[reaction: see text] A commercially available pharmaceutical, tetramisole, was found to be a competent enantioselective acylation catalyst. Its benzannellated analogue, benzotetramisole (BTM), produced outstanding enantioselectivities in kinetic resolution of secondary benzylic alcohols.

Homobenzotetramisole (HBTM), a ring-expanded analogue of the previously reported catalyst BTM, displays higher catalytic activity and a different structure-selectivity profile. It displays good enantioselectivities in kinetic resolution of secondary benzylic alcohols but is particularly effective for 2-aryl-substituted cycloalkanols.

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Abstract1,2,4-Triazole anion has been identified as an active acyl transfer catalyst suitable for the aminolysis and transesterification of esters.Neutral nucleophiles (Figure 1), such as 4-dialkylaminopyridines (1), 1 N-alkylimidazoles (2), 2 phosphines (3), 3 imidazolylidene carbenes (4), 4 1,2-diamines (5), 5 and the recently introduced bicyclic amidines (6) and isothioureas (7), 6 have proved to be effective acyl transfer catalysts. As such, they have found a variety of applications in organic synthesis. 7 Their chiral derivatives have demonstrated considerable utility in catalyzing enantioselective transformations. 8 By contrast, the potential of anionic nucleophiles in acyl transfer catalysis remains much less explored.In the course of our studies on enantioselective acyl transfer catalysis we became interested in achieving catalytic acylation of amines using easily accessible achiral acyl donors. 9 Carboxylic esters would be especially attractive in this regard, since their uncatalyzed reaction with amines is typically very slow at ambient temperature. However, the aforementioned neutral Lewis base catalysts, 7 which successfully promote acylations with carboxylic anhydrides (1-3, 6 and 7) or acyl chlorides (5), can attack only highly activated esters. Imidazolylidene carbenes 4, which have gained popularity as transesterification catalysts, 4 have also proved to be ineffective in promoting ester aminolysis. 10 Recently, Mioskowski et al. reported that a variety of unactivated esters undergo efficient aminolysis under solvent-free conditions in the presence of TBD 8 (Figure 2), which was proposed to act as a bifunctional Lewis base catalyst. 11 Its catalytic activity, however, is only moderate, requiring a high catalyst loading (30 mol%). E-mail: birman@wustl.edu. We considered the possibility of catalyzing ester aminolysis with anionic nucleophiles, which might be expected a priori to be more nucleophilic than their neutral counterparts, and therefore better able to attack the ester group. Although the anions of protic nucleophiles 9-12 have been reported in the literature to promote this reaction, their catalytic activities were usually rather modest. 12 NIH Public AccessIn an effort to identify more active anionic acyl transfer catalysts potentially suitable for asymmetric catalyst design, we tested the aforementioned 9-12 and several other commercially available protic nucleophiles (8, 13-21) for their ability to promote the reaction of phenyl acetate with isopropylamine in the presence of stoichiometric amounts of DBU (Table 1). For comparison, we also included DMAP 1, a powerful aprotic Lewis base acylation catalyst. Most compounds tested showed only negligible effect. Among the previously reported catalysts, only catechol and cyanide anions effected significant rate acceleration (entries 6 and 7). The most remarkable results were obtained in the azole series (entries 11-16). 1,2,4-Triazole 18 displayed by far the greatest activity among all the nucleophiles tested. Diminished activity was also foun...

Computational studies provide support for the involvement of intermolecular π-interactions in the chiral recognition of secondary benzylic alcohols by the enantioselective acyl transfer catalyst CF 3 -PIP.Nonenzymatic enantioselective acyl transfer catalysis has been an active area of research for over a decade. 1 Many of the catalysts developed to date have demonstrated varying degrees of enantioselectivity in kinetic resolution 2 of secondary alcohols. Secondary benzylic alcohols have enjoyed particular popularity as substrates in this reaction. 3,4a-c However, the origin of enantioselectivity in this process has not been elucidated. In this Communication, we present the results of our computational studies, which support the involvement of π-interactions in the chiral recognition of this class of substrates. 5In 2004, we introduced a new class of enantioselective acyl transfer catalysts. Among the firstgeneration catalysts, CF 3 -PIP 1 proved to be particularly effective in kinetic resolution of secondary benzylic alcohols (2). Structure-selectivity trends observed in this initial study led us to hypothesize that the chiral recognition depends on π-π and cation-π interactions between the pyridinium ring of the N-acylated catalyst and the benzene ring of the substrate, as shown in the proposed transition state model 4 (Scheme 1). 4a Later, this hypothesis proved to be valuable as a guide in the development of subsequent generations of related catalysts. 4b,c,f Their application to benzylic, 4a-c,f allylic 4b and propargylic 4d alcohols, 4-arylhouk@chem.ucla.edu; birman@wustl.edu. Supporting Information Available: Kinetic resolution, computational and X-ray data. These materials are available free of charge via the Internet at http://pubs.acs.org. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript oxazolidinones 4e and 2-aryl-cycloalkanols 4f produced results that were also consistent with the π-stacking mechanism.Recently, we were able to obtain an X-ray structure of the N-acetylated CF 3 -PIP in the form of hexafluoroantimonate 5a, which was in accord with the expected conformation. However, the involvement of π-interactions in the transition state is inherently difficult to verify by direct experimental observation. Therefore, we initiated a computational study aimed at elucidating the origin of the enantioselectivity. To the best of our knowledge, the role of intermolecular π-interactions in chiral recognition has not been previously investigated by computational methods. 6, 7The energy-minimized geometry of N-acetyl-(R)-CF 3 -PIP + (5, X omitted) obtained at the B3LYP/6-31G* level of theory 8,9 was consistent with the X-ray structure of 5a, the acyl carbonyl being nearly coplanar with the pyridine ring. Transition state geometries for reactions of 5b and the R-and S-enantiomers of 1-phenylethanol (2, R 1 = Me) were investigated next. The acetate anion hydrogen-bound to the hydroxyl group of the substrate was included in the calculations, as suggested by the...