Towards the total synthesis of calyculin C: preparation of the C9–C25 spiroketal-dipropionate unit

Abstract

An asymmetric synthesis of the C 9 -C 25 spiroketal fragment of calyculin C is described. Key steps include two crotylation reactions using successively Brown's reagent and (Z)-crotyltrifluorosilane for the formation of the anti, anti, anti stereotetrad, ynone formation by a Pd-catalyzed coupling of a thiol ester with a terminal alkyne and a double intramolecular hetero-Michael addition for the stereoselective construction of the spiroketal framework.

Conjugated Ynones in Organic Synthesis

“…167 When treated with p-TsOH, the resulting ynone (166) gave a spiroketal, which is the C15−C25 fragment of the marine sponge natural product calyculin C. Koskinen and co-workers further reported the preparation the C9−C25 spiroketal dipropionate unit for the synthesis of the intermediate ynone 168 by coupling of thiol ester 164 with alkyne 167 in only 50% yield, due to dimerization of 167. 168 Fuwa and co-workers found out that p-toluenethiol esters 169 gave better results than the ethanethiol esters using Pd 2 (dba) synthesis of ynones, but the yields were only moderate (Scheme 55). 171 The reaction took place with 2 eq of CuI and 10 mol % of Pd(PPh 3 ) 4 in Et 3 N as solvent at room temperature.…”

“…The cross-coupling of thiol ester 164 with the terminal acetylene 165 under Fukuyama’s conditions took place in a moderate 55% yield due to a competitive Glaser type diyne formation (Scheme ). When treated with p -TsOH, the resulting ynone ( 166 ) gave a spiroketal, which is the C15–C25 fragment of the marine sponge natural product calyculin C. Koskinen and co-workers further reported the preparation the C9–C25 spiroketal dipropionate unit for the synthesis of the intermediate ynone 168 by coupling of thiol ester 164 with alkyne 167 in only 50% yield, due to dimerization of 167 …”