Kinetic Resolution Procedure Research Articles

Isothiourea-Catalyzed Acylative Kinetic Resolution of Tertiary α-Hydroxy Esters.

A highly enantioselective isothiourea‐catalyzed acylative kinetic resolution (KR) of acyclic tertiary alcohols has been developed. Selectivity factors of up to 200 were achieved for the KR of tertiary alcohols bearing an adjacent ester substituent, with both reaction conversion and enantioselectivity found to be sensitive to the steric and electronic environment at the stereogenic tertiary carbinol centre. For more sterically congested alcohols, the use of a recently‐developed isoselenourea catalyst was optimal, with equivalent enantioselectivity but higher conversion achieved in comparison to the isothiourea HyperBTM. Diastereomeric acylation transition state models are proposed to rationalize the origins of enantiodiscrimination in this process. This KR procedure was also translated to a continuous‐flow process using a polymer‐supported variant of the catalyst.

Isothiourea‐Catalyzed Acylative Kinetic Resolution of Tertiary α‐Hydroxy Esters

AbstractA highly enantioselective isothiourea‐catalyzed acylative kinetic resolution (KR) of acyclic tertiary alcohols has been developed. Selectivity factors of up to 200 were achieved for the KR of tertiary alcohols bearing an adjacent ester substituent, with both reaction conversion and enantioselectivity found to be sensitive to the steric and electronic environment at the stereogenic tertiary carbinol centre. For more sterically congested alcohols, the use of a recently‐developed isoselenourea catalyst was optimal, with equivalent enantioselectivity but higher conversion achieved in comparison to the isothiourea HyperBTM. Diastereomeric acylation transition state models are proposed to rationalize the origins of enantiodiscrimination in this process. This KR procedure was also translated to a continuous‐flow process using a polymer‐supported variant of the catalyst.

ChemInform Abstract: Kinetic Resolution of 2‐Hydroxy‐2‐aryl‐ethylphosphonates by a Non‐enzymatic Acylation Catalyst.

Optically pure hydroxyphosphonates are widely used as derivatizable compounds that can be incorporated into a variety of synthetic strategies for the preparation of other high value organic products. A non-enzymatic kinetic resolution procedure to obtain chiral 2-hydroxy-2-arylethylphosphonates from the easily available racemic counterparts is described. A range of 2-hydroxy-2-arylethylphosphonates was efficiently resolved employing a planar-chiral DMAP derived catalyst with good selectivities (up to S=68). The chiral hydroxyphosphonates were isolated in good yields and high enantiomeric excess (>94% ee).

Kinetic resolution of 2-hydroxy-2-aryl-ethylphosphonates by a non-enzymatic acylation catalyst

Optically pure hydroxyphosphonates are widely used as derivatizable compounds that can be incorporated into a variety of synthetic strategies for the preparation of other high value organic products. A non-enzymatic kinetic resolution procedure to obtain chiral 2-hydroxy-2-arylethylphosphonates from the easily available racemic counterparts is described. A range of 2-hydroxy-2-arylethylphosphonates was efficiently resolved employing a planar-chiral DMAP derived catalyst with good selectivities (up to S=68). The chiral hydroxyphosphonates were isolated in good yields and high enantiomeric excess (>94% ee).

ChemInform Abstract: Enantioselective Synthesis of 4‐Heterosubstituted Cyclopentenones.

AbstractA highly effective palladium‐catalyzed kinetic resolution procedure via nucleophilic allylic substitutions is presented.

Non-enzymatic kinetic resolution of 1,2-azidoalcohols using a planar-chiral DMAP derivative catalyst

Optically pure 1,2-azidoalcohols are widely used as precursors for other high value organic products. A non-enzymatic kinetic resolution procedure for the stereoselective synthesis of chiral 1,2-azidoalcohols from the readily available racemic counterparts has been developed, employing a planar-chiral DMAP derivative catalyst. Following this procedure, a range of aromatic 1,2-azidoalcohols was obtained in good selectivities (up to S=45) and high enantiomeric excess (up to 99% ee).

ChemInform Abstract: Rhodium‐Catalyzed Enantioselective Intermolecular Hydroacylation Reactions

AbstractReview: 55 refs.

Rhodium-catalyzed enantioselective intermolecular hydroacylation reactions

Rhodium-catalyzed enantioselective hydroacylation reactions allow rapid access to chiral substituted ketones. However, due to the low reactivity of disubstituted alkenes in intermolecular versions of this process, only a small number of asymmetric intermolecular reactions have been described. Strategies employed to avoid reactivity issues include the use of norbornadienes, linear dienes, acrylamides, and allenes as the alkene components. In addition, our laboratory has recently reported the rhodium-catalyzed enantioselective inter-molecular alkyne hydroacylation reaction, leading to the formation of enone products via a kinetic resolution procedure.

ChemInform Abstract: Rhodium‐Catalyzed Intermolecular Alkyne Hydroacylation: The Enantioselective Synthesis of α‐ and β‐Substituted Ketones by Kinetic Resolution.

AbstractThe Rh‐catalyzed asymmetric addition of α‐ (VII) or β‐substituted S‐chelating aldehydes (I), (V) towards terminal alkynes (II) is successfully used as kinetic resolution procedure to afford the corresponding α‐ and β‐substituted enones in up to 90% optical purity.

Rhodium‐Catalysed Intermolecular Alkyne Hydroacylation: The Enantioselective Synthesis of α‐ and β‐Substituted Ketones by Kinetic Resolution

Cleared up! Intermolecular alkyne hydroacylation represents a new addition to the range of transition-metal-catalysed hydroacylation reactions that can be performed in an enantioselective manner. By using a kinetic resolution procedure, both racemic α- and β-substituted aldehydes can be converted into the corresponding enantiomerically enriched substituted enone products (see scheme).

Chemoenzymatic Synthesis of Rivastigmine Based on Lipase-Catalyzed Processes

A straightforward chemoenzymatic synthesis of enantiomerically pure rivastigmine has been efficiently carried out under mild reaction conditions, with Candida antarctica lipase B responsible for the stereoselective acetylation of the corresponding (R)-alcohol or amine. An exhaustive enzymatic study has been developed exploring the possibilities of carry out enzyme recycling, scaling up the enzymatic process and development of a dynamic kinetic resolution procedure for the production of adequate enantiomerically pure precursors of rivastigmine. Total chemoenzymatic synthesis of this pharmaceutical has been performed in good overall yield from commercially available 3-methoxyacetophenone.

Titanium‐Salan‐Catalyzed Asymmetric Oxidation of Sulfides and Kinetic Resolution of Sulfoxides with H2O2 as the Oxidant

AbstractAsymmetric oxidation of sufides to sulfoxides by aqueous hydrogen peroxide with catalysis by titanium‐salan complexes is presented. Optically active sulfoxides have been obtained with good to high enantioselectivities (up to 97 % ee) by a tandem enantioselective oxidation and kinetic resolution procedure, the catalyst performing over 500 turnovers with no loss of enantioselectivity.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

Convenient total synthesis of taranabant (MK-0364), a novel cannabinoid-1 receptor inverse agonist as an anti-obesity agent

Being obese has various health problems that are related to type 2 diabetes mellitus, cardiovascular disease, hypertension, hyperlipidemia, and fibrinolytic abnormalities. Merck's taranabant (MK-0364), a CB1R inverse agonist, is currently in Phase 3 clinical trials, and is being actively pursued by Merck toward obesity market. Merck intends to file for FDA approval of taranabant in 2008. In order to overcome practical difficulty involved in lab-scale preparation of taranabant with a dynamic kinetic resolution procedure developed by Merck's process group, we developed a ‘user-friendly’ method to install stereogenic centers by adopting Evans asymmetry chemistry. This method allowed us to prepare readily sub-gram scale of the target compound in a convenient way.

Differentiation of hydroxyl-aluminum species at lower OH/Al ratios by combination of 27Al NMR and Ferron assay improved with kinetic resolution

The hydroxyl-Al polymers are the most effective components in PACl coagulants, but their chemical speciation is often indistinct especially at lower molar OH/Al ratios ( B). Two sets of hydroxyl-Al solutions with different B values and preparation temperatures were studied with both Ferron assay and 27Al NMR spectroscopy. By using the modified kinetic resolution procedure to fit the scanning absorbance data, the reactive polymeric Al species (Al b) could be differentiated further into two fractions: the faster reacting polymers Al b1 and slower reacting polymers Al b2. They were distinguished by their distinct rate constants of reactions with Ferron. It was identified simultaneously by the 27Al NMR spectroscopy that the Al b2 fraction closely corresponded to Al 13 of Keggin-structure in most samples, while the Al b1 at the moderate OH/Al ratios of B < 2 would be assigned to the species of Al 6-type series which were undetectable in current 27Al NMR spectrum (Al un). Conventional 27Al NMR spectroscopy in combination with Ferron assay improved with kinetic resolution can better explore the chemical speciation for hydroxyl-Al polymers in partially neutralized Al solutions and thus give a better explanation of coagulation mechanisms of these species when they were applied in water treatment.

Lipase-promoted dynamic kinetic resolution of racemic β-hydroxyalkyl sulfones

A series of racemic aryl β-hydroxyalkyl sulfones have been successfully transformed into the corresponding optically active O-acetyl derivatives in high yields (up to 80%) with enantiomeric excesses more than 99% using a dynamic kinetic resolution procedure, in which a lipase-promoted kinetic resolution is combined with a concomitant ruthenium-catalysed racemization of the substrates.

Asymmetric synthesis and Lewis acid mediated type II carbonyl ene cyclisations of ( R)-2-isopropyl-5-methylhex-5-enal

The asymmetric synthesis of ( R)-2-isopropyl-5-methylhex-5-enal in 98% ee is described. It was discovered that the key alkylation step employing an Evans chiral auxiliary and 3-methylbut-3-en-1-yl trifluoromethanesulphonate as the alkylating agent led to significant competing O-alkylation, a phenomenon not previously reported. Type II carbonyl ene cyclisation of the aldehyde with a range of Lewis acids led to either the ( R, R)- or ( R, S)-5-methylidenecyclohexanols without concurrent racemisation of the alpha stereogenic centre of the aldehyde. Conditions for effecting the easy racemisation of a model enantiomerically pure aldehyde, ( S)-2-methylbutanal, were developed. In an effort to secure a dynamic kinetic resolution procedure, these conditions were applied to ( R)-2-isopropyl-5-methylhex-5-enal. However, a competing and dominant Prins cyclisation occurred instead leading to a mixture of all possible cycloadducts, all of which were obtained in 98% ee. Any unreacted aldehyde was found to be enantiomerically pure.

A convenient resolution of long-chain alkyl epoxides with Jacobsen's salen(Co)III(OAc) catalysts

Non-racemic terminal long-chain alkyl epoxides are prepared from racemic epoxides and 1 mol% ( R, R)- and ( S,S)-salen(Co)III catalysts following a modified procedure for kinetic resolution. The ee's for all epoxides (C-10, C-12, C-14, C-16, C-18, C-20) exceed 95% and the chemical yields range from 85% to 95%.

An improved procedure for the lipase-catalysed kinetic resolution of endo- endo- cis-bicyclo[3.3.0]octane-2,6-diol—synthesis of potential C2-symmetric enantiomerically pure bidentate auxiliaries

An improved procedure for the kinetic resolution of endo- endo- cis-bicyclo[3.3.0]octane-2,6-diol rac- 1 ) by transesterification with vinyl acetate catalysed by lipase from Pseudomonas cepacia in an organic solvent which yields both enantiomers with an enantiomeric excess of >95% is described. The configuration at both stereogenic centres bearing hydroxy groups has been inverted by treatment of the corresponding mesylates with caesium acetate in the presence of 18-crown-6 to afford, after deacetylation, the corresponding enantiomerically pure diastereoisomeric exo- exo- cis-diols.

Synthesis and absolute stereochemistry of the two diastereoisomers of P3-1-(2-nitrophenyl)ethyl adenosine triphosphate (‘caged’ ATP)

1 -(2-Nitrophenyl)ethanol was resolved by fractional crystallisation of its diastereoisomeric (1S)-cam-phanates. The absolute stereochemistry of the (S)-alcohol was determined using the Horeau kinetic resolution procedure, and subsequently confirmed by X-ray crystallography of its (1S)-camphanate ester. The resolved alcohols were converted to (R)- and (S)-1-(2-nitrophenyl)ethyl phosphates, each of which was condensed with adenosine diphosphate to give the (R)- and (S)-1-(2-nitro-phenyl)ethyl P3-esters of adenosine triphosphate.

Asymmetric synthesis of α-substituted o-methoxybenzyl alcohols via stereoselective additions to kinetically resolved o-anisaldehyde(tricarbonyl)chromium

Homochiral (+)-o-anisaldehyde(tricarbonyl)chromium, prepared by a kinetic resolution procedure involving selective hydrolysis of the diastereoisomeric L-valinol derived imines, undergoes completely stereoselective addition reactions with methyl- and ethyl-magnesium iodide to give enantiomerically pure (–)-(S)-1-(o-methoxyphenyl)ethanol and (–)-(S)-1-(o-methoxyphenyl)propanol.