Enantioselective MSPV Reduction ofKetimines Using 2-Propanol and(BINOL)AlIIIChristopher R. Graves, Karl A. Scheidt,* and SonBinh T. Nguyen*Department of Chemistry and Institute for EnVironmental Catalysis, NorthwesternUniVersity, 2145 Sheridan Road, EVanston, Illinois [email protected]; [email protected] January 14, 2006ABSTRACTA highly enantioselective Meerwein−Schmidt−Ponndorf−Verley (MSPV) reduction ofN-phosphinoyl ketimines by (BINOL)AlIII/2-propanol isreported. Yields ranging between 79 and 85% with high enantiomeric excesses (93−98%) are observed for a wide range of structurally diverseketimines. A [2.0.4] bicyclic chelation model is proposed to account for this high selectivity.The synthesis of chiral secondary amines is an importantendeavor given the extensive presence of this functionalgroup in natural products, pharmaceutical agents, and finechemicals.1While several synt h e t i c pathways toward thisclass of compounds can be envisioned,1cone of the moststandard routes is the direct enantiosele c t i v e reduction ofprochiral ketimines.2,3In contrast to the major successes inthe asymmetric reduction of ketones,4practical and highlystereoselective strategies for the corresponding ketiminereductions are not as prevalent.3,5Prominently, Noyori hasreported a protocol for the ruthenium-catalyzed asymmetrictransfer hydrogenation of imines with a formic acid-triethylamine mixture.5fWhile high asymmetric inductionwas obtained for cyclic N-benzylic imines, there was amarked decrease in selectivity for the corresponding reduc-tion of exocyclic and acyclic N-alkyl substrates. Hence, theasymmetric reduction of other classes of imines, especially(1) For examples, see: (a) Clifton, J. E.; Collins, I.; Hallet, P.; Hartley,D.; Lunts, L. H. C.; Wicks, P. D. J. Med. Chem. 1982, 25, 670-679. (b)Duthaler, R. O. Tetrahedron 19 94, 50, 1539-1650. (c) Johanssson, A.Contemp. Org. Synth. 1995, 2, 393-408. (d) Cardellicchio, C.; Ciccarella,G.; Naso, F.; Schingaro, E.; Scordari, F. Tetrahedron: Asymmetry 1998,9, 3667-3675.(2) Brunel, J. M. Rec. Res. DeV. Org. Chem. 2003, 7, 155-190.(3) Spindler, F.; Blaser, H.-U. In Transition Metals for Organic Synthesis,2nd ed.; Beller, M., Bolm, C., Eds.; Wiley-VCH Verlag GmbH & Co:Weinheim, Germany, 2004; Vol. 2, pp 113-123.(4) For relevant reviews, see: (a) Singh, V. K. Synthesis 1992, 7, 607-617. (b) Noyori, R.; Hashiguchi, S. Acc. Chem. Res. 1997, 30, 97-102. (c)Fehring, V.; Selke, R. Angew. Chem., Int. Ed. 1998, 37, 1827-1830. (d)Itsuno, S. Org. React. 1998, 52, 395-576. (e) Wills, M.; Hannedouche, J.Curr. Opin. Drug DiscoV. DeVel. 2002, 5, 881-891.(5) For pertinent references, see: (a) Krzyzanowska, B.; Stec, W. J.Synthesis 1982, 4, 270-273. (b) Hutchins, R. O.; Abdel-Magid, A.; Stercho,Y. P.; Wambsgans, A. J. Org. Chem. 1987, 52, 702-704. (c) Chan, Y. N.C.; Osborn, J. A. J. Am. Chem. Soc. 1990, 112, 9400-9401. (d) Bakos, J.;Orosz, A.; Heil, B.; Laghmari, M.; Lhoste, P.; Sinou, D. J. Chem. Soc.,Chem. Commun. 1991, 1684-1685. (e) Kawate, T.; Nakagawa, M.;Kakikawa, T.; Hino, T. Tetrahedron: Asymmetry 1992, 3, 227-230. (f)Uematsu, N.; Fujii, A.; Hashiguchi, S.; Ikariya, H. T.; Noyori, R. J. Am.Chem. Soc. 1997, 118, 44916-4917. (g) Nishikori, H.; Yoshihara, R.;Hosomi, A. Synlett 2003, 561-563. (h) Yamada, T.; Nagata, T.; Sugi, K.D.; Yorozu, K.; Ikeno, T.; Ohtsuka, Y.; Miyazaki, D.; Mukaiyama, T. Chem.Eur. J. 2003, 9, 4485-4509. (i) Lipshutz, B. H.; Shimizu, H. Angew. Chem.,Int. Ed. 2004, 43, 2228-2230. (j) Gosselin, F.; O’Shea, P. D.; Roy, S.;Reamer, R. A.; Chen, C.-Y.; Volante, R. P. Org. Lett. 2005, 7, 355-358.(k) Nolin, K. A.; Ahn, R. W.; Toste, F. D. J. Am. Chem. Soc. 2005, 127,12462-12463.ORGANICLETTERSxxxxVol. 0, No. 0A-D10.1021/ol060110w CCC: $33.50 © xxxx American Chemical SocietyPAGE EST: 3.3Published on Web 02/24/2006those containing easily removable N-protecting groups,continues to be a major research focus in synthetic organicchemistry.5At the same time, reduction strategies thatcircumvent the use of transition metals and metal hydrideshave attracted significant attention in recent years due to theincreasing demand for environmentally friendly, inexpen-sive, and efficient synthetic methods. The aluminum-basedMeerwein-Schmidt-Ponndorf-Verley (MSPV) reduction6-8is a reaction that not only satisfies these criteria but alsoholds substantial promise for further asymmetric develop-ments. While employing an inexpensive and innocuousmetal, this reaction proceeds under relatively mild conditionsand utilizes simple secondary alcohols, such as 2-propanol,as the reducing agent.9A catalytic protocol for our aluminum-based enantioselective MSPV reduction of ketones employ-ing a chiral complex formed in situ between enantiomericallypure 2,2′-dihydroxy-1,1′-binaphthyl (BINOL),10AlMe3, and2-propanol has recently been reported.11,12In this paper, wedisclose a highly enantioselective reduction of N-phosphinoylketimines based on the use of this reagent combination.The identification of a viable imine electrophile to pairwith our aluminum system was a critical first step. Encour-aged by our recent success in the addition of acyl anions toN-diphenylphosphinoyl imines,13we reasoned that theseelectrophilic compounds might also undergo MSPV reduc-tion. Furthermore, these imines have recently been employedas electrophiles in a number of asymmetric transforma-tions,14,15and the resulting amides are easily converted intouseful intermediates.16Hence, we were gratified to observethe stereoselective reduction of imine 1 by 2-propanol in thepresence of stoichiometric amounts of (S)-BINOL and AlMe3during our initial experiments (Table 1). While reaction 1does not proceed at room temperature (Table 1, entry 1),quantitative conversion is observed at 80 °C, albeit in 84%ee (Table 1, entry 4). Lowering the reaction temperature to40 °C results in an increase in enantioselectivity (99% ee),but a decrease in conversion to 50% (Table 1, entry 2).Ultimately, increasing the concentration (to 80 mM) andtemperature (to 60 °C) with 1.2 equiv of (S)-BINOL/AlMe3affords the desired amide 11 in 92% conversion withexcellent selectivity (96% ee, Table 1, entry 5). The use ofa catalytic amount of the (S)-BINOL/AlMe3mixture onlyaffords a commensurate conversion of the imine, suggestinga single-turnover event (Table 1, entry 6).The conditions of Table 1, entry 5, are highly selectivefor a wide range of structurally diverse N-phosphinoylimines.For
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