Structure of a κ-opioid receptor misfit: (1S,5R,8R,9R)-2'-hydroxy-5,9-dimethyl-8,2-epoxyethano-6,7-benzomorphan hydrochloride

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.

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Asymmetric Synthesis of Antimicrotubule Biaryl Hybrids of Allocolchicine and Steganacin

Joncour

Décor

Liu

et al. 2007

Chemistry A European J

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Synthesis and tubulin-binding properties of new allocolchicinoids

Boyer

Dubois

Thoret

et al. 2010

Bioorganic Chemistry

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Structure of a κ-opioid receptor misfit: (1S,5R,8R,9R)-2'-hydroxy-5,9-dimethyl-8,2-epoxyethano-6,7-benzomorphan hydrochloride

Abstract: Abstract. C 16H22NO2+.C1 -, M r --295.808, monoclinic, P21, a = 11.967 (1), b = 12.529 (1), c= 9.9369 (9)A, fl=93.00(1) °, V=1487.8 (2) A 3, Z=4, Din=

Cited by 2 publications

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Asymmetric Synthesis of Antimicrotubule Biaryl Hybrids of Allocolchicine and Steganacin

Asymmetric Synthesis of Antimicrotubule Biaryl Hybrids of Allocolchicine and Steganacin

Synthesis and tubulin-binding properties of new allocolchicinoids

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