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

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%.

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

References

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<A NAME="RG31701ST-9">9</A>

(R,S)-4d: NOE’s were observed between: CHN↔NCH ₂, CHCH_{3 (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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<A NAME="RG31701ST-14">14</A>

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.

<A NAME="RG31701ST-15">15</A>

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.

<A NAME="RG31701ST-16">16</A>

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