Spirastrellolide studies. Synthesis of the C(1)–C(25) southern hemispheres of spirastrellolides A and B, exploiting anion relay chemistry

Abstract

Construction of the C(1)–C(25) southern fragments of both spirastrellolide A and B are described. Highlights of the syntheses include effective use of the three component anion relay chemistry (ARC) tactic recently introduced by our laboratory, a stereoselective spirocyclization via concomitant Ferrier reaction to elaborate the BC spiroketal and use of two dithiane unions to install the A ring as well as C(22)–C(25) fragment. The synthesis proceeded with longest linear sequences of 33 and 32 steps respectively for spirastrellolide A and spirastrellolide B.

Synthesis of 5,6- and 6,6-Spirocyclic Compounds

“…The requisite dihydroxyketones are commonly assembled via iterative aldol coupling reactions [1], but other methods including Nef reactions [17,18], acetylide additions [19,20], 1,3-dipolar nitrile oxide cycloadditions [21], iterative alkylation of dithianes [22][23][24][25][26][27][28], hydrazones [29], oximes [30], nitriles [31], or dihalomethylene species [32][33][34], cross-metathesis/hydroboration/oxidation [35], iterative substitution of a xanthate [36], dihydroxylation/desymmetrization of alkenes [37], Horner-Wadsworth-Emmons olefinations [38,39], allylmetallations [40], and alkyne-alkyne cross-coupling [41] have also been reported.…”

“…Smith et al [28] have made use of an initially unanticipated Ferrier rearrangement for the synthesis of the southern hemisphere of spirastrellolide B (Scheme 106).…”

“…Thus, the reaction sequence was optimized to maximize the yield of 439, proposed to arise from dehydration of the intermediate hemiacetal 441, followed by Ferrier rearrangement (Scheme 107). By inclusion of Scheme 105 Anionic homo-Fries rearrangement in the synthesis of a spiroacetal [202] Scheme 106 Unexpected Ferrier rearrangement in the synthesis of the southern hemisphere of spirastrellolide B [28] Scheme 107 Optimization of the Ferrier rearrangement in the synthesis of the southern hemisphere of spirastrellolide B [28] PTSA in the reaction sequence, the yield of the unsaturated spiroacetal 443 could be improved from 24 % to 62 %.…”

Through‐Bond/Through‐Space Anion Relay Chemistry Exploiting Vinylepoxides as Bifunctional Linchpins

“…[3] (+)-rimocidin, [4] (+)-spirastrellolide A and B, [5] the indolizidine alkaloids (À)-223AB and (À)-205B, [6] and the Cryptocarya family of polyhydroxylated pyrone natural products. [7] For the future, the development of new bifunctional linchpins that permit the reaction of diverse building blocks is essential for the synthetic utility of the ARC method.…”

Spirastrellolide E: synthesis of an advanced C(1)–C(24) southern hemisphere

“…Our interest in the spirastrellolides began in 2007, resulting early on in completed approaches to advanced fragments for a southern hemisphere relevant to spirastrellolide A and B 22,23 and a northern hemisphere relevant to B and E. 26 With these routes established, we considered a total synthesis venture; however it quickly became apparent that our first generation southern hemisphere synthesis, totaling 33 steps for the longest linear sequence, was not amenable to advancing ample material for a successful synthetic campaign. We therefore set out to design a second-generation route.…”