DOI: 10.1002/chem.201100850 Bifunctional N-Acyl-Aminophosphine-Catalyzed Asymmetric [4 + 2] Cycloadditions of Allenoates and Imines Hua Xiao, [a] Zhuo Chai, [b] Hai-Feng Wang, [b] Xiao-Wei Wang, [b] Dong-Dong Cao, [a] Wen Liu, [a] Ying-Peng Lu, [b] Ying-Quan Yang, [a] and Gang Zhao* [a, b] Tetrahydropyridines are important structural motifs pres- ent in a huge number of pharmaceutically interesting sub- stances and bioactive natural products. For example, the ergot alkaloid derivative lysergic acid diethylamide (LSD, 1), a strongly psychedelic agent; tadalafil (2), a drug which has been marketed for the treatment of erectile dysfunction and pulmonary hypertension, and the cytotoxic bisindole al- kaloid Leucoridine B (3) all share the chiral tetrahydropyri- dine structure. [1] Although many powerful synthetic methods for accessing these nitrogen-containing six-membered het- erocycles have been established, [2] the development of cata- lytic asymmetric approaches allowing for the construction of these structures in optically active forms remains an attrac- tive goal in organic synthesis. [3] Since the seminal work of Lu and co-workers reported in 1995, [4] the phosphine-catalyzed cycloaddition reactions of allenoates have evolved to be an efficient method for the construction of a variety of synthetically useful carbo- and heterocycles due to intensive research efforts. [4–8] In addition to the initial fruitful use of unsubstituted allenoates as a “C3 synthon” in this type of reaction with various electrophiles, the incorporation of a and/or g-substituted allenoate into these reactions has greatly expanded the reaction scope. [8] Particularly, in 2003, Kwon pioneered the use of a-substitut- ed allenoates in the annulation reaction with imines, leading to a novel [4 + 2] cycloaddition reaction in which the alle- noates served as novel “C4 synthons”. [8a] Such a reaction provides an efficient and atom-economical access to multi- functional tetrahydropyridines. Later, this kind of [4 + 2] cy- cloaddition was further successfully extended to electron-de- ficient alkenes and trifluoromethylketones to give highly functionalized cyclohexenes [8c] and dihydropyrans. [8h] Despite the above impressive progress achieved in phos- phine-catalyzed cycloaddition reactions of allenoates, the development of enantioselective variants remains rather lim- ited and unbalanced. Up to now, most enantioselective an- nulations in this field were achieved only with non-substitut- ed allenoates and electron-deficient species, namely asym- metric [3 + 2] cycloadditions. [9, 10] To the best of our knowl- edge, there is only one report on an asymmetric a-substitut- ed allenoate–imine [4 + 2] cycloaddition catalyzed by a chiral monodentate phosphine developed by Fu in 2005, two years after Kwons finding of the non-enantioselective reac- tion. [8d] Therefore, there is still a great potential for asym- metric catalysis to be fulfilled in this field. Inspired by the works from Miller and Jacobsen, [10a–b] our group have recent- ly developed simple bifunctional N-acyl aminophosphines derived from amino acids as organocatalysts for highly regio- and enantioselective [3 + 2] cycloadditions between allenoates and dual-activated olefins. [11] Besides their acces- sibility and air stability, these bifunctional catalysts could also obviate some demanding reaction conditions such as an inert atmosphere and anhydrous solvents usually required for chiral monodentate phosphine catalysts. As part of our efforts to extend the application of these catalysts in asym- metric synthesis, we describe herein the highly diastereose- lective and enantioselective [4 + 2] cycloadditions between allenoates and tosylaldimines catalyzed by bifunctional N- acyl aminophosphines. Initially, the reaction between 2-(2-ethoxy-2-oxoethyl)-2, 3-butadienoate and N-tosylbenzaldimine in CH 2 Cl 2 was chosen to probe the catalytic efficiency of the bifunctional phosphines (Table 1). Interestingly, the isoleucine-derived catalyst 7f , the best catalyst identified in our previous asym- metric [3 + 2] cycloaddition, also proved the best one in this [4 + 2] cycloaddition, giving the desired cycloadduct 6a in 85 % yield and with 90 % enantiomeric excess (ee) (Table 1, [a] H. Xiao, D.-D. Cao, W. Liu, Y.-Q. Yang, Prof.Dr. G. Zhao Department of Chemistry University of Science and Technology of China Hefei, Anhui 230026 (P.R. China) Fax: (+ 86) 21-64166128 E-mail : zhaog@mail.sioc.ac.cn [b] Z. Chai, H.-F. Wang,X.-W. Wang, Y.-P. Lu, Prof.Dr. G. Zhao Laboratory of modern synthetic chemistry Shanghai institute of organic chemistry 354 Fenglin Road, Shanghai, 200032 Chinese Academy of Sciences (P.R. China) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201100850.  2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Chem. Eur. J. 2011, 17, 10562 – 10565 10562