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  • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
  • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
  • B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
  • B01J31/2495—Ligands comprising a phosphine-P atom and one or more further complexing phosphorus atoms covered by groups B01J31/1845 - B01J31/1885, e.g. phosphine/phosphinate or phospholyl/phosphonate ligands
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  • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
  • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
  • B01J31/22—Organic complexes
  • B01J31/2282—Unsaturated compounds used as ligands
  • B01J31/2295—Cyclic compounds, e.g. cyclopentadienyls
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  • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
  • C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
  • C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
  • C07C29/143—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of ketones
  • C07C29/145—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of ketones with hydrogen or hydrogen-containing gases
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  • C07C67/00—Preparation of carboxylic acid esters
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  • C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form
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  • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
  • C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
  • C07F15/0046—Ruthenium compounds
  • C07F15/0053—Ruthenium compounds without a metal-carbon linkage
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  • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
  • B01J2231/60—Reduction reactions, e.g. hydrogenation
  • B01J2231/64—Reductions in general of organic substrates, e.g. hydride reductions or hydrogenations
  • B01J2231/641—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes
  • B01J2231/643—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes of R2C=O or R2C=NR (R= C, H)
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  • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
  • B01J2531/02—Compositional aspects of complexes used, e.g. polynuclearity
  • B01J2531/0202—Polynuclearity
  • B01J2531/0205—Bi- or polynuclear complexes, i.e. comprising two or more metal coordination centres, without metal-metal bonds, e.g. Cp(Lx)Zr-imidazole-Zr(Lx)Cp
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  • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
  • B01J2531/80—Complexes comprising metals of Group VIII as the central metal
  • B01J2531/82—Metals of the platinum group
  • B01J2531/821—Ruthenium
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  • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
  • B01J2531/80—Complexes comprising metals of Group VIII as the central metal
  • B01J2531/82—Metals of the platinum group
  • B01J2531/825—Osmium
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  • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
  • B01J2531/80—Complexes comprising metals of Group VIII as the central metal
  • B01J2531/84—Metals of the iron group
  • B01J2531/842—Iron
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  • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
  • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
  • B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
  • B01J31/1845—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms the ligands containing phosphorus
  • B01J31/1875—Phosphinites (R2P(OR), their isomeric phosphine oxides (R3P=O) and RO-substitution derivatives thereof)
  • B01J31/188—Amide derivatives thereof
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  • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
  • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
  • B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
  • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
  • B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
  • B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
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  • C07B2200/09—Geometrical isomers

Definitions

• This invention pertains to certain novel ruthenium complexes of phosphine-aminophosphine ligands and to a process for the preparation thereof.
• the ruthenium complexes may be used to catalyze large number of reactions of a wide variety of substrates such as asymmetric hydrogenations, asymmetric reductions, asymmetric hydroborations, asymmetric olefin isomerizations, asymmetric hydrosilations, asymmetric allylations, and asymmetric organometallic additions.
• Asymmetric catalysis is the most efficient method for generating products with high enantiomeric purity, as the asymmetry of the catalyst is multiplied many times over in generating the chiral product. These chiral products have found numerous applications as building blocks for single enantiomer pharmaceuticals as well as in some agrochemicals.
• the asymmetric catalysts employed can be enzymatic or synthetic in nature. The latter types of catalyst have much greater promise than the former due to much greater latitude of applicable reaction types.
• Synthetic asymmetric catalysts are usually composed of a metal reaction center surrounded by one or more organic ligands. The ligands usually are generated in high enantiomeric purity, and are the agents inducing the asymmetry. These ligands are in general difficult to make and therefore expensive.
• the asymmetric hydrogenation of ⁇ -ketoesters to ⁇ -hydroxyesters has received significant attention, particularly as these products have a number of industrial applications, not the least of which is a synthetic intermediate in the synthesis of atorvastatin.
• the complexes that are used for this type of hydrogenation are largely ruthenium-based, with the most effective catalysts derived from axially chiral ligands such as BINAP. See, for example, Mashima et al. J. Org. Chem. 1994, 59, 3064-3076; and Kitamura, et al., Org. Synth. 1992, 71, 1-13.
• methallyl species are generally prepared using multistep processes with harsh reaction conditions (e.g., strong acid), which may not be compatible with phosphine-aminophosphine ligands.
• One of the simplest preparations of ruthenium complexes is by ligand displacement from commercially available species such as tris(triphenylphosphine)ruthenium dichloride. These preparations have generally involved the reaction of chiral bidentate bis-phosphine ligands with the latter complex and result in ruthenium dichloride complexes containing one chiral bidentate ligand and one (achiral) triphenylphosphine (Mezzetti, A.; Consiglio, G. J. Chem. Soc, Chem.
• ruthenium complex compounds comprising a ruthenium compound having formula 1
• R, R 2 , and R 3 are, independently, substituted or unsubstituted, branched- or straight-chain C 1 -C20 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C6-C 2 o carbocyclic aryl, and substituted or unsubstituted C 4 -C20 heteroaryl having one to three heteroatoms wherein the heteroatoms are selected from sulfur, nitrogen, and oxygen;
• R 1 is substituted or unsubstituted, branched- or straight-chain C 1 -C 2O alkyl, substituted or unsubstituted, branched- or straight-chain CrC 2O alkoxy, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 cycloalkoxy, substituted or unsubstituted C 6 -C 20 carbocyclic aryl, substituted or unsubstituted C 6 -C 2O carbocyclic aryloxy;
• X is fluoride, chloride, bromide, or iodide, and .
• L is a divalent chiral radical selected from substituted or unsubstituted, branched- or straight-chain C 1 -C 2 O alkylene, substituted or unsubstituted C 3 -Cs cycloalkylene, substituted or unsubstituted C 6 -C 20 carbocyclic arylene, substituted or unsubstituted C 4 -C 20 heteroarylene
• heteroatoms having one to three heteroatoms wherein the heteroatoms are selected from sulfur, nitrogen, and oxygen, or substituted or unsubstituted metailocenylmethylene wherein L is substantially enantiomerically pure, i.e., an enantiomeric excess of 90% or greater.
• R 3 is phenyl and (R) 2 P-L-N(R 2 )P(R 1 )2 collectively represent structure 3 or 4 (the enantiomer of 3)
• R, R 1 , and R 2 are as described above;
• R 4 , R 5 , and R 6 are, independently, hydrogen, substituted or unsubstituted, branched- or straight-chain Ci ⁇ C 2 o alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 6 -C 2O carbocyclic aryl, or substituted or unsubstituted C 4 -C 2O heteroaryl having one to three heteroatoms wherein the heteroatoms are selected from sulfur, nitrogen, and oxygen; n is 0 to 3; m is 0 to 5; and M is selected from the metals of Groups IVB, VB, VIB, VIIB and ViII.
• Another embodiment of the present invention is a process for preparing the novel complex compounds which comprises contacting a ruthenium compound having formula 1
• R, R 1 , R 2 , R 3 , L and X are as defined above.
• a further embodiment of the present invention is a process for the asymmetric hydrogenation of a 1 ,3-dicarbonyl compound to produce the corresponding hydroxycarbonyl compound, which comprises contacting the dicarbonyl compound with hydrogen in the presence of a ruthenium complex comprising ruthenium compound 1 and ligand 2.
• the present invention also recites a process for the asymmetric hydrogenation of a hydroxycarbonyl compound to produce the corresponding diol compound which comprises contacting the hydroxycarbonyl compound with hydrogen in the presence of a ruthenium complex comprising ruthenium compound 1 and ligand 2.
• the alkyl groups that may represent each of R, R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 may be straight- or branched-chain aliphatic hydrocarbon radicals containing up to 20 carbon atoms and may be substituted, for example, with one to three groups selected from CrC ⁇ -alkoxy, cyano, C 2 -C 6 - alkoxycarbonyl, C 2 -C 6 -alkanoyloxy, hydroxy, aryl or halogen.
• C-i- C 6 -alkoxy denote radicals corresponding to the structures -OR 7 , -CO 2 R 7 , and -OCOR 7 , respectively, wherein R 7 is Ci-C 6 ⁇ alkyl or substituted C- ⁇ -C 6 -alkyl.
• C 3 - C ⁇ -cycloalkyl denotes a saturated, carbocyclic hydrocarbon radical having three to eight carbon atoms.
• the aryl groups that each of R, R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 represent may include phenyl, naphthyl, or anthracenyl and phenyl, naphthyl, or anthracenyl substituted with one to three substituents selected from Ci-C 6 -alkyl, substituted Ci-C 6 -alkyl, C 6 -Ci 0 aryl, substituted C 6 -Cio aryl, Ci-C 6 -alkoxy, halogen, carboxy, cyano, Ci-C 6 - alkanoyloxy, Ci-C 6 -alkylthio, Ci-C 6 -alkylsulfonyl, trifluoromethyl, hydroxy, C 2 -C 6 -alkoxycarbonyl, C 2 -C 6 -alkanoy (amino or-O-R 8 , S-R 8 -SO 2 -R 8
• the heteroaryl radicals include a 5- or 6- membered aromatic ring containing one to three heteroatoms selected from oxygen, sulfur and nitrogen.
• heteroaryl groups are thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyrimidyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, indolyl and the like.
• the heteroaryl radicals may be substituted, for example, with up to three groups such as Ci-C 6 -alkyl, Ci-C 6 -alkoxy, substituted CrC 6 -alkyI, halogen, CrC 6 - alkylthio, aryl, arylthio, aryloxy, C 2 -C 6 -alkoxycarbonyl or C 2 -Ce- alkanoylamino.
• the heteroaryl radicals also may be substituted with a fused ring system, e.g., a benzo or naphtho residue, which may be unsubstituted or substituted, for example, with up to three of the groups set forth in the preceding sentence.
• the alkoxy groups which may be represented by R 1 may be straight- or branched-chain aliphatic alkoxy radicals containing up to 20 carbon atoms and may be substituted, for example, with one to three groups selected from C- ⁇ -C 6 -alkoxy, cyano, C 2 - C 6 -alkoxycarbonyl, C 2 -C 6 -alkanoyloxy, aryl and halogen.
• Ci-C 6 - alkoxy "C 2 -C 6 -a!koxycarbonyr, and "C 2 -C 6 -alkanoyloxy” are used to denote radicals corresponding to the structures -OR 7 , -CO 2 R 7 , and -OCOR 7 , respectively, wherein R 7 is Ci-C 6 -alkyl or substituted Ci-C 6 -alkyl.
• C 3 - Cs-cycloalkoxy denotes a saturated, carbocyclic alkoxy radical having three to eight carbon atoms.
• the aryioxy groups that R 1 represent may include phenoxy, naphthyloxy, or anthracenyloxy and phenyloxy, naphthyloxy, or anthracenyloxy substituted with one to three substituents selected from Ci-C 6 -alkyl, substituted Ci-C 6 -alkyl, C 6 -C 10 aryl, substituted C 6 -Ci 0 aryl, Ci-C 6 -a!koxy, halogen, carboxy, cyano, CrC 6 - alkanoyloxy, Ci-C 6 -alkylthio, Ci-C 6 -alkylsuifonyl, trifluoromethyl, C 2 -C 6 - alkoxycarbonyl, C 2 -C 6 -alkanoylamino or -O-R 8
• R 3 is phenyl, X is chloride, and the substructure R 2 P-L-N(R 2 )PR 1 2 collectively represent a group 3 or 4 wherein R is aryl, most preferably phenyl; R 1 is aryl, C 2 -C 6 alkyl, or C 3 -C- 6 cycloalkyl, preferably phenyl, 3-fluorophenyl, 3,4- difluorophenyl, 4-fluorophenyl, 3,5-difluorophenyl, or 3,4-dichlorophenyl, most preferably 3,4-difluorophenyl; R 2 is hydrogen, Ci-C 6 alkyl, or aryl, most preferably methyl; R 4 is hydrogen or Ci to C 6 alkyl, most preferably methyl; R 5 and R
• the complex compounds provided by our invention may be prepared by contacting a ruthenium complex of formula having formula 1
• the complex compound product may be isolated by standard methods known to those in the art such as crystallization or precipitation.
• ruthenium compound 1 is contacted with phosphine-aminophosphine 3 or 4.
• the amount of ligand 3 or 4 used may be 1 to 5 moles, preferably 1 to 1.5 moles, per mole of ruthenium compound 1.
• the process is carried out in an inert solvent.
• suitable solvents include halocarbon solvents such as dichloromethane, tetrachloroethylene, and chlorobenzene; dipolar aprotic solvents such as acetonitrile, dimethylformamide, and dimethylsulfoxide; cyclic or acyclic ether solvents such as diethyl ether, diisopropyl ether, tert-butyl methyl ether and tetrahydrofuran; ketone solvents such as acetone, methyl ethyl ketone, and diethyl ketone; and aromatic hydrocarbons such as benzene, toluene, or xylene, or mixtures thereof.
• the preferred solvents are dichloromethane and toluene.
• the process may be carried out at a temperature between -5O 0 C and the boiling point of the solvent, preferably 20° to 4O 0 C.
• the ruthenium complex product may be isolated by conventional procedures such as crystallization or distillation.
• the preferred method of isolation is to precipitate the complex by adding a liquid in which the ruthenium complex is insoluble or substantially insoluble.
• non-solvent liquids include water, C 3 to C ⁇ alkanols such as n-propanol, isopropanol, n-butanol, tert-butanol, n-pentanol or n-hexanol, and aliphatic and alicyclic hydrocarbons such as hexane, heptane, and cyclohexane, optionally followed by distillative removal of the solvent from the mixture.
• the preferred non-solvents are isopropanol and heptane.
• the present invention also provides a process for the asymmetric hydrogenation of a 1 ,3-dicarbonyl compound containing from 5 to 20 carbon atoms to produce the corresponding hydroxycarbonyl compound, which comprises contacting the dicarbonyl compound with hydrogen in the presence of at least one of the ruthenium complex compounds of our invention.
• the hydrogenation reaction results in the formation of a chiral 3- hydroxycarbonyl compound, which is generally obtained in high enantiomeric excess.
• the hydrogenation process typically is carried out in the presence of an inert organic solvent.
• suitable solvents include lower alcohols such as methanol, ethanoi, and isopropanol; aliphatic hydrocarbons such as hexane, heptane, octane and the like; aromatic hydrocarbons such as toluene, xylenes, and the like; cyclic or acyclic ethers such as tert-butyl methyl ether, diisopropyl ether, tetrahydrofuran and the like; halogenated aliphatic or aromatic hydrocarbons such as dichloromethane, tetrachloroethylene, chloroform, chlorobenzene and the like; and polar aprotic solvents such as dimethylformamide, dimethyl sulfoxide and the like.
• Preferred solvents include methanol or ethanoi.
• the present invention also provides a process for the asymmetric hydrogenation of an ⁇ -hydroxycarbonyl compound containing from 3 to 20 carbon atoms to produce the corresponding 1 ,2-diol compound, which comprises contacting the hydroxycarbonyl compound with hydrogen in the presence of at least one of the ruthenium complex compounds described above.
• the hydrogenation reaction results in the formation of a chiral 1 ,2- diol compound, which is generally obtained in high enantiomeric excess.
• the hydrogenation process typically is carried out in the presence of an inert organic solvent.
• suitable solvents include lower alcohols such as methanol, ethanoi, and isopropanol; aliphatic hydrocarbons such as hexane, heptane, octane and the like; aromatic hydrocarbons such as toluene, xylenes, and the like; cyclic or acyclic ethers such as tert-butyl methyl ether, diisopropyl ether, tetrahydrofuran and the like; halogenated aliphatic or aromatic hydrocarbons such as dichloromethane, tetrachloro- ethylene, chloroform, chlorobenzene and the like; and polar aprotic solvents such as dimethylformamide, dimethyl sulfoxide and the like.
• lower alcohols such as methanol, ethanoi, and isopropanol
• aliphatic hydrocarbons such as hexane, heptane, octane and the like
• Preferred solvents include methanol or ethanol.
• the present invention also provides a process for the asymmetric hydrogenation of a ⁇ -hydroxycarbonyl compound containing from 4 to 20 carbon atoms to produce the corresponding 1,3-diol compound, which comprises contacting the ⁇ -hydroxycarbonyl compound with hydrogen in the presence of at least one of the ruthenium complex compounds described above.
• the hydrogenation reaction results in the formation of a chiral 1 ,3-diol compound, which is generally obtained in high enantiomeric excess.
• the hydrogenation process typically is carried out in the presence of an inert organic solvent.
• suitable solvents include lower alcohols such as methanol, ethanol, and isopropanol; aliphatic hydrocarbons such as hexane, heptane, octane and the like; aromatic hydrocarbons such as toluene, xylenes, and the like; cyclic or acyclic ethers such as tert-butyl methyl ether, diisopropyl ether, tetrahydrofuran and the like; halogenated aliphatic or aromatic hydrocarbons such as dichloromethane, tetrachloroethylene, chloroform, chlorobenzene and the like; and polar aprotic solvents such as dimethylformamide, dimethyl sulfoxide and the like.
• Preferred solvents include methanol or ethanol.
• the hydrogenation processes are carried out at elevated pressures by contacting a dicarbonyl or hydroxycarbonyl compound with hydrogen in the presence of a catalytic amount of at least one of the ruthenium complex compounds described above.
• the amount of ruthenium complex compound used may vary between 0.00005 and 0.5 equivalents based on the reactant compound, with more complex usually providing faster reaction rates.
• the hydrogen atmosphere may be pure hydrogen or hydrogen mixed with one or more inert gases.
• the process typically is carried out at hydrogen pressures of 0.07 to 137.9 bars gauge - barg (1-2000 pounds per square inch gauge - psig), preferably between 3.45 and 69 barg (50- 1000 psig).
• the process normally is operated at a temperature which affords a reasonable rate of conversion, which may be as low as -50°C but is usually between ambient temperature and the boiling point (or apparent boiling point at elevated pressure) of the lowest boiling component of the reaction mixture.
• the ruthenium complex compounds of the present invention also may be used to catalyze other reactions such as asymmetric reductions, asymmetric hydroborations, asymmetric olefin isomerizations, asymmetric hydrosilations, asymmetric allylations, and asymmetric organometallic additions employing a variety of reactants.
• soiid was collected by filtration, washed with isopropanol, and dried under vacuum with a nitrogen sweep to afford 303 mg (82%) of 5A-k.
• reaction mixture was pressurized with argon and vented five times and then pressurized to 20.7 barg (300 psig) with hydrogen and stirred at ambient temperature for 6 hours.
• the vessel was vented, then pressurized with argon and vented five times, and the solution was assayed by chiral GC to indicate 100% conversion to methyl (R)-3-hydroxybutyrate with 89.5% ee.
• the vessel was vented, then pressurized with argon and vented five times, and the solution was assayed by chiral GC to indicate 86.2% conversion to ethyl (R)-3-hydroxybutyrate with 87.6% ee.
• the vessel was vented, then pressurized with argon and vented five times, and the solution was assayed by chiral GC to indicate 84.8% conversion to ethyl (R)-3-hydroxybutyrate with 71.6% ee.
• the vessel was vented, then pressurized with argon and vented five times, and the solution was assayed by 1 H NMR to indicate 99% conversion to ethyl (S)-3- hydroxy-3-phenylpropionate with 94.9% ee by chiral HPLC.
• the vessel was vented, then pressurized with argon and vented five times, and the solution was assayed by chiral GC to indicate 59.2% conversion to ethyl (R)-3-hydroxybutyrate with 94.0% ee.
• the vessel was vented, then pressurized with argon and vented five times, and the solution was assayed by 1 H NMR to indicate 87% conversion to ethyl (S)-3- hydroxy-3-phenylpropionate with 91.3% ee by chiral HPLC.
• the vessel was vented, then pressurized with argon and vented five times, and the solution was assayed by chiral GC to indicate 98.8% conversion to methyl (R)-3-hydroxypentanoate with 91.9% ee.
• the vessel was vented, then pressurized with argon and vented five times, and the solution was assayed by chiral GC to indicate 99.8% conversion to ethyl (R)-3-hydroxybutyrate with 92.7% ee.
• the vessel was vented, then pressurized with argon and vented five times, and the solution was assayed by 1 H NMR to indicate 99% conversion to ethyl (S)-3- hydroxy-3-phenylpropionate with 80.2% ee by chiral HPLC.

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