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).

No abstract

No 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).

No abstract