Total Synthesis of Seco (+)- andent-(−)-Oxaduocarmycin SA:  Construction of the (Chloromethyl)indoline Alkylating Subunit by a Novel Intramolecular Aryl Radical Cyclization onto a Vinyl Chloride

Abstract

A practical, total synthesis of seco-(+)-oxaduocarmycin 3a, an analogue of the highly cytotoxic natural product, duocarmycin SA (1), is described. The 13-step synthesis features a novel and efficient intramolecular aryl radical cyclization onto a vinyl chloride as a direct entry to the (chloromethyl)indoline alkylating subunit 14. Subsequent resolution, utilizing a preparative Chiralpak AD column, provided enantiomerically pure alkylating subunits 14a and 14b which were elaborated to seco-(+) and ent-(-)-oxaduocarmycins, 3a and 3b, respectively. The natural enantiomer 3a was active at pM concentrations and exhibited 7-50-fold higher potentcy than its enantiomer 3b in in vitro cytotoxicity assays.

A Concise and Efficient Synthesis of seco‐Duocarmycin SA

“…After deprotonation of the NHBoc group in 9 with NaH, alkylation with ( E / Z )‐1,3‐dichloro‐2‐propene furnished the corresponding N ‐(3‐chloropropenyl)indole 10 . This compound was treated with tris(trimethylsilyl)silane14 and catalytic amounts of AIBN in deoxygenated benzene at 80 °C in a radical 5‐ exo ‐ trig cyclization15 to generate the fully functionalized seco ‐duocarmycin scaffold 11 in 73% over two steps (Scheme ). Radical cyclization with Bu 3 SnH as radical donor is less suitable due to the high toxicity of the reagent and the tedious separation of tin‐containing compounds from the final product.…”

Recent developments in indole ring synthesis—methodology and applications

“…245 Patel and co-workers have improved upon this method by effecting a similar 5-exo-trig cyclization onto a tethered vinyl chloride (Scheme 60). 248 Jones and co-workers have reported a similar tin-mediated cyclization of o-bromoacryloylanilides leading to oxindoles, a method which employs in situ N-silylation to bias the requisite conformation for cyclization. 249 This group has also described the radical cyclization onto a pyrrole ring leading either to spirooxindoles or to the martinelline core (pyrrolo[3,2-c]quinolone) (Scheme 61).…”

Simple indole alkaloids and those with a nonrearranged monoterpenoid unit (July 1997 to December 1998)

“…223 Several derivatives have also been synthesised, 224 including optically active CC-1065 225 and its less toxic analogues. 226,227 The use of intramolecular free radical cyclizations in the total synthesis of these compounds has been summarized by Boger. 229 It is probable that the same compound was isolated from the stems of P. madagascariensis back in 1970 but its structure was not then characterized.…”