Collective synthesis of acetylenic pharmaceuticals via enantioselective Nickel/Lewis acid-catalyzed propargylic alkylation

Abstract

Chiral acetylenic derivatives are found in many bioactive compounds and are versatile functional groups in organic chemistry. Here, we describe an enantioselective nickel/Lewis acid-catalyzed asymmetric propargylic substitution reaction from simple achiral materials under mild condition. The introduction of a Lewis acid cocatalyst is crucial to the efficiency of the transformation. Notably, we investigate this asymmetric propargylic substitution reaction for the development of a range of structurally diverse natural products. The power of this strategy is highlighted by the collective synthesis of seven biologically active compounds: (-)-Thiohexital, (+)-Thiopental, (+)-Pentobarbital, (-)-AMG 837, (+)-Phenoxanol, (+)-Citralis, and (-)-Citralis Nitrile.

Fig. 1. Design of the APS reactions for the collective synthesis of seven biological active molecules.

a Enantioselective collective synthesis of (−)-Thiohexital, (+)-Thiopental, (+)-Pentobarbital, (−)-AMG 837, (+)-Phenoxanol, (+)-Citralis, and (−)-Citralis Nitrile. b Core structure I for the enantioselective collective synthesis. c Realization of the Ni/Lewis acid-catalyzed the APS reaction of malonates to enhance the pace of drug discovery and development (this work).

Fig. 2. Substrate scope of malonate esters.

a Scope of alkyl malonate nucleophile. b Scope of methanetricarboxylates nucleophile. Unless otherwise noted, reactions were conducted with 1a (0.225 mmol), 2 (0.15 mmol), Ni(COD)₂ (10 mol%), (R)-L1 (12 mol%), and Yb(OTf)₃ (20 mol%) in DCM (2.0 mL) at room temperature for 72 h. ^aIn toluene (2.0 mL).

Fig. 3. Substrate scope of various racemic propargylic carbonates.

^aIn toluene (2.0 mL). ^bIn the absence of Lewis acid. ^cThe result for the reaction in the presence of Cu(OTf)₂ (20 mol%) as the Lewis acid under otherwise identical conditions is given in parentheses. ^dIn MeCN (2.0 mL).

Fig. 4. Application to chemical synthesis and collective synthesis of seven biologically active compounds.

a Our APS reaction was applied to the two-step enantioselective synthesis of (−)-Thiohexital. b The current methodology could allow for the rapid and enantioselective production of (+)-Thiopental and (+)-Pentobarbital. c The feasibility of the APS reaction was evaluated in the total synthesis of (−)-AMG 837. d The APS reaction provided facile access to (+)-Phenoxanol, (+)-Citralis, and (−)-Citralis Nitrile.

Fig. 5. Mechanistic studies.

a Radical scavenger experiments. b Kinetic studies. The dependence of the reaction rate by varying the Lewis acid additives. c Nonlinear relationship between the optical activity of phosphine ligand L1 and propargylated adduct 3v. d Plausible stereochemical model. TEMPO 2,2,6,6-tetramethylpiperidinyloxy, BHT butylated hydroxytoluene, 1,4-CHD 1,4-cyclohexadiene.