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Synlett 2008(2): 273-277  
DOI: 10.1055/s-2007-1000868
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthetic Routes towards Cryptophycin Unit A Diastereomers

Stefan Eißlera, Beate Neumannb, Hans-Georg Stammlerb, Norbert Sewald*a
a Department of Organic and Bioorganic Chemistry, Bielefeld University, Universitätsstraße 25, 33615 Bielefeld, Germany
Fax: +49 (521) 106 8094; e-Mail: norbert.sewald@uni-bielefeld.de;
b Department of Inorganic Chemistry, Bielefeld University, Universitätsstraße 25, 33615 Bielefeld, Germany
Further Information

Publication History

Received 29 August 2007
Publication Date:
21 December 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

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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.

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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.

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CCDC 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.