Synthesis of rac-tert-butyl 3-(benzyloxycarbonylamino)-2-(4-bromophenyl)-tetrahydrofuran-3-carboxylate

Introduction

Synthesis

tert-Butyl 2-(benzyloxycarbonylamino)-4-(methylthio)butanoate

2-(Benzyloxycarbonylamino)-4-(methylthio)butanoic acid (1, 3.00 g, 10.6 mmol) was dissolved under a nitrogen atmosphere in 50 ml of dry DCM and cooled to 0 °C in an ice bath. To this solution DMAP (108 mg, 0.88 mmol) and ^tbutanol (1.21 ml, 12.7 mmol) were added. Under vigorous stirring dicyclohexyl carbonate (2.84 g, 13.8 mmol) was slowly added in portions. The mixture was stirred at 0 °C for 2 hours, allowed to warm to room temperature and stirred for additional 12 hours. Precipitated urea was filtered off and washed twice with 25 ml of DCM. The solvent was evaporated under reduced pressure and the crude product was purified by column chromatography on silica gel (EtOAc:PE 30:70, R_f = 0.48) to give the product as colorless oil (1.84 g, 6.02 mmol, 57 %).

MS (CI, NH₃): m/z (%) = 284.0 (7) [MH⁺ - C₄H₈], 301.1 (52) [MNH₄⁺ - C₄H₈], 340.1 (15) [MH⁺], 357.1 (100) [MNH₄⁺].

IR (NEAT) [cm^-1]: $\tilde{\nu }$ = 2979, 2917, 1708, 1523, 1455, 1368, 1224, 1149, 1046, 965, 845, 738, 696.

¹H-NMR (300 MHz, CDCl₃): δ = 1.46 (s, 9 H, 13), 1.82-2.20 (m, 5 H, 14 + 17), 2.41-2.61 (m , 2 H, 15), 4.25-4.44 (m, 1 H, 9), 5.11 (s, 2 H, 5), 5.39 (d, ³J_H,H = 7.4, 1 H, 8), 7.28-7.43 (m, 5 H, H-Ar).

¹³C-NMR (75 MHz, CDCl₃): δ = 15.5 (+, 1 C, 17), 28.0 (+, 3 C, 13), 29.9 (-, 1 C, 15), 32.5 (+, 1 C, 14), 53.8 (+, 1 C, 9), 67.0 (+, 1 C, 5), 82.4 (C_quat, 1 C, 12), 128.1 (+, 2 C, 3), 128.2 (+, 1 C, 1) , 128.5 (+, 2 C, 2), 136.3 (C_quat, 1 C, 4), 155.9 (C_quat, 1 C, 7), 171.0 (C_quat, 1 C, 10).

(3-(Benzyloxycarbonylamino)-4-tert-butoxy-4-oxobutyl)dimethylsulfonium iodide (2)

tert-Butyl 2-(benzyloxycarbonylamino)-4-(methylthio)butanoate (3.00 g, 10.6 mmol) was dissolved in 32 ml of methyl iodide (3 ml/mmol) and stirred for three days at room temperature in the dark. The solution was cooled to 0 °C in an ice bath and 32 ml of heptane (3 ml/mmol) were added to precipitate the product. The mixture was kept at 0 °C in the dark for four hours to complete the precipitation. The hygroscopic and light sensitive product was obtained after filtration and washing with ice-cold heptane as a colorless solid (1.39 g, 2.89 mmol, 98%) in analytically pure form.

MP 35-37 °C.

MS (ES, DCM/MeOH + 10 mmol/l NH₄OAc): m/z (%) = 354.1 (100) [M⁺].

IR (NEAT) [cm^-1]: $\tilde{\nu }$ = 2980, 2928, 1707, 1518, 1238, 1151, 1047, 740, 698.

¹H-NMR (300 MHz, CDCl₃): δ = 1.46 (s, 9 H, 13), 2.20-2.49 (m, 2 H, 14), 3.19 (s, 3 H, 17), 3.23 (s, 3 H, 17), 3.59-3.81 (m, 1 H, 15), 3.85-4.02 (m, 1 H, 15), 4.21-4.38 (m, 1 H, 9), 5.10 (s, 2 H, 5), 6.09 (d, ³J_H,H = 7.1, 1 H, 8), 7.28-7.47 (m, 5 H, 1 -3).

¹³C-NMR (75 MHz, CDCl₃): δ = 25.7 (+, 1 C, 17), 26.0 (+, 1 C, 17), 28.0 (+, 3 C, 13), 31.9 (-, 1 C, 14), 40.5 (+, 1 C, 15), 53.2 (+, 1 C, 9), 67.2 (+, 1 C, 5), 83.5 (C_quat, 1 C, 12), 128.2 (+, 2 C, 3), 128.3 (+, 1 C, 1) , 128.6 (+, 2 C, 2), 136.3 (C_quat, 1 C, 4), 156.5 (C_quat, 1 C, 7), 169.9 (C_quat, 1 C, 10).

rac-tert-Butyl 3-(benzyloxycarbonylamino)-2-(4-bromophenyl)-tetrahydrofuran-3-carboxy­late (rac-4)

In an oven dried Schlenk flask under nitrogen atmosphere (3-(benzyloxycarbonylamino)-4-tert-butoxy-4-oxobutyl)-dimethylsulfonium iodide (2, 4.68 g, 9.73 mmol, 1.2 eq.) was dis­solved in dry acetonitrile (5 ml per 1 mmol sulfonium salt). The colorless solution was cooled to -6 °C and potassium hydroxide (546 mg, 9.73 mmol, 1.2 eq.) followed by 4-bromo­benz­aldehyde (4, 1.50 g, 8.11 mmol, 1 eq.) were added. The mixture was stirred at -6 °C for 6 h. After complete consumption of the starting material (checked via TLC, 60:40 PE:diethyl ether, R_f = 0.05) the reaction mixture was quenched with water (4 ml per mmol sulfonium salt) and extracted with diethyl ether (1 x 4 ml/mmol, 2 x 5 ml/mmol sulfonium salt). The combined organic layers were washed with brine solution and dried over MgSO₄. After removal of the solvent under reduced pressure the crude product was purified by flash chromatography [9] using a 80:20 mixture of PE:diethyl ether (R_f = 0.15) to give a white crystalline solid in 48 % yield (1.85 g, 3.90 mmol).

MP 133-135 °C.

MS (ES, DCM/MeOH + 10 mmol/l NH₄OAc): m/z (%) = 476.2 (7) [MH⁺], 495.2 (100) [MNH₄⁺], 476.1 (100) [M – H⁺], 536.2 (10) [M + CH₃COO^-].

IR (NEAT) [cm^-1]: $\tilde{\nu }$ = 3334, 2977, 2947, 2860, 1702, 1593, 1524, 1491, 1361, 1247, 1154, 1073, 1011, 986, 827, 790, 750, 697.

¹H-NMR (300 MHz, CDCl₃): δ = 1.11(s, 9 H, ^tBu), 2.54-2.81 (m, 2 H, CH₂), 4.22-4.37 (m, 2 H, O-CH₂), 5.08-5.21 (m, 3 H, CH₂–Cbz + CH), 6.00 (bs, 1 H, NH), 7.20 (d, ³J_H,H = 7.9, 2 H, CH-Ar), 7.28-7.45 (m, 7 H, CH-Cbz, CH-Ar).

¹³C-NMR (75 MHz, CDCl₃): δ = 27.4 (+, 3 C, CH₃-^tBu), 35.8 (-, 1 C, CH₂), 66.8 (-, 1 C, O-CH₂), 67.9 (-, 1 C, CH₂-Bzl), 69.5 (C_quat, 1 C, C-NH), 83.0 (C_quat, 1 C, C-^tBu), 83.8 (+, 1 C, CH) , 121.7 (C_quat, 1 C, C-Br), 127.7 (+, 2 C, CH-Bzl), 128.2 (+, 2 C, CH-Bzl), 128.3 (+, 1 C, CH-Bzl), 128.6 (+, 2 C, CH-Ar), 131.0 (+, 2 C, CH-Ar), 136.2 (C_quat, 1 C, C-Ar), 136.5 (C_quat, 1 C, C-Ar), 154.6 (C_quat, 1 C, CO-Bzl), 169.9 (C_quat, 1 C, COO^tBu).

Elemental analysis calcd. (%) for C₂₃H₂₆BrNO₅ (524.49): C 57.99, H 5.50, N 2.94; found: C 58.04, H 5.55, N 2.82.

References

1. Benedetti, B.; Bavoso, A.; Di Blasio, B.; Pavone, V.; Pedone, C.; Toniolo, C.; Bonara, G. M. Proc. Natl. Acad. Sci. U.S.A. 1982, 79, 7951–7954. [CrossRef]
2. Toniolo, C.; Crisma, M.; Formaggio, F. Biopolymers 1997, 40, 627–651.
3. Toniolo, C.; Benedetti, E. Macromolecules 1991, 24, 4004–4009.
4. Toniolo, C.; Crisma, M.; Formaggio, F.; Valle, G.; Cavicchioni, G.; Précigoux, G.; Aubry, A.; Kamphuis, J. Biopolymers 1993, 33, 1061–1072. [PubMed]
5. Polese, A.; Formaggio, F.; Crisma, M.; Valle, G.; Toniolo, C.; Bonora, G. M.; Broxterman, Q.; Kamphius, J. Chem. Eur. J. 1996, 2, 1104–1111. [CrossRef]
6. Hanson, P.; Millhauser, G.; Formaggio, F.; Crisma, M.; Toniolo, C. J. Am. Chem. Soc. 1996, 118, 7618–7625. [CrossRef]
7. Gratias, R.; Konat, R.; Kessler, H.; Crisma, M.; Valle, G.; Polese, A.; Formaggio, F.; Toniolo, C.; Broxterman, Q.; Kamphius, J. J. Am. Chem. Soc. 1998, 120, 4763–4770. [CrossRef]
8. Maity, P.; Zabel, M.; König, B. J. Org. Chem. 2007, 72, 8046–8053. [CrossRef] [PubMed]
9. Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923–2925. [CrossRef]