Catalytic Asymmetric Aziridination Research Articles

Controlled Diastereo- and Enantioselection in a Catalytic Asymmetric Aziridination

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.

Seeking Passe-Partout in the Catalytic Asymmetric Aziridination of Imines: Evolving Toward Substrate Generality for a Single Chemzyme

The asymmetric catalytic aziridination reaction (AZ reaction) of imines derived from dianisylmethyl (DAM) amine and tetra-methyldianisylmethyl (MEDAM) amine were examined with boroxinate catalysts prepared from both the VANOL and VAPOL ligands. This included an evaluation of different protocols for the preparation of the catalyst. The AZ reaction of DAM and MEDAM imines prepared from nine different aryl and aliphatic aldehydes were examined. The MEDAM imines were superior to the DAM imines in the AZ reaction, giving much higher asymmetric inductions and higher overall yields of aziridines. The MEDAM imines were found to also be superior to the previously studied diphenylmethyl (benzhydryl or Bh) and tetra-tert-butyldianisylmethyl (BUDAM) imines especially for imines derived from aliphatic aldehydes. The average asymmetric induction over the nine different MEDAM imines studied was 97% ee with the VAPOL catalyst and 96% ee with the VANOL catalyst. The MEDAM imines can be deprotected to give N-H aziridines in all cases except for some electron-rich aryl aldehydes. The MEDAM imines are much more reactive than benzhydryl imines, and this was most evident when a diazoacetate ester is replaced by a diazoacetamide. The less reactive diazoacetamides give very low yields in their reactions with benzhydryl imines but high yields with MEDAM imines.

Asymmetric Catalytic Aziridination of Cyclic Enones

The first catalytic method for the asymmetric aziridination of cyclic enones is described. The presented organocatalytic strategy is based on the use of an easily available organocatalyst that is able to convert a wide range of cyclic enones into the desired aziridines with very high enantiomeric purity and good chemical yield. Such a method may very well open up new opportunities to stereoselectively prepare complex chiral molecules that possess an indane moiety, a framework that is found in a large number of bioactive and pharmaceutically important molecules.

ChemInform Abstract: Catalytic Asymmetric Aziridination of Enol Derivatives in the Presence of Chiral Copper Complexes to Give Optically Active α-Amino Ketones.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform Abstract: Catalytic Asymmetric Aziridination with Catalysts Derived from VAPOL and VANOL

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Evidence for a Boroxinate Based Brønsted Acid Derivative of VAPOL as the Active Catalyst in the Catalytic Asymmetric Aziridination Reaction

Studies are described that were designed to determine the structure of the active catalyst in the asymmetric catalytic aziridination of imines with ethyl diazoacetate (AZ reaction). Evidence suggests that the active catalyst contains a boroxine ring in which one of the three boron atoms is spiro-fused with the two phenol groups of the VAPOL ligand. (11)B and (1)H NMR evidence supports the boroxinate structure B in which the counterion to the boroxinate is the protonated form of the imine. The boroxinate structure is also supported by two solid state structures of a VAPOL boroxinate in which the gegen cation is tetramethyl ammonium and 4-dimethylaminopyridinium.

Catalytic Asymmetric Aziridination with Catalysts Derived from VAPOL and VANOL

This Account describes the discovery and development of the catalytic asymmetric aziridination reaction (AZ reaction) that has been the subject of efforts in our laboratory over the last 12 years. The optimized catalyst system involves catalysts generated from either the VAPOL or VANOL ligand and triphenyl borate. These catalysts are effective for formation of aziridines from the reac­tion of imines that bear a N-benzhydryl substituent with stabilized diazo compounds including the commercially available ethyl diazoacetate (EDA). The reaction is general for N-benzhydryl im­ines prepared from electron-rich and electron-poor aromatic aldehydes, as well as from primary, secondary and tertiary aliphatic aldehydes. This reaction is highly enantioselective and diastereo­selective giving cis-3-substituted aziridine-2-carboxylates in excellent yields. This Account presents the scope of the AZ reaction as defined by the work that has been done in our laboratory up to the present time, as well as applications of the resulting aziridines that have been demonstrated to date.

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

The active site of the aziridination catalyst derived from either the VANOL or VAPOL ligand and B(OPh)(3) 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-tert-butyldianisylmethyl group (BUDAM) gave exceptionally high asymmetric inductions for imines of aryl aldehydes.

Catalytic Asymmetric Aziridination with Borate Catalysts Derived from VANOL and VAPOL Ligands: Scope and Mechanistic Studies

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.

Direct Access to N‐H‐Aziridines from Asymmetric Catalytic Aziridination with Borate Catalysts Derived from Vaulted Binaphthol and Vaulted Biphenanthrol Ligands.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Direct Access to N‐H‐Aziridines from Asymmetric Catalytic Aziridination with Borate Catalysts Derived from Vaulted Binaphthol and Vaulted Biphenanthrol Ligands.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Aziridinyl Vinyl Ketones from the Asymmetric Catalytic Aziridination Reaction.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Direct Access to N-H-Aziridines from Asymmetric Catalytic Aziridination with Borate Catalysts Derived from Vaulted Binaphthol and Vaulted Biphenanthrol Ligands

The asymmetric catalytic aziridination reaction (AZ reaction) of N-dianisylmethylimines (N-DAM-imines) with ethyl diazoacetate is developed with chiral catalysts prepared from triphenylborate and both the vaulted binaphthol (VANOL) and vaulted biphenanthrol (VAPOL) ligands. Catalysts derived from both ligands were equally effective in terms of asymmetric induction, but the VANOL catalyst was slightly faster. Up to 400 turnovers could be achieved with the VANOL catalyst while still maintaining>or=90% ee in the aziridine product. The ligand could be recovered in 95% yield with no loss in optical purity. Excellent asymmetric inductions were observed with arylimines, and although slightly lower inductions were observed for alkyl-substituted imines, the optical purity of the aziridines from all of the imine substrates could be enhanced to>or=99% ee with a single crystallization. Methods were developed for deprotection of the N-DAM-aziridines under acidic conditions without causing an acid-promoted opening of the ring. Excellent yields of the N-H-aziridines could be obtained with both alkyl- and aryl-substituted aziridines. Finally, activation of the N-H-aziridines was achieved with Boc, tosyl, and Fmoc groups. The activated aziridines can be converted to beta3-amino esters, and unexpectedly, the N-Boc-protected aziridine-2-carboxylate 16b with a phenyl substituent in the 3-position cis to the ester group was found to undergo ring expansion to a mixture of cis- and trans-oxazolidinones.

Aziridinyl Vinyl Ketones from the Asymmetric Catalytic Aziridination Reaction

AbstractUnder the aegis of boron Lewis acids, prepared from either the vanol or vapol ligand, vinyl aziridinyl ketones can be obtained with a high degree of asymmetric induction from the catalytic asymmetric aziridination reaction (AZ) of imines and vinyl diazomethyl ketones. The products have potential as synthons for five‐carbon chiral amines. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

Catalytic asymmetric aziridination of aryl imines

Catalytic asymmetric aziridination of aryl imines

Rigid Backbone 1,8‐Anthracene‐Linked Bis‐oxazolines (AnBOXes): Design, Synthesis, Application and Characteristics in Catalytic Asymmetric Aziridination.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Rigid backbone 1,8-anthracene-linked bis-oxazolines (AnBOXes): design, synthesis, application and characteristics in catalytic asymmetric aziridination

A series of rigid backbone 1,8-anthracene-linked bis-oxazolines (AnBOXes) have been designed, synthesized, and evaluated in the catalytic asymmetric aziridination with [ N-( p-toluenesulfonyl)imino]phenyliodinane (PhI NTs) as a nitrene source. The results indicate that highly enantioselective aziridination of chalcones catalyzed by an AnBOX and CuOTf complex with up to >99% ee and the opposite enantioselectivity, compared with the ligands of Evans et al., can be achieved. The enantioselectivity is substituent dependent with respect to chalcones. Chalcones with electron-donating substituents show higher enantioselectivities due to the stronger Lewis basicity of the oxygen of their carbonyl groups than those with electron-withdrawing substituents. The results also indicate that the coordination between the oxygen of the carbonyl group in chalcones and the ether group in alkenes with the copper in the catalyst is essential for high enantioselectivity, while the π–π stacking interaction between two reactants plays an importantly additional role for high enantioselectivity in asymmetric aziridination. An excellent backbone-controlled stereoselectivity was observed for the AnBOX ligands in asymmetric aziridination, as this will provide very important information for designing novel ligands.

Highly Diastereoselective Alkylation of Aziridine‐2‐carboxylate Esters: Enantioselective Synthesis of LFA‐1 Antagonist BIRT‐377

The benzhydryl group is the key: Efficient alkylation of 3-substituted aziridine-2-carboxylates is only possible with N-benzhydryl-protected aziridines and occurs with complete retention of the configuration at the 2-position. Sequential catalytic asymmetric aziridination and aziridine alkylation reactions have been applied to the synthesis of BIRT-377 (see structure).

Novel Ozone-Mediated Cleavage of the Benzhydryl Protecting Group from Aziridinyl Esters

[reaction: see text]. N-Benzhydryl aziridines-2-carboxylates can be readily obtained from the catalytic asymmetric aziridination reaction from N-benzhydrylimines and ethyl diazoacetate. Cleavage of the benzhydryl group by hydrogenolysis leads to ring opening when R = aryl. Surprisingly, ozone will selectively oxidize the benhydryl group in these aziridines even when R is an aryl group. This allows for a new deprotection strategy for these aziridines whose generality is explored.

Catalytic asymmetric heterogeneous aziridination of styrene using Cu2+-exchanged zeolite Y: effect of the counter-cation on enantioselectivity and on the reaction profile

Effective catalysts have Cu2+-exchange levels of ca. 40–60% of the maximum concentration for electroneutrality and, consequently, Cu-zeolite Y catalysts contain an additional counter-cation (H+, Li+, Na+, K+, Rb+, Cs+) whose effect is explored. With Li+, Na+, K+ counter-cations, the zeolite structure is not markedly affected but, with Rb+ and Cs+, there is some loss of crystallinity. Replacement of H+ by group I cations does not markedly influence the overall ee observed for aziridine indicating that the presence of protons in the Cu-HY catalysts are not detrimental to the reaction. Catalysts containing group I cations typically give decreased leaching of Cu2+ during the reaction. At low nitrene donor to styrene molar ratios (1∶1), replacement of H+ by group I cations leads to a small enhancement in the ee of aziridine, although the yield of aziridine formed is decreased under all reaction condition. At higher molar ratios of nitrene donor to styrene, the ee is suppressed, particularly with Rb and Cs. The effect of reaction time on aziridine yield reveals a reaction profile in which the reaction initially proceeds rapidly, then slows down prior to accelerating again in the latter part of the reaction. This effect is accentuated by increasing the size of the counter-cation. This reaction profile is also observed for the homogeneously catalysed pathway and, consequently, it cannot be due solely to a confinement effect within the zeolite pores. Over addition of reaction by-products (NsNH2, PhI) accentuates the shape of this reaction profile and the effect is discussed in terms of the interactions of such molecules at the active site.