Enantioselective Divergent Syntheses of Cephalotaxus Alkaloids: (−)-Cephalotaxine, (−)-Cephalotine B, and (−)-Fortuneicyclidins A and B

Abstract

A new strategy focusing on the last-stage asymmetric assembly of the ring D, which inherently possesses the densest part of stereogenic centers and functional groups in the A/B/C/D ring system of (−)-cephalotaxine, has been developed, in which a novel Rh-catalyzed asymmetric (2 + 3) annulation of tertiary enamides with enoldiazoacetates is designed and explored for enantioselective construction of the crucial cyclopentane ring D bearing a unique spirocyclic aza-quaternary stereocenter. Based on the expeditious access of chiral functionalized building block with the tetracyclic A/B/C/D ring system, a concise enantioselective total synthesis of (−)-cephalotaxine starting from readily available homopiperonyl alcohol has been achieved in nine steps with only two column chromatography purifications. Following the tactical introduction of the Meinwald rearrangement, enantioselective divergent syntheses of (−)-cephalotine B with an additional C3–O–C11 oxo-bridged bond (14 steps), (−)-fortuneicyclidin B with an unprecedented C3–C10 bond (14 steps), and its 2-epimer (−)-fortuneicyclidin A (16 steps) have been also accomplished for the first time.

Concise Synthesis of (±)‐Fortuneicyclidins and (±)‐Cephalotine B Enabled by Pd‐Catalyzed Dearomative Spirocyclization**

“…During the preparation of this manuscript, Fan and coworkers elegantly achieved the enantioselective synthesis of 5, 6, and 8 in 14, 16, and 14 steps, respectively. [19]…”

Reductive Oxy-Nazarov Cyclization toward Expedient Construction of a Cyclopenta[1,2-b]pyrrolo[1,2-a]azepine Ring System: Formal Total Syntheses of Stemonamine and Cephalotaxine

“…The derivative of cephalotaxine 3 , homoharringtonine 4 , was approved by the FDA for treatment of chronic myeloid leukemia in 2012 . Since the pioneering works reported by the Weinreb and Semmelhack groups in 1972, numerous elegant methodologies to synthesize cephalotaxine have been developed due to its intriguing polycyclic structure and important biological activities …”

Enantioselective Total Synthesis of the Cephalotaxus Alkaloid (−)-Cephalotine A

“…Given their unique chemical structures and unknown biological activities due to the scarcity of the natural sample, we embarked on their total synthesis for these alkaloids. Upon our completion of their total synthesis, very recently, Fan and co-workers reported an elegant strategy in which asymmetric total synthesis of 1 and the first total syntheses of 4 , 5 , and 6 were achieved through the late-stage asymmetric assembly of the ring D featuring a Rh-catalyzed asymmetric 2 + 3 annulation. As there is no previous synthesis for (−)-cephalotine A in the literature, we herein disclose the first total synthesis of (−)- 3 .…”