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Synlett 2006(5): 0685-0688  
DOI: 10.1055/s-2006-932495
LETTER
© Georg Thieme Verlag Stuttgart · New York

New Synthetic Routes toward Polyketide-like Macrolides

Gérald Coste, Sandrine Gerber-Lemaire*
Laboratory of Glycochemistry and Asymmetric Synthesis, Ecole Polytechnique Fédérale de Lausanne (EPFL), Batochime, 1015 Lausanne, Switzerland
Fax: +41(21)6939355; e-Mail: Sandrine.Gerber@epfl.ch.;
Further Information

Publication History

Received 12 December 2005
Publication Date:
09 March 2006 (online)

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Abstract

New pathways toward the synthesis of polyketide-like macrolides have been developed through the functionalization of long chain polyolic fragments readily obtained from 3,3′-methyl­enebis{[6-(benzyloxy)methoxy]cyclohept-3-en-1-ol} derivatives 6. This synthetic route generates a large variety of stereoisomers and thus can be applied to the preparation of a library of polyhydroxyl­ated macrocycles, analogues of natural bioactive macrolides.

Key words

long chain polyols - macrolactonization - olefination - polyketide macrolides - ring-closing metathesis

11

Analytical Data for 11. A 1:1 mixture of diastereoisomers. IR (film): 3420, 2940, 2600, 2500, 1580, 1555, 1455, 1385, 1080, 1035, 740, 700 cm-1. 1H NMR (400 MHz, MeOD): δ = 6.71-6.10 (m, 10 H), 4.52, 4.48 (2 d, 4 H, 2 J = 5.6 Hz), 4.35, 4.33 (2 d, 4 H, 2 J = 8.0 Hz), 3.98 (m, 1 H), 3.76 (m, 1 H), 3.51 (t, 2 H, 3 J = 5.2 Hz), 3.46-3.22 (m, 4 H), 3.22, 3.21, 3.19, 3.18 (4 s, 12 H), 3.64-2.31 (2 m, 2 H), 1.96-1.56 (m, 12 H) ppm. 13C NMR (100 MHz, MeOD): δ = 179.3, 139.3, 129.4, 128.9, 128.7, 95.4, 76.5, 76.2, 74.5, 74.4, 70.8, 59.4, 56.3, 43.9, 43.8, 42.0, 41.6, 40.7, 39.3, 39.2, 43.8 ppm. MALDI-MS: 673.7 [M + Na], 689.7 [M + K]. HRMS: m/z calcd for C35H54O11 + Na: 673.3564; found 673.3561.

13

Preparation and Analytical Data for Compounds 12 and 13.
seco-Acid 11 (10 mg, 0.015 mmol) was dissolved in 1 mL of MeCN. A solution of (i-Pr)2NEt in benzene (0.4 M, 1.1 mL, 0.460 mmol, 30 equiv) and a solution of 2,4,6-trichloro-benzoyl chloride in benzene (0.4 M, 770 µL, 0.307 mmol, 20 equiv) were added. The resulting mixture was stirred at 25 °C for 3 h before being diluted with 9 mL of benzene. This mixture was added via a syringe pump to a refluxing solution of DMAP (315 mg, 2.55 mmol, 50 equiv) in 18 mL of benzene over 7 h. The reaction mixture was poured into a sat. aq solution of NaHCO3 (15 mL) and extracted with EtOAc (15 mL, 3 times). The combined organic extracts were washed with brine (10 mL), dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography (MeOH-CH2Cl2, 3:97) afforded 12 and 13 as a pale yellow oil (9.5 mg, 100%).
IR (film): 2930, 1730, 1650, 1580, 1455, 1385, 1280, 1165, 1100, 860 cm-1. 1H NMR (400 MHz, C6D6): δ = 7.35-7.27 (m, 6 H), 7.12-7.08 (m, 4 H), 4.79, 4.76 (2 d, 4 H, 2 J = 6.8 Hz), 4.63, 4.57 (2 s, 4 H), 4.42-4.38 (m, 1 H), 4.32-4.23 (2 m, 1 H), 4.06-4.04 (m, 1 H), 3.63-3.39 (m, 4 H), 3.15-3.12 (m, 12 H), 2.69-2.40 (m, 2 H), 2.09-1.47 (m, 12 H) ppm. 13C NMR (100 MHz, C6D6): δ = 170.3, 138.7, 138., 128.4, 128.0, 127.7, 94.1, 93.7, 93.5, 75.8, 75.7, 75.6, 75.5, 74.7, 74.4, 72.7, 72.3, 71.8, 71.4, 69.6, 69.5, 60.7, 60.6, 56.4, 56.3, 56.2, 56.1, 55.9, 55.8, 55.7, 41.2, 39.8, 40.6, 39.4, 38.8, 38.4, 37.9, 36.8 ppm. MALDI-MS: m/z = 655.75 [M + Na], 671.72 [M + K]. Anal. Calcd for C35H52O10: C, 66.40; H, 8.33. Found: C, 66.63; H, 8.39.

15

Preparation and Analytical Data for Compound 18.
seco-Acid 17 (32 mg, 0.052 mmol) was dissolved in 1 mL of MeCN. A solution of (i-Pr)2NEt in benzene (0.4 M, 3.9 mL, 1.55 mmol, 30 equiv) and a solution of 2,4,6-trichloro-benzoyl chloride in benzene (0.4 M, 2.6 mL, 1.05 mmol, 20 equiv) were added. The resulting mixture was stirred at 25 °C for 3 h before being diluted with 12.5 mL of benzene. This mixture was added via a syringe pump to a refluxing solution of DMAP (315 mg, 2.55 mmol, 50 equiv) in 25 mL of benzene over 6 h. The reaction mixture was poured into H2O (30 mL) and extracted with EtOAc (30 mL, 3 times). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography (2% of MeOH in CH2Cl2) afforded 18 as a pale yellow oil (15 mg, 49%). IR (film): 3420, 2930, 1735, 1580, 1450, 1375, 1275, 1160, 1120, 1040, 740, 700 cm-1. 1H NMR (400 MHz, MeOD): δ = 7.35-7.27 (m, 10 H), 4.77-4.74, 4.68-4.66 (2 m, 4 H), 4.66-4.59 (m, 4 H), 4.56-4.52 (m, 2 H), 4.05-3.87 (m, 6 H), 2.40-2.30 (m, 2 H), 2.10-1.90 (2 m, 16 H) ppm. 13C NMR (100 MHz, MeOD): δ = 164.3, 138.3, 138.2, 128.4, 128.0, 127.7, 94.5, 94.3, 75.2, 73.4, 69.8, 69.2, 67.1, 66.9, 64.9, 58.5, 45.3, 45.0, 44.9, 43.6, 42.8, 38.4, 38.3, 34.7, 20.6 ppm. MALDI-MS: m/z = 627.10 [M + Na], 643.06 [M + K]. HRMS: m/z calcd for C33H48O10 + Na: 627.3145; found: 627.3142.

16

Preparation and Analytical Data for Compound 20.
To a solution of 19 (245 mg, 0.371 mmol) in 2 mL of dry CH2Cl2, were added 4 Å MS (185 mg), 4-methylmorpholine N-oxide (105 mg, 0.778 mmol, 2.1 equiv) and tetrapropyl-ammonium perruthenate (13 mg, 0.037 mmol, 0.1 equiv). The mixture was stirred at 25 °C for 1 h and then filtered over a pad of Celite®. The solvent was removed under reduced pressure and filtration of the residue over a short pad of silica (6% MeOH in CH2Cl2) afforded the corresponding dialdehyde as a brown oil. Triphenylphosphonium methyl bromide (450 mg, 1.256 mmol, 5 equiv) was dissolved in 2 mL of anhyd THF. The mixture was cooled at -78 °C and n-BuLi (1.5 M in THF, 800 µL, 1.256 mmol, 5 equiv) was added dropwise. The solution was warmed to 25 °C for 45 min. A solution of the crude dialdehyde in THF (1 mL) was added to the resulting yellow mixture at -78 °C. At the end of the addition the cooling bath was removed and the reaction mixture was stirred for 3 h at 25 °C. The mixture was poured into H2O (15 mL) and extracted with EtOAc (20 mL, 3 times). The combined organic extracts were washed with brine (50 mL), dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography (EtOAc-PE, 1:7) afforded 20 as a colorless oil (75 mg, 31% over two steps). IR (film): 2940, 1640, 1440, 1390, 1100, 1040, 915, 740, 700 cm-1. 1H NMR (400 MHz, MeOD):
δ = 7.35-7.27 (m, 10 H), 5.85 (ddd, 2 H, 3 J = 17.2, 10.0, 6.0 Hz), 5.08 (d, 2 H, 3 J = 17.2 Hz), 5.03 (d, 2 H, 3 J = 10.0 Hz), 4.82, 4.78 (2 d, 4 H, 2 J = 6.0, 7.0 Hz), 4.63, 4.61 (2 d, 4 H, 2 J = 5.2, 4.9 Hz), 4.12-3.92 (m, 4 H), 3.91-3.88, 3.87-3.78 (2 m, 4 H), 2.34, 2.32 (2 dd, 4 H, 3 J = 6.4, 5.6 Hz), 1.62-1.37 (m, 10 H), 1.33, 1.29, 1.27 (3 s, 12 H) ppm. 13C NMR (100 MHz, MeOD): δ = 138.4, 138.3, 134.8, 128.4, 127.8, 127.7, 116.7, 100.5, 98.8, 94.5, 94.2, 75.2, 74.1, 69.7, 69.6, 66.0, 65.8, 63.7, 63.3, 43.3, 42.3, 42.1, 40.0, 39.9, 38.6, 37.5, 29.5, 19.2, 24.4, 24.3 ppm. MALDI-MS: m/z = 675.441 [M + Na]. Anal Calcd for C39H56O8: C, 71.75; H, 8.65. Found: C, 71.78; H, 8.67.

18

Analytical Data for 21.
IR (film): 3415, 2935, 1640, 1435, 1375, 1100, 1035, 915, 740, 695 cm-1. 1H NMR (400 MHz, MeOD): δ = 7.35-7.27 (m, 10 H), 5.88-5.82 (m, 2 H), 5.11-5.03 (m, 4 H), 4.83 (s, 4 H), 4.64, 4.62 (2 s, 4 H,), 4.10-3.95 (m, 6 H), 2.39-2.33 (m, 4 H), 1.62-1.50 (m, 10 H) ppm. 13C NMR (100 MHz, MeOD): δ = 138.3, 134.9, 134.8, 128.4, 128.0, 127.7, 116.7, 94.2, 75.0, 74.8, 69.8, 69.7, 69.2, 67.1, 66.8, 64.7, 45.3, 45.0, 44.9, 43.0, 42.6, 39.9, 39.8 ppm. MALDI-MS: m/z = 573.84 [M + Na].

19

Preparation and Analytical Data for 22.
To a solution of 21 (25 mg, 0.044 mmol) in dry CH2Cl2 (25 mL, 0.002 mM), tricyclohexylphosphine [1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene][benzyl-idine] ruthenium(IV) dichloride (7.5 mg, 8.731 µmol, 0.2 equiv) was added. The resulting pink solution was heated at 50 °C for 7 h. The solvent was removed under reduced pressure and the residue was filtered on a pad of silica (3-10% MeOH in CH2Cl2) affording a brown oil that was dissolved in EtOAc (2 mL) and treated with a catalytic amount of palladium (10% on activated charcoal) under 1 atm of H2. After 1 h at 25 °C, the resulting mixture was filtered over a pad of Celite®. Removal of the solvent under reduced pressure and purification of the residue was by flash chromatography (3-10% MeOH in CH2Cl2) afforded 22 as a pale yellow oil (7.5 mg, 32%). IR (film): 3410, 2940, 2515, 1425, 1380, 1165, 1100, 1040, 740, 700 cm-1. 1H NMR (400 MHz, MeOD): δ = 7.34-7.25 (m, 20 Harom), 4.79 (s, 8 H), 4.58 (s, 8 H), 4.10-3.90 (m, 8 H), 3.90-3.80 (m, 4 H), 1.80-1.50 (m, 28 H), 1.50-1.35 (m, 8 H) ppm. 13C NMR (100 MHz, MeOD): δ = 138.4, 128.4, 127.9, 127.7, 94.2, 94.1, 93.9, 75.4, 75.2, 75.1, 75.0, 69.7, 69.6, 68.3, 68.2, 66.8, 66.7, 66.6, 66.5, 65.1, 64.9, 45.4, 45.3, 45.1, 45.0, 44.9, 42.8, 42.7, 42.1, 42.0, 37.8, 34.9, 25.1, 25.0, 24.9, 24.8 ppm. MALDI-MS: m/z = 1116.35 [M + Na], 1131.36 [M + K]. HRMS: m/z calcd for C62H92O16 + Na: 1115.6283; found: 1115.6287. Anal. Calcd for C62H92O16: C, 68.11; H, 8.51. Found: C, 68.00; H, 8.48.