Enantioselective Synthesis of Oasomycin A, Part II: Synthesis of the C29–C46 Subunit

Abstract

Syntheses of the C1–C12 and C13–C28 oasomycin A subunits were described in the preceding Communication. Herein we describe the synthesis and assemblage of the C29–C46 portion of this polyketide natural product. According to the synthesis plan, the C29–C46 fragment targeted as aldehyde I is considered as one of the complex subgoals. Julia disconnection of the D olefin in I affords fragments II and III of comparable complexity (Scheme 1). On the basis of the elegant studies of Wasserman et al., the decision was made to mask the C46 carboxy terminus in sulfone II as its derived 4,5-diphenyloxazole, thus preserving its oxidation state. The singlet-oxygen-mediated liberation of this carboxy moiety could, in principle, be executed at numerous stages in the synthesis because of the compatibility of this transformation with the multitude of other oxygen-protecting groups in the assembled or partially assembled subunits. The C29–C38 fragment III (Scheme 1) is composed of both polyacetate and polypropionate subunits. The latter motif could be introduced by a Sn-mediated syn-selective aldol addition of dipropionyl synthon IV to aldehyde V—a reaction which was developed by us some years ago. The synthesis of aldehyde V began with a chiral Lewis acid catalyzed aldol addition of the Chan diene 1 to benzyloxy acetaldehyde 2 promoted by the Cu complex 3 (5 mol%) that was previously developed by our research group (Scheme 2). The resultant ketoester 4 (95% ee) was reduced with Me4NBH(OAc)3 [7] to afford a 1,3-anti diol (91:9 d.r.). Silylation of the diol (TBSCl, imidazole) followed by a reduction using DIBALH provided aldehyde 5 (77%, 3 steps). The dipropionyl synthon IVwas next introduced by a Sn-mediated aldol addition of b-ketoimide 6 to aldehyde 5 thus providing 7 as a 95:5 mixture of diastereomers. Immediate treatment of 7 with Me4NBH(OAc)3 [7] afforded the anticipated anti diol 8a (90:10 d.r.) which was readily purified by flash chromatography. Selective protection (TBSOTf, lutidine) of the less sterically hindered C33 hydroxy group gave the TBS ether 8b in 75% yield (2 steps). Since we were unable to directly protect the hindered C31 hydroxy group as the PMB ether, the wellprecedented three-step procedure consisting of reductive removal of the chiral auxiliary with LiBH4, protection of the diol as the p-methoxybenzylidene acetal, and selective reduction of the acetal with borane, catalyzed by Sc(OTf)3, [9] was then accomplished (80%, 3 steps). Interestingly, when the aforementioned acetal reduction was attempted with DIBALH, none of the desired product was obtained and the reaction resulted in loss of the TBS group at C37. Alcohol 9 was then silylated (TESOTf, lutidine) and the resulting product was hydrogenated (H2, dry Pd(OH)2/C, EtOAc) to give the alcohol at C38 that was then oxidized with Dess– Martin reagent to afford the desired C29–C38 subunit 10. The construction of sulfone II (Scheme 1) began with the preparation of a,b-unsaturated aldehyde 12 from the known 4,5-diphenyloxazole 11 (Scheme 3). The aldol addition of oxazolidinone 13 to aldehyde 12 catalyzed by magnesium chloride afforded the corresponding anti aldol adduct that Scheme 1. Retrosynthetic analysis of oasomycin A. Bn=benzyl.