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DOI: 10.1055/s-2007-1000868
Synthetic Routes towards Cryptophycin Unit A Diastereomers
Publikationsverlauf
Publikationsdatum:
21. Dezember 2007 (online)
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Abstract
Unit A of cryptophycin 1 is a δ-hydroxy acid with four stereogenic centres. Our unit A synthesis introduces the first two stereogenic centres by a catalytic, asymmetric dihydroxylation, whereas the remaining two stereogenic centres are established by diastereoselective reactions. In this letter, we focus on the diastereoselectivity of these reactions and discuss the accessibility of cryptophycin unit A diastereomers.
Key words
diastereoselectivity - addition reactions - oxidations - cuprates - natural products
-
1a
Schwartz RE.Hirsch CF.Sesin DF.Flor JE.Chartrain M.Fromtling RE.Harris GH.Salvatore MJ.Liesch JM.Yudin K. J. Ind. Microbiol. 1990, 5: 113 -
1b
Trimurtulu G.Ohtani I.Patterson GML.Moore RE.Corbett TH.Demchik FA. J. Am. Chem. Soc. 1994, 116: 4729 -
1c
Golakoti T.Ogino J.Heltzel CE.Husebo TL.Jensen CM.Larsen LK.Patterson GML.Moore RE.Mooberry SL.Corbett TH.Valeriote FA. J. Am. Chem. Soc. 1995, 117: 12030 -
1d
Kobayashi M.Kurosu M.Ohyabu N.Wang W.Kitagawa I. Chem. Pharm. Bull. 1994, 42: 2196 -
1e
Kobayashi M.Aoki S.Ohyabu N.Wang W.Kitagawa I. Tetrahedron Lett. 1994, 35: 7969 - For reviews, see:
-
1f
Eißler S.Stončius A.Nahrwold M.Sewald N. Synthesis 2006, 3747 -
1g
Eggen M.Georg GI. Med. Res. Rev. 2002, 22: 85 -
1h
Tius MA. Tetrahedron 2002, 58: 4343 - 2
Al-awar RS.Corbett TH.Ray JE.Polin L.Kennedy JH.Wagner MM.Williams DC. Mol. Cancer Ther. 2004, 9: 1061 -
3a
Gardinier KM.Leahy JW. J. Org. Chem. 1997, 62: 7098 -
3b
Liang J.Moher ED.Moore RE.Hoard DW. J. Org. Chem. 2000, 65: 3143 -
3c
Pousset C.Haddad M.Larchevêque M. Tetrahedron 2001, 57: 7163 -
3d
Li L.-H.Tius MA. Org. Lett. 2002, 4: 1637 -
3e
Mast CA.Eißler S.Stončius A.Stammler H.-G.Neumann B.Sewald N. Chem. Eur. J. 2005, 11: 4667 -
3f
Eißler S.Nahrwold M.Neumann B.Stammler H.-G.Sewald N. Org. Lett. 2007, 9: 817 - 4
Stončius A.Mast CA.Sewald N. Tetrahedron: Asymmetry 2000, 11: 3849 - 6
Yamamoto Y.Maruyama K. J. Am. Chem. Soc. 1978, 100: 3240 -
7a
Yamamoto Y.Chounan Y.Nishii S.Ibuka T.Kitahara H. J. Am. Chem. Soc. 1992, 114: 7652 -
7b
Dorigo AE.Morokuma K. J. Am. Chem. Soc. 1989, 111: 6524 -
8a
Cram DJ.Elhafez FAA. J. Am. Chem. Soc. 1952, 74: 5828 -
8b
Cram DJ.Wilson DR. J. Am. Chem. Soc. 1963, 85: 1245 -
8c
Chérest M.Felkin H. Tetrahedron Lett. 1968, 2205 -
8d
Anh NT. Top. Curr. Chem. 1980, 88: 145 -
8e
Anh NT.Eisenstein O. Nouv. J. Chim. 1977, 1: 61 -
8f
Anh NT.Eisenstein O. Tetrahedron Lett. 1976, 3: 155 -
8g For a review, see:
Mengel A.Reiser O. Chem. Rev. 1999, 99: 1191 - 9
Leonard J.Mohialdin S.Reed D.Ryan G.Swain PA. Tetrahedron 1995, 51: 12843 - 10
Oppolzer W. Tetrahedron 1987, 43: 1969 - 11
Hanessian S.Wang W.Gai Y.Olivier E. J. Am. Chem. Soc. 1997, 119: 10034 - 12
Morizawa Y.Yasuda A.Uchida K. Tetrahedron Lett. 1986, 27: 1833
References and Notes
Synthesis of 4b
Copper(I) iodide (25.34 mmol, 4.826 g) was dried for 2 h in high vacuum at 100 °C, deoxygenated three times with argon and suspended in anhyd toluene (52 mL). The mixture was cooled to -78 °C, then MeLi (1.4 M) in Et2O (18.1 mL) was added over 20 min. While the reaction mixture was warmed to -40 °C for 15 min, the suspension turned bright yellow. The mixture was cooled to -78 °C again and BF3·OEt2 (25.2 mmol, 3.58 g, 3.10 mL) was added dropwise and the mixture was stirred for 15 min at -78 °C. Then a solution of (E)-ethyl 3-[(4R,5R)-2,2-dimethyl-5-phenyl-1,3-dioxolan-4-yl]acrylate (3, 7.24 mmol, 2.000 g) in anhyd toluene (5 mL) was added dropwise and after the addition was complete, the reaction mixture was stirred for 16 h at -78 °C. A 9:1 mixture of aq NH4Cl solution and 25% aq NH4OH solution (6 mL) was added over 30 min at -78 °C, and the cooling bath was removed. Then, H2O (50 mL) and hexane (200 mL) were added to the reaction, and the mixture was filtered through a pad of Celite®. The layers of the filtrate were separated, the aqueous phase was extracted three times with hexane (50 mL) and the combined organic layers were washed with sat. NaCl solution (30 mL) and dried over Na2SO4. The solvent was removed under vacuum (50 °C). The crude product was purified by flash chromatography (hexane-EtOAc, 12:1) yielding (R)-ethyl 3-[(4R,5R)-2,2-dimethyl-5-phenyl-1,3-dioxolan-4-yl]butanoate (4b, 1.106 g, 52%, 92% de) as a slightly yellow, highly viscous oil. For the analytical data see ref. 4.
Synthesis of 7b: NaHMDS (2 M, 0.68 mmol, 0.34 mL) in THF (2.14 mL) was cooled to -78 °C, then a solution of (R)-ethyl 3-[(4R,5R)-2,2-dimethyl-5-phenyl-1,3-dioxolan-4-yl]butanoate (4b, 0.68 mmol, 0.200 g) in anhyd THF (1.6 mL) was added over 15 min and the mixture was stirred at -78 °C over 75 min. Then, racemic 3-phenyl-2-(phenyl-sulfonyl)-1,2-oxaziridine (0.95 mmol, 0.248 g,) in anhyd THF (1.6 mL) was added over 15 min and the mixture stirred at -78 °C until the reaction was complete (approx. 1 h). Then, sat. NH4Cl solution (1.5 mL) was added over 15 min at -78 °C and the mixture allowed to reach r.t. Afterwards, Et2O (50 mL) and H2O (10 mL) were added, the layers separated and the aqueous layer extracted three times with Et2O (50 mL). The combined organic layers were washed twice with H2O (25 mL) and sat. NaCl solution (25 mL), dried over Na2SO4, and the solvent was evaporated under vacuum. The residue was purified twice by chromatography (silica gel 60, hexane-EtOAc, 4:1) to obtain reasonably pure (2R,3R)-ethyl 3-[(4R,5R)-2,2-dimethyl-5-phenyl-1,3-di-oxolan-4-yl]-2-hydroxybutanoate (7b, 0.56 mmol, 0.173 g, 82% yield, 77% de). Crystallisation from n-hexane gives a diastereomerically enriched material (0.104 g, 0.34 mmol, 50%, 88% de); [α]D 22 -4.44 (c 1.1, MeOH). 1H NMR (500 MHz, CDCl3): δ = 7.25-7.45 (m, 5 H), 4.73 (d, J = 8.1 Hz, 1 H), 4.61 (dd, J = 5.0, 2.2 Hz, 1 H), 4.27 (m, 2 H), 4.02 (dd, J = 8.4, 8.4 Hz, 1 H), 2.94 (d, J = 5.0 Hz, 1 H), 2.24 (qdd, J = 8.7, 6.9, 1.9 Hz, 1 H), 1.56 (s, 3 H), 1.51 (s, 3 H), 1.31 (t, J = 7.1 Hz, 3 H), 0.59 (d, J = 7.1 Hz, 3 H). 13C NMR (126 MHz, CDCl3): δ = 174,5, 138.3, 128.6, 128.5, 127.9, 109.0, 83.5, 83.2, 71.2, 61.7, 40.2, 27.4, 27.3, 14.3, 10.2. IR (neat): 3437, 3065, 3029, 2983, 2933, 2902, 1729, 1496, 1456, 1383, 1306, 1248, 1225, 1173, 1156, 1132, 1096, 1053, 1034, 924, 880, 814, 754, 697. ESI-MS: m/z calcd for C17H24O5Na+: 331.15 [M + Na]+; found: 331.0; m/z calcd for C34H48O10Na+ 639.31 [2 M + Na]+; found: 638.7.
14CCDC 668175 (7b) and 668176 (9a) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.