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Synlett 2003(5): 0635-0638
DOI: 10.1055/s-2003-38371
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Asymmetric Aldol Reactions Using a Fluorous Oxazolidinone Chiral Auxiliary

Jason E. Hein, Philip G. Hultin*
Department of Chemistry, University of Manitoba, Winnipeg, MB, R3T 2N2, Canada
e-Mail: hultin@cc.umanitoba.ca;
Further Information

Publication History

Received 12 December 2002
Publication Date:
28 March 2003 (online)

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Abstract

A new class of supported oxazolidinone chiral auxiliary has been synthesized from l-phenylalanine. The use of a perfluorooctyl chain as a support facilitates enolate reactions under standard solution conditions, with reaction products rapidly isolated by solid-phase extraction on fluorous silica. Reactions employing a syn-oxazolidinone afforded yields and stereoselectivities in titanium-mediated aldol reactions that were comparable to those reported in the literature using the standard Evans-type auxiliaries under similar conditions. These results are the first demonstration of asymmetric enolate chemistry using fluorous compounds.

Key words

aldol reactions - asymmetric synthesis - chiral auxiliaries - fluorous extraction - fluorous supported synthesis

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Hultin, P.G. unpublished results.

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Synthesis of 2( S )-(Ethoxycarbonylamino)-4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-heptadecafluoro-1-phenyl-undecan-3-one(4). Ester 3 (0.5 g, 1.99 mmol) was dissolved in anhyd Et2O (250 mL). BF3⟨OEt2 (0.25 mL, 2.18 mmol) was added to the solution, followed by C8F17I (0.6 mL, 2.18 mmol). The reaction mixture was cooled to
-78 °C and MeLi-LiBr (2.18 mL, 1.5 M solution in Et2O) was added drop wise over 15 min. The reaction proceeded at -78 °C for 2 h, and was then quenched with dilute NH4Cl (20 mL) before allowing the solution to warm to r.t. The aq layer was then extracted with Et2O (2 ¥ 50 mL). The combined diethyl ether extracts were washed with brine, dried with MgSO4, and evaporated to dryness. The crude material (1.2 g) was dissolved in n-PrOH (2 mL) and applied to a column of Tridecafluoro-2TM. The column was washed with 250 mL of 2:3 n-PrOH-H2O removing any organic and inorganic by-products. Fluorous material was then recovered by eluting with acetone (ca. 50 mL). The product was further purified using flash chromatography on silica gel, eluting with a solvent gradient (hexane to 9:1 hexane:EtOAc) allowing us to isolate 0.483g (38%) of ketone 4. Mp 55-57 °C. 1H NMR (300 MHz, acetone-d 6): δ = 7.24 (m, 5 H, C6H5), 5.34 (d, 1 H, 3 J = 8.3 Hz, NH), 5.15 [m, 1 H, BnCH(NHR)CO-], 4.06 (q, 2 H, 3 J = 7.2 Hz, -OCH 2CH3), 3.25 (dd, 1 H, 3 J 1 = 14.07 Hz, 3 J 2 = 4.33 Hz, PhCHH-), 2.90 (dd, 1 H, 3 J 1 = 13.80 Hz, 3 J 2 = 7.94 Hz, PhCHH-), 1.17 (t, 3 H, 3 J = 7.21 Hz, -OCH2CH 3). 13C (75 MHz, CDCl3): δ = 14.22 (-OCH2 CH3), 36.65 (PhCH2-), 57.10 [BnCH(NHR)CO-], 61.6 (-OCH2CH3), 127.53-134.21 (C 6H5-), 155.52 (RNHCOO-), 193.13 (-COC8F17). Anal. Calcd for C20H14F17NO3: C, 37.58; H, 2.21; N, 2.19. Found: C, 37.42; H, 2.01; N, 2.04.

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General Procedure for Aldol Reactions: Propionyl derivative 10 (0.1 g, 0.15 mmol) was dissolved in CH2Cl2 (5 mL), and cooled to -20 °C. TiCl4 (0.169 mL, 1 M solution in CH2Cl2) was added dropwise over ca. 5 min. DIEA (0.742 mL, 0.38 mmol) was then added and the reaction stirred for 20 min, resulting in the development of a deep-red color characteristic of a titanium enolate. Benzaldehyde (0.0386 mL, 0.38 mmol) was added drop wise, and the solution was stirred at -20 °C for 3 h. The reaction was quenched with sat. NH4Cl (5 mL), and extracted with Et2O (2 ¥ 10 mL). The combined extracts were dried with MgSO4 and evaporated to yield a crude residue (0.25 g). This residue was dissolved in n-PrOH (2 mL) and applied to a column charged with Tridecafluoro-2TM. Eluting with 250 mL of 2:3 n-PrOH-H2O removed all inorganic and organic impurities. Fluorous material was then isolated by eluting with ca. 20 mL of acetone to give 0.11 g (95%) of the product 11, which was analyzed by HPLC.