Stereoselective Total Synthesis and Absolute Configuration of the Natural Decanolides (−)-Microcarpalide and (+)-Lethaloxin. Identity of (+)-Lethaloxin and (+)-Pinolidoxin

Abstract

[reaction: see text] Convergent, stereoselective syntheses of the pharmacologically active, naturally occurring lactones (-)-microcarpalide and (+)-lethaloxin have been achieved from the commercially available, chiral reagents (R)-glycidol, (S,S)-tartaric acid, and d-ribose as the starting materials. These syntheses have further served to establish the hitherto unknown absolute configuration of (+)-lethaloxin and to show its identity with (+)-pinolidoxin.

Synthetic Studies of Natural 10-Membered Lactones, Mueggelone, Microcarpalide, and Sch 642305, Which Have Interesting Bioactivities

“…Connection of two fragments 35 and 37 was carried out under the Yamaguchi conditions, 14) and the resulting ester 38 was subjected to RCM using 1st-generation Grubbs catalyst. 26) High dilution conditions (1.4 mM) brought a result similar to Marco's group, 22,23) giving a 2:1 E/Z mixture of 10-membered lactone 39 in good yield. After purification of E-isomer, deprotection successfully afforded microcarpalide.…”

“…As reported by Marco, 22,23) Davoli, 35,36) Prasad,41) and Fürstner,46) the use of 1st-generation Grubbs catalyst 26) showed moderate or high E selectivity, while the use of 2nd-generation Grubbs catalyst resulted 20) in enhanced formation of Z-isomer. The similar phenomenon was observed in synthesis of other medium-sized rings 27) and this must be an important characteristic of RCM.…”

“…First synthesis of microcarpalide by Marco et al The first synthesis of microcarpalide was achieved by Marco and co-workers in 2002 (Scheme 2 [1]). 22,23) Their key reaction was the RCM 4) of ester 18 to form 10-membered lactone, and four stereocenters were derived from commercially available chiral pools. (R)-Glycidol was converted to alcohol 16 by epoxide opening with n-pentyl cuprate and subsequent chelation-controlled allylation.…”

“…Banwell's group (2004, entmicrocarpalide), 44) Chavan's group (2005), 45) and Fürst-ner's group (2007) 46) employed precursor 18 (or ent-18), the same intermediate as in Marco's synthesis. 22,23) Synthesis of ent-microcarpalide by Banwell and Loong is shown in Scheme 2 [5]. 44) They constructed the intermediate ent-18 by cross metathesis 4,19) of , -unsaturated ester 44 using 2nd-generation Grubbs catalyst 20) under ethylene, because direct methylenation of hemiacetal 43 (conversion to ent-18) was not successful, and RCM of , -unsaturated ester 44 did not proceed.…”

“…All of three groups reported that RCM of 18 (or ent-18) resulted in E/Z selectivity similar to that of Marco's group. 22,23) (5) Consideration of the synthesis of microcarpalide by RCM…”