Collective Asymmetric Total Synthesis of C‐11 Oxygenated Cephalotaxus Alkaloids

Abstract

While numerous studies pertaining to the total synthesis of Cephalotaxus alkaloids have been reported, only two strategies have been reported to date for the successful synthesis of the C-11 oxygenated subset, due to the additional synthetic challenge posed by the remote C-11 stereocenter. Herein, we report the collective asymmetric total synthesis of C-11 oxygenated Cephalotaxus alkaloids using achiral proline both as as tarting material and as the only chirality source.A tetracyclic advanced intermediate was synthesized in ah ighly stereoselective manner from l-proline in 8s teps involving sequential chirality transfer steps such as ad iastereoselective N-alkylation, stereospecific Stevens rearrangement and intramolecular Friedel-Crafts reaction via an unusual O-acyloxocarbenium intermediate.F rom ac ommon intermediate,t he asymmetric total synthesis of six C-11 oxygenated Cephalotaxus alkaloids was completed by as eries of oxidation state adjustments.

Recent Total Syntheses of Cephalotaxine‐Type Alkaloids (2016–2021)

“…Only two strategies for the synthesis of 18 were reported by Fuchs [35] and Stoltz, [36] until Kim's synthesis reported in 2021. [59] Kim and coworkers applied their diastereoselective N-allylation/[2,3]-Stevens rearrangement protocol with the concept of C to N to C chirality transfer [57,58] As shown in Scheme 25, the synthesis commenced with the preparation of bicyclic 146, which employed Lewis acidpromoted cyclization of 148, which in turn can be readily prepared from l-proline. They obtained (S)-146 as the major stereoisomer, and their computational and experimental studies revealed (S)-146 to be a thermodynamically stable isomer.…”

“…The synthesis of these congeners requires control of the C11 remote stereocenter, rendering them challenging targets for chemical synthesis. Only two strategies for the synthesis of 18 were reported by Fuchs [35] and Stoltz, [36] until Kim's synthesis reported in 2021 [59] . Kim and co‐workers applied their diastereoselective N ‐allylation/[2,3]‐Stevens rearrangement protocol with the concept of C to N to C chirality transfer [57,58] to the synthesis of diverse C11 oxygenated cephalotaxine‐type alkaloids.…”

“…Scheme 26. Completion of the collective total synthesis of C11 oxygenated cephalotaxine-type alkaloids(Kim, 2021). PCC = pyridinium chlorochromate; mCPBA = meta-chloroperoxybenzoic acid.…”

Synthesis of Bridged Oxabicycles via Cascade Reactions involving O-Acyloxocarbenium Ion Intermediates

“…We recently reported that AOI involved the Friedel–Crafts reaction en route to the total synthesis of Cephalotaxus alkaloids (Figure f) . For the formation of the AOI intermediate B , O -acyl hemiacetal A was treated with a Brønsted acid.…”

“…6 We recently reported that AOI involved the Friedel−Crafts reaction en route to the total synthesis of Cephalotaxus alkaloids (Figure 1f). 7 For the formation of the AOI intermediate B, O-acyl hemiacetal A was treated with a Brønsted acid. This transformation is analogous, in part, to the most widely applied method for the formation of Nacyliminium ions from N-acyl hemiaminal ether.…”