Development of a New Dimeric Cyclophane Ligand: Application to Enhanced Diastereo- and Enantioselectivity in the Catalytic Synthesis of -Lactams Harald Wack, Stefan France, Ahmed M. Hafez, William J. Drury III, Anthony Weatherwax, and Thomas Lectka* Department of Chemistry, New Chemistry Building, Johns Hopkins University, 3400 North Charles Street, Baltimore, Maryland 21218 lectka@jhu.edu Received February 3, 2004 Abstract: We detail the synthesis of a new C 2 -symmetric bis(cyclophane) ligand system that can be thought of as electronically analogous to binol, but which possesses the added “third dimension” of cyclophane chirality. The ligand synthesis involves a spontaneous (but unexpected) atrop- isomerization to the desired product. We have employed this ligand to form a metal complex that is an effective cocatalyst for the highly enantio- and diastereoselective catalytic asymmetric synthesis of a -lactam. We thought it would be of interest to devise a new sterically bulky biaryl ligand system wherein the chiral bulk not only projects “horizontally” back from the metal center but also “vertically,” up and down from the site of catalysis, taking advantage of the added “third dimen- sion” of cyclophane chirality, 1 in contrast to binol, which projects much less steric bulk in the vicinity of the metal. The result is a ligand system that possesses both planar and axial chirality and which may be appropriate for applications in which the use of binol is unsatisfactory. To demonstrate, in a preliminary fashion, the utility of this new ligand system, we apply an Al(III)-based com- plex of ligand 1 in the bifunctional, catalytic, asymmetric synthesis of -lactams. The use of the ligand-metal complex in conjunction with a cinchona alkaloid cocata- lyst provides enhanced yields of product in high diaste- reo- and enantioselectivity. We envisioned the construction of ligand 1 from dimer- ization of a suitably functionalized cyclophane monomer, such as 4 (Scheme 1). The synthesis of 4 can be ac- complished straightforwardly starting with the known carbamate 2, 2 conveniently available in either racemic or optically pure forms as described by Pamperin et al. Iodination of either racemic or (R)-2, followed by depro- tection by ethereal hydrazine and reprotection as the methyl ether, afforded the coupling precursor 4 in 87% overall yield from 2. 3 Formation of a di-(()-copper(I)-ate complex from iodide (()-4 and its oxidation with molecular oxygen gave two new major products. 4 These were shown to be both the “quasi-meso” (a racemic mixture of (S,R p ,R) 5 and (R,R p ,S) in 12% yield) and the “quasi-dl” form of the dimer 5 ((S,R p ,S) and (R,S p ,R), 21% yield) (eq 1). To our satisfaction, repeating the reaction with optically pure 4 produces one major dimeric product 5. A single-crystal X-ray structure of 5 obtained from the coupling of (R)-4 established its absolute configuration as (S,R p ,S), 6 the opposite of what we had desired. Surprisingly, treatment of (R,S p ,R)-5 with BBr 3 at -40 °C not only resulted in the removal of one methyl ether but also initiated a concomitant atropisomerization to the desired (R,R p ,R)-6 diastereomer (eq 2). Its configuration was also implied by the presence of an intramolecular hydrogen bond in the IR spectrum, necessitating proxim- ity between the methoxy and hydroxyl groups. Depro- (1) For some examples of the use of cyclophanes as ligands, see: (a) Worsdorfer, U.; Vo ¨gtle, F.; Nieger, M.; Waletzke, M.; Grimme, S.; Glorius, F.; Pfaltz, A. Synthesis 1999, 4, 597-602. (b) Hou, X.-L.; Wu, X.-W.; Dai, L.-X.; Cao, B.-X.; Sun, J. Chem. Commun. 2000, 1195- 1196. (c) Dahmen, S.; Brase, S. Chem. Commun. 2002, 26-27. (d) Inoue, M. B.; Velazquez, E. F.; Medrano, F.; Ochoa, K. L.; Galvez, J. C.; Inoue, M.; Fernando, Q. Inorg. Chem. 1998, 37, 4070-4075. (e) Pye, P. J.; Rossen, K.; Reamer, R, A.; Tsou, N. N.; Volante, R. P.; Reider, P. J. J. Am. Chem. Soc. 1997, 119, 6207-6208. (2) Hopf, H.; Grahn, W.; Barrett, D. G.; Gerdes, A.; Hillmer, J.; Hucker, J.; Y. O.; Kaida, Y. Chem. Ber. 1990, 123, 841-845. (3) Pamperin, D.; Schulz, C.; Hopf, H.; Syldatk, C.; Pietzsch, M. Eur. J. Org. Chem. 1998, 7, 1441-1446. (4) Whitesides, G. M.; SanFilippo, J. J.; Casy, C. P.; Panek, E. J. J. Am. Chem. Soc. 1967, 89, 5302-5303. (5) The stereochemical assignment for the coupled products adhere to the following denotation: (A, Bp,C): where A represents the absolute stereochemistry of the first cyclophane moiety; Bp represents the stereochemistry about the pivot bond (pivot or axial isomers); and C represents the configuration of the second cyclophane moiety. SCHEME 1. Synthesis of Diol Coupling Precursor 4 10.1021/jo049804d CCC: $27.50 © 2004 American Chemical Society J. Org. Chem. 2004, 69, 4531-4533 4531 Published on Web 05/25/2004