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

Abstract

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.

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

“…Cephalotaxus alkaloids, which exist in plants of the Cephalotaxus genus (the only genus of Cephalotaxaceae family), have been known for six decades in the community of organic and medicinal chemistry. , Since the first Cephalotaxus alkaloid cephalotaxine (Figure ) was isolated from Cephalotaxus drupacea and Cephalotaxus fortunei by Paudler in 1963, approximately 100 members featuring structurally rigid polycyclic scaffolds have been recorded in the literature . Among them, homoharringtonine (syn.…”

“…Over the past half century, a number of elegant chemical syntheses of Cephalotaxus alkaloids , have been revealed since the landmark synthesis of (±)-cephalotaxine by Weinreb and Semmelhack in 1972 . Chemically, as shown in Figure , the characteristic structural feature of these Cephalotaxus alkaloids represented by cephalotaxine relies mainly on the tetracyclic backbone bearing the A/B/C/D ring system (type I ), wherein the five-membered ring D inherently possesses three stereocenters (C3/C4/C5 including one aza-quaternary carbon), one hydroxyl group (C3–OH), one amino group (C5–N), and one oxygenated double bond (C1C2), constituting the densest part of stereogenic centers and functional groups of cephalotaxine.…”

Alkylation of N,N-Dibenzylaminoacetonitrile: From Five- to Seven-Membered Nitrogen-Containing Heterocyclic Systems

“…For example, tylophorine and related phenanthrene-based analogues, present antiproliferative effects against various cell lines, whereas the lipophilic alkaloid gephyrotoxine presents antimuscarinic effects and selectively inhibits the postsynaptic nicotinic Ach receptor channels . Conversely, the pyrrolo­[1,2 a ]­azepine ring system has been found in a restricted number of natural products, such as alkaloid 275A, or (−)-cephalotaxine, which proved to be efficient in the treatment of chronic myeloid leukemia …”

Recent Advances in the Total Synthesis of Cephalotane-Type Norditerpenoids from Cephalotaxus sinensis

“…in 2017, 12 whilst Jeon focused attention on the most recent 10 total syntheses of this type of alkaloid reported between 2016 and 2021. 8 In addition, Cephalotaxus alkaloids have featured as a chapter in a book named 'The Alkaloids'. 4b Another type of natural product with important pharmacological activities and unique structural characteristics has also attracted widespread attention.…”

“…Furthermore, many synthetic chemists have demonstrated their outstanding talents and ideas for synthesizing Cephalotaxus alkaloids. 8 In fact, the total synthesis of racemic cephalotaxine was completed independently in 1975 by Weinreb 9 and Semmelhack 10 using different strategies. These proved to be groundbreaking efforts.…”