A Novel Cyclisation Strategy for the Synthesis of Lactonamycin: A New Route to Highly Functionalised Heterocyclic Rings

Philip J. Parsons; Johnathan Board; Alexander J. Waters; Peter B. Hitchcock; Florian Wakenhut; Daryl S. Walter

doi:10.1055/s-2006-951542

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Synlett 2006(19): 3243-3246
DOI: 10.1055/s-2006-951542

LETTER

A Novel Cyclisation Strategy for the Synthesis of Lactonamycin: A New Route to Highly Functionalised Heterocyclic Rings

Philip J. Parsons*^a, Johnathan Board^a, Alexander J. Waters^a, Peter B. Hitchcock^a, Florian Wakenhut^b, Daryl S. Walter^c
^a Department of Chemistry, School of LifeSciences, University of Sussex, Falmer, Brighton, East Sussex BN1 9QJ, UK
Fax: +44(1273)678861; e-Mail: P.J.Parsons@sussex.ac.uk;
^b Pfizer Ltd., Ramsgate Road, Sandwich, Kent CT13 9MJ, UK
^c GlaxoSmithKline Research & Development Ltd., New Frontiers Science Park, Third avenue, Harlow, Essex CM19 5AW, UK

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Publication History

Received 8 September 2006
Publication Date:
23 November 2006 (online)

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Abstract

A novel thermal cascade reaction equivalent to the well-known [2+2+2] cycloaddition has been developed which is clean and reliable and does not involve the use of metal ions. This highly efficient method has been used to construct a model for the synthesis of the antibiotic lactonamycin. The utility of this new sequence for the formation of furans is also reported.

Key words

lactonamycin - furan - cascade - cyclisation - thermal

References and Notes

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A typical experimental procedure for the thermal cyclisation is shown below.
Synthesis of 6-Methyl-9-trimethylsilanyl-5,6,9,10-tetrahydrofuro[10,11- e ]isoindol-7-one(15). To 9-trimethylsilanyl-propynoic acid [4-(bromoallyl-oxy)but-2-ynyl]methyl amide (14, 0.342 g, 1.0 mmol) in toluene (10 mL) was added 1-epoxyhexene (1.00 g, 1.21 mL, 10.0 mmol). The solution was stirred at reflux for 1 h, after which time TLC showed the reaction to be complete. Toluene and 1-epoxyhexene were removed in vacuo and the product purified by column chromatography (Et₂O-hexane 7:3) to give the title compound as a bright yellow oil (0.235 g, 0.9 mmol, 90% yield). ¹H NMR (CDCl₃): δ = 7.31 (s, 1 H, C2), 7.14 (s, 1 H, C12), 4.15-4.24 (d, 1 H, J = 18.3 Hz, C5), 3.92-4.01 (m, 1 H, C5), 3.05 (s, 3 H, C13), 2.74-2.91 (m, 2 H, C9, C10), 2.32 (d, 1 H, J = 7.0 Hz, C10), -0.11 (s, 9 H, C14, C15, C16). ¹³C NMR (CDCl₃): δ = 173.6 (C7), 139.8 (C2), 138.3 (C4), 138.0 (C12), 137.1 (C8), 123.3 (C3), 121.4 (C11), 54.4 (C5), 32.0 (C13), 24.6 (C9), 21.9 (C10), 0.0 (C14, C15, C16). IR (neat): 3104, 2953, 2235, 1673, 1562, 851 cm^-1. MS (ES+): m/z = 284 [M + Na].