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Synlett 2007(4): 0655-0657  
DOI: 10.1055/s-2007-967971
LETTER
© Georg Thieme Verlag Stuttgart · New York

A Regioselective Total Synthesis of the Fungal Sesquiterpene (±)-Lagopodin A

A. Srikrishna*, R. Ramesh Babu, P. C. Ravikumar
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, India
Fax: +91(80)3600683; e-Mail: ask@orgchem.iisc.ernet.in;
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Publication History

Received 28 November 2006
Publication Date:
21 February 2007 (online)

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Abstract

A highly regiocontrolled total synthesis of fungal ­sesquiterpene lagopodin A, employing a combination of Claisen ­rearrangement-intramolecular diazoketone cyclopropanation and a highly regioselective cyclopropane ring cleavage, is described.

Key words

natural products - total synthesis - rearrangement - ring closure - ring cleavage

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Yields refer to isolated and chromatographically pure compounds. All the compounds exhibited spectral data (IR, 1H NMR, 13C NMR, and HRMS) consistent with their structures.
Selected Spectral Data
Ethyl 3-(2,5-Dimethoxy-4-methylphenyl)-3,4-dimethyl-pent-4-enoate (15): IR (neat): νmax = 1732, 1638, 1505 cm-1. 1H NMR (300 MHz, CDCl3 + CCl4): δ = 6.68 (1 H, s), 6.59 (1 H, s), 4.77 (1 H, s), 4.70 (1 H, s), 3.92-3.80 (2 H, m), 3.75 (3 H, s), 3.69 (3 H, s), 3.35 (1 H, d, J = 13.2 Hz), 2.63 (1 H, d, J = 13.2 Hz), 2.17 (3 H, s), 1.61 (3 H, s), 1.55 (3 H, s), 0.98 (3 H, t, J = 7.2 Hz). 13C NMR (75 MHz, CDCl3 + CCl4): δ = 171.8 (C), 151.9 (C), 151.7 (C), 151.2 (C), 131.2 (C), 125.2 (C), 114.9 (CH), 111.2 (CH), 108.6 (CH2), 59.4 (CH2), 55.8 (CH3), 55.7 (CH3), 45.3 (C), 42.8 (CH2), 25.9 (CH3), 20.5 (CH3), 15.9 (CH3), 14.0 (CH3). HRMS: m/z calcd for C18H26O4Na [M + Na]: 329.1729; found: 329.1733.
4-(2,5-Dimethoxy-4-methylphenyl)-4,5-dimethyl-bicyclo[3.1.0]hexan-2-one (18) - minor isomer: IR (neat): νmax = 1724, 1674, 1505 cm-1. 1H NMR (300 MHz, CDCl3 + CCl4): δ = 7.05 (1 H, s), 6.65 (1 H, s), 3.81 (3 H, s), 3.74 (3 H, s), 2.60 and 2.07 (2 H, 2 × d, J = 18.3 Hz), 2.19 (3 H, s), 1.71 (1 H, dd, J = 8.4, 2.7 Hz), 1.51 (3 H, s), 1.50 (2 H, s), 1.45-1.20 (2 H, m). 13C NMR (75 MHz, CDCl3 + CCl4): δ = 212.5 (C), 152.0 (C), 151.1 (C), 132.0 (C), 125.3 (C), 114.8 (CH), 110.9 (CH), 56.1 (CH3), 55.6 (CH3), 48.5 (CH2), 44.5 (C), 36.1 (C), 35.4 (CH), 25.2 (CH3), 23.8 (CH2), 18.6 (CH3), 16.1 (CH3); major isomer: IR (neat): νmax = 1725, 1666, 1511 cm-1. 1H NMR (300 MHz, CDCl3 + CCl4): δ = 6.78 (1 H, s), 6.65 (1 H, s), 3.80 (3 H, s), 3.66 (3 H, s), 2.29 (1 H, d, J = 18.0 Hz), 2.19 (3 H, s), 2.13 (1 H, d, J = 18.0 Hz), 1.81 (1 H, dd, J = 9.0, 3.0 Hz), 1.56 (3 H, s), 1.20-1.00 (2 H, m), 0.81 (3 H, s). 13C NMR (75 MHz, CDCl3 + CCl4): δ = 212.3 (C), 151.6 (C), 151.2 (C), 132.4 (C), 125.7 (C), 114.3 (CH), 110.9 (CH), 56.1 (CH3), 54.8 (CH3), 49.4 (CH2), 44.0 (C), 38.1 (CH), 35.4 (C), 24.1 (CH3), 19.7 (CH2), 17.3 (CH3), 16.0 (CH3). HRMS: m/z calcd for C17H22O3Na [M + Na]: 297.1467; found: 299.1467.
3-(2,5-Dimethoxy-4-phenyl)-3,4,4-trimethylcyclo-pentanone (11): IR (neat): νmax = 1740, 1714, 1506 cm-1. 1H NMR (300 MHz, CDCl3 + CCl4): δ = 6.70 (1 H, s), 6.65 (1 H, s), 3.76 (3 H, s), 3.67 (3 H, s), 3.19 (1 H, d, J = 18.3 Hz), 2.34 (1 H, d, J = 18.3 Hz), 2.33 (1 H, d, J = 18.0 Hz), 2.18 (3 H, s), 2.10 (1 H, d, J = 18.0 Hz), 1.50 (3 H, s), 1.18 (3 H, s), 0.82 (3 H, s). 13C NMR (75 MHz, CDCl3 + CCl4): δ = 217.1 (C), 151.7 (C), 151.4 (C), 131.1 (C), 125.9 (C), 115.7 (CH), 112.5 (CH), 55.9 (CH3), 55.4 (CH3), 53.2 (CH2), 52.3 (CH2), 48.3 (C), 43.0 (C), 26.1 (2 C, CH3), 25.1 (CH3), 15.9 (CH3). HRMS: m/z calcd for C17H24O3Na [M + Na]: 299.1623; found: 299.1615.

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Varying amount of the corresponding cyclopentanol (by over-reduction) was also obtained, which was reoxidised to ketone 11 with PCC and silica gel.