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

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.

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

References

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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: R_f 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): R_f 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): R_f 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): R_f 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.

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