Sarkomycin A methyl esters and functionalized cyclopentane blocks for brefeldin A

Abstract

Sarkomycin A methyl esters and functionalized cyclopentane blocks for brefeldin A were synthesized starting from diastereoisomeric (1R,2S)-and (1S,2R)-2-hydroxymethyl-N-[(1R)-1-phenylethyl]cyclopent-3-ene-1-carboxamides. III, V, VIII, R = α-OH; IV, VI, VII, R = β-OH. Chiral cyclopentene blocks are key synthons for the preparation of natural cyclopentanoids and their analogs [1-3]. We previously described [4] a practical procedure for the synthesis of individual vicinally functionalized diastereoisomeric cyclopentenes I and II which were used to develop rational synthetic approaches to enantiomeric cyclosarkomycins [5]. Up to now interest in sarkomycin A [6] and brefeldin A [7] as antimicrobial, anticancer, and antiviral antibiotics remains fairly strong. Studies are performed to improve methods of their synthesis [8-12], and new aspects of their application are revealed [13].In the present work we demonstrated the possibility of using compounds I and II as chiral templates by the synthesis of enantiomeric sarkomycin A methyl esters and most important cyclic precursors of brefeldin A. The structures of the target products and the retrosynthetic sequence starting from compounds I and II are shown in Scheme 1.We initially examined functionalization of the double bond in lactone IX which was obtained by acid hydrolysis of compound I in dioxane-9 N H 2 SO 4 [4]. However, seemingly promising approaches to blocks V-VIII directly from compound IX via epoxidationreduction to X, IV, and VI, reduction with BH 3 and oxidation to XI [14], and bromohydroxylation to XII and XIII turned out to be inappropriate; all these reactions led to the formation of isomer mixtures which

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…”

“…1 One of these products, PGD 2 , is a plentiful prostaglandin in several mammalian tissues. PGD 2 activates G-proteincoupled receptors on its target cells, but PGD 2 also undergoes dehydration in vivo and in vitro to generate cyclopentenone metabolites of the J series, such as PGJ 2 , D 12 -PGJ 2 , and 15deoxy-D 12,14 -PGJ 2 (15d-PGJ 2 ). 2 Most prostaglandins exert proinflammatory effects, but cyclopentenone prostaglandins reportedly exert anti-inflammatory effects.…”

Total Synthesis of (R)-Sarkomycin via Asymmetric Rhodium-Catalyzed Conjugate Addition

“…Further analytical data were in accordance with those in the literature. 6b 3-Ethenyl-2-methylenecyclopentanone (8). A solution of trans-3-ethenyl-2-hydroxymethylcyclopentanone (7, 95.0 mg, 0.678 mmol from the Yb(OTf) 3 -catalyzed transformation) in CH 2 Cl 2 (3.2 mL) was treated with NEt 3 (395 μL, 2.83 mmol) and MsCl (309 mg, 2.70 mmol), and the reaction mixture was stirred for 24 h at rt.…”

A New Approach to the Synthesis of Chiral Blocks for Cyclopentanoids

“…The potential of using orthogonally functionalized chiral cyclopentane blocks was demonstrated by the development of approaches to sarkomycin A [27] and brefeldin A [28]. Here, regioisomeric lactones 24 were used as key intermediates [29] (Figure11). Compounds 29a and 29b were then subjected to acid hydrolysis and subsequent treatment with Bu 3 SnH in boiling benzene, which led to the desired lactones (-)-26 and (+)-26 ( Figure 14).…”

“…The potential of using orthogonally functionalized chiral cyclopentane blocks was demonstrated by the development of approaches to sarkomycin A [27] and brefeldin A [28]. Here, regioisomeric lactones 24 were used as key intermediates [29] (Figure11). In approaches to 24 during fictionalization of lactone (-)-2 and epoxide (-)-17 by using hydroboration-oxidation, bromohydroxylation and reduction of epoxide, a mixture of stereo-and regioisomers was prepared (Figure 12).…”