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Synlett 2004(2): 0291-0294  
DOI: 10.1055/s-2003-45008
LETTER
© Georg Thieme Verlag Stuttgart · New York

3-Substituted and 2,3-Disubstituted Cyclopentanones via an Asymmetric Tandem 1,4-Addition/Dieckmann Cyclization [1]

Ulrich Groth*, Wolfgang Halfbrodt, Aris Kalogerakis, Thomas Köhler, Paul Kreye
Fachbereich Chemie der 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 21 October 2003
Publication Date:
19 December 2003 (online)

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Abstract

A new stereoselective method for the synthesis of 3-substituted and 2,3-disubstituted cyclopentanones is described. The key step is the 1,4-addition of a cuprate to a chilar Michael-acceptor derived from (-)-8-phenylmenthol or the Helmchen auxiliary followed by Dieckmann cyclization of the obtained chiral enolates. The resultant 2,3-cyclopentanones can be transformed after methanolysis and demethoxycarbonylation to the related 3-substituted ­cyclopentanones.

Key words

asymmetric synthesis - cyclopentanones - cuprate - chiral auxiliary - 1,4-addition - Dieckmann cyclization - natural products

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Vinyllithium was prepared via reaction of tetravinyltin with n-BuLi.

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Experimental Procedure: A solution of 10.0 mmol organolithium compound in Et2O (10 mL) was added to a solution of 5.0 mmol copper(I) cyanide in Et2O (10 mL)at
-80 °C. After 2 h stirring 5.0 mmol BF3·Et2O were added and the resultant mixture was cooled at -95 °C. A solution of 1.0 mmol chiral enoate 5 in Et2O (10 mL) was added via canulla and the obtained mixture was allowed to warm under stirring to r.t. (18 h). The reaction mixture was quenched with aq sat. NH4Cl solution (30 mL), extracted with Et2O (2 × 20 mL), the combined organic layer dried over MgSO4 and evaporated in vacuum. Purification of the residue by flash chromatography provided the 2,3-substituted cyclopentanone 7.
Analytical data of selected compounds (Figure [1] ).
Compound 7e: Rf 0.41 (Et2O-petroleum ether, 1:5). IR(film): 3040 (alkene CH), 1740 (C=O), 1725 (OC=O), 1650 (alkene C=C), 1610 (arom. C=C) cm-1. 1H NMR (250 MHz, CDCl3): δ = 0.87 (d, 3 J = 6.5 Hz, 1 H, H-5′), 1.19 (s, 3 H, CH3), 1.27 (s, 3 H, CH3), 0.80-1.84 (m, 7 H, H-1′, H-3′, H-4′, H-6′), 1.88-2.40 (m, 3 H, H-4, H-5, H-2′), 3.46 (d,
3 J = 11 Hz, 1 H, H-2), 2.83-3.05 (m, 1 H, H-3), 4.81 (ddd,
3 J = 10.5, 10.5, 4 Hz, 1 H, COOCH, H-1′), 5.09 (ddd, J cis = 10 Hz, J = 1.5, 1.5 Hz, 1 H, CH=CH2), 5.125 (ddd, J trans = 17 Hz, J = 1.5, 1.5 Hz, 1 H, CH=CH2), 5.745 (ddd, J trans = 17 Hz, J cis = 10 Hz, J = 7 Hz, 1 H, CH=CH2), 7.06-7.20 (m, 1 H, arom. H), 7.23-7.38 (m, 4 H, arom. H). 13C NMR (62.5 MHz, CDCl3): δ = 21.74 [22.75] (CH3), 25.68 (CH3), 26.58 (cyclopentane-CH2), [26.43] 26.65 (cyclohexane-CH2), 27.37 [27.51] (CH3), [29.52] 31.28 (CHCH3, C-5′), 34.52 [34.68] (cyclohexane-CH2), 37.79 [38.25] (cyclopentane-CH2), 39.70 [39.87] (C(CH3)2), 41.38 [41.73] (cyclohexane-CH2), 43.73 [46.20] (CHCH=CH2, C-3), 49.96 [50.48] (C-2¢), 60.90 [62.07] (COCHCO, C-2), 75.96 [76.30] (C-1′), 115.78 [116.24] (CH = CH2), 124.87 [125.18], 125.45 [125.56], [127.84] 127.97 (3 × C-arom.), 138.62 [140.67] (CH=CH2), 151.51 (C-arom.), 167.34 [168.13] (COO), 210.22 (CO) (signals of the 2R,3S-configured diastereomer in brackets). EI-MS (70 eV): m/z (100) = 119 [PhC(CH3)2] (100), 249 (4) [M+ - PhC(CH3)2)], 368 (2) [M+]. Anal. Calcd for C24H32O3 (368.5): C, 78.22; H, 8.75. Found: C, 78.39; H, 8.85.
Compound 7f (Table 1, entry 11): Rf 0.46 (Et2O-petroleum ether, 1:1); mp: 59-63 °C. IR(nujol): 3060, 3040 (arom. CH), 1750 (C=O), 1730 (OC=O), 1640 (C=C), 1610, 1595 (arom. C=C), 1350, 1165 (CSO2N) cm-1. 1H NMR (250 MHz, CDCl3): δ = 0.82 (s, 3 H, CH3), 0.88 (s, 3 H, C-1-CH3), 1.04 (s, 3 H, CH3), 0.90-2.45 (m, 9 H, CH, CH2), 2.02 (s, 3 H, arom. CH3), 2.32 (s, 3 H, arom. CH3), 3.33 (d, J trans = 11.2 Hz, 1 H, H-2′), 3.34-3.50 (m, 1 H, H-3′), 4.25 (ddd, J = 8.8 Hz, J = 3.4 Hz, 4 J = 1.0 Hz, 1 H, H-3), 5.11 (ddd, J cis = 10.6 Hz, 2 J = 1.2 Hz, 4 J = 1.2 Hz, 1 H, CH=CH2), 5.27 (ddd, J trans = 17.0 Hz, 2 J = 1.2 Hz, 4 J = 1.2 Hz, 1 H, CH=CH2), 5.46 (d, J = 8.8 Hz, 1 H, H-2), 5.78 (s, 1 H, arom. H), 5.98 (ddd, J trans = 17.0 Hz, J cis = 10.6 Hz, J = 6.6 Hz, 1 H, CH=CH2), 6.83 (s, 1 H, arom. H), 7.11 (s, 1 H, arom. H), 7.28-7.57 (m, 5 H, arom. H). 13C NMR (62.5 MHz, CDCl3): δ = 14.30 (C-10), 19.41 (C-8), 19.51 (C-9), 19.69 (C-5), 20.98, 21.29 (2 × arom. CCH3), 26.59 (C-6), 26.62 (C-4′), 38.13 (C-5′), [35.53] 43.46 (C-3′), 45.71 (C-7), 49.38 (C-4), 51.30 (C-1), 59.35 (C-3), 60.77 [63.27] (C-2′), 77.59 (C-2), 115.38 (CH=CH2), 127.49, 128.12, 129.33, 129.89, 132.46 (arom. C), 138.64 (CH=CH2), 136.98, 137.05, 138.16, 139.04 (arom. C), 167.88 (CHCOO), 210.70 [212.35] (C=O) (signals of the 2′R,3′S-configured diastereomer in brackets). EI-MS (70 eV): m/z (%) = 549 (3) [M+], 395(11) [M+ - C8H10O3], 254 (100) [M+ - C8H10O3 - SO2C6H5], 105 (22) [C8H9 +]. Anal. Calcd for C32H39O5NS (549.7): C, 69.92; H, 7.15. Found: C, 69.87; H, 7.28.
Compound 8e (Table 2, entry 5): Rf 0.31 (Et2O-petroleum ether, 1:2). [α]D 20 +82.3 (c 1.5, CHCl3). Bp. 65-70 °C (2 torr). IR(film): 3065 (alkene CH), 1750 (C=O), 1730 (OC=O), 1635 (C=C) cm-1. 1H NMR (250 MHz, CDCl3):
δ = 1.54-1.86 (m, 1 H, CH), 2.16-2.60 (m, 3 H, CH, CH2), 3.03 (dd, 3 J = 11.6 Hz, 4 J = 0.6 Hz, 1 H, C-2-H), 3.14-3.29 (m, 1 H, C-3-H), 3.76 (s, 3 H, OCH3), 5.10 (ddd, 3 J cis = 10.0 Hz, 2 J = 1.2 Hz, 4 J = 1.2 Hz, 1 H, CH=CH2), 5.17 (ddd,
3 J trans = 17.0 Hz, 2 J = 1.2 Hz, 4 J = 1.2 Hz, 1 H, CH=CH2), 5.84 (ddd, 3 J trans = 17.0 Hz, 3 J cis = 10.0 Hz, 3 J = 6.6 Hz, 1 H, CH=CH2). 13C NMR (62.5 MHz, CDCl3): δ = 27.25 (C-4), 38.12 (C-5), 44.83 (C-3), 52.48 (OCH3), 60.77 (C-2), 115.95 (CH=CH2), 135.95 (CH=CH2), 169.10 (COOCH3), 210.71 (C-1). EI-MS (70 eV): m/z (%) = 168 (86) [M+], 137 (85) [M+ - OCH3], 109 (90) [M+ - COOCH3], 81 (100) [M+ - C2H3O2 - C2H3 - H]. HRMS: m/z calcd for C9H12O3 (168.2): 168.0786; found: 168.0786.
Compound 10e (Table 2, entry 5): Rf 0.41 (Et2O-petroleum ether, 1:10). [α]D 20 +3.3 (c 1.4, CHCl3). IR(film): 3065 (alkene CH), 1635 (C=C) cm-1. 1H NMR (250 MHz, CDCl3): δ = 1.21-1.27 (m, 6 H, CH3), 1.31-2.08 (m, 6 H, CH2), 2.46-2.74 (m, 1 H, CHCH=CH2), 3.47-3.66 (m, 2 H, OCH), 4.91 (ddd, 3 J cis = 10.0 Hz, 2 J = 1.5 Hz, 4 J = 1.5 Hz, 1 H, CH=CH2), 5.00 (ddd, 3 J trans = 17.2 Hz, 2 J = 1.5 Hz, 4 J = 1.5 Hz, 1 H, CH=CH2), 5.79 (ddd, 3 J trans = 17.2 Hz, 3 J cis = 10.0 Hz, 3 J = 7.2 Hz, 1 H, CH=CH2). 13C NMR (62.5 MHz, CDCl3): δ = 16.86 (CH3), 16.95 (CH3), 30.57, 37.98 (CH2), 42.16 (C-7), 44.43 (CH2), 78.21 (CHCH3), 78.26 (CHCH3), 113.07 (CH=CH2), 116.84 (OCO), 141.98 (CH=CH2). EI-MS (70 eV): m/z (%) = 182 (3) [M+], 114 (100) [C6H10O2 +], 54 (26) [C4H8 +]. Anal. Calcd for C11H18O2 (182.3): C, 72.49; H, 9.95. Found: C, 72.36; H, 9.84.

20

For 9c (R = t-Bu): [α]D 20 = +134.8 (c 1.13, CHCl3); ref.19b