N/N/O versus N/O/O and N/O amino isoborneols in the enantioselective ethylation of benzaldehyde Toma´s de las Casas Engel, Beatriz Lora Maroto, Antonio Garcı ´a Martı ´nez and Santiago de la Moya Cerero * Departamento de Quı´mica Orga´ nica I de la Universidad Complutense de Madrid, Facultad de Ciencias Quı´micas, Ciudad Universitaria s/n, 28040 Madrid, Spain Received 20 December 2007; accepted 8 January 2008 Abstract—Enantiopure 10-(4-methylpiperazin-1-yl)isoborneol, a N/N/O-tridentate chiral diamino isoborneol, has been obtained from enantiopure ketopinic acid and its catalytic activity (as chiral ligand in the enantioselective addition of diethylzinc to benzaldehyde) mea- sured and compared with the previously reported data for related N/N/O, N/O/O, and N/O isoborneols. It is demonstrated that the pentacoordinated-zinc Oppolzer’s model for transition states is useful for explaining the catalytic behavior of N/N/O-tridentate ligands. In such cases, stable syn- or anti-type transition states can be proposed depending on the catalyst’s conformational flexibility. Ó 2008 Elsevier Ltd. All rights reserved. 1. Introduction The enantioselective addition of organozinc reagents to aldehydes catalyzed by chiral ligands 1 is one of the most important asymmetric processes of synthetic utility, since the optically active secondary alcohols obtained are the key intermediates for the preparation of important biologi- cally active compounds (including several synthetic drugs) and new materials with interesting optical properties. 2 Since Noyori et al. demonstrated the high efficiency of 3-exo-(dimethylamino)isoborneol (DAIB) 1 (Fig. 1), an N/O-bidentate b-amino alcohol, as a chiral ligand for the enantioselective addition of diethylzinc to benzaldehyde, 3 explaining such activity in terms of activated bimetallic species formed from a reactive zinc-chelate catalyst, 4 many other chiral N/O-bidentate ligands, specially b-amino alco- hols, 5 have been prepared and tested in this reaction. On the other hand, chiral ligands with three coordination sites have been far less studied. 6,7 It is expected that a tridentate chiral ligand should confer more rigidity to the reactive zinc-chelate catalyst than a bidentate one, and thus may enhance the enantioselectivity of the addition reaction. 7d Nevertheless, the role played by the third coordination site is more complicated and unknown. Thus, the very few reported comparison studies between bidentate and tridentate ligands 7 show different tendencies, from unchanged enantioselectivities 7b,d to enantioselectivity reversal. 7a Herein we report the factors controlling the catalytic activ- ity of tridentate amino alcohols as chiral ligands for the enantioselective addition of diethylzinc to benzaldehyde, by a comparison of the catalytic behavior of a series of N/O, N/N/O, and N/O/O 10-aminoisoborneols described previously by Oppolzer and Aoyama, with a new related N/N/O ligand obtained and tested by us. 2. Results and discussion In 1988, Oppolzer described that both N/O amino isobor- neol 2 and N/N/O diamino isoborneol 3 (Fig. 2) are able to OH 1 N Figure 1. DAIB, a N/O-bidentate chiral amino alcohol. 0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetasy.2008.01.012 * Corresponding author. Tel.: +34 91 394 5090; fax: +34 91 394 4103; e-mail: santmoya@quim.ucm.es Available online at www.sciencedirect.com Tetrahedron: Asymmetry 19 (2008) 269–272