A Concise Total Synthesis of (−)‐Himalensine A

Abstract

The daphniphyllum alkaloids are a structurally fascinating and remarkably diverse family of natural products. General strategies for the chemical synthesis of their challenging architectures are highly desirable for efficiently accessing these intriguing alkaloids and addressing their pharmaceutical potential. Herein, a concise strategy designed to provide general and diversifiable access to various daphniphyllum alkaloids is described and utilized in the asymmetric synthesis of (−)‐himalensine A, which was accomplished in 14 steps. Key features of this strategy include a Cu‐catalyzed nitrile hydration, a Heck reaction to construct the challenging 2‐azabicyclo[3.3.1]nonane motif, a Meinwald rearrangement reaction, six, pot‐economic reactions, and the minimal use of protecting groups, which significantly improved the overall synthetic efficiency.

A General Strategy for the Construction of Calyciphylline A‐Type Alkaloids: Divergent Total Syntheses of (−)‐Daphenylline and (−)‐Himalensine A

“…Next, the direct transformation of diene 24 into (−)‐himalensine A was tested via a sequence of hetero [4+2] reaction with singlet oxygen followed by Kornblum–DeLaMare rearrangement [26] of the resulting endoperoxide. Unexpectedly, the TPP‐sensitized photooxygenation of diene 24 led to an interesting Schenck‐ene hydroperoxide, treatment of which with acetic anhydride in situ afforded Xu's intermediate 27 in 63 % yield, which could be further converted to (−)‐himalensine A ( 7 ) in two steps [11a] . However, an alternative access to (−)‐himalensine A was developed.…”

Recent progress in the total synthesis of calyciphylline A-type <italic>Daphniphyllum</italic> alkaloid himalensine A

“…他们从二噻烷和 溴代物出发, 经过5步反应得到不饱和酯61. 接着通过 图 7 徐晶课题组 [28] 对于(−)-himalensine A的全合成 Figure 7 Total synthesis of (−)-himalensine A by the Xu group [28] 图 8 高栓虎课题组 [37] 对于(±)-himalensine A的全合成 Figure 8 Total synthesis of (±)-himalensine A by the Gao group [37] The evergreen plants of the genus Daphniphyllum are found mainly in the Asia-Pacific region and have played important roles in Traditional Chinese Medicine. Their leaves, barks and fruits have long been used to treat a variety of ailments including asthma, rheumatism, inflammation and fever.…”

Asymmetric total synthesis of yuzurimine-type Daphniphyllum alkaloid (+)-caldaphnidine J

“…It possesses a hexacyclic scaffold with six contiguous stereogenic centers, two quaternary centers, and an α,β,γ,δ-unsaturated carboxylic ester thus signifying a formidable synthetic challenge. Following our long-lasting interest in the synthesis of the Daphniphyllum alkaloids 31 – 33 , 51 , 52 , we now wish to report an asymmetric total synthesis of yuzurimine-type alkaloid, (+)-caldaphnidine J. Our approach is featured with a Pd-catalyzed regioselective hydroformylation that furnishes the critical aldehyde motif, and the construction of the 5/5 bicyclic system using a SmI 2 -promoted pinacol coupling and a one-pot Swern oxidation/ketene dithioacetal Prins reaction.…”

“…To date, about 20 elegant total syntheses of the Daphniphyllum alkaloids, from seven subfamilies, have been reported by the research groups of Heathcock [8][9][10][11][12][13][14][15] , Carreira 16 , Li [17][18][19][20] , Smith 21,22 , Hanessian 23 , Fukuyama/Yokoshima 24 , Zhai 25 , Dixon 26 , Qiu 27 , Gao 28 , and Sarpong 29,30 groups, respectively. Moreover, our group has recently accomplished the asymmetric total syntheses of himalensine A 31 , dapholdhamine B 32 , and caldaphnidine O 33 . However, despite extensive synthetic studies [34][35][36][37][38][39][40][41][42][43][44][45][46][47][48] , total synthesis of yuzurimine-type alkaloids-the largest subfamily of the Daphniphyllum alkaloids-has not been achieved so far.…”