Elsevier

Tetrahedron Letters

Volume 42, Issue 20, 14 May 2001, Pages 3407-3410
Tetrahedron Letters

Synthesis of a potent (±)-4-(2-hydroxyphenyl) analogue of the acromelic acids by dearomatising cyclisation of a lithiated N-p-methoxybenzyl-4-methoxy-1-naphthamide

https://doi.org/10.1016/S0040-4039(01)00501-9Get rights and content

Abstract

Dearomatising anionic cyclisation of N-cumyl-N-p-methoxybenzyl-4-methoxy-1-naphthamide 8 diastereoselectively generates a pyrrolidinone-fused tetralone 12 which may be transformed in seven steps to the racemic form of a known non-natural member of the aryl kainoid family 4 having potent biological activity. Key steps of the synthesis are ruthenium-catalysed oxidation of the C2-p-methoxybenzyl ring of 12 to a carboxylic acid and Baeyer–Villiger cleavage of the tetralone to a lactone whose hydrolysis reveals the two-carbon substituent at C3 and the 2-hydroxyphenyl substituent at C4. Selective reduction of the lactam yields the kainoid 4. Control of epimerisation at the C-4 centre during the lactone hydrolysis leads to either the (active) 3,4-cis or the (inactive) 3,4-trans epimers of the target.

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Acknowledgements

The authors are grateful to the EPSRC for studentships (to A.A. and R.A.B.), to the Leverhulme Trust for a grant, to Merck, Sharp and Dohme and to Oxford Asymmetry International for support, and to Drs. M. Rowley and O. Ichihara for many helpful and illuminating discussions.

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