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Synlett 2005(11): 1716-1720  
DOI: 10.1055/s-2005-871554
LETTER
© Georg Thieme Verlag Stuttgart · New York

Asymmetric Ortholithiation of Amides by Conformationally Mediated Chiral Memory: An Enantioselective Route to Naphtho- and Benzofuranones

Jonathan Clayden*a, Christopher C. Stimsona, Martine Keenanb
a School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, UK
Fax: +44(161)2754939; e-Mail: clayden@man.ac.uk;
b Eli Lilly & Co. Ltd., Erl Wood Manor, Windlesham, Surrey GU20 6PH, UK
Further Information

Publication History

Received 15 April 2005
Publication Date:
28 June 2005 (online)

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Abstract

An enantiomerically pure sulfinyl group ortho to an aromatic amide imposes absolute stereochemistry on the conformation of its Ar-CO axis. Sulfoxide-lithium exchange followed by addition to an aldehyde relays the chirality of the amide axis to the new hydroxyl-bearing stereogenic centre with good stereochemical fidelity. Lactonisation of the hydroxyamide gives naphthofuranones and benzofuranones, including the fungal metabolite isoochracein, but with substrate-dependent stereoselectivity.

Key words

chiral memory - amide - sulfoxide - directed metallation - benzofuranone

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17

See ref. 7h. The level of conformational selectivity has recently been determined in related compounds to be of the order of 200:1 (Clayden, J.; Helliwell, M.; Mitjans, D.; Regan, A. C. manuscript in preparation).

19

The major diastereoisomer was identified by comparison with known compounds whose structure had been confirmed by X-ray crystallography (ref. 10). Absolute stereochemistry was deduced from the preferred orientation of amides adjacent to enantiomerically pure sulfoxides and from the absolute stereochemistry of comparable atropisomeric amides obtained by quenching with simple, ‘non-prochiral’ electrophiles (see ref. 7h).

20

An alternative explanation, that the sulfoxide by-product of the reaction, tert-butyl tolyl sulfoxide, which may be generated in enantiomerically pure form, could mediate the asymmetric formation of the new centre, seems unlikely, given this dependence on amide structure.

24

Ortholithiation, addition to aldehydes, and lactonisation under acid conditions is an established way of making benzofuranones from aromatic amides: see ref. 1b and references therein, and ref. 27.