Gypsetin, synthesis

Prenylboration of generated in situ 3-chloroindolenine derivatives was used in synthesis of gypsetin and triptostatin B6. 

Nucleophilic tert-prenylation. When using prenylboranes instead of tert-prenylboranes, tert-prenylation of 3-chloroindolenines becomes possible. The Danishefsky tert-prenylation has also been extensively used for the synthesis of 3-tert-prenylindoles which can be obtained from 2-tert-prenylated precursors (see Sect. 4). The 1995 synthesis of the acyl-CoA-cholesterol acyltransferase inhibitor gypsetin (94) [91, 92] was the first occasion to publish that elegant reaction (Scheme 19) [88, 93]. On treatment of phthalimide-protected tryptophan methyl ester (85) with tcrt-BuOCl, the 3-chloroindolenine is formed in sim, which is nucleophilicaUy attacked by prenyl-9-BBN with regioinversion of the prenyl group. Hydrazinolysis afforded 2-tert-prenyltryptophan methyl ester (91). 

Scheme 19 Synthesis of gypsetin by Danishefsky prenylation and oxidative cyclisation by DMDO [88]...

Danishefsky and coworkers developed a method for introducing the tcrt-prenyl group at the indole C-2 position based on C-3 chlorination followed by nucleophilic delivery of the ferf-prenyl group from a borane [99]. The intermediate was used in synthesis of gypsetin and breviamide E, both of which contain the 2-(tert-prenyl) substituent. 

Danishefsky and coworkers utilized a nucleophilic displacement of chloride to synthesize 2,3-disubstituted indoles and, more specifically, to realize the total synthesis of gypsetin (not shown) [34, 35]. Tryptamine derivative 68 is transformed into chloroindolenine 69 by f-butyl hypochlorite. The chloroindolenine 69 undergoes attack at C-2 by various nucleophiles, including indole, to produce, after tautomerization, the 2,3-disubstituted indoles (22-79%). The addition of a Lewis acid, Bp3-OEt2 was found to be necessary for high yields for reagents other than prenyl-9-BBN. 

Schkayantz JM, Woo JCG, SUiphaivanh P, Depew KM, Danishefsky SJ (1999) Total synthesis of gypsetin, deoxybrevianamide E, brevianamide E, and tryprostatin B novel constmctions of 2, 3-disubstituted indoles. J Am Chem Soc 121 11964-11975... 

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