General Enantioselective and Stereochemically Divergent Four-Stage Approach to Fused Tetracyclic Terpenoid Systems

Abstract

Tetracyclic terpenoid-derived natural products are a broad class of medically relevant agents that include well-known steroid hormones and related structures, as well as more synthetically challenging congeners such as limonoids, cardenolides, lanostanes, and cucurbitanes, among others. These structurally related compound classes present synthetically disparate challenges based, in part, on the position and stereochemistry of the numerous quaternary carbon centers that are common to their tetracyclic skeletons. While de novo syntheses of such targets have been a topic of great interest for over 50 years, semisynthesis is often how synthetic variants of these natural products are explored as biologically relevant materials and how such agents are further matured as therapeutics. Here, focus was directed at establishing an efficient, stereoselective, and molecularly flexible de novo synthetic approach that could offer what semisynthetic approaches do not. In short, a unified strategy to access common molecular features of these natural product families is described that proceeds in four stages: (1) conversion of epichlorohydrin to stereodefined enynes, (2) metallacycle-mediated annulative cross-coupling to generate highly substituted hydrindanes, (3) tetracycle formation by stereoselective forging of the C9–C10 bond, and (4) group-selective oxidative rearrangement that repositions a quaternary center from C9 to C10. These studies have defined the structural features required for highly stereoselective C9–C10 bond formation and document the generality of this four-stage synthetic strategy to access a range of unique stereodefined systems, many of which bear stereochemistry/substitution/functionality not readily accessible from semisynthesis.

Asymmetric Total Syntheses of Euphol and Tirucallol

“…With our next goal of accomplishing a stereoselective intramolecular Friedel–Crafts cyclization, we applied a two-step sequence that first introduces a C9 methyl group by 1,2-addition of MeMgBr to the ketone of 11 . As we have previously shown, treatment of the tertiary alcohol product of this reaction with BF 3 ·OEt 2 results in a highly stereoselective cyclization that establishes the C9 stereocenter of 12 with ≥20:1 ds . Desilylation followed by oxidation to the enone provided access to compound 14 via the intermediacy of ketone 13 .…”

Progress Toward the Asymmetric De Novo Synthesis of Limonoids

“…This resulted in a 3:1 mixture of diasteroisomeric products, the major of which possessed the β-methyl group at C8 characteristic of the limonoid class. 12 From there, Saeguasa−Ito oxidation resulted in the production of enone 11, which was isolated in 48% yield over the threestep sequence. Tetracycle formation then ensued by initial 1,2addition of MeMgBr to the ketone of 11, followed by SnCl 4mediated Friedel−Crafts cyclization to deliver tetracycle 12 in 87% yield over two steps.…”

“…This cyclization process is slightly different than related reactions of substrates bearing a C8−C14 alkene, 13 and no evidence was found for the production of regio-or stereoisomeric products in this ring-forming reaction. Notably, cyclization delivers a product (12) possessing vicinal stereogenic quaternary centers at C8 and C9; the construction of such structural motifs are well appreciated to be challenging in synthetic organic chemistry. 14 Finally, a four-step sequence was used to convert this tetracyclic intermediate to a substrate of interest for the oxidative rearrangement reaction.…”

Toward the Asymmetric Synthesis of Cardenolides and Related Steroidal Systems: syn-SN2′ of Organometallics with C14–C17 Vinylepoxides

“… Simple three-step conversion to a stereodefined enyne ( 5 ) is followed by metallacycle-mediated annulation to generate a substituted hydrindane ( 6 ). Subsequent C9–C10 bond formation establishes 9-substituted estranes ( 7 ) that can be further advanced to synthetic androstanes ( 8 ) through an oxidative dearomatization and group selective alkyl shift from C9 to C10. Unfortunately, this concise and convergent synthesis strategy delivers steroidal products that lack substitution at C17 ( 7 and 8 ).…”