Nitrile biotransformations for the efficient synthesis of highly enantiopure 1-arylaziridine-2-carboxylic acid derivatives and their stereoselective ring-opening reactions

Catalyzed by the Rhodococcus erythropolis AJ270 whole cell catalyst under very mild conditions, biotransformations of racemic 1-arylaziridine-2-carbonitriles proceeded efficiently and enantioselectively to produce highly enantiopure S-1-arylaziridine-2-carboxamides and R-1-arylaziridine-2-carboxylic acids in excellent yields. Although the nitrile hydratase exhibits no selectivity against all nitrile substrates, the amidase is highly R-enantioselective towards 1-arylaziridine-2-carboxamides. When treated with benzyl bromide, 1-phenylaziridine-2S-carboxamide underwent a highly regioselective and enantiospecific ring-opening reaction to afford an almost quantitative yield of R-beta-[(benzyl)phenylamino]-alpha-bromopropanamide (C-2 attack) and R-alpha-[(benzyl)phenylamino]-beta-bromopropanamide (C-3 attack) in a 10.5:1 ratio. Further treatment of the resulting ring-opening products with an N-nucleophilic reagent such as amine and azide led to, through most probably the aziridinium intermediate, the formation of S-alpha-substituted-beta-[(benzyl)phenylamino]propanamides in good chemical yields with high enantiomeric purity.     

Nitrile biotransformations for the synthesis of enantiomerically enriched Baylis-Hillman adducts

Catalysed by the nitrile hydratase/amidase-containing Rhodococcus sp. AJ270 cells, a number of beta-aryl- and beta-alkyl- beta-hydroxy-alpha-methylenepropiononitriles (the Baylis-Hillman nitriles) 1 underwent hydrolysis under mild conditions to produce the corresponding enantiomerically enriched Baylis-Hillman amides 2 and acids 3. The enantioselectivity of the biotransformations was strongly determined by the steric effect of the substituents at the beta-position of the substrates. The protection of the free hydroxy of beta-phenyl-beta-hydroxy-alpha-methylenepropiononitrile 1a by methylation led to the enhancement of enantiocontrol of the biohydrolysis.     

Synthesis of enantiomerically pure 3-aminochroman derivatives

Enantiomerically pure (3R)-amino-5-methoxy-3,4-dihydro-2H-1-benzopyran was successfully synthesised in nine steps starting from l-serine. The same synthetic pathway was used to prepare the (3S)-aminochroman derivative starting from d-serine. The enantiomeric purity of the final aminochroman derivatives was determined by capillary electrophoresis using β-cyclodextrin as the chiral selector.     

On differences between racemic and enantiomerically pure forms of aziridine-2-carboxamide*

Synthesis, X-ray, and cytotoxicity studies of (S)- and (R)-aziridine-2-carboxamide (Leakadine) are described. X-ray data for the enantiomerically pure form are compared with those for racemic aziridine-2-carboxamide in order to explain the 21°C large melting point difference between both series. It was found that despite their overall low cytotoxicity (S)-aziridine-2-carboxamide is slightly more cytotoxic than (R)-aziridine-2-carboxamide.     

Use of enantiomerically pure methylsulfinylmethylisoxazolines in the stereoselective synthesis of 1,5,6,7-tetrahydroxy-3-heptanone derivatives

Aldol-type reactions of enantiomerically pure 4,5-diphenyl-3-(methylsulfinyl)methylisoxazolines and 2,3-O-isopropylidene- -glyceraldehyde were examined in order to establish the stereochemical preferences. Catalytic hydrogenation of the resulting trihydroxyisoxazoline derivatives using a Raney-Ni/H₃BO₃ system provides an access to diastereomerically pure 1,5,6,7-tetrahydroxy-3-heptanones.     

Efficient synthesis of enantiomerically pure alpha-alkyl cyclopropanecarbonitrile derivatives from pyrazolines

[reaction: see text] Thermolysis of enantiopure sulfonyl pyrazolines 4 and 5, easily obtained from (Z)-3-p-tolylsulfinylacrylonitriles (1), afforded sulfonyl cyclopropanes (6, 7) in a completely stereoselective manner in almost quantitative yields. Both cyclopropanes and alkylidenecyclopropanes, containing one or two chiral carbon atoms, one of them being quaternary, were obtained by hydrogenolysis of the C-S bonding and under the conditions reported by Julia, respectively. The highly stereoselective extrusion of nitrogen suggests a concerted mechanism.     

The synthesis of enantiomerically pure [2.2]paracyclophane derivatives

[2.2]Paracyclophane is a fascinating molecule that offers great potential in a wide range of chemical disciplines. Currently, the synthesis of the majority of enantiomerically pure [2.2]paracyclophane derivatives is based on the resolution of a small number of starting materials or individual resolution procedures are developed for each new compound. The development of more general routes to these valuable compounds via the resolution of a common intermediate is discussed. Ultimately, it would be preferable to synthesise these valuable compounds without recourse to resolution and ideas for this rewarding goal are postulated.     

Intramolecular alkene carboamination reactions for the synthesis of enantiomerically enriched tropane derivatives

The synthesis of tropane derivatives via intramolecular Pd-catalyzed alkene difunctionalization reactions is described. Enantiopure N-aryl-γ-aminoalkenes bearing an aryl or alkenyl halide adjacent to the amino group were converted to benzo- or cycloalkenyl-fused tropane products in good yield and with no loss of enantiopurity.     

Diastereo- and enantiomerically pure allylboronates: their synthesis and scope

Allylboronates are highly attractive reagents for allyl additions. Enantiomerically pure, stable reagents with a stereogenic centre in alpha-position to boron are especially versatile, albeit often difficult to synthesize. Starting from boron-containing allyl alcohols 6 and 7, which are discussed in detail herein, a set of reagents were obtained via [3,3]-sigmatropic rearrangements and consecutive transformations in the side chain. The configurations could be established first by chemical correlation, but also by X-ray crystallography (16, 18, 34, and 39). Allyl additions were performed resulting in the formation of predominantly (Z)-configured homoallylic alcohols (31, 43-45) with high enantiomeric excess. Detailed investigations on the matched-mismatched interaction between the reagents 15/16 (and ent-15/ent-16, respectively) and isopropylidene glyceraldehyde 42d are presented.     

Novel synthesis of enantiomerically pure natural inositols and their diastereoisomers

The various inositol polyphosphates have been found to trigger many important biological processes. Although the knowledge of this phosphoinositide signaling system has been discovered in the past 10 years, many factors remain unclear. For this reason, there is an increased demand for supplies of D-myo-inositol and particularly of novel analogues to investigate these biological mechanisms in more detail. Herein, we report the efficient syntheses of all diastereoisomers of inositol starting with 6-O-acetyl-5-enopyranosides. Conversion of 6-O-acetyl-5-enopyranosides into the corresponding substituted cyclohexanones (Ferrier-II rearrangement) was found to proceed efficiently with a catalytic amount of palladium dichloride. Stereoselective reduction of beta-hydroxy ketones obtained provided the precursors to all inositol diastereoisomers in good to excellent yields and with high stereoselectivities. Good accessibility of these enantiomerically pure inositol diastereoisomers results in the efficient syntheses of D-myo-inositol 1,4,5-trisphosphate and D-myo-inositol 1,3,4,5-tetrakisphosphate.     

Novel synthesis of enantiomerically pure natural inositols and their diastereomers

A novel synthesis of all stereoisomers of natural inositols has been developed. The key strategy is the stereoselective reduction of substituted β-hydroxy cyclohexanones, which are prepared from a variety of 6-O-acetyl 5-enopyranosides via Ferrier-II reaction catalyzed by palladium chloride. The utility of this approach is demonstrated by the synthesis of D-myo-inositol 1,4,5-tris(phosphate)(IP₃).     

Asymmetric synthesis of β-hydroxyacetamides mediated by enantiomerically pure sulphinyl derivatives

The aldol-type condensation of enantiomerically pure α-sulphinylacetamides is described. The stereochemical outcome of the reaction mainly depends on the nature of the base used to generate the enolate. Experimental evidences allow the identification of preferred reaction paths.     

A stereospecific synthesis of conjugated fluorodienes by a ring-opening reaction of gem-difluorocyclopropane derivatives

Ring-opening reactions of trans- and cis-gem-difluorocyclopropane derivatives (1) with appropriate bases proceeded stereospecifically to give (E, E)- and (E, Z)-fluorodiene derivatives (2), respectively.     

A convenient synthesis of activated enantiomerically pure 2-ethynylaziridines

2,3-cis- and 2,3-trans-N-Arylsulfonyl-2-ethynylaziridines with high enantiomeric purity have been synthesized. N-Protected amino aldehydes synthesized from natural α-amino acids were successively treated with Ph₃PC(Br)CO₂Me, DIBAL, MsCl–Et₃N, NaH in DMSO, and tert-BuOK in THF to yield 2-ethynylaziridines in good to high yields.     

Asymmetric synthesis of alpha,alpha-difluoro-beta-amino acid derivatives from enantiomerically pure N-tert-butylsulfinimines

Addition of the Reformatsky reagent derived from ethyl bromodifluoroacetate to alkyl- and aryl-substituted N-tert-butylsulfinimines furnishes beta-tert-butylsulfinamyl-beta-substituted alpha,alpha-difluoroproponiates in diastereomeric ratios ranging from 80:20 to 95:5. The diastereomers are easily separated and the enantiomerically pure, protected beta-amino esters are readily transformed to the corresponding acid, amide, and amine derivatives as useful synthons for medicinal chemistry targets.     

Asymmetric synthesis of β-hydroxythioacetamides mediated by enantiomerically pure sulphiny1 derivatives

Enantiomerically pure $\text{P}$-tolyl sulphinyl-N,N-dimethylthioacetamide (1) was prepared starting from (-)-(S)-menthyl toluene-$\text{p}$-sulphinate. Aldol-type condensation of (1) and subsequent removal of the Sulphinyl group open an entry to optically active β-hydroxy thioacetamides in 40–90% e.e.     

Asymmetric synthesis of enantiomerically pure 7-isopropenyl-4a-methyl-3-methyleneoctahydrochromen-2-ones

Four stereoisomers of 7-isopropenyl-4a-methyl-3-methyleneoctahydrochromenon-2-one have been obtained for the first time. The key step of the synthesis involves asymmetric Michael addition of chiral enamines derived from dihydrocarvone to acrylate 1. Absolute configurations were established by X-ray analysis.     

Asymmetric synthesis of enantiomerically pure zingerols by lipase-catalyzed transesterification and efficient synthesis of their analogues

The achiral zingerone 1, readily available from ginger, can be easily transformed into chiral derivatives. Zingerol 2, a reduced product of zingerone 1 is expected to be an important new medicinal lead compound. We have achieved a concise synthesis of optically active zingerol (R)-2 and (S)-2 by the lipase-catalyzed stereoselective transesterification of racemic 2. Under the optimized conditions, a lipase from Alcaligenes sp. (Meito QLM) and vinyl acetate in i-Pr₂O or hexane at 35 °C within 1 h gave the alcohol (S)-2 and the acetate (R)-9 with high enantioselectivity without producing acetylated by-products. Since optically active (S)-2 and (R)-9 were obtained through lipase-catalyzed transesterification, other enantiomerically pure novel compounds could all be synthesized.     

Regio- and stereospecific ring-opening reactions of 4-substituted basketanes and seco-basketanes

Homoketonization of basketane acetates6 and 10 on brief treatment with NaOMe in MeOH afforded the seco-basketanones7 and11, respectively, in a stereo-and regiospecific cage opening reaction. As shown by deuterium labeling experiments, both for 6 and 10, this homoketonization proceeds with retention of configuration. Prolonged basic treatment of10 led to the exclusive formation of bicyclo[2.2.2]octenyl-acetates12. Under identical conditions6 produced a complex mixture of products. Upon treatment of seco-basketanones7 and 11 with aq HC1 in MeOH, a rapid regiospecific cationic rearrangement to homobrendanone 14 was observed. This structure was established by X-ray analysis. The effect of a one carbon cage expansion on the base induced cage opening process by extension of the methylene bridge in the homocubane system into an ethylene bridge in the basketane system, is discussed.