (0.233 g, 68 %) after flash chromatography (8:1 v/v Et2O : hexane); RF 0.53; (8:1 v/v Et2O : hexane); Vmax/cm"1; 3276, 3085, 2980, 2958,
2926, 2869, 1737; δH (500 MHz, CDCl3); 7.25 (2H3 d, ArH5 J5 7.9 Hz), 7.14 (2H5 d,
ArH, J5 7.9 Hz)5 5.30 (IH5 s, C=CH), 5.07 (1Η, s, C=CH)5 4.14 - 4.10 (2Η, q, CO- 2CH2, J5 7.1 Hz), 4.03 (IH, d, NH, J, 8.3 Hz); 4.0 - 3.9 (IH, m, EtO2CCH); 3.00 (IH, dd, 5.4, 14.3 Hz); 2.80 (IH, dd, J, 7.6, 14.3 Hz); 2.35 (3H, s, ArMe); 1.24 (3H, t, CO2CH2CH3, J, 7.1 Hz); 1.16 (9Η, s, C(CH3)3); δc (75 MHz, CDCl3); 173.34 (C=O), 143.84 (H2C=Q3 137.96 (Ar), 137.48 (Ar), 129.54 (Ar), 126.63 (Ar), 116.09 (C=CH2), 61.99(CO2CH2), 57.28 (NC), 56.52 (SC), 40.85 (H2C=CCH2), 22.96 (C(CH3)3), 21.48 (CO2CH2CH3), 14.47 (ArCH3); m/z; (ES) 338 (MH+)
Figure imgf000041_0001
Ethyl 2S,4S-(2-methyl-propane-2-sulfinylamino)- 4-(4-trifluoromethyI-phenyl)- pent-4-enoate
Prepared by the general procedure on a 2 mmol scale. Obtained as a colourless oil (422 mg, 54 %) after flash chromatography RF0A6 (Et2O); [af° + 82.2; Found; C, 55.0; H, 6.3; N, 3.6; S, 8.1 %; C18H24NSO4F3 requires; C, 55.2; H, 6.2; N, 3.6; S, 8.2; F, 14.6 %; vmjcm \ 3453, 3283 (NH), 3088, 2982, 2961, 2907, 2871, 1738 (CO), 1616; δH (500 MHz, CDCl3); 7.60 (2H, ArH, d, J, 8.2 Hz), 7.47 (2H, ArH, d, J, 8.2 Hz), 5.41 (IH, s, C=CH), 5.23 (IH, s, C=CH), 4.12 (2Η, m, CO2CH2), 4.04 (1Η, d, NH, 7.5 Hz), 3.97 (IH, dt, NCH, J, 5.6, 7.5, Hz), 3.05 (IH, dd, H2C=CCH, J, 5.6, 14.3 Hz), 2.86 (IH, dd, H2C=CCH, J, 7.5, 14.3 Hz), 1.25 (3H, CO2CH2CH3, t, J, 7.19), 1.16 (9Η, s, C(CH3)3); m/z (ES+); 392 (MH+).
Figure imgf000041_0002
Ethyl 2R,4R-(2-methyl-propane-2-sulfϊnylamino)- 4-(4-trifluoromethyl-phenyl)- pent-4-enoate
Prepared by the general procedure on a 2 mmol scale. Obtained as a colourless oil (385 mg, 49 %); after flash chromatography RF0Λ6 (Et2O); [ά$ - 80.4; Found; C, 55.0; H5 6.2; N, 3.7; S5 8.3 %; C18H24NSO4F3 requires; C5 55.2; H5 6.2; N5 3.6; S5 8.2; F5 14.6 %; Vmax/cm"1; 3459, 3282 (NH)5 2982, 3088, 2982, 2961, 2907, 287I5 1738 (CO), 1616, 1573; δH (500 MHz, CDCl3); 7.60 (2H5 ArH5 d, J, 8.2 Hz); 7.47 (2H, ArH, d, J, 8.2 Hz); 5.41 (IH5 s, C=CH); 5.23 (IH5 S5 C=CH); 4.19 - 4.06 (2H5 m5 CO2CH2); 4.03 (IH, d, NH, J5 7.5 Hz); 3.97 (IH, dt, NCH, J5 5.6, 7.5 Hz); 3.04 (IH, dd, H2C=CCH, J, 5.6, 14.3 Hz); 2.87 (IH5 dd, H2C=CCH, J, 7.5 Hz5 14.3 Hz); 1.25 (3H, CO2CH2CH3, t, J, 7.19); 1.16 (9Η, s, C(CH3)3); m/z (ES+); 392 (MH+)
Figure imgf000042_0001
Ethyl 2S,4S-(2-methyl-propane-2-suIfϊnylammo)- 4-(4-pyrroI-l-yI-phenyl)-pent- 4-enoate
Prepared on a 1.5 mmol scale. Obtained as pale yellow prisms (0.227 g, 39 %) after flash chromatography RF 0.21 (Et2O); M.pt 70 - 72 0C; Found; C, 64.8; H5 7.2; N5 7.1; S5 8.3 %; C21H28N2O3S requires; C5 64.9; H5 7.3; N5 7.2; S5 8.3 %; vmJcmA 3254, 3193, 2979, 2952, 2868, 1910, 1831, 1739, 1721, 1629, 1610; δH (500 MHz5 CDCl3); 7.42 (2H5 d, ArH, J5 8.6 Hz); 7.36 (2H, d, ArH, J, 8.6 Hz); 7.09 (2H, t, ArH, J, 2.1 Hz); 6.35 (2H, t, ArH, J, 2.1 Hz); 5.37 (IH5 s, =CH); 5.14 (IH, s, =CH); 4.19 - 4.06 (2H5 m, CO2CH2); 4.03 (1Η, d, NH, J5 7.5 Hz); 3.97 (IH5 dt5 NCH5 J5 5.6, 7.5 Hz); 3.04 (IH5 dd, NCHCH, J5 5.6, 14.5 Hz); 2.85 (IH, dd, NCHCH5 J5 7.7, 14.5 Hz); 1.26 (3H5 1, OCH2CH3, J, 7.2 Hz); 1.17 (9H, s, C(CH3)3); m/z (ES+); 389 (MH+)
Figure imgf000043_0001
Ethyl 2R,4R-(2-methyl-propane-2-sulfinylamino)- 4-(4-pyrrol-l-yl-phenyl)- pent-4-enoate
Prepared on a 1 mmol scale. Obtained as pale yellow prisms (0.187 g, 48 %) after flash chromatography RF 0.21 (Et2O) [af° ; M.pt 70 - 72 0C; Found; C, 64.7; H, 7.3; N, 7.0; S5 8.4 %; C21H28N2O3S requires; C, 64.9; H, 7.3; N, 7.2; S, 8.3 %; vmax/cm4; 3254, 3194, 3110, 3046, 2979, 2952, 2868, 1739, 1721, 1629, 1610; δH (500 MHz, CDCl3); 7.42 (2H, d, ArH, J, 8.6 Hz); 7.36 (2H, d, ArH, J, 8.6 Hz); 7.09 (2H, t, ArH, J, 2.1 Hz); 6.35 (2H, t, ArH, J, 2.1 Hz); 5.37 (IH, s, =CH); 5.14 (IH, s, =CH); 3.04 (IH, dd, NCHCH, J, 5.6, 14.5 Hz); 2.85 (IH, dd, NCHCH, J, 7.7, 14.5 Hz); 1.26 (3H, t, OCH2CH3, J, 7.2 Hz); 1.17 (9H, s, C(CH3)3); m/z (ES+); 389 (MH+)
Figure imgf000043_0002
2-(S)-2-Amino-4-phenyl-pent-4-enoic acid Prepared by the general procedure. Obtained as colourless prisms (0.156 g, 100 %) [αβ° + 26.4; HRMS; 192.1021; C11H13NO2 requires; 192.1019J Vm3xZCm-1; 3030 (br, OH), 2065, 1590 (C=O), 1395, 1340; δH (500 MHz, D2O); 6.90 (2H, d, ArH, 7.8 Hz); 6.85 - 6.75 (3H, m, ArH); 4.98 (IH, s, =CH); 4.73 (IH, s, =CH); 3.45 (IH, dd, NCH, J, 5.1, 8.6 Hz); 2.76 (IH, dd, NCHCH, J, 5.1, 15.4 Hz); 2.47 (IH5 dd, NCHCH, J, 8.6, 15.4 Hz); δc (75 MHz5 D2O); 171.00 (CO)5 140.85 (H2C=Q5 137.72 (Ar)5 128.62 (Ar)5 128.36 (Ar)5 126.12 (Ar)5 118.04 (=CH2)5 51.23 (NCH)5 35.55 (NCH5CH2); m/z (ES+); 192 (MH+)
Figure imgf000044_0001
2-(R)-2-Amino-4-phenyl-pent-4-enoic acid
Prepared by the general procedure. Obtained as colourless prisms (0.095 g, 100 %) [af° - 26.2; HRMS; 192.1017; C11H13NO2 requires; 192.1019; vmjcm l; 3024 (br, OH)3 2075, 1822, 1668, 1594, 1524, 1443, 1400, 1359; δH (500 MHz5 D2O); 7.15 (2H, d, ArH, 8.1 Hz); 7.09 - 6.98 (3H, m, ArH); 5.21 (IH, s, =CH); 4.95 (IH, s, =CH); 3.69 (IH, dd, NCH, J, 5.1, 8.6 Hz); 2.98 (IH, dd, NCHCH, J, 5.1, 15.4 Hz); 2.71 (IH, dd, NCHCH, J, 8.6, 15.4 Hz); δc (75 MHz, D2O); 171.31 (CO), 141.18 (H2C=C), 138.08 (Ar), 128.93 (Ar), 128.67 (Ar), 126.47 (Ar), 118.40 (=CH2), 51.44 (NCH), 35.80 (NCH5CH2); m/z (ES+); 192 (MH+)
Figure imgf000044_0002
2-(S)-2-Amino-4-p-tolyl-pent-4-enoic acid
Obtained as colourless prisms (0.073 g, 61 %) after ion exchange chromatography. M.pt 165 - 167 0C; [a]™ + 10.8; Found, C, 68.7; H5 7.2; N, 6.6 %; C12H15NO2.O.5M H2O requires C5 68.7; H5 7.4; N, 6.7 %; HRMS 205.1097; C12H15NO2 requires 205.1097J Vm3xZCm"1 3034 (br5 OH)5 2089, 1912, 1818, 1671 (CO)5 1594, 1518, 1450, 140O5 1359; δH (300 MHz5 D2O); 7.24 (2H, ArH, d, J, 8.0 Hz); 7.07 (2H, ArH, d, J5 8.0 Hz); 5.37 (IH, s, C=CH2); 5.10 (1Η, s, C=CH2); 3.88 (1Η, dd, H2NCH, J 5.0, 8.7 Hz); 3.16 (IH, dd, H2C=CCH2, J5 5.0 Hz, 14.9 Hz)5 2.87 (IH5 dd, H2C=CCH2, J5 8.7 Hz, 14.9 Hz); 2.14 (3H, s, ArCH3); δc (75 MHz5 D2O); 171.60 (C=O); 141.2 (H2C=Q; 139.4 (Ar); 135.2 (Ar); 129.7 (Ar); 126.6 (Ar); 117.8 (H2C=C); 51.7 (ArMe); 36.0 (H2NC); 20.4 (H2NCQ; m/z (ES) 206 (MH+).
Figure imgf000045_0001
2-(R)-2-Amino-4-p-tolyl-pent-4-enoic acid
Obtained as colourless prisms (0.084 g, 51 %) after ion exchange chromatography. M.pt 165 - 167 0C; [ά\% - 10.6; Found, C5 69.3; H, 7.2; N, 6.6 % C12H15NO2.O.25M H2O requires C, 69.2; H, 7.4; N5 6.7 %, HRMS 205.1099; C12H15NO2 requires 205.1097; vmax/cm4 3030 (br, OH)5 2087, 1818, 1670 (CO), 1594, 1518, 1450, 1401, 1359; δH (300 MHz, D2O); 7.30 (2H, ArH, d, J, 8.0 Hz); 7.13 (2H, ArH, d, J5 8.0 Hz); 5.43 (IH, s, C=CH2); 5.16 (IH5 s, C=GH2); 3.93 (IH5 dd, H2NCH, J, 5.0, 8.7 Hz ); 3.22 (IH, dd, H2C=CCH2, J, 5.0 Hz, 14.9 Hz), 2.92 (IH, dd, H2C=CCH2, J5 8.7 Hz5 14.9 Hz); 2.20 (3H, s, ArCH3); δc (75 MHz5 D2O); 171.66 (C=O); 141.2 (H2C=Q; 139.4 (Ar); 135.3 (Ar); 129.8 (Ar); 126.6 (Ar); 117.8 (H2OC); 51.7 (ArMe); 36.1 (H2NC); 20.5 (H2NCC); m/z (ES) 206 (MH+).
Figure imgf000045_0002
2-(S)-2-Amino-4-(3,4-dichloro-phenyl)-pent-4-enoic acid
Obtained as colourless prisms (0.107 g, 82%) after ion exchange chromatography. [af° + 33.1; Found; C5 50.8; H5 4.5; Cl5 27.4; N5 5.3%; C11H11Cl2NO2 requires C5 50.8; H, 4.3; Cl5 27.3; N5 5.4%; vmjcm l; 3025 (br OH)5 2064, 1899, 1840, 1761, 1670, 1579, 1517; δH (500 MHz, D2O); 7.54 (IH, s, ArH), 7.40 (IH, d, ArH, J5 8.4 Hz), 7.26 (IH, d, ArH, J, 8.4 Hz)5 5.48 (IH, s, C-CH), 5.26 (IH5 s, C=CH), 3.96 (IH, dd, HO2CCH5 J5 5.1, 5.5 Hz)5 3.15 (IH5 dd, H2C=CCH, J5 5.5, 13.2 Hz), 2.98 (IH, dd, H2C=CCH, J, 5.1, 13.2 Hz); δc (75 MHz, D2O); 165.14 (CO); 142.0 (H2C=Q; 141.14 (Ar); 134.78 (Ar); 134.39 (Ar); 133.30 (Ar); 131.07 (Ar); 128.91 (Ar); 120.84 (H2C=C); 54.02 (H2NC); 38.21 (H2NCQ; m/z (ES+); 260 (MH+), 262 (MH+), 264 (MH+)
Figure imgf000046_0001
2-(R)-2-Amino-4-(3,4-dichloro-phenyl)-pent-4-enoic acid
Obtained as colourless prisms (0.094g, 73 %) after ion exchange chromatography. [af° - 30.0; Found; C, 49.3; H, 4.6; N, 4.7%; C11H11Cl2NO2-CSM H2O Requires C, 49.1; H, 4.5; N, 5.2%; HRMS 259.0164; C11H11Cl2NO2 requires 259.0161; v^/cm"1; 3033 (br, OH), 1669, 1576, 1516; δH (500 MHz, D2O); 7.54 (IH, s, ArH), 7.40 (IH, d, ArH, J, 8.4 Hz), 7.26 (IH, d, ArH, J, 8.4 Hz), 5.48 (IH3 s, C=CH), 5.26 (IH5 s, C=CH), 3.96 (IH, dd, HO2CCH, J, 5.1, 5.5 Hz)5 3.15 (IH, dd, H2C=CCH, J, 5.5, 13.2 Hz), 2.98 (IH, dd, H2C=CCH5 J, 5.1, 13.2 Hz); δc(75 MHz5 D2O); 171.48 (CO); 142.0 (H2C=Q; 141.14 (Ar); 134.78 (Ar); 134.39 (Ar); 133.30 (Ar); 131.07 (Ar); 128.91 (Ar); 120.84 (H2C=C); 54.02 (H2NC); 38.21 (H2NCQ; m/z (ES+); 260 (MH+), 262 (MH+), 264 (MH+)
Figure imgf000046_0002
2-(S)-2-Amino-4-(4-trifluoromethyl-phenyl)-pent-4-enoic acid
Obtained as colourless prisms (0.223g, 99 %) M.pt. 141 - 143 0C; [fl]∞ + 29.0, Found; C, 55.5; H, 4.8; N, 5.3% C12H13NO2F3 requires; C, 55.6; H, 4.7; F, 22.0; N, 5.4 %; Vmax/cm"1; 3007 (br, OH)5 2128, 1831, 1614 (CO), 1508, 1455, 1427, 1406, 1328; δH (500 MHz, CD3OD); 7.95 (2H5 d5 ArH5 J, 8.3 Hz), 7.88 (2H, d, ArH5 J5 8.3 Hz)5 5.86 (IH, s, C=CH), 5.62 (IH, s, C=CH), 3.73 (IH, dd, H2NCCH, J5 3.6, 10.5 Hz), 3.66 (IH, dd, H2NCCHCH, J, 5.0, 15.1 Hz)5 3.00 (IH5 dd, H2NCCHCH, J, 10.5, 15.1 Hz); m/z (ES+); 260 (MH+)
Figure imgf000047_0001
2-(R)-2-Amino-4-(4-trifluoromethyl-phenyl)-pent-4-enoic acid
Prepared by the general procedure. Obtained as a colourless prisms (0.193 g, 99 %); M.pt. 141 - 143 0C; [af° - 32.7; Found; C, 54.8; H5 4.8; N5 5.2 %; C12H13NO2F3.0.25M H2O requires; C5 54.7; H5 4.8; F5 21.6; N5 5.3 %; δH (500 MHz5 CD3OD); 6.84 (2H5 d, ArH5 J5 8.3 Hz)5 6.80 (2H5 d5 ArH5 J5 8.3 Hz)5 4.86 (IH5 s, C=CH)5 4.66 (IH5 s, C=CH)5 3.26 (IH5 dd, H2NCCH5 J5 5.O5 9.1 Hz)5 2.60 (IH5 dd, H2NCCHCH5 J5 5.O5 15.1 Hz)5 2.30 (IH5 dd, H2NCCHCH5 J5 9.1, 15.1 Hz)5 m/z (ES+); 260 (MH+)
Figure imgf000047_0002
2-(S)-2-Amino-4-(3-methoxy-phenyl)-pent-4-enoic acid
Obtained as colourless prisms (0.088 g5 97 %) M.pt. 144 - 147 0C; [af£ + 10.9; HRMS; 222.1126; C12H15NO3 requires; 222.1125; VnJCm"1; 3009 (br, OH)5 2593, 2288, 2085, 1843, 1576 (CO), 1491, 1457, 1398; δH (500 MHz5 D2O); 7.22 (IH5 dd5 ArH5 J5 7.7, 8.1 Hz); 6.99 (IH5 d, ArH5 J5 7.7 Hz); 6.94 (IH5 s, ArH); 6.84 (IH5 d, ArH5 J5 8.1 Hz); 5.45 (IH5 S5 =CH); 5.20 (IH, S5 =CH); 3.93 (IH, dd, NCH, J, 5.1, 8.1 Hz); 3.69 (3H5 s, OMe); 3.18 (IH, dd, NCHCH, J, 5.1, 15.4 Hz); 2.96 (IH, dd, NCHCH, J5 8.1, 15.4 Hz); δc (75 MHz5 D2O); 171.57 (CO); 159.40 (H2C=Q; 141.21 (Ar); 140.10 (Ar); 130.41 (Ar); 119.67 (Ar); 119.05 (=CH2); 114.96 (Ar); 112.57 (Ar); 55.70 (OMe); 51.70 (NC); 36.09 (NCCH2); m/z (ES+); 222 (MH+)
Figure imgf000048_0001
2-(R)-2-Amino-4-(3-methoxy-phenyl)-pent-4-enoic acid
Obtained as colourless prisms (0.115 g, 80 %) M.pt. 144 - 147 0C; [α]∞ - 8.0; Found; C, 63.6; H5 6.8; N, 6.3 %; C12H15NO3.0.25M H2O requires; C, 63.8; H, 6.9; N5 6.2 %; HRMS; 222.1125; C12H15NO3 requires; 222.1125; Vm^/cm"1; 3009 (br, OH), 2593, 2086, 1818, 1668, 1575 (CO), 1525, 1493; δH (500 MHz5 CD3OD); 7.18 (IH, t, ArH5 J5 8.1 Hz); 7.01 (IH, d, ArH5 J, 7.7 Hz); 6.99 (IH5 d, ArH, J, 2.1 Hz); 6.77 (IH, dd, ArH, J, 8.1 Hz); 5.41 (IH, S5 =CH); 5.17 (IH, s, =CH); 3.71 (3H, s, OMe); 3.44 (IH, dd, NCHCH, J5 5.1, 15.4 Hz); 3.34 (IH3 dd, NCHCH, J, 5.1, 15.4 Hz); m/z (ES+); 222 (MH+)
Figure imgf000048_0002
2-(S)-2-Amino-4-(3,5-bis-trifluoromethyl-phenyl)-pent-4-enoic acid
Obtained as colourless prisms (0.178g, 89 %) [a]∞ + 10.9; HRMS; 328.0765; C13H11F6NO2 requires; 328.0767; vmJcmA; 3456 (NH); 3049 (br, OH), 2929, 1854, 1622 (CO)5 1524, 1398, 1334, 1277; δH (500 MHz, CD3OD); 8.01 (2H5 s, ArH); 7.83 (IH, S5 ArH), 5.55 (IH5 S5 =CH); 5.40 (IH5 s, =CH); 3.40 (IH5 dd, NCH5 J, 4.1, 9.7 Hz); 3.33 (IH, dd, NCHCH, J5 4.1, 15.4 Hz); 2.79 (IH5 dd, NCHCH5 J5 9.7, 15.4 Hz); m/z (ES+); 328 (MH+)
Figure imgf000048_0003
2-(R)-2-Amino-4-(3,5-bis-trifluoromethyl-phenyl)-pent-4-enoic acid
Obtained as colourless prisms (0.167 g, 68 %) [af£ - 9.5; Found; C, 47.5; H3 3.3; 4.2 %; C13HnF6NO2 requires; C, 47.7; H, 3.4; F, 34.8; N, 4.3 %; v^/cm 1; 3683, 2929 (br, OH), 2065, 1832, 1634 (CO), 1510, 1444; δH (500 MHz, D2O); 7.40 (2H, s, ArH); 7.36 (IH, s, ArH), 5.12 (IH, s, =CH); 4.95 (IH, s, =CH); 3.48 (IH, dd, NCH, J, 5.5, 8.0 Hz); 2.78 (IH, dd, NCHCH, J, 5.5, 15.3 Hz); 2.79 (IH, dd, NCHCH, J, 8.0, 15.4 Hz); m/z (ES+); 328 (MH+)
Figure imgf000049_0001
2-(S)-2-Amino-4-(6-chloro-pyridin-2-yl)-pent-4-enoic acid
Prepared by the general procedure. Obtained as colourless prisms (0.066 g, 79 %) [af° + 30.0; Found; C, 52.0; H, 5.0; N, 11.7 %; C10H1 !ClN2O2.0.25 M H2O requires; C, 52.0; H, 5.0; N, 12.1 %; v^/cm 1; 3456, (br, OH), 3049, 2929, 1854, 1630 (CO), 1523; δH (500 MHz, D2O); 8.43 (IH, d, ArH, J, 2.1 Hz); 7.97 (IH, dd, 2.1, 8.3 Hz); 7.51 (IH, d, ArH, J, 8.3 Hz); 5.61 (IH, =CH); 5.43 (IH, =CH); 4.03 (IH, dd, NCH J, 6.0, 7.7 Hz); 3.21 (IH, dd, NCHCH, J, 6.0, 15.4 Hz); 3.11 (IH, dd, NCHCH, J, 7.7, 15.4 Hz); m/z (ES+); 227 (MH+), 229 (MH+)
Figure imgf000049_0002
2-(R)-2-Ammo-4-(6-chloro-pyridin-2-yl)-pent-4-enoic acid
Prepared by the general procedure. Obtained as colourless prisms (0.123 g, 79 %)
[a]∞ - 32.1; vmjcm l; 3051 (br, OH)5 2093, 1893, 1607 (CO), 1555, 1474, 1454, 1410; δH (500 MHz, D2O); 8.17 (IH5 d5 ArH, J5 2.4 Hz)5 7.89 (IH5 dd, ArH5 J5 2.4, 8.8 Hz)5 7.89 (IH, d, ArH, J, 8.8 Hz), 5.23 (IH5 s5 =CH), 5.09 (IH, s, =CH), 3.54 (IH5 dd, NCH5 J, 6.2, 7.7 Hz), 2.74 (IH, dd, NCHCH, J, 6.2, 15.5 Hz), 2.64 (IH, dd, NCHCH, J, 7.7, 15.5 Hz); δc (75 MHz3 D2O); 170.51 (CO)5 145.16 (H2C=Q5 143.94 (Ar)5 141.87(Ar)5 136.22 (Ar)5 135.02 (Ar)5 127.31 (Ar)5 123.78 (=CH2)5 50.89 (NC), 34.60 (NCQ; m/z (ES+); 227 (MH+), 229 (MH+)
Figure imgf000050_0001
Ethyl IR^R-SS Cl-benzenesulfonyl-S-methylene^jS-dihydro-Uy-indol^-y^-Cl- methyl-propane-2-sulfinylamino)-acetate
Obtained as pale yellow crystals (0.23 Ig, 48 %) after flash chromatography (Et2O); + 4.9; RF 0.14 (Et2O); Found; C23H28N2O5S2 requires C, 58.0; H5 5.9; N5 5.9; S5 13.5 %; Vmax/cm"1 3294, 3085, 3014, 2985, 1732 (CO), 1648, 160O5 1584; δH (500 MHz5 CDCl3); 7.71 (IH5 d, ArH, J5 8.1 Hz); 7.55 (2H, d, ArH5 8.2 Hz); 7.49 (IH, d5 ArH, J5 7.5 Hz)5 7.34 (2H5 t, ArH5 J, 7.9 Hz); 7.27 - 7.23 (2H, m, ArH); 7.05 (IH5 1, ArH5 J5 7.5 Hz); 5.44 (IH, S5 C=CH); 5.08 (IH5 S5 C=CH); 4.97 (IH5 d, NH, J, 1.6 Hz); 4.37 (IH, d5 SO2PhNCH5 J, 7.6 Hz); 4.33 (2H, m, CO2CH2); 4.15 (IH5 dd5 EtO2CCH, J5 1.6, 7.6 Hz); 1.32 (3Η, t, CO2CH2CH3, J5 7.2 Hz); 0.91 (9H5 S5 C(CH3)3); δc(75 MHz, CDCl3); 170.09 (C=O); 144.73 (H2C=Q; 143.14 (Ar); 136.75 (Ar); 133.91 (Ar); 131.61 (Ar); 130.57 (Ar); 129.44 (Ar); 127.61 (Ar); 121.19 (Ar); 118.02 (H2C=C); 68.14 (SO2NCH); 64.46 (SC); 62.90 (SNC); 56.45 (CO2CH2); 22.50 (C(CH3)3); 14.41 (CO2CH2CH3) m/z (ES) 477 (MH+)
Figure imgf000050_0002
Ethyl 2S,4S,5R (3-methylene-2,3-dihydro-benzofuran-2-yl)-(2-methyl-propane- 2-sulfmylamino)-acetate Obtained as a pale orange oil (0.108g, 64 %); δc (75 MHz, CDCl3); 170.45 (CO), 163.13 (Ar), 144.48 (Ar), 131.14 (Ar), 126.52 (Ar), 124.27 (Ar), 121.39 (Ar), 121.11 (Ar), 110.67 (Ar), 102.69 (-CH2), 85.78 (OCH), 62.99 (OCH2), 62.65 (NC), 56.73 (C(CH3)3), 22.57 (C(CH3)3), 14.50 (CO2CH2CH3).
Figure imgf000051_0001
Ethyl (S)-((R)-3-methylene-2,3-dihydro-benzofuran-2-yl)-((S)-2-methyl-propane -2-sulfinylamino) acetate
Obtained as a pale yellow oil (0.110 g, 64 %) after flash chromatography (Et2O); RF 0.11 (Et2O); δH (500 MHz, CDCl3); 7.33 (IH, d, ArH, J, 7.6 Hz); 7.19 (IH, t, ArH, J,
7.6 Hz); 6.87 (IH, t, ArH, J, 7.6 Hz); 6.84 (IH, d, ArH, J, 7.6 Hz); 5.54 (2H, m,
NCH, =CH); 5.09 (IH, s, =CH); 4.32 (2H, q, OCH2, J, 7.3 Hz); 4.21 (2H, m, NCH,
OCH); 1.32 (3H, t, OCH2CH3, J, 7.3 Ηz);δc (75 MHz, CDCl3); 170.45 (CO), 163.13
(Ar), 144.48 (Ar), 131.14 (Ar), 126.52 (Ar), 124.27 (Ar), 121.39 (Ar), 121.11 (Ar), 110.67 (Ar), 102.69 (=CH2), 85.78 (OCH), 62.99 (OCH2), 62.65 (NC), 56.73
(C(CH3)3), 22.57 (C(CHs)3), 14.50 (CO2CH2CH3);
Figure imgf000051_0002
Ethyl (R)-((S)-3-methylene-2,3-dihydro-benzofuran-2-yl)-((R)-2-methyl-propane -2-sulfinylamino) acetate
Obtained as a pale yellow oil (0.108 g, 64 %) after flash chromatography (Et2O); RF 0.11 (Et2O); δH (500 MHz, CDCl3); 7.33 (IH, d, ArH, J, 7.6 Hz); 7.19 (IH, t, ArH, J, 7.6 Hz); 6.87 (IH, t, ArH, J, 7.6 Hz); 6.84 (IH5 d, ArH, J, 7.6 Hz); 5.54 (2H, m, NCH, =CH); 5.09 (IH, s, =CH); 4.32 (2H, q, OCH2, J, 7.3 Hz); 4.21 (2H, m, NCH, OCH); 1.32 (3H, t, OCH2CH3, J, 7.3 Hz); δc (75 MHz, CDCl3); 170.43 (CO), 163.12 (ArQ, 144.46 (Ar), 131.12 (Ar), 126.51 (Ar), 121.37 (Ar), 121.10 (Ar), 110.67 (Ar)5 102.64 (=CH2), 85.76 (OCH), 62.94 (OCH2), 62.62 (NC), 56.68 (C(CH3)3), 22.65 (C(CHs)3), 14.49 (CO2CH2CH3); m/z (ES+) 338 (MH+).
Figure imgf000052_0001
Ethyl (S)-((R)-l-benzenesulfonyl-3-methylene-2,3-dihydro-liϊ-indol-2-yl)-((S)-2- methyl-propane-2-sulfinyIamino) acetate
Obtained as colourless prisms (0.110 g, 46 %) after flash chromatography (Et2O); [ά\o ; ~ 7.0; RF 0.14 (Et2O); VmJcm 1 3294, 3085, 3014, 2985, 1732 (CO), 1648, 1600, 1584; δH (500 MHz, CDCl3); 7.71 (IH, d, ArH, J, 8.1 Hz); 7.55 (2H, d, ArH, 8.2 Hz); 7.49 (IH, d, ArH, J, 7.5 Hz), 7.34 (2H, t, ArH, J, 7.9 Hz); 7.27 - 7.23 (2H, m, ArH); 7.05 (IH, t, ArH, J, 7.5 Hz); 5.44 (IH, s, =CH); 5.08 (IH, s, =CH); 4.97 (IH, d, NH, J 1.6 Hz); 4.37 (IH, d, SO2PhNCH, J, 7.6 Hz); 4.33 (2H, m, CO2CH2); 4.15 (1Η, dd, EtO2CCH, J, 1.6, 7.6 Hz); 1.32 (3H, t, CO2CH2CH3, J, 7.2 Hz); 0.91 (9H, s, C(CH3)3); δc (75 MHz, CDCl3); 170.09 (C=O); 144.73 (H2C=C); 143.14 (Ar); 136.75 (Ar); 133.91 (Ar); 131.61 (Ar); 130.57 (Ar); 129.44 (Ar); 127.61 (Ar); 121.19 (Ar); 118.02 (H2C=C); 68.14 (SO2NCH); 64.46 (SC); 62.90 (SNC); 56.45 (CO2CH2); 22.50 (C(CH3)3); 14.41 (CO2CH2CH3); m/z (ES+) 477 (MH+).
Figure imgf000053_0001
Ethyl (R)-((S)-l-benzenesuIfonyl-3-methyIene-2,3-dihydro-lJϊ-indoI-2-yl)-((R)-2 -methyl-propane-2-sulfϊnylamino) acetate
Obtained as colourless prisms (0.23 Ig, 48 %) after flash chromatography (Et2O); [α]∞ ; + 4.9; RF 0.14 (Et2O); Found, C, 58.0; H, 5.9; N5 5.9; S5 13.6 %; C23H28N2O5S2 requires C5 58.0; H5 5.9; N5 5.9; S, 13.5 %; vmjcm l 3294, 3085, 3014, 2985, 1732 (CO), 1648, 1600, 1584; δH (500 MHz, CDCl3); 7.71 (IH, d, ArH, J, 8.1 Hz); 7.55 (2H, d, ArH, 8.2 Hz); 7.49 (IH, d, ArH, J, 7.5 Hz), 7.34 (2H, t, ArH, J, 7.9 Hz); 7.27 - 7.23 (2H, m, ArH); 7.05 (IH, t, ArH, J, 7.5 Hz); 5.44 (IH, s, =CH); 5.08 (IH, s, =CH); 4.97 (IH, d, NH, J, 1.6 Hz); 4.37 (IH, d, SO2PhNCH, J, 7.6 Hz); 4.33 (2H, m, CO2CH2); 4.15 (1Η, dd, EtO2CCH, J, 1.6, 7.6 Hz); 1.32 (3H, t, CO2CH2CH3, J, 7.2 Hz); 0.91 (9Η, s, C(CH3)3); δc (75 MHz, CDCl3); 170.09 (C=O); 144.73 (H2C=Q; 143.14 (Ar); 136.75 (Ar); 133.91 (Ar); 131.61 (Ar); 130.57 (Ar); 129.44 (Ar); 127.61 (Ar); 121.19 (Ar); 118.02 (H2C=C); 68.14 (SO2NCH); 64.46 (SC); 62.90 (SNC); 56.45 (CO2CH2); 22.50 (C(CH3)3); 14.41 (CO2CH2CH3); m/z (ES+) 477 (MH+).
Figure imgf000053_0002
Ethyl (S)-((R)-4-methylene-isochroman-3-yl)-((S)-2-methyl-propane-2-sulfinyl amino) acetate
Obtained as a pale yellow oil (0.108 g, 62 %) after flash chromatography (Et2O); [a]∞ - 41.0; RF 0.14 (Et2O); vmax/cm4 3296 (NH), 3126, 2980, 2960, 2905, 2868, 2841, 1738(CO), 1628; δH (500 MHz, CDCl3); 7.57 (IH, d, ArH3 J, 2.5 Hz); 7.25 - 7.22 (2H, m, ArH5); 7.03 (IH, m, ArH5); 5.72 (IH5 S5 =CH); 5.11 (IH5 s, =CH); 4.89 (IH5 dd, OCH5 J5 1.7, 3.8 Hz); 4.75 (IH5 d5 ArCH5 J5 14.5 Hz)5 4.62 (IH5 d, ArCH5 J5 14.5 Hz); 4.32 (IH5 dd5 NCH5 J 3.8, 8.6 Hz); 4.27 (2H5 dq, CO2CH2, J 1.3, 7.3 Hz); 1.29 (3H, t, OCH2CH3, J5 7.1 Hz); 1.09 (9H, s, C(CH3)3); δc (75 MHz5 CDCl3); 171.49 (CO), 138.88 (=C), 134.58 (Ar), 132.32 (Ar), 128.33 (Ar)5 127.83 (Ar)5 124.89 (Ar)5 124.14 (Ar)5 110.09 O=CH2), 79.17 (NCQ5 66.91 (OCH2), 62.40 (CO2Q, 62.06 (NC), 56.84 (SC), 22.96 (C(CH3)3), 14.51 (OCH2CH3); m/z (ES+) 352 (MH+).
Figure imgf000054_0001
Ethyl (R)-((S)-4-methylene-isochroman-3-yl)-((R)-2-methyl-propane-2-sulfinyl amino) acetate
Obtained as a pale yellow oil (0.101 g, 58 %) after flash chromatography (Et2O); [α]∞ + 41.5; RF 0.14 (Et2O); vmax/cm"13450, 3297 (NH), 2959, 2868, 1738 (CO), 1628, 1576; δH (500 MHz, CDCl3); 7.57 (IH, dd, ArH5 J, 4.3, 9.0 Hz); 7.23 (2H5 m, ArH); 7.03 (IH, dd, ArH5 J, 4.3, 6.0 Hz); 5.72 (IH5 s =CH); 5.11 (IH5 s =CH); 4.89 (IH, m, NH); 4.75 (IH, d, OCH, J, 14.5 Hz), 4.62 (IH, d, OCH, J, 14.5 Hz); 4.32 (IH5 dd, NCH, J 3.8, 8.6 Hz); 4.29 - 4.24 (3H5 m, CO2CH2, OCH); 1.30 (3H5 t, OCH2CH3, J5 7.1 Hz); 1.09 (9H5 S5 C(CH3)3); δc (75 MHz5 CDCl3); 170.08 (CO)5 137.44 (=C), 133.15 (Ar)5 130.89 (Ar)5 126.90 (Ar)5 126.40 (Ar), 123.46 (Ar)5 122.71 (Ar), 108.66 (=CH2), 77.74 (NCQ, 65.48 (OCH2), 60.98 (CO2Q, 60.92 (NC), 55.39 (SC), 21.53 (C(CHs)3), 13.09 (OCH2CH3); m/z (ES+) 352 (MH+).
Figure imgf000054_0002
Ethyl (S)-((R)-2-methyI-4-methylene-l-oxo-l,2,3,4-tetrahydro-isoquinolin-3-yl)- ((S)-2-methyl-propane-2-sulfinylamino) acetate
Obtained as a pale yellow oil (0.052 mg, 28 %) after flash chromatography (EtOAc); [α]∞ - 7.3; vWcm 1 3459 (NH), 3274, 2961, 2239, 1739 (CO), 1648 (CO), 1602, 1573; δH (500 MHz, CDCl3); 8.09 (IH, d, ArH, J, 7.7 Hz); 7.51 (IH, d, ArH, J5 7.7 Hz); 7.47 (IH, td, ArH, J, 0.9, 7.7 Hz); 7.40 (IH, td, ArH5 J, 0.9, 7.7 Hz); 5.74 (IH, s, =CH); 5.31 (IH5 S5 =CH); 4.38 (IH5 d, MeNCH5 J5 4.7 Hz); 4.27 (IH, d, NH, J5 8.1 Hz); 4.11 (IH5 dd5 NCH5 J5 4.7, 8.1 Hz); 3.90(1H5 dq, OCH5 J5 7.35 10.7 Hz); 3.54(1H5 dq5 OCH5 J5 7.3, 10.7 Hz); 3.22 (3H5 S5 NCH3); 1.15 (9H, S5 C(CH3)3); 1.13 (3H5 t5 OCH2CH3, J, 7.3 Hz); δc (75 MHz5 CDCl3); 170.53 (CO)5 163.29 (NCO)5 136.20 (=C)5 134.46 (Ar), 132.19 (Ar)5 128.10 (Ar), 127.83 (Ar)5 127.27 (Ar)5 123.68 (Ar)5 115.76 O=CH2), 68.33 (MeNQ5 62.34 (OC)5 59.54 (SNC)5 56.22 (SC), 35.14 (NCH3), 22.53 (C(CHs)3), 10.97 (OCH2CH3); m/z (ES+) 379 (MH+).
Figure imgf000055_0001
Ethyl (R)-((S)-2-methyl-4-methylene-l-oxo-l,2,3,4-tetrahydro-isoquinιolin-3-yl)- ((R)-2-methyl-propane-2-sulfinylamino) acetate
Obtained as a pale yellow oil (0.130 g, 69 %) after flash chromatography (EtOAc); δπ (500 MHz5 CDCl3); 8.09 (IH5 d5 ArH5 J5 7.8 Hz); 7.51 (IH5 d, ArH5 J5 7.7 Hz); 7.47 (IH5 td, ArH5 J5 0.9, 7.7 Hz); 7.40 (IH, td, ArH, J, 0.9, 7.7 Hz); 5.74 (IH, s, =CH); 5.31 (IH, s, =€H); 4.39 (IH, d, MeNCH, J, 4.7 Hz); 4.27 (IH, d, NH, J5 8.1 Hz); 4.14 (IH5 dd5 NCH, J, 4.5, 8.1 Hz); 3.90(1H5 dq, OCH5 J5 7.35 10.7 Hz); 3.54(1H5 dq5 OCH, J5 7.3, 10.7 Hz); 3.23 (3H5 s5 NCH3); 1.15 (9H5 s, C(CH3)3); 1.13 (3H, t, OCH2CH3, J, 7.3 Hz);
Figure imgf000056_0001
Ethyl (S)-4-benzofuran-(3E)-yIidenemethyl-2-((S)-2-methyl-propane-2-sulfinyl amino)-pent-4-enoate
Obtained as a pale yellow oil (0.096 g, 49 %) after flash chromatography (Et2O); [α]∞ - 7.1; RF0.20 (Et2O); δH (500 MHz, C6D6); 7.96 (IH, d, ArH, J5 7.7 Hz); 6.97 (IH5 dd, ArH, J, 7.3, 8.1 Hz); 6.85 (IH, d, ArH, 8.1 Hz); 6.69 (IH5 dd, ArH5 7.3, 7.7 Hz); 5.44 (IH5 s, H); 5.35 (IH5 S5 H); 5.11 (IH5 s H); 4.71 (2H5 d, OCH2, J5 3.0 Hz); 4.30 (IH5 d, NH5 J5 7.7 Hz); 4.16 (IH5 NCH5 ddd, J5 6.2, 6.8, 7.7 Hz); 4.0 - 3.84 (2H5 m5 OCH2); 2.59 (IH5 dd5 NCHCH5 J, 6.2, 13.7 Hz), 2.51 (IH, dd, NCHCH, J5 6.8, 13.7 Hz); 1.03 (9H, S5 C(CHs)3); 0.90 (3H, t, OCH2CH5, J, 6.8 Hz);
Figure imgf000056_0002
Ethyl (R)-4-benzofiiran-(3E)-ylidenemethyl-2-((R)-2-methyl-propane-2-sulfinyl amino)-pent-4-enoate Obtained as a pale yellow oil (0.118g, 63 %) after flash chromatography (Et2O); Rf 0.20 (Et2O); Vmax/cm"1 3444, 3279, 2979, 2869, 1735, 1604, 1588, 1469; δH (500 MHz5 C6D6); 7.97 (IH5 d5 ArH5 J5 7.7 Hz); 6.97 (IH5 dd, ArH5 J5 7.3, 8.1 Hz); 6.85 (IH5 d, ArH5 8.1 Hz); 6.69 (IH5 dd5 ArH5 7.3, 7.7 Hz); 5.44 (IH, s, H); 5.35 (IH, s, H); 5.11 (IH, s H); 4.71 (2H, d, OCH2, J5 3.0 Hz); 4.30 (IH5 d, NH, J, 7.7 Hz); 4.16 (IH5 NCH5 ddd, J5 6.2, 6.8, 7.7 Hz); 4.0 - 3.84 (2H, m, OCH2); 2.59 (IH, dd, NCHCH5 J5 6.2, 13.7 Hz)5 2.51 (IH5 dd, NCHCH, J, 6.8, 13.7 Hz); 1.03 (9H, s, C(CH3)3); 0.90 (3H, t, OCH2CH5, J5 6.8 Hz); δc (75 MHz, C6D6); 173.35; 166.34; 141.13; 137.83; 131.46; 131.03; 125.24; 121.04; 117.57; 112.93; 76.10; 61.93; 56.90; 55.99; 42.28; 22.79; 14.21;
Figure imgf000057_0001
Ethyl (R)-4-[l-benzenesulfonyl-l,2-dihydro-indol-(3E)-ylidenemethyl]-2-((R)-2- methyl-propane-2-sulfinylamino) pent-4-enoate
Obtained as a pale yellow oil (0.177 g, 69 %) after flash chromatography (Et2O); [α]∞ - 23.7; vmJcmA 3286 (NH), 2977, 1730 (CO), 1603, 1545, 1447, 1363; δH (500 MHz, C6D6); 7.84 - 7.78 (3H, m, ArH); 7.73 (IH, d, ArH, J, 8.1 Hz); 7.57 (IH, t, ArH, J, 7.5 Hz); 7.47 (2H, m, ArH); 7.24 (IH, t, ArH5 J, 7.5 Hz); 6.89 (IH5 1, ArH, J5 7.7 Hz); 5.80 (IH, s, =CH); 5.25 (IH5 S5 =CH); 5.16 (IH5 s, =CH); 4.54 (IH, s, SO2PhNCH); 4.52 (1Η, s, SO2PhNCH); 4.14 - 4.07 (3Η, m, NH5 OCH2); 4.04 - 3.96 (IH5 m, NCH); 2.60 (2H, qd, NCHCH2, J5 5.6, 14.1 Hz); 1.19 (9H, s, C(CH3)3); 1.15 (2H51, OCH2CH3, J5 6.8 Hz); m/z (ES+) 517 (MH+).
Figure imgf000057_0002
Ethyl (R)-4-isochroman-(4E)-ylidenemethyl-2-((R)-2-methyl-propane-2-sulfιnyl amino)-pent-4-enoate Obtained as a pale yellow oil (0.186 g, 95 %) after flash chromatography (Et2O); [af° + 19.7 Vmax/cm'1 3460, 3279 (NH), 3037, 2978, 2959, 2868, 2833, 1736 (CO), 1619; δH (500 MHz, CDCl3); 7.74 (IH, d, ArH, J, 7.3 Hz); 7.13 (IH, t, ArH, J, 7.3 Hz); 7.03 (IH, t, ArH, J, 7.3 Hz); 6.94 (2H, d, ArH, J, 7.3 Hz); 5.86 (IH, s, =CH); 5.15 (IH, s, =CH); 5.05 (IH, s, =CH); 4.75 (2H, s, ArCH2); 4.20 (2H, s, OCH2); 4.13 - 4.05 (4Η, m, NH, NCHCH, CO2CH2); 2.67 (1Η, dd, NCΗCH, J, 5.6, 13.7 Hz); 2.47 (IH, dd, NCHCH, J, 7.7, 13.7 Hz); 1.16 (9H, s, C(CH3)3); 1.14 (3H, t, OCH2CH5, J, 7.0 Hz); δc (75 MHz, CDCl3); 171.82 (CO), 139.51 (H2C-Q, 134.79 (HC=C), 130.60 (Ar), 130.14 (Ar), 126.89 (Ar), 126.75 (Ar)5 124.89 (Ar), 124.56 (Ar), 123.39 (=CH), 117.98 (=CH2), 71.39 (ArCH2), 68.36 (OCH2), 60.70 (CO2Q, 56.02 (SC), 55.07 (NC), 39.82 (NCQ, 21.60 (C(CH3)3)5 13.02 (CO2CH2CH3); m/z (ES+) 392 (MH+).
Figure imgf000058_0001
Ethyl 2R,4R-4-[2-Methyl-l-oxo-2,3-dihydro-lH-isoquinolin-(4E)-ylidenemethyl] -2-(2-methyl-propane-2-sulfinylamino)-pent-4-enoate
Obtained as a pale yellow oil (0.138 g, 66 %) after flash chromatography δπ (500 MHz, C6D6); 8.49 (IH, dd, ArH, J5 1.9, 7.7 Hz); 7.71 (IH, dd, ArH, J, 6.8, 1.9 Hz); 7.09 (2H5 m, ArH); 5.87 (IH5 S5 =CH); 5.04 (IH5 s5 =CH); 4.95 (IH5 s5 =CH); 4.40 (IH5 d5 NH, J5 7.7 Hz); 4.12 (IH, q, OCH, 6.8 Hz); 3.95 - 3.87 (2H5 m, OCH, SNCH); 3.41 (2H5 s, NCH2); 2.83 (3H5 s, NCH3); 2.59 (IH5 dd, NCHCH, J, 5.6, 14.1 Hz); 2.49 (IH, dd, NCHCH, J5 6.7, 14.1 Hz); 0.93 (3H5 1, OCH2CH3, J5 6.8 Hz);
Figure imgf000059_0001
Ethyl (R)-amino-((S)-4-methylene-isochroman-3-yl)-acetic acetate
Obtained as a pale yellow oil (0.093 g, 53 %) after aqueous work-up [a]2° + 45.7; δH
(500 MHz, C6D6); 7.45 (IH, d, ArH3 J, 7.5 Hz); 7.02 (IH, t, ArH5 J, 7.5 Hz); 6.96 (IH, t, ArH5 J, 7.5 Hz); 6.59 (IH5 d, ArH5 J5 7.5 Hz); 5.52 (IH5 s, =CH); 4.96 (IH5 s,
=CH); 4.80 (IH5 d, OCH 3.8 Hz); 4.52 (IH5 d, ArCH5 J, 14.6 Hz); 4.41 (IH5 d,
ArCH5 J5 14.6 Hz); 4.06 - 3.95 (2H5 m, OCH2); 3.79 (IH5 d5 NCCH5 J5 3.8 Hz); 0.96
(3H5 1, OC2CH3, J5 7.2 Hz); δc (75 MHz, C6D6); 173.60 (CO); 139.95 (-C); 135.13
(Ar); 132.82 (Ar); 127.98 (Ar); 127.71 (Ar); 124.97 (Ar); 124.29 (Ar); 108.95 (=CH2); 80.01 (NC); 67.10 (CO2Q; 61.08 (OC); 58.47 (NCQ; 14.49 (OCH2CH3); m/z (ES+) 248 (MH+).
Figure imgf000059_0002
(R)-Amino-((S)-4-methyIene-isochroman-3-yl)-acetic acid Obtained as colourless prisms (0.070 g, 82 %) after ion exchange chromatography M.Pt. 178 - 180 0C; [α]∞ + 34.2; vmJcmΛ 3231 (br5 OH)5 2986, 2855, 1655 (CO)5 1594, 1490, 1394; δH (500 MHz, C6D6); 7.31 (IH, d, ArH J, 7.3 Hz); 6.99 (IH, t, ArH5 J, 7.3 Hz) ; 6.93 (IH, t, ArH5 J5 7.3 Hz) ; 6.49 (IH5 d, ArH5 J 7.3 Hz); 5.49 (IH5 s, -CH); 4.72 (IH5 s, -CH); 4.59 (IH, S5 NCH); 4.34 (IH5 s, NCH); 4.29 (2H5 s, NH2); 4.24 (IH5 d5 ArCH5 J, 14.1 Hz); 4.02 (IH, d5 ArCH5 J5 14.1 Hz); δc (75 MHz5 D2O); 172.34 (CO); 137.32 (=C); 134.35 (Ar); 130.76 (Ar); 129.01 (Ar); 128.24 (Ar); 125.26 (Ar); 124.28 (Ar); 110.68 (=CH2); 76.46 (NC); 67.09 (OC); 57.50 (NCQ;
Figure imgf000060_0001
Ethyl methyl-2-((R)-2-methyl-propane-2-sulfinylamino)-4-phenyl-pent-4-enoate
Obtained as a pale yellow oil (0.055g, 33 %); δH (500 MHz, CDCl3)(Major isomer) 7.34 - 7.30 (5H, m, ArH); 5.29 (IH, s, =CH); 5.11 (IH, s, =CH); 4.03 (IH3 s, NH); 3.95 - 3.80 (2H, m, OCH2); 3.06 (IH5 d, NCCH, J3 10.5 Hz); 3.03 (IH, d, NCCH, J, 10.5 Hz); 1.58 (3H, s, CH3); 1.07 (3H, t, OCH2CH3, J, 7.3 Hz); 1.06 (9H, s, C(CH3)3) (Minor isomer); 7.34 - 7.30 (5H, m, ArH); 5.35 (IH, s, =CH); 5.29 (IH, s, =CH); 4.08 (IH, s, NH); 3.73 - 3.66 (IH, m, OCH2); 3.54 - 3.48 (IH, m, OCH2); 3.17 (IH, d, NCCH, J, 13.7 Hz); 2.89 (IH, d, NCCH, J, 13.7 Hz); 1.59 (3H, s, CH3); 1.17 (3H, t, OCH2CH3, J, 6.8 Hz); 1.14 (9H, s, C(CH3)3)

Claims

1. A compound, or derivative thereof, of formula I
Figure imgf000061_0001
wherein
R is an optionally substituted alkenyl, alkynyl or cyclic group wherein each substitutable carbon atom in R is optionally and independently substituted with one or more of halogen, Cl -12 alkyl, C 1-6 fluoroalkyl, cycloalkenyl, cycloheteroalkenyl, heterocyclyl, aryl, alkylOR14, CN, COOR14, COR14, NO2, OR14, SR14, NR14 2, CONR14 2, SOOR14, SONR14, SOR14, SOONR14, NR14COR14, NR14CONR14 2, NR14COR14, NR14COOR14, NR14SOOR14 wherein R14 is H, Cl-6 alkyl or Cl-6 fluroalkyl;
R1 is optionally substituted NR7 2, NR7COR7, NR7CONR7 2, NR7COOR7, NR7SOR7, NR7SOOR7 or NR7CSNR7 2 wherein R7 is H or optionally substituted Cl-6 alkyl or Cl-6 haloalkyl;
R2 is optionally substituted CO2R8 or CONR9R10 wherein R8, R9 and R10 are H, Cl-6 alkyl, aryl or heteroaryl; and wherein R and R , which are from the same compound, or from two different compounds, of formula I, are optionally joined together to form a cyclic compound of ring size C3-C8 of formula II or III;
Figure imgf000062_0001
wherein R11 and R12 are H or optionally substituted alkyl, alkylaryl, aryl, alkylheteroaryl, heteroaryl wherein each substitutable carbon atom in R11 and R12 may be optionally and independently substituted with one or more of OR13, SR13, CO2R13, or NR13 2 wherein R13 is H, optionally substituted C 1-6 alkyl, C 1-6 haloalkyl, aryl or heteroaryl; and wherein R12 and R7 are optionally joined together to form a cyclic compound of ring size C3-C8;
R3 is H or optionally substituted alkyl (C 1-8), alkylaryl, aryl, alkylheteroaryl or heteroaryl;
R4 and R5 are H, alkyl (C 1-8), aryl, heteroaryl, vinyl, amide, ester, alkyl (C1-C8) amide or alkyl (C1-C8) ester and wherein R4 and/or R5 are optionally joined together or to R to form an optionally substituted cyclic optionally fused to one or more 5 or 6 membered hydrocarbon rings;
R s which may be absent, is H, optionally substituted alkyl, aryl or heteroaryl;
or a pharmaceutically acceptable salt, and other pharmaceutically acceptable biohydrolysable derivatives thereof, and including the proviso that the compound is not 2-Amino-4-methylene-hex-5-enoic acid, 2-Amino-5-methyl-4-methylene-hex-5- enoic acid or 2-Amino-4-phenyl-pent-4-enoic acid. 2. A compound as claimed in claim 1 wherein R is an optionally substituted 5 or 6 membered cyclohydrocarbyl or heterocyclyl group.
3. A compound as claimed in claim 2 wherein the cyclohydrocarbyl or heterocyclyl group is fused to one or more 5 or 6 membered hydrocarbon rings.
4. A compound as claimed in claim 3 wherein the 5 or 6 membered hydrocarbon ring to which R is attached is an optionally substituted cyclohydrocarbyl or heterocyclyl group.
5. A compound as claimed in claim 1 wherein R is an optionally substituted aryl or heteroaryl group.
6. A compound as claimed in claim 5 wherein the optionally substituted aryl or heteroaryl group is fused to a saturated or unsaturated 5 or 6 membered hydrocarbon ring.
7. A compound as claimed in claim 6 wherein the 5 or 6 membered hydrocarbon ring includes between one and three heteroatoms.
8. A compound as claimed in claim 6 wherein the 5 or 6 membered hydrocarbon ring to which the optionally substituted aryl is attached is a phenyl ring.
9. A compound as claimed in any of claims 5 to 8 wherein the aryl group, or optionally the ring to which it is fused, is substituted with one or more of halogen,
Cl-6 alkyl or Cl-6 fluoroalkyl.
10. A compound as claimed in claim 1 wherein R is a substituted phenyl group wherein each substitutable carbon atom in R is optionally and independently substituted with one or more Cl-6 alkyl. 11. A compound as claimed in claim 1 wherein the compound is of formula II
Figure imgf000064_0001
12. A compound as claimed in any preceding claim wherein compound is the S- enantiomer or the R-enantiomer.
13. A compound as claimed in claim 1 wherein the compound is selected from the group consisting of
Ethyl 2S,4S-(2-methyl-propane-2-sulfinylamino)-4-phenyl-pent-4-enoate,
Ethyl 2R,4R-(2-methyl-propane-2-sulfinylamino)-4-phenyl-pent-4-enoate,
Ethyl 2S,4S-(2-methyl-propane-2-sulfmylamino)-4-thiophen-2-yl-pent-4-enoate,
Ethyl 2R,4R-(2-methyl-propane-2-sulfinylamino)-4-thiophen-2-yl-pent-4-enoate,
Ethyl 2S,4S-(3 -methoxy-phenyl)-2-(2-methyl-propane-2-sulfinylamino)-pent- 4-enoate,
Ethyl 2R,4R-(3-methoxy-phenyl)-2-(2-methyl-propane-2-sulfinylamino)-pent- 4-enoate, Ethyl 2S,4S-(2-methyl-propane-2-sulfinylamino)-4-ρyrazin-2-yl-pent-4-enoate,
Ethyl 2R,4R-(2-methyl-propane-2-sulfinylamino)-4-pyrazin-2-yl-pent-4-enoate,
Ethyl 2S,4S-(354-dichloro-phenyl)-2-(2-methyl-propane-2-sulfinylamino)-pent- 4-enoate,
Ethyl 2R,4R-(3,4-dichloro-phenyl)-2-(2-methyl-propane-2-sulfinylamino)-pent- 4-enoate,
Ethyl 2S,4S-(6-chloro-pyridin-2-yl)-2-(2-niethyl-propane-2-sulfinylamino)-pent- 4-enoate,
Ethyl 2R,4R-(6-chloro-pyridin-2-yl)-2-(2-niethyl-propane-2-sulfinylamino)-pent- 4-enoate,
Ethyl 2S,4S-(3,5-bis-trifluoromethyl-phenyl)-2-(2-methyl-propane-2-sulfinylamino)- pent-4-enoate,
Ethyl 2R,4R-(3 ,5-bis-trifluoromethyl-phenyl)-2-(2-methyl-propane-2-sulfmylaπώio)- pent-4-enoate,
Ethyl 2S,4S-(2-methyl-propane-2-sulfinylamino)-4-p-tolyl-pent-4-enoate,
Ethyl 2R,4R-(2-methyl-propane-2-sulfinylamino)-4-j?-tolyl-pent-4-enoate,
Ethyl 2S,4S-(2-methyl-propane-2-sulfinylamino)- 4-(4-trifluoromethyl-phenyl)-pent- 4-enoate,
Ethyl 2R,4R-(2-methyl-propane-2-sulfϊnylamino)- 4-(4-trifluoromethyl-phenyl)-pent- 4-enoate, Ethyl 2S,4S-(2-methyl-propane-2-sulfinylamino)- 4-(4-pyrrol- 1 -yl-phenyl)-pent- 4-enoate,
Ethyl 2R,4R-(2-methyl-propane-2-sulfinylatnino)- 4-(4-pyrrol- 1 -yl-phenyl)-pent- 4-enoate,
Ethyl 2R,4R,5S (l-benzenesulfonyl-3-methylene-2,3-dihydro-lH-indol-2-yl)-(2- methyl-propane-2-sulfinylamino)-acetate,
Ethyl 2S,4S,5R (l-benzenesulfonyl-3-methylene-2,3-dihydro-lH-indol-2-yl)-(2- methyl-propane-2-sulfinylamino)-acetate,
Ethyl 2S,4S,5R (3-methylene-2,3-dihydro-benzofuran-2-yl)-(2-methyl-propane-2- sulfinylamino)-acetate,
Ethyl 2R,4R,5S (3-methylene-2,3-dihydro-benzofttran-2-yl)-(2-methyl-propane-2- sulfinylamino)-acetate,
2-(S)-2-Amino-4-phenyl-pent-4-enoic acid,
2-(R)-2-Amino-4-phenyl-pent-4-enoic acid,
2-(S)-2-Amino-4-p-tolyl-pent-4-enoic acid,
2-(R)-2-Amino-4-p-tolyl-pent-4-enoic acid,
2-(S)-2-Amino-4-(3 ,4-dichloro-phenyl)-pent-4-enoic acid,
2-(R)-2- Amino-4-(3 ,4-dichloro-phenyl)-pent-4-enoic acid,
2-(S)-2-Amino-4-(4-trifluoromethyl-phenyl)-pent-4-enoic acid, 2-(R)-2-Amino-4-(4-trifluorometliyl-phenyl)-pent-4-enoic acid,
2-(S)-2-Amino-4-(3 -methoxy-phenyl)-pent-4-enoic acid,
2-(R)-2-Amino-4-(3-methoxy-phenyl)-pent-4-enoic acid,
2-(S)-2-Amino-4-(355-bis-txifluorometliyl-phenyl)-pent-4-enoic acid,
2-(R)-2-Amino-4-(3,5-bis-trifluoromethyl-plienyl)-pent-4-enoic acid,
2-(S)-2-Amino-4-(6-chloro-pyridin-2-yl)-pent-4-enoic acid,
2-(R)-2-Amino-4-(6-chloro-pyridin-2-yl)-pent-4-enoic acid,
Ethyl 2S,4S-(2-methyl-propane-2-sulfinylamino)-4-pyrazin-2-yl-pent-4-enoate,
Ethyl 2R,4R-(2-methyl-propane-2-sulfinylamino)-4-pyrazin-2-yl-pent-4-enoate,
2S-2-Amino-4-pyrazin-2-yl-pent-4-enoic acid,
2R-2-Amino-4-pyrazin-2-yl-pent-4-enoic acid,
Ethyl 2S,4S-biphenyl-4-yl-2-(2-methyl-propane-2-sulfinylamino)-pent-4-enoate,
Ethyl 2R,4R-biphenyl-4-yl-2-(2-methyl-propane-2-sulfinylamino)-pent-4-enoate,
2S-Amino-4-biphenyl-4-yl-pent-4-enoic acid,
2R-Amino-4-biphenyl-4-yl-pent-4-enoic acid, Ethyl 2S,4S-(1 ,3-dimethyl-2,4-dioxo-l ,23,44etrahydro-pyrimidin-5-yl)-2-(2-methyl- propane-2-sulfmylamino)-pent-4-enoate,
Ethyl 2R,4R-(l,3-dimethyl-2;4-dioxo-l,2354-tetrahydro-pyrimidin-5-yl)-2-(2- methyl-propane-2-sulfinylamino)-pent-4-enoate,
2S-Amino-4-(l,3-dimethyl-2,4-dioxo-l,23,4-tetrahydro-pyrimidin-5-yl)-pent-4- enoic acid,
2R-Amino-4-(l,3-dimethyl-2,4-dioxo-l,2,3,4-tetrahydro-pyrimidin-5-yl)-pent-4- enoic acid,
Ethyl 2S,4S-methyl-2-(2-methyl-propane-2-sulfinylamino)-4-phenyl-pent-4-enoate,
Ethyl 2R,4R-methyl-2-(2-methyl-propane-2-sulfinylamino)-4-phenyl-pent-4-enoate,
2S-Amino-2-methyl-4-phenyl-pent-4-enoic acid,
2R-Amino-2-methyl-4-phenyl-pent-4-enoic acid,
Ethyl 2S,4S-3,3-dimethyl-2-(2-methyl-propane-2-sulfinylamino)-4-phenyl-pent-4- enoate,
Ethyl 2R,4R-3,3-dimethyl-2-(2-methyl-propane-2-sulfinylamino)-4-phenyl-pent-4- enoate,
2S-Amino-3 ,3 -dimethyl-4-phenyl-pent-4-enoic acid,
2R- Amino-3 ,3 -dimethyl-4-phenyl-pent-4-enoic acid,
Ethyl 2S,4S-3-cyclohexyl-2-(2-methyl-propane-2-sulfinylamino)-4-phenyl-pent-4- enoate, Ethyl 2R,4R-3-cyclohexyl-2-(2-methyl-propane-2-sulfmylaniino)-4-phenyl-pent-4- enoate,
2S-Amino-3-cyclohexyl-4-phenyl-pent-4-enoic acid and
2R-Amino-3 -cyclohexyl-4-phenyl-pent-4-enoic acid
2S,3R-2-Amino-(3-methylene-2,3-dihydro-benzofuran-2-yl)-acetic acid
2R,3S-2-Amino-(3-methylene-2,3-dihydro-benzofuran-2-yl)-acetic acid
2S3R-2-Amino-(l-benzenesulfonyl-3-methylene-2,3-dihydro-lH'-indol-2-yl)-acetic acid
2R,3S-2-Amino-(l-benzenesulfonyl-3-methylene-2,3-dihydro-lH-indol-2-yl)-acetic acid
Ethyl (S)-((R)-3-methylene-2,3-dihydro-benzofuran-2-yl)-((S)-2-metliyl-ρropane-2- sulfinylamino) acetate
Ethyl (R)-((S)-3-methylene-2,3-dihydro-benzofuran-2-yl)-((R)-2-methyl-propane-2- sulfinylamino) acetate
Ethyl (S)-((R)-l-benzenesulfonyl-3-methylene-2,3-dihydro-lH-indol-2-yl)-((S)-2- methyl-propane-2-sulfinylamino) acetate
Ethyl (R)-((S)-l-benzenesulfonyl-3-methylene-2,3-dihydro-lH-indol-2-yl)-((R)-2- methyl-propane-2-sulfinylamino) acetate
Ethyl (S)-((R)-4-methylene-isochroman-3 -yl)-((S)-2-methyl-propane-2-sulfinyl amino) acetate Ethyl (R)-((S)-4-methylene-isochroman-3-yl)-((R)-2-methyl-propane-2-svilfinyl amino) acetate
Ethyl (S)-((R)-2-methyl-4-methylene- 1 -oxo- 1 ,2,3 ,4-tetrahydro-isoquinolin-3 -yl)-((S)- 2-methyl-propane-2-sulfinylamino) acetate
Ethyl (R)-((S)-2-methyl-4-methylene- 1 -oxo- 1 ,2,3 ,4-tetrahydro-isoquinolin-3 -yl)-((R) -2-methyl-propane-2-sulfinylamino) acetate
Ethyl (S)-4-benzofuran-(3E)-ylidenemethyl-2-((S)-2-methyl-propane-2-sulfinyl amino)-pent-4-enoate
E1iiyl (R)-4-benzofuran-(3E)-ylidenemethyl-2-((R)-2-methyl-propane-2-sulfinyl amino)-pent-4-enoate
Ethyl (R)-4-[l-benzenesulfonyl-l,2-dihydro-indol-(3E)-ylidenemethyl]-2-((R)-2- methyl-propane-2-sulfinylamino) pent-4-enoate
Ethyl (R)-4-isochroman-(4E)-ylidenemethyl-2-((R)-2-methyl-propane-2-sulfinyl aniino)-pent-4-enoate
Ethyl 2R,4R-4-[2-Methyl-l-oxo-2,3-dihydro-lH-isoquinolin-(4E)-ylidenemethyl]-2- (2-methyl-propane-2-sulfinylamino)-pent-4-enoate
Ethyl (R)-amino-((S)-4-methylene-isochroman-3-yl)-acetic acetate
(R)-Amino-((S)-4-methylene-isochroman-3-yl)-acetic acid
Ethyl methyl-2-((R)-2-methyl-propane-2-sulfinylamino)-4-phenyl-pent-4-enoate
15. A compound as claimed in any preceding claim for use in medicine. 16. A compound as claimed in any of claims 1 to 15 for use in agriculture.
17. A process for the manufacture of a compound of formula I which comprises reacting the following compounds in the presence of a catalyst:
i) a compound selected from a) a compound of formula R-X wherein R is an optionally substituted alkenyl, alkynyl or cyclic group wherein each substitutable carbon atom in R is optionally and independently substituted with one or more of halogen, Cl- 12 alkyl, C 1-6 fluoroalkyl, cycloalkenyl, cycloheteroalkenyl, heterocyclyl, aiyl, alkylOR14, CN, COOR14, COR14, NO2, OR14, SR14, NR14 2, CONR14 2, SOOR14, SONR14, SOR14, SOONR14, NR14COR14, NR14CONR14 2, NR14COR14, NR14COOR14, NR14SOOR14 wherein R14 is H, Cl-6 alkyl or Cl- 6 fluroalkyl; and X is halide or triflate;
b) a compound of formula (VI) wherein R16 and R17, one or both of which may be absent, are H, alkyl (C 1-8), aryl, heteroaryl, cycloalkenyl, cycloheteralkenyl and wherein R1 and R 7 are optionally joined together to form an optionally substituted cyclic compound of ring size C3-C8 including aryl, heteroaryl, cycloalkenyl or cycloheteroalkenyl; R18 and R19 are O, S, CO, CS, NR23, CR23R23, NNR23 2, NOR23, R23NNCOR23, R23NNCO2R23 or NNSO2R23 wherein R23 is H or optionally substituted Cl-8 alkyl, halogen, Cl-6 haloalkyl, carbocyclyl or heterocyclyl and wherein n is an integer between O and 6; R20 is optionally substituted alkenyl or alkynyl wherein each substitutable carbon atom in R20 may be optionally and independently substituted with one or more of H, alkyl, alkylaryl, alkylheteroaryl, aryl, heteroaryl or CR24R24 wherein R24, which may be absent, is H, aryl or heteroaryl; or
Figure imgf000072_0001
c) a compound of formula (VII) wherein R16 and R17 , one or both of which may be absent, are H, C 1-8 alkyl, aryl, heteroaryl, cycloalkenyl or cycloheteralkenyl and wherein R and R17 are optionally joined together to form an optionally substituted cyclic compound of ring size C3-C8 including an aryl, heteroaryl, cycloalkenyl or cycloheteroalkenyl cyclic group; R18 and R19 are O, S, CO, CS, NR23, CR23R23, NNR23 2, NOR23, R23NNCOR23, R23NNCO2R23, NNSO2R23 wherein R23 is H or optionally substituted Cl -8 alkyl, halogen, C 1-6 haloalkyl, carbocyclyl or heterocyclyl and wherein n is an integer between 0 and 6; R20 is C; R21 is CR24R24 wherein R24 is H, aryl or heteroaryl;
R21
Figure imgf000072_0002
ii) where compound (i) above is (a) or (b) only, allene gas or a substituted allene; and iii) an α-iminoester derivative of formula (V)
Figure imgf000072_0003
wherein R is as defined herein; and wherein when R is a chiral auxiliary group, Y is a protecting group; wherein when R15 is H or optionally substituted C 1-8 alkyl, aryl, heteroaryl, cycloalkyl, Y is a chiral auxiliary group; v.) optionally removing R15 and/or Y to obtain a compound of Formula I.
18. A process as claimed in claim 17 wherein the process comprises reacting a compound of formula R-X (as in (a) above) with allene gas or a substituted allene and an α-iminoester derivative of formula (V) in the presence of a catalyst.
19. A process as claimed in claim 18 wherein the α-iminoester is a sulphinylimino ester.
20. A process as claimed in claim 18 or 19 wherein the catalyst is a palladium catalyst combined with indium.
21. A process for preparing a compound of formula II as claimed in claim 11 which process comprises reacting a compound of formula I with a compound of formula IV wherein R is H and wherein R and R are joined together to form a cyclic compound of ring size C3-C8 to form a dipeptide followed by cyclisation of the dipeptide to provide a compound of formula II.
Figure imgf000073_0001
22. A pharmaceutical, nutraceutical or agrochemical agent comprising one or more compounds as claimed in any of claims 1 to 14.
23. An agent as claimed in claim 23 wherein the agent is a peptide, peptidomimetic, amino acid or amino acid analog. 24. A pharmaceutical, nutraceutical or agrochemical composition comprising one or more compounds as claimed in any of claims 1 to 14 and a pharmaceutically, nutraceutically or agrochemically acceptable carrier.
25. A peptide or protein comprising a residue of a compound as claimed in claim 1 wherein the residue is of formula (X)
Figure imgf000074_0001
wherein
R is an optionally substituted alkenyl, alkynyl or cyclic group wherein each substitutable carbon atom in R is optionally and independently substituted with one or more of halogen, Cl -12 alkyl, C 1-6 fluoroalkyl, cycloalkenyl, cycloheteroalkenyl, heterocyclyl, aryl, alkylOR14, CN, COOR14, COR14, NO2, OR14, SR14, NR14 2, CONR14 2, SOOR14, SONR14, SOR14, SOONR14, NR14COR14, NR14CONR14 2, NR14COR14, NR14COOR14, NR14SOOR14 wherein R14 is H, Cl-6 alkyl or Cl-6 fluroalkyl;
R3 is H or optionally substituted alkyl (C 1-8), alkylaryl, aryl, alkylheteroaryl or heteroaryl;
R4 and R5 are H, alkyl (C 1-8), aryl, heteroaryl, vinyl, amide, ester, alkyl (C1-C8) amide or alkyl (C1-C8) ester and wherein R4 and/or R5 are optionally joined together or to R to form an optionally substituted cyclic optionally fused to one or more 5 or 6 membered hydrocarbon rings; R6 , which may be absent, is H, optionally substituted alkyl, aryl or heteroaryl.
PCT/GB2005/003546 2004-09-16 2005-09-14 Amino acid WO2006030208A1 (en)

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