A Formal Synthesis of (-)-Cephalotaxine

Abstract

An enantioselective formal synthesis of the alkaloid (-)-cephalotaxine has been completed, using an alkylidene carbene 1,5-CH insertion reaction as a key step to construct the spiro[4.4]azanonane core D/E-ring system. A Heck-type cyclization was used to close the tetrahydroazepine C-ring and a selective epoxidation-rearrangement sequence was used to elaborate the E-ring.

Palladium catalyzed cyclizations of oximeesters with 1,1-disubstituted alkenes: synthesis of α,α-disubstituted dihydropyrroles and studies towards an asymmetric protocol

“…12 Spirocyclic systems can be accessed by intramolecular alkylidene carbene 1,5-C-H insertion reactions involving enantioenriched precursors. 13 Strategies based upon asymmetric catalysis, which do not rely on chiral starting materials, have also been reported but do not offer general substrate scope. In specific cases, catalytic enantioselective intra-or intermolecular trapping of transiently generated iminium ions is effective.…”

Asymmetric Total Synthesis of (－)-Cephalotaxine

“…直至 1995 年, 才有 Mori 等 [12] 完成了天然 三尖杉碱的首次不对称全合成, 至今已有 18 个小组发 展了 23 条合成策略. 2012 年, Nay 等 [13] 对三尖杉碱家族 化合物的化学多样性及合成研究工作进行了系统综述, 但关于天然三尖杉碱不对称全合成研究工作的综述仅 有 O'Doherty 等 [14a] 于 2009 年对 Ishibashi 小组 [15] 和 Hayes 小组 [16] 的工作进行了简要评述, 以及 2016 年曾步兵 等 [14b]…”

“…如图 3 所示, 应用手性源法, 从 1995 年至今, 有 10 个研究组基于 8 种不同的手性原料发展了 11 条策略, 实现天然三尖杉碱的不对称全合成. Mori [12] 、Ikeda [17] 和 Hayes [16,18] 三个小组采用的 D-(＋)-脯氨酸、 Royer 小组 [19] 采用的手性 α-萘乙胺 26、 Ishibashi 小组 [15] 采用的 D-(-)-酒石酸二乙酯, Gin 小组 [20] 采用的 D-核酸, Stoltz 小 组 [21] 采用的手性胡椒基羟基乙酸 54, Renaud 小组 [22] 采 用的羟基环戊烯(S)-92 和(-)-103, 姜标小组 [23] 采用的 手性亚磺酰胺 108.…”

Expedient Synthesis of Mequitazine an Antihistaminic Drug by Palladium Catalyzed Allylic Alkylation of Sodium Phenothiazinate

“…[21][22][23] To the best of our knowledge, this selective epoxide rearrangement has never been reported earlier for bicyclo[2,2,2]heterocycles containing epoxides. [24][25][26][27][28][29] While three type of products could be obtained, allyl alcohols, aldehyde and saturated alcohols, arising most likely by carbenoid insertion processes, 24-26) the transformation was highly selective and afforded the desired crucial allyl alcohol 6 exclusively, in 96% of isolated yield (see Experimental).…”

“…[21][22][23] To the best of our knowledge, this selective epoxide rearrangement has never been reported earlier for bicyclo[2,2,2]heterocycles containing epoxides. [24][25][26][27][28][29] While three type of products could be obtained, allyl alcohols, aldehyde and saturated alcohols, arising most likely by carbenoid insertion processes, 24-26) the transformation was highly selective and afforded the desired crucial allyl alcohol 6 exclusively, in 96% of isolated yield (see Experimental).Alternatively, we have also discovered that 6 could be efficiently generated via the Shapiro reaction, [30][31][32] by the known trisylhydrazone 7 with excess n-BuLi followed by quenching the nucleophilic vinyllithium reagent with paraformaldehyde.33) After acetylation of the alcohol 6 under standard conditions affording the allylic acetate 8, 34) the critical allylic alkylation step was studied and optimized. Palladium-catalyzed allylic amination is a well-established method for the synthesis of allyl amines.…”