Enantiodivergent synthesis of ()-methylenolactocin and (+)-methylenolactocin from D-mannitol Manju Ghosh * , Sritama Bose, Soumitra Maity, Subrata Ghosh * Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700 032, India article info Article history: Received 15 September 2009 Revised 1 October 2009 Accepted 5 October 2009 Available online 8 October 2009 Keywords: Anti-tumor compounds Asymmetric synthesis Lactone Stereocontrol abstract An enantiodivergent synthesis of both enantiomers of methylenolactocin is described through stereocon- trolled addition of n-pentyl magnesium bromide to two D-mannitol-derived diastereomerically related aldehydes having an a-chiral center with a b hetero atom. Ó 2009 Elsevier Ltd. All rights reserved. Natural products containing a substituted c-butyrolactone unit with a carboxylic acid at b position, commonly known as paraconic acids, 1 are ubiquitous. Many of these compounds exhibit a wide range of interesting biological activities. Among them, methyleno- lactocin 1 2 has attracted considerable attention because of its strong antitumor, antibiotic activity, and densely functionalized structure. A number of approaches have been developed for the synthesis of 1 in racemic 3,4 as well as in enantiomerically pure form. 5 The asymmetric route, reported so far, mainly dealt with the synthesis of the natural enantiomer, ()-methylenolactocin. However, only a few approaches address the synthesis of (+)- methylenolactocin. As part of our continued interest 6 in asymmet- ric synthesis of natural products containing c-lactone unit, we planned to develop a strategy that would afford both enantiomers of methylenolactocin from a single enantiomer. A major challenge in the synthesis of methylenolactocin is the control of trans stereochemistry between the 4,5-substituents. However, total stereocontrol was observed only in a few ap- proaches. We visualized that addition of an appropriate nucleo- philic species to the aldehyde 2 would proceed stereoselectively (Scheme 1). The ketal unit would play the crucial role in dictating the stereochemical outcome. Generation of the carboxylic acid moiety from the ketal unit at a latter stage would accomplish the synthesis of 1. Thus, while 2 would provide one enantiomer of methylenolactocin, its C-3 diastereoisomer would provide the other enantiomer. To begin with, D-mannitol was transformed to the masked suc- cinates 4 and 5 following the protocol developed earlier by us 7 (Scheme 2). Oxidative cleavage (OsO 4 –NaIO 4 ) of the vinyl group in 4 afforded the aldehyde 2 8 in 80% yield. Synthesis of methyleno- lactocin from 2 required stereocontrolled addition of the appropri- ate nucleophilic species to the aldehyde group in 2. In case, addition of a Grignard reagent to the aldehyde 2 having an a-chiral center proceeds through Felkin-Anh model 6, a trans disubstituted product 7 is expected (Fig. 1). However, the aldehyde 2 has also an oxygen atom at b to the aldehyde unit and addition might proceed through a chelated intermediate 8. This would give rise to a cis disubstituted product 9. Addition of Grignard reagent to an alde- hyde having an a-chiral center with a hetero atom at b position has been reported to proceed non-stereoselectively. 9 With this background, the aldehyde 2 was allowed to react with n-pentyl magnesium bromide. To our delight, addition to the aldehyde 2 proceeded in a highly stereoselective fashion with spontaneous lactonization of the hydroxy-ester 7 (R = n-C 5 H 11 ) to give exclu- sively the lactone 10 in 60% yield (Scheme 2). The lactone 10 could 0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2009.10.011 * Corresponding authors. Tel.: +91 33 2473 4971; fax: +91 33 2473 2805 (S.G.). E-mail address: ocsg@iacs.res.in (S. Ghosh). O O CO 2 H C 5 H 11 CHO O O O OEt H 1 2 3 2 3 1 HO HO OH HO OH OH Scheme 1. A retrosynthetic route to methylenolactocin. Tetrahedron Letters 50 (2009) 7102–7104 Contents lists available at ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet