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Synlett 2002(2): 0304-0306
DOI: 10.1055/s-2002-19766
LETTER
© Georg Thieme Verlag Stuttgart · New York

Asymmetric Synthesis of β-Amino-cyclohexyl Sulfonates via azaMichael Addition

Dieter Enders*, Stefan Wallert
Institut für Organische Chemie, Rheinisch-Westfälische Technische Hochschule, Professor-Pirlet-Straße 1, 52074 Aachen, Germany
Fax: +49(241)8092127; e-Mail: enders@rwth-aachen.de;
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Publication History

Received 29 October 2001
Publication Date:
02 February 2007 (online)

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Abstract

The Lewis acid catalyzed asymmetric synthesis of β-amino-cyclohexyl sulfonates via aza-Michael addition is reported. As key step the addition of (S)-1-amino-2-methoxymethyl-pyrrolidine (SAMP) or (R,R,R)-2-amino-3-methoxymethyl-2-azabicyclo[3.3.0]-octane (RAMBO) to alkenyl-cyclohexyl sulfonates is applied, to give β-hydrazino sulfonates in moderate to good yields and diastereomeric excesses (yield = 41-85%, de = 55-90%). The epimers are separated by preparative HPLC, followed by reductive N-N bond cleavage with BH3·THF and protection of the resulting amines with CbzCl to afford N Cbz-protected-β-amino-cyclohexyl sulfonates in moderate to good yields (38-68%, 2 steps) and enantiomeric excesses (ee) of ≥96%.

Key words

asymmetric synthesis - Michael addition - sulfonates - hydrazines - Lewis acid

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(R,S)-4d: NOE’s were observed between: CHN↔NCH 2, CHCH3 (a)↔CH 2CH 3, CH-Cy↔CH 2SO2. (S,R,R,R)-4j: NOE’s were observed between: CHCH3↔CH 2CH 3, CHCH 3 (a)↔CH 2CH 3, CH-Cy↔NH, CHNH↔NCHCH 2CH2.

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General procedure for the preparation of compounds 4-6. Synthesis of β-hydrazino-cyclohexyl sulfonates 4a-k:
ZnBr2 (0.2 equiv) was dissolved in dry MeOH (1 mL/mmol 3) under argon atmosphere. The sulfonate 3 was added to the mixture and the solution was stirred for 10 min at room temperature. Then 3 equiv (S)-1 or (R,R,R)-2 was added and the reaction mixture was stirred for 7-14 d at room temperature. The solution was poured into a mixture of n-pentane and diethyl ether (2:1, 30 mL/mmol 3) to precipitate the Lewis acid. After filtration through Celite® the crude product was purified by column chromatography (SiO2, n-pentane-diethyl ether) to afford 4 as colorless oils.
Synthesis of β-amino-cyclohexyl sulfonates 5:
The β-hydrazino-sulfonates 4a-k were dissolved in dry THF (10 mL/mmol 4) under argon atmosphere. BH3·THF (10 equiv, 1.0 M in THF) was added and the reaction mixture was refluxed for 5 h. After cooling to r.t. the solution was slowly quenched with MeOH (3 mL/mmol 4). The solvents were carefully evaporated and the mixture was treated again with MeOH (30 mL/mmol 4). The solution was refluxed for 30 min after which the solvent was removed under reduced pressure and the crude amines were used in the next reaction step without further purification.
Synthesis of Cbz-protected amines 6:
The crude product 5 was dissolved in a mixture of CH2Cl2 and H2O (4:1, 10 mL/mmol 4). Na2CO3 (6 equiv) and CbzCl (3 equiv) were added at r.t. The reaction mixture was refluxed for 1-3 d. After separation of the organic layer the aqueous phase was extracted with CH2Cl2 (3 × 20 mL). The combined organic layers were washed with saturated aqueous Na2CO3 solution and brine. After drying over MgSO4 the solvent was evaporated and the products were purified by column chromatography (SiO2, n-pentane-Et2O) to afford 6 as colorless solids.

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Selected analytical and spectroscopic data of compounds 4 and 6. Analytical data of compound (S,R,R,R)-4h: [α]D 24 = +17.7 (1.0, CHCl3); 1H NMR (400 MHz, CDCl3): δ = 0.9 (t, J = 7.4 Hz, 3 H, CH2CH 3); 1.1-2.1 (m, 22 H, CH 2CH 2CH 2, CH 2CH 2CH3, CHCH 2CH, CH 2-Cy), 2.4 (q, J = 8.79 Hz, 1 H, NCHCH), 2.7 (sex, J = 5.40 Hz, 1 H, NCHCH2O), 3.1 (dd, J = 14.3, 5.5 Hz, 2 H, NCHCH, CHHSO2), 3.3 (m, 2 H, CHHSO2, CHHOCH3), 3.3 (s, 3 H, OCH 3), 3.5 (m, 2 H, CHHOCH3, CHNH), 4.7 (sep, J = 4.3 Hz, 1 H, CH-Cy); 13C NMR (100 MHz, CDCl3): δ = 14.60, 18.61, 23.84, 24.50, 25.23, 33.16, 33.42, 33.89, 35.10, 35.72, 38.93, 54.01, 55.00, 59.23, 68.81, 75.58, 75.91, 81.24; MS (EI) m/z 402, 320, 277, 276, 275, 169, 67; IR (CHCl3): 3260, 2938, 2863, 2371, 1649, 1451, 1348, 1265, 1240, 1195, 1168, 1119, 1033, 1004, 937, 870, 833, 792, 737, 702, 643, 603, 564, 531, 490, 463 cm-1; Anal. Calcd. for: C20H38N2O4S: C, 59.70; H, 9.45; N, 6.97. Found: C, 59.50; H, 9.64; N, 7.16.
Analytical data of compound (R,S)-4e: [α]D 24 = -55.7 (1.0, CHCl3); 1H NMR (400 MHz, CDCl3): δ = 1.1-2.1 (m, 16 H, NCH2CH 2CH 2, CH 2-Cy, CH 2CH2Ar), 2.3 (q, J = 8.70 Hz, 1 H, CHHN), 2.6-2.8 (m, 3 H, OCH2CHN, CH2CH 2Ar), 2.9 (s, 1 H, NH), 3.1 (dd, J = 14.56, 4.12 Hz, 1 H, CHHSO2), 3.2 (dd, J = 14.43, 7.50 Hz, 1 H, CHHSO2), 3.3 (s, 3 H, OCH 3), 3.3-3.5 (m, 3 H, CHNH, CHHO, CHHN), 3.5 (dd, J = 9.06, 4.12 Hz, 1 H, CHHO), 4.7 (sep, J = 4.3 Hz, 1 H, CH-Cy), 7.2-7.3 (m, 5 H, CH-Ar); 13C NMR (100 MHz, CDCl3): δ = 21.24, 23.69, 25.07, 26.39, 31.45, 32.95, 33.02, 34.53, 54.36, 54.43, 57.16, 59.26, 66.15, 75.04, 81.39, 126.14, 128.59, 128.62, 141.90; MS (EI) m/z 424, 342, 299, 298, 297, 129, 91, 70; IR (CHCl3): 3639, 3281, 3085, 3061, 3026, 2937, 2862, 2312, 1947, 1805, 1724, 1603, 1583, 1496, 1454, 1344, 1265, 1169, 1118, 1031, 1003, 935, 870, 829, 747, 700, 644, 595, 533, 489, 457 cm-1; Anal. Calcd. for: C22H36N2O4S: C, 62.26; H, 8.49; N, 6.60. Found: C, 62.33; H, 8.80; N, 6.69.
Analytical data of compound (R,S)-6k: 1H NMR (300 MHz, CDCl3): δ = 0.9 (t, J = 7.2 Hz, 3 H, CH 3), 1.2-2.0 (m, 14 H, CH 2-Cy, CH 2CH 2CH3), 3.3 (dd, J = 14.43, 4.21 Hz, 1 H, CHHSO2), 3.4 (dd, J = 14.42, 5.60 Hz, 1 H, CHHSO2), 4.1 (m, 1 H, CHNH), 4.7 (sep, J = 4.12 Hz, 1 H, CH-Cy), 5.1 (s, 2 H, OCH 2), 5.2 (s, 1 H, NH), 7.3-7.4 (m, 5 H, H-Ar); 13C NMR (75 MHz, CDCl3): δ = 23.71, 25.06, 32.51, 32.94, 32.99, 35.29, 47.78, 55.12, 67.16, 82.05, 126.47, 128.34, 128.48, 128.82, 128.67, 136.53, 140.86, 155.89; IR (KBr): 3854, 3839, 3751, 3676, 3362, 3030, 2936, 2863, 2344, 1691, 1533, 1498, 1454, 1409, 1384, 1328, 1294, 1247, 1214, 1170, 1127, 1049, 1010, 930, 905, 874, 832, 776, 742, 728, 699, 614, 585, 559, 528, 493, 458 cm-1; Anal. Calcd. for: C24H31NO5S: C, 64.72; H, 7.00; N, 3.15. Found: C, 64.63; H, 7.44; N, 3.06.

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