The fusion of click chemistry, fluorogenic chemodosimetry and a solid support offers advantages in identifying compounds in complex natural product mixtures.

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.

The first asymmetric synthesis and configurational elucidation of (−)-cephalezomine G was achieved. The highly functionalized Cα-substituted proline derivative was prepared from d-proline as the only chiral source via a C → N → C chirality transfer method consisting of stereoselective N-allylation and [2,3]-Stevens rearrangement. The azaspiranic tetracyclic backbone was constructed using ring-closing metathesis and the Friedel–Crafts reaction. Two contiguous hydroxyl groups were introduced in the later stages.

The first total syntheses of (-)-isowondonin A and (-)-isowondonin B, which are unusual imidazole marine alkaloids, has been accomplished through the development of methods for the selective formation of styryl sulfate group and regioselective alkylation of the imidazole. Application of the Noyori asymmetric hydrogenation of ketones allows the asymmetric synthesis. These results in conjunction with ECD calculations led to the determination of the absolute configuration of isowondonins.

Asymmetric synthesis of α‐substituted proline derivatives has been accomplished by an efficient chirality‐transfer method. High diastereoselectivity of the N‐alkylation of the proline ester (C→N chirality transfer) was achieved when a 2,3‐disubstituted benzyl group was used as the N‐substituent. DFT calculations provided a mechanistic rationale for the high degree of stereoselectivity. The generated N‐chirality of the quaternary ammonium salt was transferred back to the α‐carbon through a stereoselective [2,3]‐Stevens rearrangement (N→C chirality transfer) to give α‐substituted proline ester.

Over the past decades, scientists have obtained a diverse range of interesting natural products, including alkaloids, terpenoids, and flavonoids from the genus Cephalotaxus. Among them, cephalotaxine-type alkaloids have attracted considerable attention from chemists because of their intriguing pentacyclic structures as well as the diversity of naturally occurring analogs. Notably, homoharringtonine (Trade name: Synribo®) is a pharmaceutical drug, which was approved by the FDA in 2012 for the treatment of chronic myeloid leukemia, implying that cephalotaxine-type alkaloids have medicinal value. Since the first total synthesis of cephalotaxine, almost 70 total syntheses of cephalotaxinetype alkaloids have been reported, involving various synthetic methodologies. Because of their potential as molecular platforms for the development of organic chemistry, the total synthesis of cephalotaxine-type alkaloids has been extensively studied. This review focuses on the recent 10 total syntheses of cephalotaxine-type alkaloids reported in the period, 2016-2021. In addition, synthetic hallmarks, such as common synthetic routes and ring-opening features of this class, were also addressed.

An efficient strategy for the asymmetric synthesis of Cα-tetrasubstituted proline derivatives from proline has been established. A nitrogen-fused bicyclic system was devised to control the stereodynamics of proline. Through N-quaternizations with allylic electrophiles followed by [2,3]-rearrangements, the bicyclic proline system delivered enantioenriched Cα-tetrasubstituted prolines. This strategy was applied to the concise total synthesis of (−)-amathaspiramide F.

Bioisosteric analogues of pachastrissamine that contain sulfur and selenium atoms replacing the oxygen in the ring system, were efficiently prepared from a cyclic sulfate intermediate by sequential intermolecular and intramolecular S(N)2 displacement reactions of the dianions. The analogues exhibited cytotoxicities comparable to that of pachastrissamine.