Total Synthesis of Brevetoxin A: Part 3: Construction of GHIJ and BCDE Ring Systems

Abstract

Successful syntheses of highly complex intermediates 2 (GHIJ ring system) and 3 (BCDE ring system) for the total synthesis of brevetoxin A (1) are described. Several of our methodologies were utilized to achieve this goal: i) hydroxy epoxide cyclizations of intermediates 22 and 30 (rings I and H, respectively); ii) hydroxy dithioketal cyclization of 45 (ring G); and, iii) palladium-catalyzed coupling with bis(cyclic ketene acetal phosphate) 68 (rings B and D). With the knowledge gained from our previous model studies, 2 and 3 were expected to be pivotal intermediates on the synthetic route to brevetoxin A.

Vinylepoxides in Organic Synthesis

“…The regio-and stereoselective intramolecular opening of vinylepoxides provides an efficient route to tetrahydropyran and oxepane systems and has successfully been applied in several syntheses of natural products, a pertinent example being that of the neurotoxic marine polycyclic ether brevetoxin B [106][107][108]. Cyclization of hydroxy epoxide 33a under acidic conditions results in tetrahydrofuran 34a as the sole isomer in excellent yield (Table 9.4, Entry 1).…”

Enantioselective Total Synthesis of Brevetoxin A: Unified Strategy for the B, E, G, and J Subunits

“…[3] The bioactivity of brevetoxin A is attributed to strong binding to the α subunit of the voltage-sensitive sodium ion channels, effecting an increase in the mean channel open time and inhibiting channel inactivation. [3a] The landmark total synthesis reported in 1998 by Nicolaou[4] stands as the only completed synthesis of this captivating target.…”

“…The first disconnection directed the simplification of the natural product into two tetracyclic halves of similar complexity ( 2 and 3 ), which would be united in a stereoselective Horner–Wittig reaction precedented by the previous synthesis by Nicolaou (Scheme 1). [4,5] The Horner–Wittig coupling partners 2 and 3 would be obtained from advanced fragments 4 and 5 respectively, which would be further disconnected into two subunits each. Specfically, the the BCDE fragment 4 [6a] would be prepared from the B and E ring subunits 6 and 7 through a novel convergent [X + 2 + X] strategy,[1c] and the GHIJ subunit 5 [6b] would be prepared in an analogous way from the G and J ring subunits 8 and 9 .…”

Total Synthesis of Brevetoxin A

“…Ketal 3 would be obtained through the stereoselective Horner—Wittig coupling6 of phosphine oxide 5 and aldehyde 6 . This route was attractive not only because it allowed for optimal convergence by simplifying the natural product into two halves of similar complexity, but also because it found precedent in the strategy previously reported by Nicolaou 4. Further, it was reasoned that the dithioketal moiety of aldehyde 6 could serve as a stabilized precursor to mixed ketal 3 , or lead to sulfone 4 in the event that formation or reductive etherification of mixed ketal 3 proved problematic.…”

“…Diol 9 was protected as the bis-TBS ether, whereupon selective cleavage of the primary TBS ether with HF·pyr afforded alcohol 10 . Alcohol 10 was smoothly transformed to phosphine oxide 11 via a sequence which involved mesylation of the alcohol, nucleophilic displacement of the mesylate to provide the alkyl diphenylphosphine, and finally, oxidative workup of the phosphine with H 2 O 2 4,6. Cleavage of the TBS ether with n -Bu 4 NF and formation of the methoxypropyl (MOP) acetal delivered the required phosphine oxide 5 in high yield 8…”