Chiral blocks for the synthesis of cyclopentanoids from [2 + 2]-cycloadduct of dichloroketene and dimethylfulvene

Abstract

Opening of the α,α-dichlorocyclobutanone ring in the [2 + 2]-cycloadduct of dichloroketene and dimethylfulvene with (+)-α-methylbenzylamine gave diastereoisomeric 2-dichloromethyl-5-isopropylidene-N-(α-methylbenzyl)cyclopent-3-ene-1-carboxamides, and hydrolysis of the latter at the dichloromethyl group afforded the corresponding bicyclic aminals which can be readily separated by chromatography on silica gel. The subsequent removal of the α-methylbenzylamine fragment via reduction and hydrolysis resulted in the formation of enantiomerically pure (-)-and (+)-6-(1-methylethylidene)-3,3a,6,6a-tetrahydro-1H-cyclopenta[c]-furan-1-ones.Chiral polyfunctionalized cyclopentane blocks are used in the synthesis of biologically active cyclopentanoids such as prostaglandins, cyclopentenone antibiotics, carbanucleosides, and their analogs [1][2][3]. Gimazetdinov et al. [4] recently synthesized individual enantiomeric lactones II from racemic [2 + 2]-cycloadduct I of dichloroketene and cyclopentadiene [5] by the action of (+)-or (-)-α-methylbenzylamine and subsequent chromatographic separation of diastereoisomers and their transformation.With a view to obtain new enantiomerically pure vicinally substituted cyclopentenone blocks A we performed analogous reaction sequence with racemic bicyclic compound III. As might be expected, opening of the strained dichlorocyclobutanone ring in III readily occurred by the action of (+)-α-methylbenzylamine with formation of a mixture of chromatographically indistinguishable (TLC) diastereoisomeric amides IVa and IVb at a ratio of 1 : 1 (according to the 1 H NMR data). Hydrolysis of amides IVa and IVb at the dichloromethyl group on heating in a boiling 1.5 : 1 mixture of acetonitrile with water containing barium oxide gave 50% of lactams Va and Vb (Scheme 1). The yield of compounds Va and Vb considerably increased (87%; conversion 82%) when the reaction was carried out using sodium hydrogen carbonate instead of barium oxide. Unlike amides IVa and IVb, bicyclic lactams Va and Vb were characterized by appreciably different R f values (TLC), and they were readily separated by column chromatography on silica gel. Thus the cyclization of the hydrolysis products of amides IVa and IVb gave only two diastereoisomeric

Development of a new approach for the synthesis of (+)-15-deoxy-Δ12,14-prostaglandin J2 methyl ester based on the [2+2]-cycloadduct of 5-trimethylsilylcyclopentadiene and dichloroketene

“…The generality of this approach was subsequently successfully demonstrated with other readily available derivatives of cyclopentadiene: 5-trimethylsilylcyclopentadiene 4 12 (Scheme 2) and dimethylfulvene. 13 In the course of further studies, based on the obtained chiral bicyclic lactones, both total (sarcomycin A methyl ester, 14 cyclosarcomycin, 15 homocyclosarcomin, 6,12 entecavir, 17 and didesmethylmethylenomy-cin A methyl ester 18 ) and formal (brefeldin A, analogues of spinosyn A, and iso- and neuroprostanes 19 ) syntheses of a number of biologically active cyclopentanoids were developed. 20…”

A New Approach to the Synthesis of Chiral Blocks for Cyclopentanoids

“…[2+2]-Cycloadduct of 6,6-dimethylfulvene and dichloroketene: The application of the methodology for the preparation of chiral cyclopentenes developed by us to bicycle 48 open up access to the enantiomeric blocks 49 with an exocyclic double bond in the cyclopentane fragment [34] (Figure 23). The key steps of the approach are: a) easy cleavage of dichlorocyclobutanone cycle 48 by treatment with a chiral auxiliary (+)-α-methylbenzylamine with formation of the mixture of diastereomeric amides 50; b) transformation of these amides into Bicyclic aminals 51, which could be easily separated by column chromatography on silica gel.…”