Kinetic Resolution Conditions Research Articles

Towards Chemoenzymatic Syntheses of Both Enantiomers of Phosphoemeriamine.

An enzyme-promoted addition of nitromethane to the appropriate phosphorylated imine (aza-Henry reaction) intended to be used in the synthesis of the title phosphoemeriamine, a phospha-analog of emeriamine (aminocarnitine), failed due to the tautomerization of the imine to the corresponding enamine. Nevertheless, both enantiomers of phosphoemeriamine were synthesized in high yield and enantiomeric purity using another chemoenzymatic approach, starting with a crucial step involving a CAL-B-mediated acetylation of the appropriate racemic precursor-diethyl 2-amino-3-dimethylaminopropylphosphonate-under kinetic resolution conditions. The enzymatic reaction was very efficient and provided each enantiomeric product in acceptable yield and with enantiomeric excess of 91 and 92%. The following appropriate chemical transformations led to the desired enantiomers of phosphoemeriamine in the form of phosphoemeriamine sesquichloride with enantiomeric excess up to 90%.

Enzymatic Approach to the Synthesis of Enantiomerically Pure Hydroxy Derivatives of 1,3,5-Triaza-7-phosphaadamantane.

A series of enantiomerically pure derivatives of 6-(1-hydroxyalkyl)-1,3,5-triaza-7-phosphatricyclo[3.3.1.1]decane 5 were successfully synthesized for the first time. A series of hydrolytic enzymes was applied in a stereoselective acetylation performed under kinetic resolution conditions. Although the secondary alcohols: α-aryl-hydroxymethyl-PTA (phosphines) 5b–d′, PTA-oxides 8b–d′, and PTA-sulfides 9b–d′ were found to be totally unreactive in the presence of all the enzymes and various conditions applied, the primary alcohols, i.e., the hydroxymethyl derivatives PTA oxide 8a and PTA sulfide 9a, were successfully resolved into enantiomers with moderate to good enantioselectivity (up to 95%). The absolute configurations of the products were determined by an X-ray analysis and chemical correlation.

Asymmetric Transfer Hydrogenation of Arylidene-Substituted Chromanones and Tetralones Catalyzed by Noyori-Ikariya Ru(II) Complexes: One-Pot Reduction of C═C and C═O bonds.

3-Arylidenechroman-4-ones and 2-arylidene-1-tetralones are hydrogenated to cis-benzylic alcohols in dr's and er's up to 99:1 via a C═C and C═O one-pot reduction in the presence of 2-5 mol % Noyori-Ikariya-type RuII chiral complexes and HCO2Na as a hydrogen source under asymmetric transfer hydrogenation-dynamic kinetic resolution (ATH-DKR) conditions. The oxidation of theses substrates resulted in the enantioselective synthesis of the natural homoisoflavanone dihydrobonducellin and its carba-analogues.

Efforts towards a Noyori reduction of a 3-fluorpiperidin-4-one with dynamic kinetic resolution

A Noyori reduction of racemic 1-Boc-3-fluoropiperidin-4-one has been achieved under dynamic kinetic resolution conditions that results in a single cis enantiomer being obtained with both diastereo- and enantioselectivity > 90%. This medicinal chemistry building block can be generated on multi-gram scale using the developed conditions to a single enantiomer in a 60% yield after employing a crystallisation procedure.

Manganese-Catalyzed anti-Selective Asymmetric Hydrogenation of α-Substituted β-Ketoamides.

A Mn-catalyzed diastereo- and enantioselective hydrogenation of α-substituted β-ketoamides has been realized for the first time under dynamic kinetic resolution conditions. anti-α-Substituted β-hydroxy amides, which are useful building blocks for the synthesis of bioactive molecules and chiral drugs, were prepared in high yields with excellent selectivity (up to >99 % dr and >99 % ee) and unprecedentedly high activity (TON up to 10000). The origin of the excellent stereoselectivity was clarified by DFT calculations.

Asymmetric Synthesis of a Key Intermediate for Tofacitinib via a Dynamic Kinetic Resolution-Reductive Amination Protocol

We report the first example of a catalytic asymmetric reductive amination under dynamic kinetic resolution (DKR) conditions for the preparation of a chiral amine as a key intermediate toward Tofacitinib, an active pharmaceutical ingredient developed by Pfizer. Such a protocol allows the preferential formation of a single product out of four possible diastereomers of the chiral amine starting from the corresponding racemic ketone. The chiral iridium catalyst able to perform such a feast was discovered through a mix of high-throughput screening, racemization study, and reaction optimization.

Stereoselectivity Switch in the Trapping of Polar Organometallics with Andersen's Reagent-Access to Highly Stereoenriched Transformable Biphenyls.

The trapping of racemic polar carbometallic species with (-)-menthyl ( SS)- p-toluenesulfinate (Andersen's reagent) typically proceeds with a very low level of resolution. In this paper, we describe a strategy that allows access to highly atropo-enriched and functionalizable biphenyls by means of Andersen's reagent under kinetic resolution conditions. In particular, useful enantiopure 2-iodobiphenyls could be obtained and were employed in a challenging hypervalent iodine-catalyzed oxidation reaction.

Enzyme-promoted kinetic resolution of acetoxymethyl aryl sulfoxides

A simple and efficient method of the synthesis of enantiomerically enriched, unknown acetoxymethyl aryl sulfoxides has been developed which is based on an enzyme-catalyzed hydrolysis of racemic substrates under the kinetic resolution conditions. The hydrolysis was performed not only in a buffer solution but also in diisopropyl ether in the absence of the external water added to give in some cases the products with ee up to 98%. The enantioselectivity of both procedures was dependent on the enzyme used and the aryl substituent, being lower for p-tolyl than for phenyl. A comparative asymmetric synthesis based on the oxidation of the corresponding sulfides using chiral oxidizing reagent turned out to be inferior to the method described. Absolute configuration of the newly synthesized compounds was ascribed on the basis of CD spectra.

Preparation of chiral glycerol derivatives using chemoenzymatic approaches

Following our preparation of dissymmetric chlorohydrin esters from glycerol, we have used several lipases and whole cells to examine the kinetic resolution (KR) and dynamic kinetic resolution (DKR) of 3-chloro-2-hydroxypropyl esters. Regarding the KR, PS-IM, MmL and CALB lipases and whole cells of Aspergillus flavus showed the best selectivity and activity, depending on the compound studied. PS-IM allowed the isolation of (R)-3-chloro-2-hydroxypropyl pivaloate in 34% yield and with >99% enantiomeric excess (ee). DKR was carried out combining the biocatalysts that performed best for KR and suitable reaction conditions for racemization. Whole cells of A. flavus allowed the preparation of enantioenriched (S)-3-chloro-2-acetoxypropyl-2-methyl-2-phenyl propanoate in 43% yield and with 79% ee. Lipozyme from Mucor miehei used in a reaction subsequent to DKR allowed the purification of the corresponding enantioenriched (S)-3-chloro-2-acetoxypropyl pivaloate.

Scope and Mechanistic Analysis of the Enantioselective Synthesis of Allenes by Rhodium-Catalyzed Tandem Ylide Formation/[2,3]-Sigmatropic Rearrangement between Donor/Acceptor Carbenoids and Propargylic Alcohols

Rhodium-catalyzed reactions of tertiary propargylic alcohols with methyl aryl- and styryldiazoacetates result in tandem reactions, consisting of oxonium ylide formation followed by [2,3]-sigmatropic rearrangement. This process competes favorably with the standard O-H insertion reaction of carbenoids. The resulting allenes are produced with high enantioselectivity (88-98% ee) when the reaction is catalyzed by the dirhodium tetraprolinate complex, Rh(2)(S-DOSP)(4). Kinetic resolution is possible when racemic tertiary propargylic alcohols are used as substrates. Under the kinetic resolution conditions, the allenes are formed with good diastereoselectivity and enantioselectivity (up to 6.1:1 dr, 88-93% ee), and the unreacted alcohols are enantioenriched to 65-95% ee. Computational studies reveal that the high asymmetric induction is obtained via an organized transition state involving a two-point attachment: ylide formation between the alcohol oxygen and the carbenoid and hydrogen bonding of the alcohol to a carboxylate ligand. The 2,3-sigmatropic rearrangement proceeds through initial cleavage of the O-H bond to generate an intermediate with close-lying open-shell singlet, triplet, and closed-shell singlet electronic states. This intermediate would have significant diradical character, which is consistent with the observation that the 2,3-sigmatropic rearrangement is favored with donor/acceptor carbenoids and more highly functionalized propargylic alcohols.

Investigations on enzyme catalytic promiscuity: The first attempts at a hydrolytic enzyme-promoted conjugate addition of nucleophiles to α,β-unsaturated sulfinyl acceptors

Abstract Looking for new examples of enzyme catalytic promiscuity, attempts were made to use hydrolytic enzymes as catalysts for a conjugate addition of nucleophiles toα,β-unsaturated sulfinyl derivatives. The addition of piperidine to phenyl vinyl sulfoxide in chloroform proceeded both in the enzyme-catalyzed and non-catalyzed process, while in the former case the reaction was 2.5-fold faster. On the contrary, the conjugate addition of benzenethiol to phenyl vinyl sulfoxide proceeded only in the presence of enzymes and when ethanol was used as solvent. In no case were the products enantiomerically enriched. However, the addition of benzenethiol to a better Michael acceptor, namely a cyclic α-sulfinylalkenylphosphonate, performed in the presence of various lipases under kinetic resolution conditions gave in certain instances both the product and the recovered substrate with up to 25% optical purity. Although the stereoselctivity and the rates of these reactions were quite low, this are the first examples of the lipase-catalyzed Michael addition of heteroatom nucleophiles to α,β-unsaturated heteroorganic acceptors. Some mechanistic considerations are presented.

Facile conversion of racemic ibuprofen to (S)-ibuprofen

Abstract The methyl ester of ibuprofen was quantitatively formed by Fischer esterification and converted into ( S )-ibuprofen in 94% yield with an ee of 94% under dynamic kinetic resolution conditions at pH 9.8, using Candida rugosa lipase, and 20% DMSO. The ( R )-methyl ibuprofen ester was observed to racemize by chiral HPLC without the Candida rugosa lipase present. The rates of in situ racemization and enzymatic hydrolysis for the dynamic kinetic resolution were determined to be 0.026 ± 0.004 and 0.053 ± 0.004 h −1 , respectively. The rate of enzymatic hydrolysis when no DMSO was present was twice as fast but no racemization occurred. A facile purification of enriched ( S )-ibuprofen was developed. Overall, 88% of racemic ibuprofen by weight was converted into ( S )-ibuprofen with an ee of 99.7%.

ChemInform Abstract: Catalytic Synthesis of Nonracemic Azaproline Derivatives by Cyclization of β‐Alkynyl Hydrazines under Kinetic Resolution Conditions.

AbstractAn α‐selective hydrazination of mixtures containing allene/alkyne components [cf.

Catalytic Synthesis of Nonracemic Azaproline Derivatives by Cyclization of β‐Alkynyl Hydrazines under Kinetic Resolution Conditions

No metals required: Starting from readily accessible γ-silyl allenyl esters, β-alkynyl hydrazines were prepared in one step and subsequently cyclized in the presence of ammonium and phosphonium catalysts leading to dehydroazaproline products (see scheme; X=O, S). These heterocycles were also produced in high enantiomeric excesses using chiral ammonium phase-transfer catalysts by a kinetic resolution.

Catalytic Synthesis of Nonracemic Azaproline Derivatives by Cyclization of β‐Alkynyl Hydrazines under Kinetic Resolution Conditions

Metallfrei: Ausgehend von leicht zugänglichen γ-Silylallenylestern wurden zunächst in einer Stufe β-Alkinylhydrazine aufgebaut, die dann in Gegenwart von Ammonium- oder Phosphoniumkatalysatoren zu Dehydroazaprolinen cyclisierten (siehe Schema; X=O, S). Diese Heterocyclen waren auch in hohen Enantiomerenschüssen durch kinetische Racematspaltung mit chiralen Ammoniumsalzen als Phasentransferkatalysatoren erhältlich.

Stereoselective Synthesis of Three Isomers of tert‐Butyl 5‐Hydroxy‐4‐methyl‐3‐oxohexanoate through Alcohol Dehydrogenase‐Catalyzed Dynamic Kinetic Resolution

AbstractRegioselective reduction of the 5‐keto group of tert‐butyl 4‐methyl‐3,5‐dioxohexanoate (1) leads to a stereodiad of tert‐butyl 5‐hydroxy‐4‐methyl‐3‐oxohexanoate (2). Alcohol dehydrogenases from Lactobacillus brevis (LBADH), Rhodococcus sp. (RS 1‐ADH) and Saccharomyces cerevisiae (YGL157w) reduce 1 under dynamic kinetic resolution conditions, thereby establishing two chiral carbons with a single reduction step. While it had been shown previously that LBADH reduction of 1 stereoselectively leads to syn‐(4S,5R)‐2, alcohol dehydrogenase‐mediated dynamic kinetic resolution now allows easy access to syn‐(4R,5S)‐2 (RS 1‐ADH; 97.6% ee, syn:anti=92:8, 66% conversion, 37% isolated yield) and anti‐(4S,5S)‐2 (YGL157w; 90% ee, anti:syn=93:7, 64% conversion, 42% isolated yield), as well. Thus three out of four possible stereoisomers were formed selectively upon reduction of 1.

Lipase-mediated kinetic resolution of racemic and desymmetrization of prochiral organophosphorus P-boranes

Enantiomerically enriched alkoxy(hydroxymethyl)phenylphosphine boranes were obtained via a lipase-catalyzed acetylation performed under kinetic resolution conditions. The reaction was slow and proceeded with a rather low enantioselectivity. A lipase-catalyzed acetylation of prochiral bis(2-hydroxyethyl)phenylphosphine borane resulted in its desymmetrization and gave the enantiomerically enriched monoacetyl derivative with ee up to 90%.

Primary and Secondary Allyltitanium(IV) Reagents in Aldehyde Allylation II: Application to an Enantioselective Preparation of a C1-C7 Fragment of Spiramycin

A synthetic approach to the eastern part of spiramycin, an important antibiotic compound, is described. Introduction of the side chain was first envisaged through a Hoppe aldehyde allylation. This reaction was carried outbetween an optically pure aldehyde 32 and a (′)-γ-alkoxy allyltitanium(IV) species derived from a primary γ-alkoxy allyl (diisopropyl)carbamate. Under kinetic resolution conditions, the anti-Cram compound 35 was obtained in an 80:20 mixture, with the Cram isomer 34, in 81% yield. Employing the optically pure (S)-γ-alkoxy allyl (diisopropyl)carbamate 36, the corresponding (R)-γ-alkoxy allyltitanium (R)-'Ti'-III was generated under n-BuLi.TMEDA/Ti(Oi-Pr) 4 conditions, that reacted with aldehyde 32 in double stereodifferentiation to deliver the expected Cram compound 40 in 80% yield (95% de). This latter corresponded to the C1-C7 fragment of spiramycin.

Enantiomerically pure disulfides: key compounds in the kinetic resolution of chiral P III-derivatives with stereogenic phosphorus

Enantiomerically pure disulfides were reacted with various chiral P III-derivatives with stereogenic phosphorus such as tertiary phosphines, halogenophosphines, phosphinite and phosphole under kinetic resolution conditions to afford enantiomerically enriched phosphine oxides or sulfides with ee values up to 50%. Enantiomeric excess rose to 70% under dynamic kinetic resolution conditions in the case of tert-butylphenylchlorophosphine.

One-Pot Chemoenzymatic Cascade Polymerization under Kinetic Resolution Conditions

A novel concept for the metal-free synthesis of block copolymers combining enzymatic ring-opening polymerization and nitroxide-mediated living free-radical polymerization from a bifunctional initiator is presented. Block copolymers comprising a poly(styrene) and poly(caprolactone) block were obtained in two consecutive polymerization steps (macroinitiation) and in a one-pot cascade approach without intermediate transformation or work up step. By optimization of the reaction conditions a high selectivity of both transformations could be realized in the cascade polymerization, resulting in high block copolymer yields. The same concept was successfully applied to enzymatic resolution polymerization of racemic 4-methyl-ε-caprolactone combined with the living free-radical polymerization of styrene yielding block copolymers with high enantiomeric excess in the 4-methyl-ε-caprolactone block.