Enantioselective One-Pot Synthesis of α-Amino Esters by a Phosphine-Catalyzed [3+2]-Cycloaddition Reaction

Phosphine-catalyzed [3+2]cycloaddition reactions of electron-deficient allenes and alkynes with a,b-unsaturated carbonyl compounds can give access to important highly functionalized cyclopentenes. The seminal example of such a transformation was first reported by Lu et al. in 1995, and its asymmetric version in 1997 by the group of Zhang. However, it took another ten years before the potential of this annulation strategy using chiral phosphine catalysts was studied more intensively. The last decade has witnessed considerable progress in the development of suitACHTUNGTRENNUNGable new chiral phosphine catalysts and their application in asymmetric [3+2]-cycloaddition reactions. Recently, readily available olefinic azlactones have emerged as amino acid precursors in organocatalysis. Therefore, we decided to develop a novel asymmetric phosphine-catalyzed [3+2]-cycloaddition reaction of olefinic azlactones with allenes for the synthesis of highly functionalized chiral amino esters. The cycloaddition between olefinic azlactones 1 and allenes 2 using a chiral phosphine catalyst would thereby give access to enantioenriched cyclopentenyl derivatives 3 and 4 (Scheme 1). To the best of our knowledge, the optically active cyclopentenyl derivatives 3 and 4 have until now only been synthesized efficiently in a racemic manner. Herein, we report the results of our studies on the enantioselective onepot synthesis of cyclic a-amino esters by a phosphine-catalyzed [3+2]-cycloaddition reaction of azlactones with allenes. In general, two pathways are possible for this reaction, affording regioisomers resulting from aor g-addition. Since b-substituted exocyclic enones preferentially undergo g-addition, we assumed that the g-adduct would be favored, giving access to aspartic acid derivatives 5 after a ring-opening reaction of the azlactone moiety. At the outset, a number of chiral phosphine catalysts were evaluated for the [3+2]-cycloaddition reaction of (Z)olefinic azlactone 1a with ethyl buta-2,3-dienoate 2a (see the Supporting Information). Among the catalysts tested, (S)-BINEPINE afforded the highest regioand enantioselectivities. As anticipated, it was found that the g-addition was favored, providing a 12:1 regioisomeric ratio (i.r.) of products 3a and 4a with an enantiomeric excess of 94% ee of 3a (Scheme 2). Additional screening of solvents and concentrations showed that the best results were obtained in toluene and a concentration of 0.1m provided a better solubility of the azlactone. It should be noted that no difference in the reaction outcome was observed when the reaction was performed under air or inert conditions, which enhances the practicability and usefulness of this phosphine-catalyzed cycloaddition. A screening of different allenes showed that the ethyl ester 2a in combination with an azlactone containing a phenyl group at the C2 position (R=Ph, see Scheme 1), provided the highest, yet disappointing, conversion and selectivities. The cycloaddition with Me-substituted azlactone (R=Ph, R=Me) resulted in inferior results. Since only partial conversion of the azlactone 1a, and therefore a low combined yield of products 3a and 4a, was [a] Dr. M. Steurer, K. L. Jensen, Dr. D. Worgull, Prof. Dr. K. A. Jørgensen Center for Catalysis, Department of Chemistry Aarhus University, 8000 Aarhus C (Denmark) Fax: (+45)8619 6199 E-mail : [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201103502.