Asymmetric Mannich Reactions with α-Silylated Trimethylsilyl Enol Ethers and N-Alkoxycarbonyl Imines

Abstract

The Mannich reaction of enantiomerically pure α-dimethylthexylsilylated trimethylsilyl enol ether (Z,S)-2 with titanium complexes of N-alkoxycarbonyl imines afforded αŽ-silylated α,β-disubstituted β-amino ketones (S,R,S)-4a-e in good to excellent yields (70-92%) and diastereomeric excesses (de ≥ 96%). Removal of the directing silyl group gave N-protected and anti-configured β-amino ketones (R,S)-5a-e in excellent yields (90-95%) and stereoselectivities (de, ee ≥ 96%- > 98%).

asymmetric synthesis - Mannich reaction - α-silyl ketones - α-amino sulfones - β-amino ketones

References

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<A NAME="RG22301ST-15">15</A>

Asymmetric Mannich Reactions: Method A: 1.2 Equiv potassium hydride was added to a solution of 1.1 equiv carbamate 3 in dry CH₂Cl₂ (5 mL/mmol 3) under argon. After stirring for 1 h at r.t. the reaction mixture was cooled to -78 °C. After addition of 1.1-1.5 equiv TiCl₄ (1.0 N in CH₂Cl₂) and stirring for 20 min at this temperature the solution was cooled to -90 °C. 1 equiv Silyl enol ether 2 in dry CH₂Cl₂ (1 mL/mmol 2) was added dropwise. The reaction mixture was stirred for 75 min at
-90 °C → -78 °C, then quenched with a saturated solution of NaHCO₃, extracted with CH₂Cl₂ and dried over MgSO₄. After evaporation of the solvent, the crude Mannich adducts 4 were purified by flash chromatography (SiO₂, n-pentane/Et₂O). Method B: A solution of 1.1 equiv carbamate 3 in dry CH₂Cl₂ (5 mL/mmol) under argon was cooled to -78 °C. After addition of 1.1-1.5 TiCl₄ (1.0 N in CH₂Cl₂) and stirring for 20 min at this temperature the solution was cooled to -90 °C. 1 equiv Silyl enol ether 2 in dry CH₂Cl₂ (1 mL/mmol 2) was added dropwise. (Further procedure see Method A).
Analytical data of compound (S,R,S)-4a:
[α]_D ²⁴ = -93.6 (CHCl₃, c = 0.50). ¹H NMR [400 MHz, (CD₃)₂ CO]: δ = 0.08 (s, 3 H, SiCH ₃), 0.16 (s, 3 H, SiCH ₃), 0.90 (d, 3 H, J = 6.8, CHCH ₃), 0.91 (d, 3 H, J = 6.9, CH ₃CHCH₃), 0.93 (d, 3 H, J = 6.9, CH₃CHCH ₃), 0.94 (s, 3 H, CH ₃CCH₃), 0.95 (s, 3 H, CH₃CCH ₃), 1.40 (s, 9 H, OC(CH ₃)₃), 1.77 (sept, 1 H, J = 6.9, CH₃CHCH₃), 2.77 (m, 1 H, CHHC₆H₄Br), 3.07 (qd, 1 H, J = 6.9, 3.3, CHCH₃), 3.13-3.24 (m, 2 H, CHHC₆H₄Br, SiCH), 4.70 (d, 1 H, J = 8.3, CHNH), 6.00 (m, 1 H, NH), 6.66 (m, 2 H, CH-Ph), 7.10-7.47 (m, 7 H, CH-C₆H₄Br, m/pCH-Ph) ppm. ¹³C NMR [100 MHz, (CD₃)₂CO]: δ = -3.7 (SiCH₃), -2.0 (SiCH₃), 13.3 (CH₃), 18.9 (CH₃CHCH₃), 19.1 (CH₃CHCH₃), 21.5 (CH₃CCH₃), 21.8 (CH₃CCH₃), 25.7 (CH₃ CCH₃), 28.5 (OC(CH₃)₃), 33.7 (CH₂C₆H₄Br), 34.9 (CH₃ CHCH₃), 47.4 (SiCH), 53.1 (CHCH₃), 56.5 (CHNH), 79.1 (OC(CH₃)₃), 120.0 (C-C₆H₄Br), 127.2 (pCH-Ph), 127.4 (CH-Ph), 128.4 (mCH-Ph), 131.2 (CH-C₆H₄Br), 132.0 (CH-C₆H₄Br), 140.4 (C-Ph), 142.1 (C-C₆H₄Br), 155.6 (OC=O), 211.8 (C=O) ppm. MS (CI, isobutane): m/z (%): 591(35), 590 (100, M⁺ + 1), 589(33), 588(90), 534(47), 533(28), 532(48), 529(8), 526(6), 512(6), 511(22), 510(59), 504(7), 502(6), 491(14), 490(50), 489(14), 488(46), 454(15), 447(20), 446(12), 411(11), 410(36), 368(7), 305(7), 206(20), 150(9), 106(20). Anal. Calcd. for C₃₁H₄₆NO₃SiBr (588.70): C, 63.25; H, 7.88; N, 2.38. Found: C, 63.22; H, 7.75; N, 2.30.

<A NAME="RG22301ST-16">16</A>

For removal of the dimethylthexylsilyl group see ref. 11b. Analytical data of compound (R,S)-5a:
[α]_D ²⁴ = -29.0 (CHCl₃, c = 0.50). ¹H NMR (400 MHz, CDCl₃): δ = 1.14 (d, 3 H, J = 6.9, CHCH ₃), 1.41 (s, 9 H, OC(CH ₃)₃), 2.15-2.70 (m, 4 H, CH ₂CH ₂), 3.05 (m, 1 H, CHCH₃), 4.81 (m, 1 H, CHNH), 5.87 (m, 1 H, NH), 6.87 (d, 2 H, J = 8.3, CH-Ph), 7.10-7.35 (m, 7 H, CH-C₆H₄Br, m/pCH-Ph) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 15.1 (CH₃), 28.3 (OC(CH₃)₃), 28.4 (CH₂C₆H₄Br), 44.2 (CH₂CO), 51.0 (COCHCH₃), 57.0 (CHNH), 79.4 (OC(CH₃)₃), 119.6 (C-C₆H₄Br), 125.9 (pCH-Ph), 127.1 (CH-Ph), 128.4 (mCH-Ph), 129.8 (CH-C₆H₄Br), 131.2 (CH-C₆H₄Br), 139.6 (C-Ph), 141.0 (C-C₆H₄Br), 155.3 (OC=O), 213.2 (C=O) ppm. MS (EI, 70 eV): m/z (%): 447 (1, M⁺), 390(23), 389(21), 211(4), 207(4), 206(34), 184(4), 182(4), 170(13), 169(13), 151(9), 150(100), 147(4), 134(4), 132(7), 118(15), 117(9), 107(6), 106(70), 104(9), 77(5), 57(59). Anal. Calcd. for C₂₃H₂₈NO₃Br (446.38): C 61.89, H 6.23, N 3.14. Found: C, 61.82; H, 6.30; N, 3.00.

<A NAME="RG22301ST-17">17</A>

All new compounds showed suitable spectroscopic data (NMR, MS, IR) and correct elemental analyses.