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Synlett 2007(18): 2841-2846  
DOI: 10.1055/s-2007-990961
LETTER
© Georg Thieme Verlag Stuttgart · New York

Weinreb Amide Based New Synthetic Equivalents for Convenient Access to Immunosuppressive Agent FTY720 and Analogues

Sivaraman Balasubramaniam, Senthilmurugan Annamalai, Indrapal Singh Aidhen*
Department of Chemistry, Indian Institute of Technology Madras, Chennai 600 036, India
Fax: +91(44)22574202; e-Mail: isingh@iitm.ac.in;
Further Information

Publication History

Received 3 August 2007
Publication Date:
19 October 2007 (online)

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Abstract

Three new synthetic equivalents containing Weinreb amide functionality for the central core of FTY720, an immunosuppressive agent, have been developed. These synthetic equivalents enabled incorporation of the polar head group of FTY720, through Julia, Wittig, and Horner-Wadsworth-Emmons reactions and also allowed for variation in the chain length of the lipophilic side chain in target, through the Weinreb amide functionality therein. The use of tris(hydroxymethyl)aminomethane, commercially available at low cost for the polar head group offers a distinct advantage. Convenient reactions and simple functional group interconversions in good to high yield highlight the strength of the new route developed for the synthesis of clinically important FTY720.

Key words

FTY720 - Weinreb amide - sulfone - olefination

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4-{(Benzo[ d ]thiazol-2-ylsulfonyl)methyl}- N -methoxy- N -methylbenzamide (4) Yield 85-88%; R f = 0.35 (hexane-ethyl acetate, 6:4); colorless crystals, mp 142-145 °C. 1H NMR (400 MHz, CDCl3): δ = 3.32 (s, 3 H), 3.47 (s, 3 H), 4.79 (s, 2 H), 7.33 (d, 2 H, J = 8.0 Hz), 7.56-7.62 (m, 3 H), 7.63-7.69 (m, 1 H), 7.94 (d, 1 H, J = 8.0 Hz), 8.26 (d, 1 H, J = 8.0 Hz). 13C NMR (100 MHz, CDCl3): δ = 32.6, 59.7, 60.1, 121.3, 124.6, 126.8, 127.2, 127.8, 127.9, 129.8, 133.9, 136.1, 151.6, 164.1, 168.0. IR (CH2Cl2): 1152, 1332, 1469, 1639, 2929, 2972 cm-1. HRMS (EI): m/z calcd for C17H16N2O4S2 [M + H]+: 377.0630; found: 377.0618.

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General Procedure for Olefination
A suspension of sulfone (0.3 mmol), aldehyde (0.33 mmol, 1.1 equiv), and K2CO3 (0.9 mmol, 3 equiv) in a mixture of THF (1.8 mL) and DMF (0.6 mL; 3:1 mixture) was heated at 70 °C for 17 h. After completion of the reaction, THF was evaporated and the reaction mixture was quenched with H2O and then extracted with EtOAc. The washed organic layer was dried over anhyd Na2SO4, filtered, concentrated, and then purified by silica gel flash chromatography. The spectral and analytical details for selected compounds are given below.
4-[4-(5,5-Dimethyl-1,3-dioxan-2-yl)styryl]- N -methoxy- N -methylbenzamide (8c) Yield 64% (E:Z = 3:1). E-Isomer: R f = 0.35 (hexane-EtOAc, 7:3); white crystalline solid, mp 121-124 °C. 1H NMR (400 MHz, CDCl3): δ = 0.73 (s, 3 H), 1.22 (s, 3 H), 3.28 (s, 3 H), 3.48 (s, 3 H), 3.58 (d, 2 H, J = 10.8 Hz), 3.70 (d, 2 H, J = 11.2 Hz), 5.32 (s, 1 H), 7.03 (d, 1 H, J = 16.0 Hz), 7.10 (d, 1 H, J = 16.4 Hz), 7.41-7.46 (m, 6 H), 7.62 (d, 2 H, J = 8.0 Hz). 13C NMR (100 MHz, CDCl3): δ = 20.8, 22.0, 29.2, 32.8, 60.0, 76.7, 100.4, 125.0, 125.6, 127.1, 127.6, 127.8, 129.1, 131.9, 136.5, 137.2, 138.6, 168.5. Z-Isomer: R f = 0.42 (hexane-EtOAc, 7:3); colorless viscous liquid. 1H NMR (400 MHz, CDCl3): δ = 3.27 (s, 3 H), 3.49 (s, 3 H), 3.57 (d, 2 H, J = 10.4 Hz), 3.69 (d, 2 H, J = 11.2 Hz), 5.28 (s, 1 H), 6.51 (d, 1 H, J = 12.4 Hz), 6.57 (d, 1 H, J = 12.4 Hz), 7.17-7.21 (m, 4 H), 7.30 (d, 2 H, J = 8.0 Hz), 7.46 (d, 2 H, J = 8.0 Hz). 13C NMR (100 MHz, CDCl3): δ = 20.9, 22.1, 29.2, 33.0, 59.9, 76.7, 100.6, 125.2, 127.3, 127.5, 127.8, 128.6, 130.2, 131.6, 136.4, 136.6, 138.6, 168.7. IR (CH2Cl2): 1097, 1383, 1417, 1638, 2850, 2954 cm-1. HRMS (EI): m/z calcd for C23H27NO4 [M + H]+: 382.2018; found: 382.2029.
N -Methoxy- N -methyl-4-(2-nitrostyryl)benzamide (8d) Yield 70% (E:Z = 9:1); R f = 0.4 (hexane-EtOAc,7:3); yellow solid, mp 60-63 °C. 1H NMR (400 MHz, CDCl3): δ (E-isomer) = 3.38 (s, 3 H), 3.58 (s, 3 H), 7.09 (d, 1 H, J = 16.0 Hz), 7.42-7.46 (m, 1 H), 7.57 (d, 2 H, J = 8.4 Hz), 7.62 (d, 1 H, J = 7.6 Hz), 7.67 (d, 1 H, J = 16.4 Hz), 7.73 (d, 2 H, J = 8.4 Hz), 7.77 (d, 1 H, J = 7.2 Hz), 7.98-8.00 (m, 1 H); δ (Z-isomer, nonoverlapped signals) = 3.32 (s, 3 H), 3.52 (s, 3 H), 6.77 (d, 1 H, J = 12.0 Hz), 6.97 (d, 1 H, J = 12.0 Hz), 7.49 (d, 2 H, J = 8.0 Hz), 7.81 (d, 1 H, J = 8.0 Hz), 7.93 (d, 1 H, J = 8.0 Hz). 13C NMR (100 MHz, CDCl3): δ (E-isomer) = 33.2, 60.5, 124.4, 124.8, 126.1, 127.8, 127.9, 128.4, 132.2, 132.4, 132.7, 133.3, 138.2, 147.6, 168.8; δ (Z-isomer, nonoverlapped signals) = 60.6, 124.3, 128.2, 130.4, 131.7, 132.8. IR (CH2Cl2): 1264, 1345, 1523, 1635, 3054 cm-1. HRMS (EI): m/z calcd for C17H16N2O4 [M + H]+: 313.1188; found: 313.1194.
4-(3,4-Dimethoxystyryl)- N -methoxy- N -methyl Benzamide (8e) Yield 66% (E:Z = 3:1); R f = 0.37 (hexane-EtOAc, 7:3); yellow viscous liquid. 1H NMR (400 MHz, CDCl3): δ (E-isomer) = 3.28 (s, 3 H), 3.49 (s, 3 H), 3.82 (s, 3 H), 3.86 (s, 3 H), 6.78 (d, 1 H, J = 8.0 Hz), 6.89 (d, 1 H, J = 16.4 Hz), 6.97-6.99 (m, 2 H), 7.04 (d, 1 H, J = 16.0 Hz), 7.43 (d, 2 H, J = 8.4 Hz), 7.62 (d, 2 H, J = 8.4 Hz); δ (Z-isomer, nonoverlapped signals) = 3.26 (s, 3 H), 3.46 (s, 3 H), 3.54 (s, 3 H), 3.77 (s, 3 H), 6.43 (d, 1 H, J = 12.4 Hz), 6.51 (d, 1 H, J = 12.4 Hz), 6.65-6.68 (m, 2 H), 6.72-6.74 (m, 1 H), 7.24 (d, 2 H, J = 8.4 Hz), 7.47 (d, 2 H, J = 8.4 Hz). 13C NMR (100 MHz, CDCl3): δ = 33.8, 55.8, 55.9, 61.1, 108.8, 111.2, 120.3, 121.9, 125.7, 128.2, 128.5, 128.8, 130.2, 131.2, 132.3, 139.9, 149.1, 149.3, 169.5; δ (Z-isomer non-overlapped signals) = 55.5, 55.8, 60.9, 110.9, 111.7, 125.8, 127.9, 128.6, 129.4, 130.0, 140.2, 148.3, 148.4, 169.6. IR (CH2Cl2): 1264, 1514, 1635, 3053 cm-1. HRMS (EI): m/z calcd for C19H21NO4 [M + H]+: 328.1549; found: 328.1546.
tert -Butyl {3-[4-Methoxy(methyl)carbamoyl]styryl}-1 H -indole-1-carboxylate (8f) Yield 56% (E:Z = 3:2); Rf = 0.27 (hexane-EtOAc, 7:3); pale yellow viscous liquid. 1H NMR (400 MHz, CDCl3): δ (E-isomer) = 1.70 (s, 9 H), 3.38 (s, 3 H), 3.58 (s, 3 H), 7.21 (d, 1 H, J = 17.2 Hz), 7.32-7.38 (m, 4 H), 7.55 (d, 2 H, J = 8.4 Hz), 7.72 (d, 2 H, J = 8.4 Hz), 7.77 (s, 1 H), 7.90 (d, 1 H, J = 7.2 Hz), 8.20 (d, 1 H, J = 8.0 Hz); δ (Z-isomer, nonoverlapped signals) = 3.33 (s, 3 H), 3.52 (s, 3 H), 6.68-6.75 (m, 2 H), 7.08-7.12 (m, 1 H), 7.23-7.29 (m, 2 H), 7.35 (d, 2 H, J = 8.4 Hz), 7.48 (s, 1 H), 7.56 (d, 2 H, J = 8.4 Hz), 8.11 (d, 1 H, J = 8.0 Hz). 13C NMR (100 MHz, CDCl3): δ (E-isomer) = 28.2, 33.8, 61.1, 84.1, 115.5, 118.7, 119.9, 121.7, 123.1, 124.5, 124.8, 125.6, 127.8, 128.5, 128.9, 132.4, 140.1, 149.5, 169.6; δ (Z-isomer, nonoverlapped signals) = 83.8, 115.1, 117.0, 121.5, 122.5, 124.4, 128.3, 129.2, 130.4, 132.6, 135.2. IR (CH2Cl2): 1261, 1457, 1604, 1723, 2853, 2923, 2956 cm-1. HRMS (EI): m/z calcd for C24H26N2O4 [M + H]+: 407.1971; found: 407.1981.
4-[2-(Furan-2-yl)vinyl]- N -methoxy- N -methyl Benzamide ( 8g)
Yield 75% (E:Z = 5:4); Rf = 0.3 (hexane-EtOAc, 7:3); yellow viscous liquid. 1H NMR (400 MHz, CDCl3): δ (E-isomer) = 3.26 (s, 3 H), 3.46 (s, 3 H), 6.18-6.23 (m, 1 H), 6.29-6.37 (m, 4 H), 6.85 (d, 1 H, J = 16.0 Hz), 6.94 (d, 1 H, J = 16.4 Hz), 7.37-7.41 (m, 4 H), 7.56-7.60 (m, 3 H); δ (Z-isomer, nonoverlapped signals) = 3.27 (s, 3 H), 3.48 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ (E-isomer) = 33.8, 61.0, 109.5, 111.8, 118.0, 125.7, 126.0, 128.8, 132.6, 139.4, 142.5, 152.9, 169.5; δ (Z-isomer, nonoverlapped signals) = 110.7, 111.3, 118.9, 126.7, 128.1, 128.3, 139.8, 141.9, 151.7, 169.7. IR (CH2Cl2): 1378, 1416, 1639, 2929 cm-1. HRMS (EI): m/z calcd for C15H15NO3 [M + H]+: 258.1130; found: 258.1138.

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( E )- tert -Butyl (5-{4-[Methoxy(methyl)carbamoyl]sty-ryl}-2,2-dimethyl-1,3-dioxan-5-yl)carbamate (9) Yield 70%; R f = 0.35 (hexane-EtOAc, 6:4); colorless solid, mp 115-118 °C. 1H NMR (400 MHz, CDCl3): δ = 1.36 (s, 9 H), 1.38 (s, 3 H), 1.40 (s, 3 H), 3.26 (s, 3 H), 3.45 (s, 3 H), 3.82-3.92 (m, 4 H), 5.27 (br s, 1 H), 6.23 (d, 1 H, J = 16.4 Hz), 6.48 (d, 1 H, J = 16.4 Hz), 7.30 (d, 2 H, J = 8.0 Hz), 7.56 (d, 2 H, J = 8.4 Hz). 13C NMR (100 MHz, CDCl3): δ = 19.6, 27.4, 28.3, 33.7, 53.0, 60.9, 66.0, 79.6, 98.3, 125.9, 128.6, 129.5, 130.0, 132.9, 138.8, 154.8, 169.4. IR (CHCl3): 1166, 1456, 1637, 1712, 2851, 2921 cm-1. HRMS (EI): m/z calcd for C22H33N2O6 [M + H]+): 421.2339; found: 421.2348.

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General Procedure for the Addition of Grignard Reagent, R ¹ MgBr to the Weinreb Amides 9 and 14 To a stirred solution of 9 or 14 (0.7 mmol) in anhyd THF (3 mL), the appropriate solution of alkyl or arylmagnesium bromide (4.2 mmol, 6 equiv) in anhyd THF (5 mL) was added under inert atmosphere at -10 °C and the mixture was stirred for 3 h between -10 °C and 0 °C. Subsequent hydrolysis was achieved by cautious addition of sat. NH4Cl solution. The aqueous layer was extracted with EtOAc, dried over Na2SO4, and concentrated to furnish the crude product, which was purified by silica gel column chromatography using hexane-EtOAc (85:15) to afford ketones 10a-e and 15, respectively. The spectral and analytical details for selected compounds are given below.
( E )- t e rt -Butyl [5-(4-Heptanoylstyryl)-2,2-dimethyl-1,3-dioxan-5-yl]carbamate (10b) Yield 65%; R f = 0.4 (hexane-EtOAc, 7:3); colorless solid, mp 86-89 °C. 1H NMR (400 MHz, CDCl3): δ = 0.89 (t, 3 H, J = 7.2 Hz), 1.29-1.35 (m, 6 H), 1.44 (s, 9 H), 1.48 (s, 3 H), 1.49 (s, 3 H), 1.68-1.74 (m, 2 H), 2.94 (t, 2 H, J = 7.6 Hz), 3.91-4.01 (m, 4 H), 5.27 (br s, 1 H), 6.35 (d, 1 H, J = 16.4 Hz), 6.58 (d, 1 H, J = 16.4 Hz), 7.43 (d, 2 H, J = 8.0 Hz), 7.90 (d, 2 H, J = 8.0 Hz). 13C NMR (100 MHz, CDCl3): δ = 14.0, 19.4, 22.5, 24.3, 27.7, 28.4, 29.0, 31.9, 38.6, 53.1, 66.1, 79.8, 98.4, 126.5, 128.5, 129.5, 131.0, 136.1, 140.9, 154.8, 200.0. IR (CHCl3): 1167, 1466, 1601, 1682, 1716, 2853, 2923 cm-1. HRMS (EI): m/z calcd for C26H40NO5 [M + H]+: 446.2906; found: 446.2899.
( E )- tert -Butyl [2,2-Dimethyl-5-(4-octanoylstyryl)-1,3-dioxan-5-yl]carbamate (10d) Yield 75%; R f = 0.4 (hexane-EtOAc, 7:3); colorless solid, mp 83-86 °C. 1H NMR (400 MHz, CDCl3): δ = 0.88 (t, 3 H, J = 7.2 Hz), 1.28-1.38 (m, 8 H), 1.44 (s, 9 H), 1.47 (s, 3 H), 1.49 (s, 3 H), 1.70-1.74 (m, 2 H), 2.93 (t, 2 H, J = 7.2 Hz), 3.91-4.00 (m, 4 H), 5.25 (br s, 1 H), 6.35 (d, 1 H, J = 16.4 Hz), 6.58 (d, 1 H, J = 16.4 Hz), 7.43 (d, 2 H, J = 8.4 Hz), 7.90 (d, 2 H, J = 8.0 Hz). 13C NMR (100 MHz, CDCl3): δ = 14.0, 19.5, 22.6, 24.5, 27.6, 28.4, 29.0, 29.3, 32.8, 38.6, 53.1, 66.1, 79.8, 98.4, 126.5, 128.4, 129.5, 131.0, 136.1, 140.9, 154.8, 199.9. IR (CHCl3): 1168, 1456, 1603, 1685, 1719, 2853, 2923 cm-1. HRMS (EI): m/z calcd for C27H42NO5 [M + H]+: 460.3063; found: 460.3076.
( E )- tert -Butyl [5-(4-Benzoylstyryl)-2,2-dimethyl-1,3-dioxan-5-yl]carbamate (10e) Yield 72%; R f = 0.4 (hexane-EtOAc, 7:3); colorless solid, mp 109-112 °C. 1H NMR (400 MHz, CDCl3): δ = 1.45 (s, 9 H), 1.48 (s, 3 H), 1.50 (s, 3 H), 3.92-4.01 (m, 4 H), 5.24 (br s, 1 H), 6.37 (d, 1 H, J = 16.4 Hz), 6.61 (d, 1 H, J = 16.4 Hz), 7.45-7.50 (m, 4 H), 7.57-7.59 (m, 1 H), 7.76-7.79 (m, 4 H). 13C NMR (100 MHz, CDCl3): δ = 19.5, 27.7, 28.4, 53.1, 66.1, 79.8, 98.4, 126.2, 128.2, 129.5, 129.9, 130.0, 132.3, 136.5, 137.7, 140.6, 154.8, 196.1. IR (CHCl3): 1165, 1494, 1601, 1655, 1711, 2927, 2976 cm-1. HRMS (EI): m/z calcd for C26H32NO5 [M + H]+: 438.2280; found: 438.2281.

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tert -Butyl (5-{4-[Methoxy(methyl)carbamoyl]styryl}2,2-dimethyl-1,3-dioxan-5-yl)carbamate (9 + Z -isomer) Yield 70% (Z:E = 3:1); R f = 0.35 (hexane-EtOAc, 6:4); colorless liquid. 1H NMR (400 MHz, CDCl3): δ (Z-isomer) = 1.32 (s, 3 H), 1.38 (s, 9 H), 1.45 (s, 3 H), 3.37 (s, 3 H), 3.56 (s, 3 H), 3.77 (d, 2 H, J = 11.6 Hz), 3.88-3.94 (m, 2 H), 5.20 (br s, 1 H), 5.65 (d, 1 H, J = 12.8 Hz), 6.68 (d, 1 H, J = 12.8 Hz), 7.30 (d, 2 H, J = 8.0 Hz), 7.64 (d, 2 H, J = 8.0 Hz); δ (E-isomer, nonoverlapped signals) = 3.35 (s, 3 H), 3.53 (s, 3 H), 3.88-3.94 (m, 4 H), 5.27 (br s, 1 H), 6.23 (d, 1 H, J = 16.4 Hz), 6.48 (d, 1 H, J = 16.4 Hz), 7.39 (d, 2 H, J = 8.0 Hz). 13C NMR (100 MHz, CDCl3): δ (Z-isomer) = 18.8, 19.4, 20.9, 27.6, 28.3, 33.7, 52.5, 60.9, 65.8, 79.4, 98.1, 125.9, 128.6, 129.5, 130.0, 132.9, 140.1, 154.4, 169.4; δ (E-isomer, nonoverlapped signals) = 53.0, 66.0, 98.3, 127.9, 131.5, 132.6, 138.8. IR (CHCl3): 1166, 1456, 1637, 1712, 2851, 2921 cm-1. HRMS (EI): m/z calcd for C22H33N2O6 [M + H]+: 421.2339; found: 421.2348.

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tert -Butyl (5-{4-[Methoxy(methyl)carbamoyl]pheneth-yl}-2,2-dimethyl-1,3-diox-an-5-yl)carbamate (14) Yield 95%; R f = 0.35 (hexane-EtOAc, 6:4); colorless solid, mp 89-91 °C. 1H NMR (400 MHz, CDCl3): δ = 1.42 (s, 3 H), 1.44 (s, 3 H), 1.48 (s, 9 H), 1.98-2.02 (m, 2 H), 2.58-2.62 (m, 2 H), 3.35 (s, 3 H), 3.55 (s, 3 H), 3.69 (d, 2 H, J = 12.0 Hz), 3.90 (d, 2 H, J = 12.0 Hz), 5.01 (br s, 1 H), 7.21 (d, 2 H, J = 8.0 Hz), 7.60 (d, 2 H, J = 8.0 Hz). 13C NMR (100 MHz, CDCl3): δ = 18.9, 27.4, 28.3, 28.6, 32.3, 32.8, 50.6, 59.9, 65.2, 78.4, 97.4 126.1, 126.9, 127.5, 130.6, 143.9, 153.9, 168.8. IR (CHCl3): 1164, 1453, 1638, 1710, 2934, 2976 cm-1. HRMS (EI): m/z calcd for C22H35N2O6 [M + H]+: 423.2495; found: 423.2486.

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tert -Butyl [2,2-Dimethyl-5-(4-octanoylphenethyl)-1,3-dioxan-5-yl]carbamate (15) Yield 70%; R f = 0.4 (hexane-EtOAc, 7:3); colorless solid, mp 60-63 °C. 1H NMR (400 MHz, CDCl3): δ = 0.88 (t, 3 H, J = 6.8 Hz), 1.25-1.35 (m, 8 H), 1.42 (s, 3 H), 1.44 (s, 3 H), 1.47 (s, 9 H), 1.70-1.74 (m, 2 H), 1.99-2.11 (m, 2 H), 2.60-2.64 (m, 2 H), 2.92 (t, 2 H, J = 7.2 Hz), 3.69 (d, 2 H, J = 12.0 Hz), 3.89 (d, 2 H, J = 12.0 Hz), 4.95 (br s, 1 H), 7.26 (d, 2 H, J = 8.0 Hz), 7.87 (d, 2 H, J = 8.0 Hz). 13C NMR (100 MHz, CDCl3): δ = 13.2, 19.0, 21.7, 23.7, 26.3, 27.6, 28.2, 28.5, 28.8, 30.8, 32.4, 37.7, 50.9, 65.5, 78.8, 97.6, 127.5, 127.7, 134.4, 146.7, 154.1, 199.3. IR (CHCl3): 1198, 1498, 1606, 1682, 1715, 2856, 2926 cm-1. HRMS (EI): m/z calcd for C27H44NO5 [M + H]+: 462.3219; found: 462.3229.