Synthetic strategy toward ineleganolide: A cautionary tale

Abstract

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Total Syntheses of (+)-Ineleganolide and (−)-Sinulochmodin C

“…It is important to note that these results indicate that obtaining the desired stereochemical outcome in the NHK macrocyclization requires advancement of the minor diastereomer derived from the aldol reaction (25, Scheme 5). In efforts to improve material throughput, we discovered the major aldol diastereomer (11) to be a superb substrate for Mitsunobu inversion and conversion to benzoate 34 (Scheme 7). Exposure of 34 to TBAF-mediated desilylation followed by one-pot Anelli oxidation/methanolysis delivers 27a.…”

“…Preliminary total synthesis efforts targeting these natural products have been disclosed by the Nicolau, Frontier, Romo, and Gaich groups, with only modest success. Furthermore, despite extensive and elegant work published by the Stoltz, − Vanderwal, and Moeller , groups, neither ineleganolide nor sinulochmodin C had succumbed to total synthesis prior to the efforts we report herein.…”

“…In planning our total synthesis, we were clearly beneficiaries of prior work, which had identified a number of difficulties associated with assembling these challenging ring systems. Notably, the embedded keto-tetrahydrofuran moiety, a structural unit present at the point of departure in Pattenden’s semisynthesis ( 7 ), has been a particular challenge in previous efforts, as it proved recalcitrant to formation via logical annulative methods. − Thus, in our efforts, we focused on developing an approach that would not only address this challenge but also allow divergent enantioselective access to both (+)- 1 and (−)- 2 from a common intermediate. Since 1 and 2 respectively possess the 5,7,6- and 5,6,7-fused carbocyclic cores found in the broader family of natural products, achieving this latter goal would potentially allow for unified access to a variety of biogenetically related nor-furanocembranoids ( e.g.…”

A Convergent Total Synthesis of (+)-Ineleganolide

“…In our own research, issues surrounding the central seven-membered ring and constructing the ether bridge at a late stage had halted previous efforts. 16 , 17 This sparked the idea of constructing the central seven-membered ring at a later stage, and instead having the tetrahydrofuran motif introduced early. Therefore, we envisioned disconnecting through the C4–C5 bond as the final step and constructing the seven-membered ring last.…”

A Convergent Total Synthesis of (+)-Ineleganolide

“…In our own research, issues surrounding the central 7membered ring and constructing the ether bridge at a latestage had halted previous efforts. 16,17 This sparked the idea of constructing the central seven membered ring at a later stage, and instead having the tetrahydrofuran motif introduced early. Therefore, we envisioned disconnecting through the C4-C5 bond as the final step, constructing the seven-membered ring last.…”