New Synthetic Routes toward Polyketide-like Macrolides

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.

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

References and Notes

For leading reviews, see for example:

<A NAME="RG37905ST-1A">1a</A> Aparicio JF. Mendes MV. Anton N. Recio E. Martin JF. Curr. Med. Chem.  2004,  11:  1645 

<A NAME="RG37905ST-1B">1b</A> Zotchev SB. Curr. Med. Chem.  2003,  10:  211 

<A NAME="RG37905ST-1C">1c</A> Rychnovsky SD. Chem. Rev.  1995,  95:  2021 

<A NAME="RG37905ST-1D">1d</A> Kerridge D. Drugs Today  1988,  24:  705 

<A NAME="RG37905ST-1E">1e</A> Crandall LW. Hamill RL. Bacteria  1986,  9:  355 

<A NAME="RG37905ST-1F">1f</A> Omura S. Tanaka H. Macrolide Antibiotics: Chemistry, Biology and Practice   Academic Press; New-York: 1984. 

<A NAME="RG37905ST-2">2</A> Zhanel GG. Dueck M. Hoban DJ. Vercaigne LM. Embil JM. Gin AS. Karlowsky JA. Drugs  2001,  61:  443 

<A NAME="RG37905ST-3A">3a</A> Pettit GR. Cichacz ZA. Gao F. Herald CL. Boyd MR. Schmidt JM. Hooper JNA. J. Org. Chem.  1993,  58:  1302 

<A NAME="RG37905ST-3B">3b</A> Pettit GR. Cichacz ZA. Gao F. Herald CL. Boyd MR. J. Chem. Soc., Chem. Commun.  1993,  1166 

<A NAME="RG37905ST-4">4</A> D’Ambrosio M. Guerriero A. Debitus C. Pietra F. Helv. Chim. Acta  1996,  79:  51 

For illustrative examples, see:

<A NAME="RG37905ST-5A">5a</A> Mickel SJ. Niederer D. Daeffler R. Osmani A. Kuesters E. Schmid E. Schaer K. Gamboni R. Chen W. Loeser E. Kinder FR. Konigsberger K. Prasad K. Ramsey TM. Repic O. Wang RM. Florence G. Lyothier I. Paterson I. Org. Process Res. Dev.  2004,  8:  122 

<A NAME="RG37905ST-5B">5b</A> Yeung KS. Paterson I. Chem. Rev.  2006,  in press 

<A NAME="RG37905ST-5C">5c</A> Turks M. Huang X. Vogel P. Chem. Eur. J.  2005,  11:  465 

<A NAME="RG37905ST-5D">5d</A> Turks M. Fonquerne F. Vogel P. Org. Lett.  2004,  6:  1053 

<A NAME="RG37905ST-5E">5e</A> Gerber-Lemaire S. Ainge SW. Glanzmann C. Vogel P. Helv. Chim. Acta  2002,  85:  417 

<A NAME="RG37905ST-5F">5f</A> Narkevitch V. Schenk K. Vogel P. Angew. Chem. Int. Ed.  2000,  39:  1806 

<A NAME="RG37905ST-5G">5g</A> Marchionni C. Vogel P. Helv. Chim. Acta  2001,  84:  431 

<A NAME="RG37905ST-5H">5h</A> Sevin A.-F. Vogel P. J. Org. Chem.  1994,  59:  5920 

<A NAME="RG37905ST-6A">6a</A> Schwenter ME. Vogel P. Chem. Eur. J.  2000,  6:  4091 

<A NAME="RG37905ST-6B">6b</A> Schwenter ME. Vogel P. J. Org. Chem.  2001,  66:  7869 

<A NAME="RG37905ST-6C">6c</A> Meilert K. Pettit GR. Vogel P. Helv. Chim. Acta  2004,  87:  1493 

<A NAME="RG37905ST-6D">6d</A> Coste G. Gerber-Lemaire S. Tetrahedron: Asymmetry  2005,  16:  2277 

<A NAME="RG37905ST-6E">6e</A> Vogel P. Gerber-Lemaire S. Carmona Asenjo AT. Meilert K. Schwenter ME. Pure Appl. Chem.  2005,  131 

<A NAME="RG37905ST-7A">7a</A> Csákӱ AG. Vogel P. Tetrahedron: Asymmetry  2000,  11:  4935 

<A NAME="RG37905ST-7B">7b</A> Gerber-Lemaire S. Vogel P. Eur. J. Org. Chem.  2003,  2959 

<A NAME="RG37905ST-8">8</A> Meilert KT. Schwenter ME. Shatz Y. Dubbaka SR. Vogel P. J. Org. Chem.  2003,  68:  2964 

<A NAME="RG37905ST-9">9</A> Gerber-Lemaire S. Carmona AT. Meilert KT. Vogel P. Eur. J. Org. Chem.  2006,  in press 

For other recent approaches toward polyketide macrolides, see:

<A NAME="RG37905ST-10A">10a</A> Kohli RM. Burke MD. Tao J. Walsh CT. J. Am. Chem. Soc.  2003,  125:  7160 

<A NAME="RG37905ST-10B">10b</A> Schmidt DR. Kwon O. Schreiber SL. J. Comb. Chem.  2004,  6:  286 

<A NAME="RG37905ST-10C">10c</A> Beeler AB. Acquilano DE. Su Q. Yan F. Roth BL. Panek JS. Porco JA. J. Comb. Chem.  2005,  7:  673 

<A NAME="RG37905ST-10D">10d</A> Zacuto MJ. Leighton JL. Org. Lett.  2005,  7:  5525 

<A NAME="RG37905ST-11">11</A>

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.

<A NAME="RG37905ST-12">12</A> Inanaga J. Hirata K. Saeki H. Katsuki T. Yamagushi M. Bull. Chem. Soc. Jpn.  1979,  52 

<A NAME="RG37905ST-13">13</A>

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.

<A NAME="RG37905ST-14A">14a</A> Aspinall IH. Cowley PM. Mitchell G. Raynor CM. Stoodley RJ. J. Chem. Soc., Perkin Trans. 1  1999,  2591 

<A NAME="RG37905ST-14B">14b</A> Harcken C. Martin SF. Org. Lett.  2001,  3:  3591 

<A NAME="RG37905ST-15">15</A>

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.

<A NAME="RG37905ST-16">16</A>

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.

<A NAME="RG37905ST-17A">17a</A> Evano G. Schaus JV. Panek JS. Org. Lett.  2004,  6:  525 

<A NAME="RG37905ST-17B">17b</A> Lee CW. Grubbs RH. Org. Lett.  2000,  2:  2145 

<A NAME="RG37905ST-18">18</A>

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].

<A NAME="RG37905ST-19">19</A>

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 H_arom), 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.