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Synthesis 2010(17): 2935-2942  
DOI: 10.1055/s-0030-1257890
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

Tetrahydropyran Synthesis by Intramolecular Conjugate Addition to Enones: Synthesis of the Clavosolide Tetrahydropyran Ring

Roderick W. Bates, Ping Song
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, 21 Nanyang Link, Singapore 637371
Fax: +65 67911961; e-Mail: Roderick@ntu.edu.sg;
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Publication History

Received 17 February 2010
Publication Date:
22 July 2010 (online)

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Abstract

The synthesis of a tetrahydropyran intermediate for ­clavosolide A is reported, employing a combination of cross-­metathesis and intramolecular oxa-Michael addition. The intramolecular oxa-Michael addition to α,β-unsaturated esters requires the use of strong bases and can result in either modest yields or stereoisomeric mixtures, and can be highly variable according to the substrate structure. In contrast, the corresponding ketones cyclise under very mild conditions to give the 2,6-cis-isomers directly. The use of appropriately substituted ketones allows efficient conversion into esters.

Key words

Michael addition - tandem reaction - cyclisation

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13

Data for the trans-isomer of tetrahydropyran 2: [α]D ²5 +90.6 (c 0.28, CH2Cl2). IR (neat): 3054, 2952, 2926, 2855, 1714, 1434, 1315, 1200, 1177, 1098, 898 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 0.99 (3 H, d, J = 6.9 Hz), 1.20-1.32 (2 H, m), 1.47 (1 H, d, J = 3.0 Hz), 1.75-1.91 (2 H, m), 1.99 (1 H, ddd, J = 12.5, 4.3, 2.6 Hz), 2.44 (1 H, dd, J = 14.5, 4.4 Hz), 2.65 (1 H, dd, J = 14.5, 11.0 Hz), 3.48-3.62 (3 H, m), 3.66 (3 H, s), 3.85-3.89 (1 H, m), 4.43 (1 H, ddd, J = 10.8, 5.1, 4.9 Hz), 4.48 (1 H, d, J = 11.8 Hz), 4.54 (1 H, d, J = 11.8 Hz), 7.26-7.36 (5 H, m). ¹³C NMR (75 MHz, CDCl3): δ = 172.0, 138.5, 128.4, 127.7, 127.5, 73.9, 73.1, 69.7, 66.9, 66.7, 51.7, 41.0, 40.4, 36.0, 33.4, 13.1. MS (EI): m/z = 345 (M + Na), 323 (M + H), 214. HRMS (EI): m/z calcd for C18H27O5 (M + H): 323.1858; found: 323.1859.

17

The enantiomer was prepared by White et al. (ref. 5b).