Total Synthesis of Isomalabaricane Triterpenoids

Abstract

The first total syntheses of (±)-rhabdastrellic acid A and (±)-stelletin E, highly cytotoxic isomalabaricane triterpenoids, have been accomplished in a linear sequence of 14 steps from commercial geranylacetone. The exceptionally strained trans-syntrans-perhydrobenz[e]indene core characteristic of the isomalabaricanes is efficiently accessed in a selective manner through a rapid, complexity-generating sequence. This process features a reductive radical polyene cyclization, an unprecedented oxidative Rautenstrauch cycloisomerization, and umpolung α-substitution of a p-toluenesulfonylhydrazone with in situ reductive transposition. A late-stage cross-coupling in concert with a modular approach to polyunsaturated side chains renders this a general strategy for the synthesis of numerous family members of these synthetically challenging and hitherto inaccessible marine triterpenoids.

Synthetic Studies on Selective, Proapoptotic Isomalabaricane Triterpenoids Aided by Computational Techniques

“…As we previously reported, conversion of electronically unbiased triketone 27 into a suitable vinyl electrophile for cross-coupling was more difficult than anticipated. Standard triflation conditions yielded exclusively the undesired endocyclic constitutional isomer 70 , despite the fact that triketone 27 was isolated almost exclusively as the exocyclic tautomer (Figure b).…”

“…With a fervent hope to build upon these pioneering studies on the isomalabaricanes, we undertook the challenge of their total synthesis with the goal of eliminating the supply problem that had hampered previous efforts in biological studies and drug development. Our initial results on the total synthesis of rhabdastrellic acid A ( 1 ) and stelletin E ( 2 ) have already been reported …”

A Chiral-Pool-Based Strategy to Access trans-syn-Fused Drimane Meroterpenoids: Chemoenzymatic Total Syntheses of Polysin, N-Acetyl-polyveoline and the Chrodrimanins

“…Two of these syntheses , pertain to the brasilicardin natural products and involved lengthy synthetic sequences to generate the key trans-syn-trans -fused tricyclic intermediates. More recently, a landmark synthesis of the isomalabaricanes (e.g., stellettin E, 5 ) by the Sarlah group has enabled initial structure–activity relationship studies on the cytotoxicity of the scaffold. , To complement the aforementioned approaches, we sought to develop an alternative strategy to collectively prepare trans-syn -fused drimane meroterpenoids through the use of a chiral pool approach. This report discloses the development of a strategy to access both trans-syn-cis- and trans-syn-trans -fused drimane meroterpenoids from sclareolide that culminates in the first total syntheses of polysin, N -acetyl-polyveoline, chrodrimanin C, and verruculide A.…”

Pivotal Reactions in the Creation of the Polycyclic Skeleton of Cryptotrione

“…An efficient approach for the total syntheses of the isomalabaricane triterpenoids (±)-rhabdastrellic acid A ( 173) and (±)-stelletin E (174) was reported by Sarlah's group. 59 As shown in Scheme 44, construction of the bicyclic ketone 172 was accomplished with a Ti(III)-mediated reductive radical polyene cyclization, generating an inconsequential 5:1 mixture of epimers at the C8 position.…”