Mapping the Active Site in a Chemzyme: Diversity in the N-Substituent in the Catalytic Asymmetric Aziridination of Imines

Abstract

The active site of the aziridination catalyst derived from either the VANOL or VAPOL ligand is larger than expected and can accommodate not only significant substitution on the diarylmethyl unit of the imine but also that alkyl (but not perfluorylalkyl) substituents on the aryl groups lead to enhanced rates and enantioselection. The screen of diarylmethyl N-substituents on the imine revealed that the 3,5-di-t-Butyldianisylmethyl group (BUDAM) gave exceptionally high asymmetric inductions for imines of aryl aldehydes.Supporting Information Available: Experimental protocols, characterization procedures, spectral data for all compounds. This material is available free of charge via the Internet at http://pubs.acs.org. Recent studies have revealed that the reaction of either VANOL or VAPOL with triphenylborate produces a mixture of the mesoborate 6 and the pyroborate 7 (Scheme 1) in favor of the latter which gives a higher asymmetric induction than the former in the AZ reaction. 1g Since 7 has two Lewis acidic centers, the question of how imine 1 interacts with the catalyst is suddenly rendered doubly complicated. It is known that the N-benzhydryl group in imine 1e (R = CHPh 2 ) was optimal among the readily available electron neutral N-protecting groups examined in the original screen of the reaction. Thus, in considering how the N-benzhydryl imine 1e will interact with the catalyst, one must include not only Lewis base/Lewis acid interactions but also any potential CH-π interactions 6 and π-π stacking interactions 7 of the phenyl rings of the benzhydryl group with the arene rings of the ligands. In addition, these interactions should be consistent with the fact that there is little difference between the VANOL and VAPOL derived catalysts. In an effort to begin to address these questions, we have undertaken an investigation designed to extensively probe the effects of changes in the conformation, electronics and sterics of the two phenyl groups in the N-benzhydryl substituent. NIH Public AccessThe results of these studies have not only provided a clearer picture of the types of interactions that are important between the catalyst and the imine substrate but also have identified an Nsubstituent that provides exceedingly clean and high yielding reactions with near perfect asymmetric inductions for aryl imines in the AZ reaction.The first set of experiments was designed to probe whether the relative orientation of the two phenyl groups in the N-substituent of the imine was important for the binding of the substrate to the active site of the VAPOL catalyst and the results are summarized in Figure 1. That two phenyl groups are required in the N-substituent of the imine is demonstrated by the fact that the AZ reaction of N-benzyl imine 1a gives aziridine 3a in 51% yield and in only 43% ee with 10 mol% of the (S)-VAPOL catalyst under the conditions shown in Scheme 1 (CH 2 Cl 2 at room temperature in 24 h). Under the same conditions the benzhydryl imine 1e gives 83% yield and 89% ee for aziridine 3e. As controls, t...

A Succinct Synthesis of the Vaulted Biaryl Ligand Vanol via a Dienone–Phenol Rearrangement

“…As indicated in Scheme , the reaction of imine 1 with ethyl diazoacetate gives cis ‐aziridine 3 in 91 % ee with a catalyst prepared from either the vanol or vapol ligand. Although higher enantioselectivities can be obtained in toluene11g as well as with different types of N‐protecting groups other than benzhydryl,11h the reaction in Scheme is presented to provide a comparison of the vanol and vapol ligands11g with binol 11b. Given the difference in the chiral pockets of vanol and vapol, it is quite remarkable that these ligands give the same enantioselectivity for aziridine 3 .…”

Chiral Magnesium BINOL Phosphate-Catalyzed Phosphination of Imines: Access to Enantioenriched α-Amino Phosphine Oxides

“…17 During the screening process we soon realized an electron-neutral, unactivated protecting group provided considerable enhancement in the yield and enantioselectivity, similar to that observed by Wulff and coworkers in an aziridination reaction. 18 …”

Chiral Diol-Based Organocatalysts in Enantioselective Reactions

“…In 1993, Wulff’s group introduced VANOL and VAPOL as chiral ligands for a metal-catalyzed asymmetric Diels–Alder reaction [ 59 ]. During subsequent decades, many modified VANOL and VAPOL derivatives have been shown to be crucial in asymmetric reactions the aziridination of imines [ 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 ], the 2-aza-Cope rearrangement [ 69 ], the Ugi reaction [ 70 ], and other reactions [ 71 ]. Since this review is focused on diol organocatalysts, those reactions involving transition metals with VANOL or VAPOL ligands will not be covered here.…”