Catalytic Asymmetric Aziridination Research Articles

Probing Catalyst Function - Electronic Modulation of Chiral Polyborate Anionic Catalysts.

Boroxinate complexes of VAPOL and VANOL are a chiral anionic platform that can serve as a versatile staging arena for asymmetric catalysis. The structural underpinning of the platform is a chiral polyborate core that covalently links together alcohols (or phenols) and vaulted biaryl ligands. The polyborate platform is assembled in situ by the substrate of the reaction, and thus a multiplex of chiral catalysts can be rapidly assembled from various alcohols (or phenols) and bis-phenol ligands for screening of catalyst activity. In the present study, variations in the steric and electronic properties of the phenol/alcohol component of the boroxinate catalyst are probed to reveal their effects on the asymmetric induction in the catalytic asymmetric aziridination reaction. A Hammett study is consistent with a mechanism in which the two substrates are hydrogen-bonded to the boroxinate core in the enantiogenic step. The results of the Hammett study are supported by a computational study in which it is found that the H-O distance of the protonated imine hydrogen bonded to the anionic boroxinate core decreases with an increase in the electron releasing ability of the phenol unit incorporated into the boroxinate. The results are not consistent with a mechanism in which the boroxinate catalyst functions as a Lewis acid and activates the imine by a Lewis acid/Lewis base interaction.

Catalytic Asymmetric Aziridination of Benzhydryl Imines and Diazoacetate­ Esters with BOROX Catalysts from 3,3′-Disubstituted VANOL Ligands

This work details the synthesis of 22 new chiral VANOL ligands that differ by the nature of the substituent in the 3- and 3′-positions of the ligand. These ligands were incorporated into boroxinate catalysts that were used to screen the catalytic asymmetric aziridination of benzhydryl imines with ethyl diazoacetate. Each catalyst was screened in the reaction of imines generated from benzaldehyde and cyclohexanecarboxaldehyde and some with 4-nitro- and 4-methoxybenzaldehyde. In addition, the first report of the effect of the ester substituent of the diazoacetate ester on the asymmetric induction in these aziridination reactions is presented. The first X-ray structure of a boroxinate catalyst generated from a VANOL-derived ligand is also reported.

Pyro-Borates, Spiro-Borates, and Boroxinates of BINOL-Assembly, Structures, and Reactivity.

VANOL and VAPOL ligands are known to react with three equivalents of B(OPh)3 to form a catalytic species that contains a boroxinate core with three boron atoms, and these have proven to be effective catalysts for a number of reactions. However, it was not known whether the closely related BINOL ligand will likewise form a boroxinate species. It had simply been observed that mixtures of BINOL and B(OPh)3 were very poor catalysts compared to the same mixtures with VANOL or VAPOL. Borate esters of BINOL have been investigated as chiral catalysts, and these include meso-borates, spiro-borates, and diborabicyclo-borate esters. Borate esters are often in equilibrium, and their structures can be determined by stoichiometry and/or thermodynamics, especially in the presence of a base. The present study examines the structures of borate esters of BINOL that are produced with different stoichiometric combinations of BINOL with B(OPh)3 in the presence and absence of a base. Depending on conditions, pyro-borates, spiro-borates, and boroxinate species can be generated and their effectiveness in a catalytic asymmetric aziridination was evaluated. The finding is that BINOL borate species are not necessarily inferior catalysts to those of VANOL and VAPOL but that, under the conditions, BINOL forms two different catalytic species (a boroxinate and a spiro-borate) that give opposite asymmetric inductions. However, many BINOL derivatives with substitutents in the 3- and 3'-positions gave only the boroxinate species and the 3,3'-Ph2BINOL ligand gave a boroxinate catalyst that gives excellent inductions in the aziridination reaction. BINOL derivatives with larger groups in the 3,3'-position will not form either spiro-borates or boroxinate species and thus are not effective catalysts at all.

Formal enantioselective synthesis of (−)-allosamizoline using chiral diamine-catalyzed asymmetric aziridination of cyclic enones

We developed a highly effective organocatalytic system for asymmetric aziridination of cyclic enones. Catalytic asymmetric aziridination of 2-cyclopenten-1-one with t-butyl p-toluenesulfonyloxy carbamate proceeded using 20 mol % of (1R,2R)-1,2-diphenylethylenediamine derivative with an N-4,4-dimethylcyclohexyl group 1h, producing chiral aziridine ketone (1R,5R)-4 in 82% yield with 99% ee. Organocatalyst 1h was also an effective catalyst for the asymmetric aziridination of other cyclic enones. The obtained chiral aziridine ketone (1R,5R)-4 could be successfully transformed into the key intermediate for the synthesis of (−)-allosamizoline, demonstrating the utility of this asymmetric aziridination for the synthesis of aminocyclopentitol derivatives.

ChemInform Abstract: Catalytic Asymmetric Synthesis of Alkynyl Aziridines: Both Enantiomers of cis‐Aziridines from One Enantiomer of the Catalyst.

Alkynyl aziridines can be obtained from the catalytic asymmetric aziridination (AZ reaction) of alkynyl imines with diazo compounds in high yields and high asymmetric inductions mediated by a chiral boroxinate or BOROX catalyst. In contrast to the AZ reaction with aryl- and alkyl-substituted imines, alkynyl imines react to give cis-substituted aziridines with both diazo esters and diazo acetamides. Remarkably, however, the two diazo compounds give different enantiomers of the cis-aziridine from the same enantiomer of the catalyst. Theoretical considerations of the possible transition states for the enantiogenic step reveal that the switch in enantiomers results from a switch from Si-face to Re-face addition to the imine, which in turn is related to a switch from reaction with an E-imine in the former and a Z-isomer of the imine in the latter.

Catalytic asymmetric synthesis of alkynyl aziridines: both enantiomers of cis-aziridines from one enantiomer of the catalyst.

Alkynyl aziridines can be obtained from the catalytic asymmetric aziridination (AZ reaction) of alkynyl imines with diazo compounds in high yields and high asymmetric inductions mediated by a chiral boroxinate or BOROX catalyst. In contrast to the AZ reaction with aryl- and alkyl-substituted imines, alkynyl imines react to give cis-substituted aziridines with both diazo esters and diazo acetamides. Remarkably, however, the two diazo compounds give different enantiomers of the cis-aziridine from the same enantiomer of the catalyst. Theoretical considerations of the possible transition states for the enantiogenic step reveal that the switch in enantiomers results from a switch from Si-face to Re-face addition to the imine, which in turn is related to a switch from reaction with an E-imine in the former and a Z-isomer of the imine in the latter.

A General Synthesis of Sphinganines through Multicomponent Catalytic Asymmetric Aziridination

AbstractA catalytic asymmetric synthesis of all four stereoisomers of sphinganine is described starting from hexadecanal. Utilizing either the (R) or (S) enantiomer of a BOROX catalyst, a multicomponent reaction of this aldehyde with an amine and ethyl diazoacetate gives rise to enantiomeric aziridine‐2‐carboxylates. Access to all diastereomers of sphinganine is realized upon ring opening of the enantiopure aziridine‐2‐carboxylate at the C‐3 position by direct SN2 attack of an oxygen nucleophile, which occurs with inversion of configuration and by ring expansion of an N‐acyl aziridine to an oxazolidinone and then hydrolysis. Overall, this process results in the formal ring opening of the aziridine with an oxygen nucleophile with retention of configuration.

Effective Synthesis of Chiral N‐Fluoroaryl Aziridines through Enantioselective Aziridination of Alkenes with Fluoroaryl Azides

Catalytic aziridination of alkenes with nitrene sources via “C2+N1” addition represents a general approach for the direct synthesis of aziridines, the smallest three-membered N-heterocycles.[1] The enantioselective version of this catalytic process allows for efficient access to chiral nonracemic aziridines, which are versatile synthetic intermediates in asymmetric synthesis.[1-2] Several classes of transition metal-based chiral catalysts, such as Mn, Fe, Cu, Rh and Co complexes, have been found effective in catalyzing asymmetric olefin aziridination with different nitrene sources.[1,3] Besides iminoiodanes and haloamines, organic azides have been actively pursued as alternative nitrene sources for metal-catalyzed aziridination as they enjoy several advantages.[3] While sulfonyl and phosphoryl azides have been effectively employed for metal-catalyzed asymmetric aziridination,[4] catalytic processes based on the use of other types of azides, such as aryl azides, have been less developed. In addition to generating environmentally friendly nitrogen gas as the only byproduct, asymmetric catalytic aziridination with readily available aryl azides provides an attractive approach for the synthesis of valuable N-aryl aziridines through direct introduction of N-aryl groups concurrently with the ring formation.[5,6] This would avoid two additional steps of deprotection and N-arylation when other types of nitrene sources are used for preparing N-aryl aziridines.[7] However, few catalytic systems have been shown to be effective for asymmetric olefin aziridination with aryl azides.[4d,6]

Multifaceted interception of 2-chloro-2-oxoacetic anhydrides: a catalytic asymmetric synthesis of β-lactams

Aziridine-2-carboxylic acids will react with oxalyl chloride to give morpholin-2,3,5-trionones, cyclic N-carboxyanhydrides or β-lactams depending on the nature of the substituent at the 3-position. All substrates can be diverted to β-lactams upon treatment with a Vilsmeier reagent. The three to four membered ring expansion is stereospecific and proceeds with high yields and diastereoselection. This method provides for an asymmetric synthesis of β-lactams from simple aldehydes via a multi-component catalytic asymmetric aziridination reaction.

Double Stereodifferentiation in the Catalytic Asymmetric Aziridination of Imines Prepared from α‐Chiral Amines

The catalytic asymmetric aziridination of imines and diazo compounds (AZ reaction) mediated by boroxinate catalysts derived from the VANOL and VAPOL ligands was investigated with chiral imines derived from five different chiral, disubstituted, methyl amines. The strongest matched and mismatched reactions with the two enantiomers of the catalyst were noted with disubstituted methyl amines that had one aromatic and one aliphatic substituent. The synthetic scope for the AZ reaction was examined in detail for α-methylbenzyl amine for cis-aziridines from α-diazo esters and for trans-aziridines from α-diazo acetamides. Optically pure aziridines could be routinely obtained in good yields and with high diastereoselectivity and the minor diastereomer (if any) could be easily separated. The matched case for cis-aziridines involved the (R)-amine with the (S)-ligand, but curiously, for trans-aziridines the matched case involved the (R)-amine with the (R)-ligand for imines derived from benzaldehyde and n-butanal, and the (R)-amine with the (S)-ligand for imines derived from the bulkier aliphatic aldehydes pivaldehyde and cyclohexane carboxaldehyde.

Multicomponent Catalytic Asymmetric Aziridination of Aldehydes

The first multicomponent catalytic asymmetric aziridination reaction is developed to give aziridine-2-carboxylic esters with very high diastereo- and enantioselectivity from aromatic and aliphatic aldehydes. This new method pushes the boundary of the aziridination reaction to substrates that failed with preformed imines.

ChemInform Abstract: Catalytic Asymmetric Aziridination of α,β‐Unsaturated Aldehydes.

AbstractThe procedure can be applied to aliphatic and aromatic enals, α‐substituted‐α,β‐unsaturated aldehydes and α,β‐disubstituted‐α,β‐unsaturated aldehydes giving trans‐aziridines in high diastereo‐ and enantioselectivity.

Catalytic Asymmetric Aziridination of α,β-Unsaturated Aldehydes

In this full paper Córdova and coworkers compile their previous results on the catalytic asymmetric aziridination of β- (Angew. Chem. Int. Ed. 2007, 46, 778) and α-substituted (Adv. Synth. Catal. 2010, 352, 3201) α,β-unsaturated aldehydes, respectively. In addition to these results a broadened substrate scope and further functionalizations of the obtained aziridines are presented. Valuable building blocks such as N-protected β-amino esters, β-carboxyl aziridines and N-protected α-hydroxy β-amino acetals were obtained in moderate to good yields and excellent enantioselectivities. Finally proposed mechanisms for the aziridination and the NHC-catalyzed ring-opening-oxidation reactions are discussed.

Practical Gram Scale Asymmetric Catalysis with Boroxinate Brønsted Acids Derived from the VAPOL and VANOL Ligands

Our laboratories have been engaged in utilizing catalysts derived from the VAPOL and VANOL ligands towards the development of efficient asymmetric processes over the last several years. Subsequent to their development, practical scale-up of these methodologies to gram scale has always been deemed necessary to demonstrate. This article will report on such successful gram scale asymmetric catalysis that has been realized in our laboratories using the boroxinate Bronsted acid catalysts derived from the VAPOL and VANOL ligands. The processes reviewed will be the catalytic asymmetric aziridination of imines and the direct catalytic asymmetric aminoallylation of aldehydes.

Catalytic Asymmetric Aziridination of α,β‐Unsaturated Aldehydes

The development, scope, and application of the highly enantioselective organocatalytic aziridination of α,β-unsaturated aldehydes is presented. The aminocatalytic azirdination of α,β-unsaturated aldehydes enables the asymmetric formation of β-formyl aziridines with up to >19:1 d.r. and 99% ee. The aminocatalytic aziridination of α-monosubstituted enals gives access to terminal α-substituted-α-formyl aziridines in high yields and up to 99% ee. In the case of the organocatalytic aziridination of disubstituted α,β-unsaturated aldehydes, the transformations were highly diastereo- and enantioselective and give nearly enantiomerically pure β-formyl-functionalized aziridine products (99% ee). A highly enantioselective one-pot cascade sequence based on the combination of asymmetric amine and N-heterocyclic carbene catalysis (AHCC) is also disclosed. This one-pot three-component co-catalytic transformation between α,β-unsaturated aldehydes, hydroxylamine derivatives, and alcohols gives the corresponding N-tert-butoxycarbonyl and N-carbobenzyloxy-protected β-amino acid esters with ee values ranging from 92-99%. The mechanisms and stereochemistry of all these catalytic transformations are also discussed.

ChemInform Abstract: Asymmetric Catalytic Aziridination of Dihydronaphthalenes for the Preparation of Substituted 2‐Aminotetralins.

Abstract An enantioselective synthesis of substituted 2-aminotetralins from dihydronaphthalenes in four steps is described. The key step is the Jacobsen’s (diimine)copper-catalyzed asymmetric aziridination of dihydronaphthalenes to the respective aziridines in 33–82% yields and 60–87% enantiomeric excess. The enantioselectivity and the yield were dependent on the properties of the nitrene precursor. p Ts NIPh appeared in general to give better results than p NsN IPh. Aziridines were ring-opened in the benzylic position by catalytic hydrogenolysis in quantitative yields, and deprotected in two steps to the respective 2-aminotetralins in 66–85% yields. The synthesis of ( S )-2-aminotetralin (>98% ee) and ( S )-2-amino-7-methoxytetralin (56% ee) were accomplished in 30 and 52% overall yields, respectively.

ChemInform Abstract: Controlled Diastereo‐ and Enantioselection in a Catalytic Asymmetric Aziridination.

AbstractIn connection with previously published results this protocol provides selective access to both trans and cis aziridines, respectively, using the same catalyst.

ChemInform Abstract: Trimethylsilyldiazomethane as a Versatile Stitching Agent for the Introduction of Aziridines into Functionalized Organic Molecules.

AbstractAcylation of trimethylsilyldiazomethane with aliphatic acid chlorides is coupled with the catalytic asymmetric aziridination of aldimines with a chiral polyborate Broensted acid catalyst, derived from the biaryl ligands VAPOL and VANOL.

Asymmetric catalytic aziridination of dihydronaphthalenes for the preparation of substituted 2-aminotetralins

An enantioselective synthesis of substituted 2-aminotetralins from dihydronaphthalenes in four steps is described. The key step is the Jacobsen's (diimine)copper–catalyzed asymmetric aziridination of dihydronaphthalenes to the respective aziridines in 33 – 82% yields and 60 – 87% enantiomeric excess. The enantioselectivity and the yield were dependent on the properties of the nitrene precursor. pTsN=IPh appeared in general to give better results than pNsN=IPh. Aziridines were ring-opened in the benzylic position by catalytic hydrogenolysis in quantitative yields, and deprotected in two steps to the respective 2-aminotetralins in 66 – 85% yields. The synthesis of ( S)-2-aminotetralin (>98% ee) and ( S)-2-amino-7-methoxytetralin (56% ee) were accomplished in 30 and 52% overall yields, respectively.

Substrate-Induced Covalent Assembly of a Chemzyme and Crystallographic Characterization of a Chemzyme−Substrate Complex

A substrate induced covalent assembly of a highly organized chemzyme known to be effective in both catalytic asymmetric aziridination and aza Diels-Alder reactions is described and the information gained from which led to an efficient one-pot aziridination protocol. The crystal structures of two chemzyme-iminium complexes were elucidated by X-ray diffraction analysis that provides critical insights into the binding of the substrates with the chemzyme.