Total Synthesis of Aplysiasecosterol A

Abstract

Aplysiasecosterol A (1) is a structurally unusual 9,11-secosteroid isolated from the sea hare Aplysia kurodai. We have accomplished the first and asymmetric total synthesis of 1 in a convergent fashion. The left-hand segment bearing three adjacent stereocenters was constructed through desymmetrizing reduction, ketalization, and radical cyclization. A strategy of asymmetric 2-bromoallylation followed by spontaneous desymmetrizing lactolization enabled a more expeditious access to this segment. The right-hand segment was prepared through two different approaches: one featuring Myers alkylation and Suzuki-Miyaura coupling and the other relying upon Aggarwal lithiation-borylation and Zweifel-Evans olefination. The two fragments were coupled by a Reformatsky type reaction. The three consecutive stereocenters embedded in the central domain of 1 were generated by an iron-mediated, hydrogen atom transfer based radical cyclization reaction.

Recent Progress in Steroid Synthesis Triggered by the Emergence of New Catalytic Methods

“…While this molecule features many functionalities present in steroids, its assembly required the development of new synthetic strategy, in particular, for the construction of the highly substituted cyclopentane ring. Li's group performed the first asymmetric total synthesis of the 9,11‐secosteroid aplysiasecosterol in 2018 A convergent synthesis was accomplished to establish the stereocenters shown in Scheme prior to a HAT based radical cyclization to construct the cyclopentaine ring of aplysiasecosterol in a selective manner.…”

“…Application of the Mukayiama hydration in the synthesis of linckosides A and B by Yu and co-workers. [37] [31] Aplysiasecosterol is a natural steroid derivative with a highly reorganized skeleton. While this molecule features many functionalities present in steroids, its assembly required the development of new synthetic strategy, in particular, for the construction of the highly substituted cyclopentane ring.…”

“…Li's group performed the first asymmetric total synthesis of the 9,11-secosteroid aplysiasecosterol in 2018. [31] A convergent synthesis was accomplished to establish the stereocenters shown in Scheme 16 prior to a HAT based radical cyclization to construct the cyclopentaine ring of aplysiasecosterol in a selective manner. The Li group found that a desymmetrizing lactolization reaction could be performed using the Roush enantioselective allylation of symmetric aldehyde 73 with boronic ester 74 to bypass the traditional Corey-Bakshi-Shibata reduction and streamline Scheme 16.…”

“…Retrosynthesis of aplysiasecosterol. [31] the synthesis providing 75 in 85 % yield and 9:1 er as determined by Mosher esterification followed by the 19 [31] For the synthesis of the right-hand segment 72, Li and coworkers initially utilized Myer's alkylation; however, the process was tedious thus decreasing the efficiency. Therefore, a different route commencing with the formation of 80 from 79 using Sharpless asymmetric dihydroxylation was developed (cf.…”

“…Synthesis of the intermediate 72 by Li and co-workers. [31] Subsequently, 71 and 72 were linked by a radical Reformatsky type of aldol addition reaction that provided the anti-aldol product in 70 % yield (Scheme 19A). This aldol addition product was converted into the corresponding aldol condensation product 70 by the elimination of water using Burgess reagent (58 %, 2 steps).…”