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Synlett 2006(14): 2223-2226  
DOI: 10.1055/s-2006-949653
LETTER
© Georg Thieme Verlag Stuttgart · New York

Total Synthesis of (-)-Chokol A by an Asymmetric Domino Michael Addition-Dieckmann Cyclization [1]

Ulrich Groth*, Christian Kesenheimer, Paul Kreye
Fachbereich Chemie, Universität Konstanz, Universitätsstraße 10, Postfach M-720, 78457 Konstanz, Germany
Fax: +49(7531)884155; e-Mail: ulrich.groth@uni-konstanz.de;
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Publication History

Received 31 May 2006
Publication Date:
24 August 2006 (online)

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Abstract

A convergent and asymmetric total synthesis of (-)-chokol A was accomplished in six steps starting from the α,β-unsaturated ester (E)-9 in an overall yield of 27% with an enantiomeric excess of 95%. The key step of this synthesis is the asymmetric tandem conjugate addition-Dieckmann cyclization of the higher-order cuprate 8 derived from vinyl bromide 7 with the α,β-unsaturated ester (E)-9.

Key words

antifungal agents - asymmetric synthesis - Michael addition - tandem reaction - total synthesis

11

(1 S ,2 S ,1′ R ,2′ S ,5′ R )-2-[1-(3-Benzyloxypropyl)vinyl]-5-oxocyclopentanecarboxylic Acid [5′-Methyl-2′-(1-methyl-1-phenylethyl)]cyclohexyl Ester ( 10a) To a solution of 2.55 g (10.0 mmol) 2-bromopentenylbenzyl ether (7) in 20 mL of abs. Et2O 10.0 mL (20.0 mmol, 2 M solution in Et2O) of t-BuLi was slowly added at -90 °C and stirred then at this temperature for 90 min. The resulting organolithium compound was then added at -80 °C via canula to a suspension of 0.45 g (5.0 mmol) copper(I) cyanide in 10 mL Et2O and stirred then for 2 h until the temperature reached -30 °C and the suspension turned into a bright-green solution. After cooling the solution again to
-80 °C 0.64 mL (5.0 mmol) BF3·OEt2 were added by syringe and stirred for 15 min, whereupon the solution was cooled to -115 °C by an EtOH-dry ice bath. After reaching this temperature a degassed solution of 0.37 g (1.0 mmol) of the chiral ester 9 in 10 mL Et2O was added (very) slowly to the solution of the higher order cuprate 8 and the resulting reaction solution was then stirred for 12 h under warming to r.t. For the work-up 30 mL of a sat. NH4Cl solution were added to the black suspension, stirred for 2-3 min and then filtered over Celite®. After phase separation the aqueous phase was extracted 3 times with 25 mL portions of Et2O. The combined organic phases were dried over MgSO4 and concentrated with a rotary evaporator at 30 °C/13 mbar. The resulting residue was then purified via column chromatography over 200 g silica gel with PE-Et2O = 2:1 as eluent, which gave 0.48 g (0.93 mmol, 93% yield) of the compound 10a (Figure [2] ). The diastereomeric excess was determined to be >95% by 13C NMR spectroscopy. R f = 0.35 (PE-Et2O = 2:1). 1H NMR (200 MHz, CDCl3): δ = 0.85 (d, 3 H, -CH3, J = 6.3 Hz), 1.18 (s, 3 H, -CH3), 1.26 (s, 3 H, -CH3), 1.34-2.39 (m, 18 H, H2-H4, H1′-H6′ and H2′′-H3′′), 2.86-2.88 (m, 1 H, H1), 3.5 (t, 2 H, H4′′, J = 6.2 Hz), 4.52 (s, 2 H, -CH2Ph), 4.76-4.83 (m, 2 H, C=CH2), 7.06-7.50 (m, 10 H, 2 × Ph). 13C NMR (50.3 MHz, CDCl3): δ = 21.71 (C5′-CH3), 26.29 [C2′-C(CH3)2Ph], 26.56 (C3′), 26.83 [C2′-C(CH3)2Ph], 26.90 (C3′′), 27.96 (C5′), 30.96 (C3), 31.25 (C2′), 34.48 (C4′), 38.09 (C4), 39.81 [C2′-C(CH3)2Ph], 41.22 (C2), 45.13 (C6′), 49.90 (C2′), 60.35 (C1), 69.66 (C4′′), 72.91 (OCH2Ph), 76.27 (C1′), 109.38 (C1′′=CH2), 124.90 (Cpara,Ph), 125.42 (Cortho,Ph), 127.48 (Cpara,Bn), 127.55 (Cortho,Bn), 127.92 (Cmeta,Ph), 128.30 (Cmeta,Bn), 138.42 (C1Bn), 148.38 (C1′′), 151.21 (C1Ph), 167.49 (-CO2R), 210.23 (C5). MS (EI, 70eV): m/z (%) = 516.4 (0.1) [M+], 302.2 (52.0) [M+ - C16H22], 119.1 (50.0) [Ph-C(CH3)2 +], 91.1 (100.0) [C7H7 +]. IR (film): 3020, 3005 (C=CH2), 1745 (C=O), 1710 (-CO2R), 1640 (C=C) cm-1. [a]D 20 +4.21 (c 1.13, CHCl3). Anal. Calcd for C34H44O4: C, 79.03; H, 8.58. Found: C, 78.90; H, 8.71.