Asymmetric 1,4-Reductions of Hindered β-substituted Cycloalkenones Using Catalytic CuH

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1 Asymmetric 1,4-Reductions of Hindered β-substituted Cycloalkenones Using Catalytic CuH Bruce H. Lipshutz,* Jeff M. Servesko, Tue B. Petersen, Patrick P. Papa, Andrew Lover Department of Chemistry & Biochemistry University of California Santa Barbara, CA Supporting Information

2 4 Representative procedure for the asymmetric hydrosilylation of isophorone (1,000 : 1 S / L). To a 5 ml round bottomed flask, flame dried and purged with argon, was added CuH PPh 3 (4 mg, mmol) and (R)-DTBM-SEGPHS (2.8 mg, mmol). Et 2 (2.5 ml) was added and the solution cooled to 35 o C. PMHS (312 µl, 4.8 mmol) was introduced via syringe and then isophorone (neat, 325 µl, 2.4 mmol) was added. The mixture was stirred at 35 o C for 12 h until the reaction was complete by TLC (20% Et 2 / ligroin). The mixture was quenched by pouring unto 3 M NaH and then diluted with Et 2 / H 2 and stirred for 2 h at rt. The aqueous layer was extracted twice with Et 2 and the combined organic layers were washed with brine, dried over anhydrous MgS 4, filtered, and concentrated by rotary evaporation with caution due to slight volatility. The residue was purified by flash chromatography (10% Et 2 / ligroin) to afford the product ketone (302 mg, 90%) as a clear oil. TLC R f = 0.5 (20% Et 2 / ligroin). Analysis by chiral GC (Chiraldex B-DM 75) indicated an ee of 98%. IR (neat): ν = 2956, 1713, 1274 cm -1 ; 1 H NMR (400 MHz, C 6 D 6 ): δ = 0.87(s, 3H), 1.01(d, J = 6.4 Hz, 3H), 1.05 (s, 3H), 1.29(dd, J = 12.8, 12.7 Hz, 1H), 1.57(m, 1H), 1.89(dd, J = 13.1, 12.8 Hz, 1H), 2.00(m, 1H), 2.05(ddd, J = 13.2, 2.3, 2.2 Hz, 1H), 2.15(d, J = 13.2 Hz, 1H), 2.31(m, 1H); 13 C NMR (125 MHz, CDCl 3 ): δ = 22.33, 25.64, 29.55,31.96, 35.15, 47.00, 49.09, 54.03, ; EIMS m/z (%) 140(M +, 25) 125(15), 83(100), 69(50), 55(36); HREIMS calcd for C 9 H 16 : ; found [α] D = o (c = 1.1, CHCl 3 ). 3 (R)-3-Methylcyclohexanone (3). Following the standard procedure, the following amounts were used: (R)-DTBM-SEGPHS (2.0 mg, mmol), Stryker s reagent (6.4 mg, mmol), pinacol borane (0.42 ml, 3.0 mmol), PhMe (2.0 ml), enone (neat, 0.22 ml, 2.0 mmol). Yield 184 mg, clear oil, 96%; chiral GC (Chiraldex G-TA 50) showed 90% ee. [α] D = o (c = 1.5,CHCl 3 ). Spectral data matched commercially available material. 2

3 Ph 5 3,3-Dimethyl-5-(2-phenylethyl)cyclohexanone. Following the standard procedure, the following amounts were used: (R)-DTBM-SEGPHS (1.9 mg, mmol), Stryker s reagent (2.3 mg, mmol), PMHS (215 µl, 3.3 mmol), PhMe (0.60 ml), enone (neat, 192 mg, 0.84 mmol). Yield 185 mg, clear oil, 95%; chiral GC (ketal from (R,R)-2,3-butanediol, Chiraldex B-DM 140) showed 99.5% ee. IR (neat) 3031, 2952, 1712, 1459, 1282, 1125, 749, 701 cm -1 1 H NMR (CDCl 3, 400 MHz) δ 0.88 (s, 3H), 1.09 (s, 3H), 1.35 (t, J = 12.4 Hz, 1H), (m, 3H), (m, 2H), 2.10 (ddd, J = 13.2, 2.2, 2.2 Hz, 1H), 2.21 (d, J = 13.2 Hz, 1H), 2.44 (ddd, J = 9.2, 2.0, 2.0 Hz, 1H), 2.64 (t, J = 8.2 Hz, 2H), (m, 5H) 13 C NMR (CDCl 3, 125 MHz) δ 25.97, 32.34, 33.24, 34.61, 35.43, 39.28, 45.29, 47.55, 54.72, , , , , EIMS m/z 230(M +,15), 215(20), 152(5), 138(9), 125(100), 91(63), 83(14), 69(10), 55(17) HRMS Calcd for C 16 H ; found Bu-n (R)-3-Butylcyclohexanone (6). Following the standard procedure, the following amounts were used: (R)-DTBM-SEGPHS (2.0 mg, mmol), Stryker s reagent (6.4 mg, mmol), pinacol borane (0.42 ml, 3.0 mmol), PhMe (2.0 ml), enone (neat, 304 mg, 2.0 mmol). Yield 277 mg, clear oil, 90%; chiral GC (Chiraldex B-DM 50) showed 96.0% ee. Spectral data matched previous literature values. 2 (R)-3,3,5-trimethylcyclohexanone (275,000 : 1 isophorone : ligand 1). Following the standard procedure, the following amounts were used: (R)-DTBM-SEGPHS (2.0 mg, mmol), CuCl (426.0 mg, 4.3 mmol), Na-t-Bu (412 mg, 4.3 mmol), PMHS (56 ml, 938 mmol), PhMe (215 ml), enone (neat, g, 469 mmol). Yield: g, clear oil, 88% (distilled). Chiral GC (Chiraldex B- DM 75) showed 98.5% ee. [α] D = o (c = 1.1, CHCl 3 ). 3

4 C 2 Me 7 (S)-Methyl 3-(3-oxocyclopentyl)propanoate. Following the standard procedure, the following amounts were used: (R)-DTBM-SEGPHS (2.7 mg, mmol), Stryker s reagent (1.9 mg, mmol), PMHS (77 µl, 1.2 mmol), THF (1.0 ml), enone (neat, 100 mg, 0.60 mmol). Yield 95mg, clear oil, 94%; chiral GC (Chiraldex G-TA 120) showed 97.0% ee. [α] D = +44 o (c = 0.9,CHCl 3 ). 1 IR (neat) 2952, 1739, 1442, 1168 cm -1 1 H NMR (C 6 D 6, 500 MHz) δ 0.78 (ddd, J = 11.0, 8.4, 2.5 Hz, 1H), (m, 3H), (m, 2H), (m, 1H), 1.85 (dddd, J = 18.0, 8.3, 3.2, 1.0 Hz, 1H), (m, 1H), 1.91 (t, J = 7.5 Hz, 2H), 3.35 (s, 3H) 13 C NMR (C 6 D 6, 125 MHz) δ 29.42, 30.97, 32.67, 36.79, 38.51, 44.73, 51.40, , EIMS m/z 170(3), 152(6), 139(23), 96(75), 83(100), 74(41), 55(68) HRMS Calcd for C 9 H (M + + H); found Ph (S)-3-Benzylcyclopentanone (8). Following the standard procedure, the following amounts were used: (R)-DTBM-SEGPHS (2.0 mg, mmol), CuCl (1.0 mg, mmol), Na-t-Bu (1.0 mg, mmol), PMHS (204 µl, 3.1 mmol), PhMe (1.50 ml), enone (neat, 71 mg, 0.41 mmol). Yield 64 mg, clear oil, 92%; chiral GC (Chiraldex G-TA 120) showed 97.3% ee. [α] D = +89 o (c = 1.7,CHCl 3 ). 1 IR (neat) 3027, 2924, 1741, 1454, 1157, 701 cm -1 1 H NMR (C 6 D 6, 500 MHz) δ (m, 1H), (m, 1H), 1.45 (dd, J = 17.7, 9.9 Hz, 1H), (m, 1H), (m, 1H), (m, 2H), 2.21 (dd, J= 13.4, 7.3 Hz, 1H), 2.23 (dd, J = 13.4 Hz, 7.5 Hz, 1H), (m, 5H) 13 C NMR (C 6 D 6, 125 MHz) δ 29.31, 38.40, 39.05, 41.90, 44.97, , , , , EIMS m/z 174(45), 117(16), 91(100), 83(37), 65(13), 55(54) 4

5 HRMS Calcd for C 12 H ; found (M + ) 9 C 6 H 13 -n (R)-3-Heptylcyclopentanone. Following the standard procedure, the following amounts were used: (R)-DTBM-SEGPHS (5.2 mg, mmol), CuCl (1.1 mg, mmol), NaMe (0.59 mg, mmol), PMHS (144 µl, 2.2 mmol), PhMe (1.00 ml), enone (neat, 200 mg, 1.1 mmol). Yield 196mg, clear oil, 97%; chiral GC (Chiraldex G-TA 120) showed 97.5% ee. IR (neat) 2925, 1743, 1460, 1157 cm -1 1 H NMR (C 6 D 6, 500 MHz) δ 0.94 (t, J = 7.1 Hz, 3H), (m, 14H), (m, 2H), 1.73 (m, 1H), 1.96 (dd, J = 17.7, 6.9 Hz, 1H), 2.06 (dd, J = 17.7, 7.6 Hz) 13 C NMR (C 6 D 6, 125 MHz) δ 14.69, 15.90, 23.43, 28.47, 29.86, 32.56, 36.19, 37.44, 38.59, 45.32, 53.67, EIMS m/z 182(15), 149(5), 125(5), 111(8), 97(17), 83(100), 69(31), 55(54), 43(57) HRMS Calcd for C 12 H (M + + H); found ,3-Dimethyl-5-(3-butene)cyclohexanone. Following the standard procedure, the following amounts were used: (R)-DTBM-SEGPHS (2.4 mg, mmol), CuCl (1.0 mg, mmol), Na-t-Bu (5.8 mg, mmol), PMHS (130 µl, 2.0 mmol), THF (0.50 ml), enone (neat, 178 mg, 1.0 mmol). Yield: 160mg, clear oil, 90%; chiral GC (Chiraldex G-TA 90) showed 99.5% ee. IR (neat) 3074, 2950, 1712, 1452, 902 cm -1 1 H NMR (CDCl 3, 500 MHz) δ 0.84 (s, 3H), 1.03 (s, 3H), 1.26 (dd, J=12.6, 12.3), (m, 1H), 1.60 (m, 1H), (m, 2H), 2.05 (m, 3H), 2.15 (d, J=13.3, 1H), 2.34 (dt, J=9.3, 1.8, 1H), 4.93(ddt, J=10.1, 2.9, 1.1, 1H), 4.98 (ddt, J=17.1, 3.4, 1.7, 1H), 5.75 (m, 1H) 5

6 13 C NMR (CDCl 3, 50 MHz) δ , , , 54.67, 47.40, 45.30, 36.44, 35.34, 34.05, 32.29, 31.00, EIMS m/z 180(M +, 6), 165(12), 138(33), 125(42), 83(80), 55(49), 49(100) HRMS Calcd for C 12 H ; found General procedure for the synthesis of β-substituted-α,β-unsaturated ketones. 5,5-Dimethyl-3-(2- phenylethyl)cyclohex-2-enone: Mg turnings (1.27 g, 52.2 mmol), THF (15.0 ml) and phenethyl bromide (1.27 ml, 9.33 mmol) were mixed in a 50 ml round-bottom flask. The resulting dark mixture was transferred via syringe into a solution of 5,5-dimethyl-3-ethoxycyclohex-2-enone (0.67 g, 3.99 mmol) in THF (3.0 ml) at 0 C, allowed to reach rt, and stirred overnight. Quenching with 1 M HCl, extracting with Et 2, washing with brine, drying over anhydrous MgS 4, concentrating in vacuo and purifying by flash chromatography (5:1 pet ether:etac) yielded 0.64 g (2.82 mmol, 71%) of the title compound as a clear oil. IR (neat) 3020, 2952, 1669, 1448, 1365, 1296, 897, 689 cm -1 1 H NMR (CDCl 3, 500 MHz) δ 1.02 (s, 6H), 2.19 (s, 2H), 2.20 (s, 2H), 2.49 (t, J = 8.0 Hz, 2H), 2.80 (t, J = 8.0 Hz, 2H), 5.89 (tt, J = 1.5, 1.5 Hz, 1H), (m, 5H) 13 C NMR (CDCl 3, 125 MHz) δ 28.28, 33.18, 33.53, 39.53, 44.01, 51.00, , , , , , , MS (EI) m/z 228(16), 213(3), 172(5), 129(9), 91(100), 65(6) HRMS calcd for C 16 H ; found (M + ) 5,5-Dimethyl-3-(3-butenyl)cyclohex-2-enone: The general procedure for the preparation of substrates using 4-bromobutene (1.9 ml, 18.7 mmol) and 5,5-dimethyl-3-methoxycyclohex-2-enone (1.45 g, 9.37 mmol) gave, after flash chromatography (5:1 pet ether:etac), the title compound as a clear oil (0.91 g, 55%). Spectroscopic data were consistent with previously reported data for this compound. 3 3-Benzylcyclopent-2-enone: The general procedure for the preparation of substrates using benzyl bromide (360 µl, 3.0 mmol) and 3-ethoxycyclopent-2-enone (194 mg, 1.5 mmol) gave, after flash chromatography (1:1 hexanes:etac), the title compound as a clear oil (214 mg, 80%). Spectroscopic data were consistent with previously reported data for this compound. 4 6

7 3-Heptylcyclopent-2-enone: The general procedure for the preparation of substrates using 1- bromoheptane (1.4 ml, 8.9 mmol) and 3-methoxycyclopent-2-enone (294 mg, 2.6 mmol) gave, after flash chromatography (3:1 pet ether:etac), the title compound as a clear oil (324 mg, 68%). Spectroscopic data were consistent with previously reported data for this compound. 5 Methyl 3-(3-oxocyclopent-1-enyl)propionate: Prepared according to a published procedure. 6 Spectroscopic data were consistent with previously reported data for this compound Moritani, Y.; Appella, D. H.; Jurkaushas, V.; Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, Jones, P.; Reddy, C. K.; Knochel, P. Tetrahedron 1998, 54, R.A. Batey, J.D. Harling, W.B. Motherwell, Tetrahedron 1996, 52, S. Collins, Y. Hong, M. Kataoka, T. Nguyen J. rg. Chem. 1990, 55, B. Corbel, J.M. Decesare, T. Durst Can. J. Chem. 1978, 56, S. Kim, P.H. Lee Tet. Lett. 1988, 29, M. Nakayama, S. hira, S. Shinke, S. Hayashi Agric. Biol. Chem. 1978, 42,