Synthesis of the C1-C9 fragment of the potent antitumor agent dictyostatin

Abstract

Descrevemos neste trabalho uma síntese curta e eficiente para o fragmento C1-C9 do potente agente antitumoral dictiostatina. Esta abordagem sintética inclui uma reação de epoxidação assimétrica de Sharpless seguida da abertura de epóxido nas condições de Myashita para introduzir os centros estereogênicos em C6 e C7 e uma reação de olefinação tipo Horner-Wadsworth-Emmons nas condições de Ando para construir a ligação com geometria /Z/do dieno 1,3-/Z/,/E/.We describe herein a short and efficient synthesis of the C1-C9 fragment of the potent antitumor agent dictyostatin. Notable features of this approach include a Sharpless asymmetric epoxidation followed by epoxide opening under Myashita's conditions to introduce the stereogenic centers at C6 and C7, and a Horner-Wadsworth-Emmons type reaction under Ando's conditions to construct the Z-double bond of the 1,3-(Z,E)-diene system.

Stereoselective Synthesis of (3S, 4R)-5-Phenylpentane-1, 3, 4-Triol

“…The protection of the hydroxy group in compound 3 with TBS-Cl, imidazole in THF gave silyl ether compound 4 in 96% yield [21]. The reduction of ester functionality in compound 4 was carried out with Dibal-H in THF at room temperature to afford allylic alcohol 5 in 92% yield [22]. Next, installation of chiral epoxide on intermediate 5, has been achieved using Sharpless asymmetric epoxidation protocol with (-)-di-isopropyl tartrate, tert-butyl hydroperaxide and titanium tetra (isopropaxide) in tert-butanol and water at -20  C for 12h, gave the chiral epoxide 6 in 91% yield [23].…”

A Highly Step‐Economical Synthesis of Dictyostatin

“…[3] This assignment was confirmed soon thereafter by total syntheses by Paterson [4] and Curran, [5] and the material thus obtained facilitated more detailed characterization of dictyostatin’s mechanism of action. [6,7] Total syntheses by Phillips [8] and Ramachandran, [9] formal syntheses by Micalizio [10] and Cossy, [11] a synthesis of C(9)-epi-dictyostatin by Gennari, [12] second generation syntheses by Paterson [13] and Curran, [14] and several fragment syntheses [15] followed these initial reports. In addition, the Paterson/Wright [16] and Curran/Day [17] teams have reported extensive SAR studies, while the Paterson/Díaz/Jiménez-Barbero [18] and Curran/Snyder [19] teams have advanced models for the interaction of dictyostatin with the taxane binding site on β-tubulin.…”