A General Synthetic Approach to the (20S)-Camptothecin Family of Antitumor Agents by a Regiocontrolled Cascade Radical Cyclization of Aryl Isonitriles

Abstract

A general and efficient synthesis of (20S)-camptothecin (1 a) is reported. A key common intermediate containing the pyridone and lactone (DE) rings of camptothecin and most derivatives was constructed from 2-trimethylsilyl-6-methoxypyridine by a series of metalation reactions and a Heck cyclization to provide an achiral bicyclic enol ether. Sharpless asymmetric dihydroxylation followed by lactol oxidation and iododesilylation produced the key intermediate in 94 % enantiomeric excess. Alkylation with propargyl bromide and a cascade radical reaction with phenyl isonitrile then produced 1 a. About 20 other pentaand hexacyclic analogues of camptothecin with differing single or multiple substituents at C7, C9, C10, C11, and/or C12 were made by changing the propargylating agent and the isonitrile. Included among these are several drug candidates and the approved drugs topotecan and irinotecan. The synthesis of the prodrug irinotecan is a direct one that does not pass through the active metabolite. The use of ortho-trimethylsilyl-substituted isonitriles allows the regioselective synthesis of camptothecin analogues in cases where isomeric mixtures are formed from the parent isonitriles. The synthesis of the derivatives relies on the broad scope and functional group tolerance of the key cascade radical reaction.

Advances in Solution- and Solid-Phase Synthesis toward the Generation of Natural Product-like Libraries

“…The synthesis of 16.5 (the key intermediate to hCPT and analogs) started with a known material, 3-formyl-4-iodo-2-methoxy-6-trimethylsilyl pyridine, 16.2. 182 Treatment of iodoformyl pyridine 16.2 with NaBH 4 in EtOH at -40°C afforded a hydroxymethyl pyridine intermediate, which was then protected with O-MOM. Treatment of this protected material with i PrMgCl at -40°C, followed by the addition of CuCN/LiCl and quenching of the resulting cuprate reagent with propionyl chloride, provided the key ketone intermediate 16.…”

Multicomponent Reactions with Isocyanides

“…Complex indole-containing natural products like the kinase inhibitor ()-K252a (39) can be synthesized starting from o-isocyanocinnamic acid amides such as 37 (via 38) by means of radical cyclizations (AIBN a,a'-azoisobutyronitrile). [61] A further famous example is the synthesis of the ABCD ring moiety of the topoisomerase II inhibitor camptothecin and numerous derivatives by Curran et al [62] The a-acidity as a striking feature of the isocyanides is increased by further electron-withdrawing substituents in the a-position such as carboxylic esters, nitriles, phosphonic esters, or sulfonyl groups. a-Metalated isocyanides are versatile starting materials for the synthesis of a,b-unsaturated isocyanides, heterocycles or amino acids.…”

Cascade cyclization of 1-(2-yl-3-phenylprop-2-enyl)-6-oxo-1,6-dihydropyridine-2-carbonitrile radical: Mechanistic insights from DFT study

“…A wide variety of approaches to these alkaloids and their derivatives have been developed [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38], which focused on constructing ring-fused molecular skeletons, as shown in Scheme 1.…”