Asymmetric Aldol Reactions Using a Fluorous Oxazolidinone Chiral Auxiliary

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.

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

References

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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
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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-2^TM. 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.

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