Asymmetric synthesis of the allocolchicinoid natural product N-acetylcolchinol methyl ether (suhailamine), solid state and solution phase conformational analysis

Abstract

An asymmetric synthesis of the allocolchicinoid N-acetylcolchinol methyl ether (NCME) from 3-methoxybenzaldehyde is reported. Comparison of 1 H and 13 C NMR spectroscopic data obtained for this sample of NCME provide concrete evidence for the assertion that this compound is congruous with the natural product that has been dubbed suhailamine, establishing NCME as a naturally-occurring allocolchicinoid. The single crystal X-ray diffraction structure of NCME is also reported for the first time, revealing a preference for adoption of the (7S,Ra,Z) form-i.e., describing the orientation of the biaryl axis and the amide N−CO bond as well as the configuration of the stereocenic centre-in the solid state. A preference for the same form in DMSO-d6 solution is revealed upon analysis by a range of NMR spectroscopic techniques, whilst an interconverting 69:24:7 mixture of the (7S,Ra,Z), (7S,Sa,Z) and (7S,Ra,E) forms is observed in CDCl3.

Nickel-Catalyzed Intermolecular Reductive Coupling of Styrene and Its Derivatives with Imines Using Methanol as a Reductant

“…To further demonstrate the synthetic utility of the method, we carried out a gram-scale reaction of 1n and 5l (Scheme 2b). The reaction afforded reductive coupling product 7d in 86% yield, which could be easily deprotected and acylated to generate 9 (for details, see the SI), a known intermediate in the synthesis of N-acetylcolchinol methyl ether (suhailamine), 20 an allocolchicinoid natural product.…”

Gram-Scale, Seven-Step Total Synthesis of (−)-Colchicine

“…Allocolchicinoids ( 2 – 5 ), a new type of synthetic derivatives of colchicine in which the tropolone ring is replaced by a benzene ring, have promising anticancer bioactivities but with reduced toxicity (Figure ). Of note, ZD6126 ( 5 ), developed by AstraZeneca, is a novel vascular-targeting agent that causes selective destruction of tumor vasculature. Although they are void of the exotic tropolone nucleus, allocolchicinoids still pose a surprisingly great synthetic obstacle in previous synthetic routes that normally require 10–20 steps .…”

“… Of note, ZD6126 ( 5 ), developed by AstraZeneca, is a novel vascular-targeting agent that causes selective destruction of tumor vasculature. Although they are void of the exotic tropolone nucleus, allocolchicinoids still pose a surprisingly great synthetic obstacle in previous synthetic routes that normally require 10–20 steps . Taken together, despite being deceptively straightforward in the structures, colchicine ( 1 ) and allocolchicinoids are synthetic challenging targets; especially for colchicine ( 1 ) much attention has been oriented to its total synthesis in recent decades.…”

“…It is noteworthy that the foregoing steps are all construction reactions. To our knowledge, in contrast with the previous syntheses that required 10–20 steps, this 4-step process stands for the most efficient means for allocolchicinoid preparation to date.…”

Synthesis of 1,3-Dioxepine-Fused (Tricyclic) Bispyrazoles Involved with Pyrazolone Derivatives and Dichloromethane

“…To illustrate the utility of the current methodology, further conversion of bis­[(pyrazol-5-yl)­oxy]­methanes 2 to novel 1,3-dioxepine-fused (tricyclic) bispyrazoles 3 was carried out (Scheme ). We optimized the cyclization conditions (see the Supporting Information) and established the optimal one [PhI­(OAc) 2 /AlCl 3 ] for intramolecular oxidative biaryl coupling . Various dipyrazoloxymethanes were cyclized smoothly to give the corresponding 1,3-dioxepine-fused (tricyclic) bispyrazoles ( 3a–3n ) in good to excellent yields.…”