Total Synthesis of (+)‐Exiguolide

Abstract

Exiguolide (1) is a unique 16-membered macrolide isolated from the marine sponge Geodia exigua Thiele (order Astrophorida, family Geodiidae).[1] It specifically inhibits fertilization of sea urchin (Hemicentrotus pulcherrimus) gametes but not embryogenesis of the fertilized egg. The macrolide structure incorporates two cis-2,6-disubstituted oxane rings, one of which carries an exocyclic enoate appendage reminiscent of bryostatins. The unique structural features and interesting biological activity of 1 has generated considerable interest in this compound, and herein we report our recent results for the total synthesis of 1.Scheme 1 shows the retrosynthetic analysis of 1. Thus, the target would be synthesized through a ring-closing olefin metathesis reaction of the carboxylate ester A followed by construction of the triene side chain. Fragments B and C are the constituents of the ester A. Fragment B may be obtained from Prins cyclization [2] of the b-alkoxyacrylate D, which should be accessible from the oxane derivative E. Fragment E may in turn be obtained by radical cyclization [3] of the b-alkoxyacrylate F.For synthesis of the B fragment, the secondary alcohol 3 was prepared from the known aldehyde 2[4] through Brown allylation, [5] hydroboration-oxidation, and protection of the primary hydroxy group with TBS (Scheme 2). The reaction of 3 with methyl propiolate in the presence of N-methylmorpholine produced the corresponding b-alkoxyacrylate derivative, which was converted into the iodide 4 by cleavage of the TBS group and iodide substitution. Radical cyclization [3] of 4 in the presence of 1-ethylpiperidinium hypophosphite and triethylborane in ethanol [6] proceeded efficiently and selectively to yield, almost quantitatively, the oxane 5. DIBAL reduction of 5 and a second Brown allylation led to a homoallylic secondary alcohol product, from which a second b-alkoxyacrylate derivative 6 was obtained by reaction with methyl propiolate. In the presence of trifluoroacetic acid, Prins cyclization [2] of 6 was successful and the products were hydrolyzed to a mixture ( % 3:1) of alcohols, which was then converted into the ketone derivative 7 by Dess-Martin oxidation. There were signs of partial ( % 7:1) racemization [7] in the Prins cyclization step. The keto ester 7 was converted into the keto acid 8 by dimethyl ketalization-hydrogenolysis, Dess-Martin oxidation, and rhodium-catalyzed methylenation [8] of the product aldehyde, followed by hydrolysisdeketalization and subsequent chromatographic separation.The known aldehyde 9 [9] served as the starting material in the synthesis of the C fragment (Scheme 3). Brown crotylation [10] of 9 produced the allylic alcohol 10, but a Sharpless kinetic resolution [11] step had to be included for improvement of the enantiomeric purity. For preparation of the final Scheme 1. Retrosynthetic analysis of exiguolide (1).

Total Synthesis and Biological Assessment of (−)‐Exiguolide and Analogues

“…We observed competitive formation of the corresponding dimer under higher concentrations (above 1 mm). Deprotection of the TIPS group of 2 KHMDS DME, À55 8C (1h) to RT (1.5 h) 37 with chiral phosphonate 38 developed by Fuji and coworkers [5,43] led to enoate 3 in 94 % yield as an approximately 5:1 mixture of Z/E isomers. Fortunately, the desired (Z)-isomer 3 could be isolated in a geometrically pure form in 75 % yield after flash chromatography on silica gel.…”

“…[12] double bond via chemoselective ringclosing olefin metathesis (RCM) [5,13] of triene 4, which could be accessible from methylene bis(tetrahydropyran) 5 through esterification. We planned to build the methylene bis(tetrahydropyran) substructure of (À)-1 in a convergent manner from readily available acyclic segments.…”

“…[4] In 2008, Lee and co-workers reported the first total synthesis of the unnatural enantiomer, (+)-1, which unambiguously determined the absolute configuration of this natural product. [5] The molecular architecture of (À)-1, characterized by the 20-membered macrolide framework embedded with the methylene bis(tetrahydropyran) substructure, resembles to that of antineoplastic marine natural products, the bryostatins. [6] In addition, it has been reported that (À)-1 specifically inhibits fertilization of sea urchin (Hemicentrotus pulcherrimus) gametes but not embryogenesis of the fertilized egg.…”

Prins‐Type Cyclization Reactions in Natural Product Synthesis

“…[20] Enol ether 25 was exposed to CF 3 CO 2 H to provide the oxocarbenium ion that reacted with the appended alkene to form a tetrahydropyranyl cation that was ultimately quenched to form a tetrahydropyranyl trifluoroacetate ester. This was illustrated by Lee and co-workers in their synthesis of the fertilization inhibitor exiguolide (Scheme 10).…”

Enantioselective Synthesis of (−)‐Exiguolide by Iterative Stereoselective Dioxinone‐Directed Prins Cyclizations

“…[5a] The current synthetic approaches to this 16-membered macrolide tend to rely on linear macrolactonization strategies by esterification to establish the primary ring system. [5] While these polyketide/macrolide strategies are effective, we sought a complimentary approach by focusing on maximum convergency and flexibility for biological studies. Indeed, this target seemed ideal to deploy a unified strategy to construct the tetrahydropyran (THP) rings and the macrocycle in an efficient manner.…”