Stereoselective Total Synthesis of the Pseudopterolide Kallolide A

A total synthesis of the pseudopterolides, kallolide A (36) and kallolide A acetate (35), has been achieved. The racemic forms were prepared from the syn adduct 20 of furan 13 and stannane 17 (BF(3).OEt(2)-promoted addition) via the 15-membered propargylic allylic ether 25. [2,3]Wittig ring contraction led to the cis, anti, cis product 26. Alcohol 26 was transformed to butenolide 34 with net retention of configuration by Pd(PPh(3))(4)-catalyzed carbonylation of the mesylate 27 and ensuing AgNO(3)-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, with inversion of stereochemistry by an S(N)1 process. Key elements of stereocontrol, including the steric outcome of the [2,3]Wittig ring contraction, the allenic ester isomerization, and the solvolysis reactions, were predicted from molecular mechanics calculations. The C8 and C2 epimers 45 and 46 of the cis, anti, cis kallolide A SEM ether precursor 34 were also prepared. The synthetic route originated from the anti adduct 19 of aldehyde 13 and the allylic chloride 16 and CuCl (cat), HSiCl(3), and i-Pr(2)NEt. Adduct 19 was subjected to the same sequence as the syn counterpart 20 to produce the trans, anti, cis [2,3]Wittig ring contraction product 42. The derived allenoate 44 afforded a 1:1 mixture of butenolides 45 and 46 upon sequential treatment with TBAF and AgNO(3). Finally, the natural enantiomer (+)-36 of kallolide A was synthesized from the enantioenriched syn adduct (+)-20, prepared by addition of allylic stannane 17 to aldehyde 13 promoted by a modified chiral acyloxyborane Lewis acid.