STEREOSELECTIVE TOTAL SYNTHESIS OF THE PSEUDOPTEROLIDE KALLOLIDE-A

A total synthesis of the pseudopterolides, kallolide A (36) and kallol ide A acetate (35), has been achieved. The racemic forms were prepared from the syn adduct 20 of furan 13 and stannane 17 (BF3. OEt2-promote d addition) via the 15-membered propargylic allylic ether 25. [2,3]Wit tig ring contraction led to the cis, anti, cis product 26. Alcohol 26 was transformed to butenolide 34 with net retention of configuration b y Pd(PPh3)(4)-catalyzed carbonylation of the mesylate 27 and ensuing A gNO3-catalyzed cyclization of the derived allenic acid 29. Solvolysis of the SEM ether (at C2) 34 in acetic acid or aqueous t-BuOH afforded racemic kallolide A acetate (35) and kallolide A (36), respectively, w ith inversion of stereochemistry by an S(N)1 process. Key elements of stereocontrol, including the steric outcome of the [2,3]Wittig ring co ntraction, the allenic ester isomerization, and the solvolysis reactio ns, were predicted from molecular mechanics calculations. The C8 and C 2 epimers 45 and 46 of the cis, anti, cis kallolide A SEM ether precur sor 34 were also prepared. The synthetic route originated from the ant i adduct 19 of aldehyde 13 and the allylic chloride 16 and CuCl (cat), HSiCl3, and i-Pr2NEt. Adduct 19 was subjected to the same sequence as the syn counterpart 20 to produce the trans, anti, cis [2,3]Wittig ri ng contraction product 42. The derived allenoate 44 afforded a 1:1 mix ture of butenolides 45 and 46 upon sequential treatment with TBAF and AgNO3. Finally, the natural enantiomer (+)-36 of kallolide A was synth esized from the enantioenriched syn adduct (+)-20, prepared by additio n of allylic stannane 17 to aldehyde 13 promoted by a modified chiral acyloxyborane Lewis acid.