An extended study of the scope and mechanism of the catalytic asymmetric aziridination of imines with ethyl diazoacetate mediated by catalysts prepared from the VANOL and VAPOL ligands and triphenylborate is described. Nonlinear studies with scalemic VANOL and VAPOL reveal an essentially linear relationship between the optical purity of the ligand and the product suggesting that the catalyst incorporates a single molecule of the ligand. Two species are present in the catalyst prepared from B(OPh)(3) and either VANOL or VAPOL as revealed by (1)H NMR studies. Mass spectral analysis of the catalyst mixture suggests that one of the species involves one ligand molecule and one boron atom (B1) and the other involves one ligand and two boron atoms (B2). The latter can be formulated as either a linear or cyclic pyroborate and the (11)B NMR spectrum is most consistent with the linear pyroborate structure. Several new protocols for catalyst preparation are developed which allow for the generation of mixtures of the B1 and B2 catalysts in ratios that range from 10:1 to 1:20. Studies with catalysts enriched in the B1 and B2 species reveal that the B2 catalyst is the active catalyst in the VAPOL catalyzed asymmetric aziridination reaction giving significantly higher asymmetric inductions and rates than the B1 catalyst. The difference is not as pronounced in the VANOL series. A series of 12 different imines were surveyed with the optimal catalyst preparation procedure with the finding that the asymmetric inductions are in the low to mid 90s for aromatic imines and in the mid 80s to low 90s for aliphatic imines for both VANOL and VAPOL catalysts. Nonetheless, the crystallinity of the N-benzhydryl aziridines is such that nearly all of the 12 aziridine products screened can be brought to >99 % ee with a single recrystallization.

The stereochemistry-determining step of the self-assembled chiral Brønsted acid-catalyzed aziridination reactions of MEDAM imines and three representative diazo nucleophiles has been studied using ONIOM(B3LYP/6-31G*:AM1) calculations. The origin of cis selectivity in the reactions of ethyldiazoacetate and trans selectivity in reactions of N-phenyldiazoacetamide can be understood on the basis of the difference in specific noncovalent interactions in the stereochemistry-determining transition state. A H-bonding interaction between the amidic hydrogen and an oxygen atom of the chiral counterion has been identified as the key interaction responsible for this reversal in diastereoselectivity. This hypothesis was validated when a 3° diazoamide lacking this interaction showed pronounced cis selectivity both experimentally and calculationally. Similar trends in diastereoselection were observed in analogous reactions catalyzed by triflic acid. The broad implications of these findings and their relevance to chiral Brønsted acid catalysis are discussed.

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Chiral polyborate based Brønsted acids prepared from the VANOL and VAPOL ligands are known to catalyze the reaction of diarylmethyl imines with diazoesters to give cis-aziridines. In the present work, this same catalyst is shown to catalyze the reaction of the same imines with diazoacetamides to give trans-aziridines with the same high asymmetric inductions as seen with cis-aziridines, enabling the development of an unprecedented universal catalytic asymmetric aziridination protocol. The substrate scope is broad and includes imines prepared from both electron-rich and electron-poor aromatic aldehydes and also from 1°, 2°, and 3° aliphatic aldehydes. The face selectivity of the addition to the imine was found to be independent of the diazo compounds. The (S)-VANOL or (S)-VAPOL derived catalyst will cause both diazoesters and diazoacetamides to add to the Si-face of the imine when cis-aziridines are formed and both to add to the Re-face of the imine when trans-aziridines are formed.

The mechanism of the chiral VANOL-BOROX Brønsted acid catalyzed aziridination reaction of imines and ethyldiazoacetate has been studied using a combination of experimental kinetic isotope effects and theoretical calculations. A stepwise mechanism where reversible formation of a diazonium ion intermediate precedes rate-limiting ring-closure to form the cis-aziridine is implicated. A revised model for the origin of enantio- and diastereoselectivity is proposed based on relative energies of the ring closing transition structures.

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...

Ahighly diastereo-and enantioselective method for the epoxidation of aldehydes with a-diazoacetamides has been developed with two different borate ester catalysts of VA NOL. Both catalytic systems are general for aromatic,aliphatic, and acetylenic aldehydes,g iving high yields and inductions for nearly all cases.One borate ester catalyst has two molecules of VA NOL and the other only one VA NOL. Catalysts generated from BINOL and VA POL are ineffective catalysts.A n application is shown for access to the side-chain of taxol.The tactical repertoire for the conversion of either an aldehyde or ketone into an epoxide largely consists of two transformations (Scheme 1): 1) the Darzens condensation of an a-halo stabilized carbanion with the ac arbonyl compound, [1,2] 2) the Corey-Chaykovskyr eaction which involves as ulfur ylide as ac arbene surrogate in the synthesis of epoxides. [3][4][5][6][7] At hird method involving the formation of epoxides from the reactions of diazo compounds are not that common and have not been particularly useful. [8][9][10] However, Scheme 1. Epoxidesf rom ketones and aldehydes.EWG = electron-withdrawing group.Scheme 2. The cis-and trans-aziridination with BOROX catalysts.

Buchwald–Hartwig amination of chloroheteroarenes has been a challenging synthetic process, with very few protocols promoting this important transformation at ambient temperature. The current report discusses about an efficient copper-based catalytic system (Cu/PTABS) for the amination of chloroheteroarenes at ambient temperature in water as the sole reaction solvent, a combination that is first to be reported. A wide variety of chloroheteroarenes could be coupled efficiently with primary and secondary amines as well as selected amino acid esters under mild reaction conditions. Catalytic efficiency of the developed protocol also promotes late-stage functionalization of active pharmaceutical ingredients (APIs) such as antibiotics (floxacins) and anticancer drugs. The catalytic system also performs efficiently at a very low concentration of 0.0001 mol % (TON = 980,000) and can be recycled 12 times without any appreciable loss in activity. Theoretical calculations reveal that the π-acceptor ability of the ligand PTABS is the main reason for the appreciably high reactivity of the catalytic system. Preliminary characterization of the catalytic species in the reaction was carried out using UV–VIS and ESR spectroscopy, providing evidence for the Cu­(II) oxidation state.