β-Silyl Styrene As a Dienophile in the Cycloaddition with 3,5-Dibromo-2-pyrone for the Total Synthesis of (±)-Pancratistatin

Abstract

A new synthetic route to (±)-pancratistatin was devised utilizing β-silyl styrene as a dienophile in the cycloaddition with 3,5-dibromo-2-pyrone. The TMS group incorporated in the cycloadduct permitted a facile elimination process for the eventual installation of the C(1)-OH function. Subsequent transformations including Curtius rearrangement and Bischler-Napieralski reactions completed the total synthesis of (±)-pancratistatin.

Synthesis of Amaryllidaceae Constituents and Unnatural Derivatives

“…[21] This synthesis was accomplished in 18 steps from d-glucose with 8.5 %overall yield. [20] Them ajor difference is the incorporation of ab oronate ester at the terminus of alkyne 15 (Scheme 9), as opposed to the previously used silyl group (Scheme 3). [20] Them ajor difference is the incorporation of ab oronate ester at the terminus of alkyne 15 (Scheme 9), as opposed to the previously used silyl group (Scheme 3).…”

“…[20] (AE)-1-epi-pancratistatin (45)w as synthesized from ester 44 in 8 steps.T he synthesis of 44 was completed in five steps from alkyne 15 in 30 %overall yield. Theorganoborane was used in order to obtain the a-configuration of the C-1 hydroxy with retention of configuration after oxidation.…”

“…[21] Fort he synthesis of (+ +)-pancratistatin (1), Alonso [21] and Sato [22] both employed classical reactions,s uch as the aldol reaction, and Michael addition, while Cho [20] utilized Diels-Alder chemistry in his synthesis to achieve the required stereochemistry. Out of these four syntheses, Alonsos reported in 2012, was the shortest, comprising 14 steps and accomplished in 8.2 %o verall yield.…”

“…In 2011, Cho and co-workers published as ynthesis of racemic pancratistatin [20] by as trategy that utilized aD iels-Alder cycloaddition [28] to construct the Cr ing. As shown in Scheme 3, the synthesis began with silylation of alkyne 15 and hydroalumination of the resulting trimethylsilylalkyne to obtain am ixture of E:Z isomers of the b-styrenes 16 and 17 in a5:1 ratio,respectively.Itwas found that the E:Z ratio was highly solvent-dependent.…”

“…Thea uthors attributed this selectivity to the stable,s ix-membered transition state,T S-1( Figure 2). TS-1 is stabilized by intramolecular hydrogen bonding,the equatorial orientation of the bulky aryl and nitro groups,and the parallel p-orbital alignment of the C = Obond of aldehyde and the C = Nb ond of nitronate.F inally, (+ +)-pancratistatin (1)w as synthesized from compound 41 in nine steps,similar to those used by Cho [20] and Alonso. [21] This synthesis was accomplished in 18 steps from d-glucose with 8.5 %overall yield.…”