Total Synthesis and Stereochemical Assignment of (−)-Ushikulide A

Abstract

We report the determination of the full stereostructure of (-)-ushikulide A (1), a spiroketal containing macrolide by total synthesis. Ushikulide A (1) was isolated from a culture broth of Streptomyces sp. IUK-102 and exhibits potent immunosuppressant activity (IC 50 = 70 nM). To embark upon an ushikulide A synthesis, a tentative assignment was made based on analogy to cytovaricin (2), a related macrolide isolated from a culture of Streptomyces diastatochromogenes whose full structure was previously established via synthesis and X-ray crystallography. This report delineates studies on several key steps, namely a direct aldol reaction catalyzed by the dinuclear zinc ProPhenol complex, a metal catalyzed spiroketalization, as well as application of an unprecedented asymmetric alkynylation of a simple saturated aldehyde with methyl propiolate to prepare the nucleophilic partner for a Marshall-Tamaru propargylation. These studies culminated in the first total synthesis and stereochemical assignment of (-)-ushikulide A and significantly extended the scope of the abovementioned methodologies.

Enantioselective ProPhenol-Catalyzed Addition of 1,3-Diynes to Aldehydes to Generate Synthetically Versatile Building Blocks and Diyne Natural Products

“…8a The chiral ligand 1 could react with 2 equivalents of a diynylmethylzinc species to generate the dinuclear zinc acetylide A . We hypothesize that in intermediate A the Zn acetylide is also coordinated to the nitrogen of the prolinol moiety and oxygen of the phenol.…”

“…Stimulated by our interest in exploring the synthetic potential of diyne carbinols as building blocks, their presence as key structural elements in biological metabolites and the difficulties associated with their asymmetric syntheses, we set out to determine if our ProPhenol ( 1 ) catalyst, which has been successfully employed in the alkynylation of aldehydes,8 could also effect a catalytic asymmetric addition of terminal 1,3-diynes to carbonyl groups. Moreover, we wanted to identify a modular diyne nucleophile which could serve as a 1,3-butadiyne equivalent.…”

Synthesis of 5,6- and 6,6-Spirocyclic Compounds

“…Similarly, Trost and O'Boyle [97] found during their total synthesis of (-)-ushikulide A 177 that gold(I)-catalyzed spirocyclization of 1,3-anti-triol 178a afforded the unsaturated 6,6-spiroacetal 179 in good yield (Scheme 42). The unsaturated product was, however, undesired (cf.…”

“…Beginning with studies toward Au(I)-or Au(III)-catalyzed synthesis of bridged acetals [92], these catalysts were soon applied to the synthesis of spiroacetals [93,94]. This method has been widely embraced by the synthetic community and used in the syntheses of a variety of complex spiroacetal natural products, including the cephalosporolides [95], okadaic acid [96], and ushikulide A [97].…”

Update 1 of: Macrolactonizations in the Total Synthesis of Natural Products

“…This methodology has been used for the efficient construction of the core of 17-, 524,525 25-, and 29-membered macrolactones. 526,527 The potential of this methodology is also nicely illustrated in the syntheses of aleuritic acid lactone, 521 547 and a CDE ring system of nakiterpiosin, 548,549 as well as in an atroposelective macrolactonization 550 in the synthesis of the C-1027 chromophore. During the synthesis of dictyostatin, Curran and co-workers have reported a problem of isomerization during the macrolactonization step.…”