A Formal Enantiospecific Synthesis of 7,20‐Diisocyanoadociane

Abstract

7,20-Diisocyanoadociane (DICA) is a potent antimalarial isocyanoterpene endowed with a fascinating tetracyclic structure composed of fused chair cyclohexanes. We report a highly stereocontrolled synthesis of a late-stage intermediate, the "Corey dione", from which DICA has been made previously. This formal synthesis features a rapid buildup of much of the complexity of the target through a sequence of enone tandem vicinal difunctionalization, Friedel-Crafts cyclodehydration, and sequential stereocontrolled reductions. Most importantly, this success establishes the broader feasibility of our previously developed general synthesis approach to the isocyanoterpene family and provides a blueprint for a very direct synthesis of DICA and related natural products.

Synthesis of (+)-7,20-Diisocyanoadociane and Liver-Stage Antiplasmodial Activity of the Isocyanoterpene Class

“…28 Highlights of the synthesis include 1. a short route to substituted polarized dendralenes via Lewis-acid mediated [2+2]/retroelectrocyclization; 2. application of these reagents (which we termed Danishefsky-type dendralenes) to the synthesis of the carbon scaffold of the adocianes; 3. use of HAT hydrogenation to establish the correct C1 stereochemistry when all other methods failed; 4. stereocontrolled installation of the axial, equatorial bis-isonitrile of 2 ; and 5. design of the reaction sequence to minimize functional group interconverions (FGI), 8 which includes the absence of protecting groups. In contrast to other approaches to this family, our route through polarized dendralenes and tert -alkyl alcohol inversion is highly stereocontrolled.…”

Concise Synthesis of the Antiplasmodial Isocyanoterpene 7,20‐Diisocyanoadociane

“…An intermolecular conjugate addition/enolate trapping strategy was devised with the goal of maximizing convergency and overall efficiency; this approach appeared to offer the flexibility to be generalizable to many ICTs . Indeed, this strategy was central to our synthesis of kalihinol B ( 2 ), many simplified yet active kalihinol analogues, and our previous formal synthesis of DICA ( 1 ) …”

“…Several subsequent formal syntheses were based on the formation of the Corey dione, and thus inherited its troublesome endgame. These achievements include a Diels–Alder approach strategically similar to Corey's from the Miyaoka group, an oxidative enolate coupling/ring‐closing metathesis approach from Robinson and Thomson and our own conjugate addition/enolate trapping strategy . Two total syntheses sought to solve the stereocontrol conundrum at the C7 and C20 isonitrile‐bearing carbons: the approach of Fairweather and Mander used stereospecific Curtius rearrangements to install tertiary carbinolamines as isonitrile precursors, and the synthesis of the Shenvi group featured their method for invertive displacement of tertiary trifluoroacetates (TMSCN, Sc(OTf) 3 ) on the bis‐trifluoroacetate derived from 8 , which provided a stereoselective counterpoint to the endgame from 7…”

“…[1] This family includes ar ange of complex polycyclic architectures (Figure 1a)t hat has inspired our group to develop au nified strategy toward seemingly topologically disparate ICT diterpenes.A mong them, 7,20-diisocyanoadociane (DICA, 1)arguably stands out as the most stereochemically complex. [4][5][6][7] Upon initiation of our efforts in this area, we identified 2isocyanodecalin fragment 6 (Figure 1b)asacommon motif in many potent ICT diterpenes and developed ageneral strategy around retron 5. Thec ompelling combination of its structure and activity originated our interest in DICA and, by extension, in the rest of the ICT family.…”

Concise Synthesis of the Antiplasmodial Isocyanoterpene 7,20‐Diisocyanoadociane

“…Thec ompelling combination of its structure and activity originated our interest in DICA and, by extension, in the rest of the ICT family. [4][5][6][7] Upon initiation of our efforts in this area, we identified 2isocyanodecalin fragment 6 (Figure 1b)asacommon motif in many potent ICT diterpenes and developed ageneral strategy around retron 5. [8] An intermolecular conjugate addition/ enolate trapping strategy was devised with the goal of maximizing convergency and overall efficiency;this approach appeared to offer the flexibility to be generalizable to many ICTs.…”