A Concise and Efficient Synthesis of seco‐Duocarmycin SA

Abstract

A short and efficient synthesis of seco‐duocarmycin SA (3), a highly potent cytostatic agent and direct precursor of the natural product duocarmycin SA (1), has been achieved. Starting from commercially available 2‐methoxy‐4‐nitroaniline (4) the synthetic protocol contains a Fischer indole synthesis to introduce the heterocyclic scaffold and a radical 5‐exo‐trig cyclization to furnish the (chloromethyl)indoline ring system as key reactions. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)

Fischer indole synthesis applied to the total synthesis of natural products

“…Besides (+)-duocarmycin SA 251 is a strongest one in cytotoxic potency and solvolytic stability and the most stable part is this class agents additionally glycosylated seco analogues of duocarmycin and CC-1065 are extremely encouraging for the critical cancer's treatment in an antibodydirected enzyme prodrug therapy. 155 A concise and signicant synthesis of seco-duocarmycin SA 251, an extremely strong cytostatic agent and direct precursor of the natural product duocarmycin SA 251, was accomplished in 2003 by Tietze and co-workers. 155 The synthetic procedure includes a FIS to show the heterocyclic moiety as a main reaction.…”

“…155 A concise and signicant synthesis of seco-duocarmycin SA 251, an extremely strong cytostatic agent and direct precursor of the natural product duocarmycin SA 251, was accomplished in 2003 by Tietze and co-workers. 155 The synthetic procedure includes a FIS to show the heterocyclic moiety as a main reaction. The total synthesis of seco-duocarmycin SA 251 was initiated by diazotation of market purchasable 2-methoxy-4nitroaniline 251, which upon two steps produced the hydrazone 253 extremely easily with an overall yield of 69%.…”

“…In the following, upon several steps seco-duocarymcin SA 251 has been synthesized in 91% yield (Scheme 52). 155 Such as Evodia officinalis and Evodia rutaecarpa, rutaecarpine 255 is the major of indoloquinazoline alkaloid, which is extracted from Rutaceous plants. Traditional medicinal has long used this plant for treatment of inammation-related symptoms.…”

Chemistry of α-Oxoesters: A Powerful Tool for the Synthesis of Heterocycles

“…In this context, Sudhakara et al 138 applied to synthesize indole moiety of seco-duocarmycin SA, a highly potent cytostatic agent, by treatment of the 2-methoxy-4-nitrophenyl hydrazone of methyl pyruvate with PPA in xylene at 120°C for 18 h. The corresponding indole-2-carboxylate was obtained in 64% yield. 139 Ethyl 5-phenyl indole-2-carboxylate was synthesized by reaction of biphenyl hydrazine hydrochloride with ethyl pyruvate in the presence of AcOH in a mixture of EtOH/water at room temperature for 2 h, followed by Fischer indolization in ethyl esters of polyphosphoric acid (PPAEE) at 80°C for 20 min. 140 Also, p-TSOH in refluxing dry benzene 141 and ethanolic HCl at room temperature 142 was performed for the Fischer indolization of aryl hydrazones of ethyl pyruvates.…”

(E)-Methyl 2-[(4-nitrophenyl)hydrazono]propanoate

“…For related literature, see: Humphrey & Kuethe (2006); Tietze et al (2003);Van Order & Lindwall (1942). independent and constrained refinement Á max = 0.29 e Å À3 Á min = À0.29 e Å À3 Table 1 Hydrogen-bond geometry (Å , ).…”