Asymmetric Synthesis of Antimicrotubule Biaryl Hybrids of Allocolchicine and Steganacin

Abstract

The asymmetric synthesis of novel axially chiral biaryl compounds 5 a-f containing a seven- or eight-membered heterocyclic medium ring is described. These molecules can be considered to be structural hybrids of allocolchicine- and steganacin-type natural products. The synthesis featured an atropo-diastereoselective biaryl Suzuki coupling in which a benzylic stereocenter efficiently transferred its stereochemical information to the biaryl axis. The coupling conditions were optimized, and two biphenylphosphane ligands (DavePhos and S-Phos) were found to give the highest yields and diastereoselectivities. A three-element stereochemical model was proposed to explain the observed diastereoselectivities. In a second key step, the medium ring of the target molecules was formed by a stereoselective S(N)1-type cyclodehydration that probably involved a configurationally stable carbocationic intermediate, as supported by calculations. Alternatively, S(N)2-type cyclizations were employed on the same Suzuki coupling products to give the target molecules in a stereodivergent or stereoconvergent manner. These cyclization methods furnished the target hybrid analogues 5 a-f with ee values above 94 %. All analogues were evaluated as antimicrotubule agents and against a panel of cancer-cell lines using colchicine (1) and N-acetylcolchinol (3) as references. Promising activities were found for R,aR-configured compounds 5 a, b and 5 f; in particular, ethyl analogue 5 b showed a twofold antimicrotubule activity relative to colchicine.

Enantioselective Synthesis of Axially Chiral Biaryls by the Pd-Catalyzed Suzuki−Miyaura Reaction: Substrate Scope and Quantum Mechanical Investigations

“…Despite increasing interest in the enantioselective Pd-catalyzed Suzuki-Miyaura coupling reaction with a range of ligands, computational studies to understand the origin of the selectivity in these processes are limited to a single molecular mechanics study by Baudoin 70. We have performed computational studies to understand why aryl halides bearing an ortho functional group with a potentially coordinating oxygen atom on either a phosphonate or amide substituent provide the highest ee values in the reaction and to understand how enantioselectivity is induced by the ligand.…”

Synthesis and application of 3‐substituted (S)‐BINOL as chiral ligands for the asymmetric ethylation of aldehydes

“…To our disappointment, only an acceptable enantiomeric excess was gained in the case of 2‐furaldehyde (entry 18). Asymmetric ethylation of piperonal proceeded effectively to generate ( S )‐1‐(benzodioxol‐5‐yl)‐1‐propanol with 82% ee (entry 19), which is ubiquitous in the fragments of many bioactive molecules and fine chemicals 52, 53…”

Synthesis of indole-derived allocolchicine congeners exhibiting pronounced anti-proliferative and apoptosis-inducing properties

“…(2) 19 and its analogues [9][10][11][20][21][22][23][24][25][26][27] were identified as promising candidates for further development. Recently, our group reported on the synthesis and biological evaluation of a series of heterocyclic allocolchicine congeners (for instance 3 and 4; Figure 1), in which ring C of the parent compound 2 is replaced by an indole 28,29 or a benzofurane 30 pharmacophore.…”