VAPOL Ligands Research Articles

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.

The Nature of meso- and pyro-Borate Precatalysts to the VANOL and VAPOL BOROX Catalysts

The structures of the meso- and pyro-borate esters generated by treatment of the VANOL and VAPOL ligands with triphenylborate have been revisited. These species were previously identified as precatalysts that could be in situ converted into VANOL and VAPOL BOROX catalysts by an imine substrate. The complete assignment of all protons for both the meso- and pyro-borate esters of both ligands was aided by the 1H NMR spectrum of each generated from pentadeuterophenol. There were significant differences between the chemical shifts for certain protons in the meso- and pyro-borate species in both the VANOL and VAPOL derivatives. Optimized structures for the meso-borates and two different isomers of the pyro-borates were determined by DFT calculations for each ligand. For each ligand the cyclic pyro-borate was found to be lower in energy than the corresponding linear pyro-borate at the B3LYP/6-311+G(d,p) level of theory. The structures of the cyclic pyro-borate esters were more consistent with the observed 1H NMR chemical shifts than the linear pyro-borates for each ligand and thus the structures of the pyro-borates esters of VANOL and VAPOL have been re-assigned as the cyclic isomers.

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.

Scalable Syntheses of the Vaulted Biaryl Ligands VAPOL and VANOL via the Cycloaddition/Electrocyclization Cascade

Synthetic approaches to the VANOL and VAPOL ligands are developed which are straightforward, inexpensive, efficient, and amenable to large-scale preparation of the ligands since minimum chromatographic purification is required. The key step in each synthesis is a cycloaddition/electrocyclic ring-opening/electrocyclic ring closure/tautomerization cascade that provides a direct one-step route to the monomers from which each ligand is prepared. Improved phenol coupling protocols are developed which provide the racemic ligands. Finally, dramatic improvements in the resolution procedures feature the reduction of the number of chemical steps and the defining of new crystallization protocols that greatly enhance the ease and reliability of the separation of diastereomeric salts.

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.

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.

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.

Regulation of orthogonal functions in a dual catalyst system. Subservient role of a nonchiral Lewis acid in an asymmetric catalytic heteroatom Diels-Alder reaction.

A catalytic asymmetric heteroatom Diels−Alder reaction of unactivated imines with Danishefsky's diene is described which gives high asymmetric induction for N-benzhydryl imines derived from a variety of aldehydes. The catalyst is derived from B(OPh)3 and the VAPOL ligand and gives good induction, but the reaction stalls and does not give high conversion (∼50%). It was found that in the presence of both the chiral catalyst and excess amounts of B(OPh)3 the reaction proceeds to completion and gives high yields of the dihydropiperidinone product. Despite the presence of large quantities of the nonchiral Lewis acid B(OPh)3, the asymmetric induction of the product remains constant (90% ee) as the amount of B(OPh)3 is steadily increased and does not drop off until the ratio of B(OPh)3 to VAPOL is 100:1 (82% ee). These observations are interpreted as involving highly separated and different activities for the chiral and nonchiral Lewis acids present in the reaction. Specifically, the excess B(OPh)3 serves to bind to the product and release the chiral catalyst to turnover more starting material. The B(OPh)3 does not compete in turning over the starting material, and a series of binding studies reveal that this is likely due to a combination of two factors. The binding studies reveal that the chiral catalyst binds to the starting imine 7 times more strongly than does B(OPh)3. However, in order to explain the constant asymmetric induction observed despite the addition of increasing amounts of B(OPh)3, the rate of the reaction of the imine complexed with the chiral catalyst must be at least 10 times faster than the reaction of the imine complexed with B(OPh)3. Finally, a catalyst generated from BINOL and B(OPh)3 does not show this phenomenon.

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)

An examination of VANOL, VAPOL, and VAPOL derivatives as ligands for asymmetric catalytic Diels–Alder reactions

Several derivatives of the vaulted biaryl ligand VAPOL were prepared and evaluated as chiral ligands for aluminum Lewis acids in the catalytic asymmetric Diels–Alder reactions of methyl acrylate and methacrolein with cyclopentadiene. The substituents on VAPOL were introduced into the 6- and 6′-positions in an effort to further extend the chiral pocket of the major groove, which contains the phenol functions at the 4- and 4′-positions. The set of four new ligands that have been prepared have the following groups introduced into the 6- and 6′-positions of VAPOL: bromide, methyl, phenyl and 3,5-di-t-butylphenyl. All of these ligands give lower asymmetric inductions than the unsubstituted VAPOL for the Diels–Alder reactions of both methyl acrylate and methacrolein. The positive cooperativity of added carbonyl compounds on the autoinduction in the Diels–Alder reaction of methyl acrylate and cyclopentadiene were also investigated with the VANOL and VAPOL ligands as well as the 6,6′-dibromo and 6,6′-diphenyl derivatives of VAPOL. Only the reaction with VAPOL showed any significant positive cooperativity. The reaction with VANOL was sluggish at –78 °C, but at higher temperatures, the reaction did exhibit positive cooperativity that was similar to that of VAPOL. Finally, no positive cooperativity was observed with the VAPOL ligand for the reaction of methacrolein and cyclopentadiene.Key words: Diels–Alder, asymmetric catalysis, vaulted biaryl ligands, VANOL, VAPOL.

New Synthesis of Vaulted Biaryl Ligands via the Snieckus Phenol Synthesis.

AbstractFor Abstract see ChemInform Abstract in Full Text.

New Synthesis of Vaulted Biaryl Ligands via the Snieckus Phenol Synthesis

[reaction: see text] In an effort to develop a synthesis of the VAPOL ligand that avoids the use of a chromium carbene complex, a route was examined that involved the annulation of a naphthalene carboxamide via the method of Snieckus. The latter derivatives could be converted in a two-step sequence to 2-phenyl-4-phenanthrols in 60-72% overall yields. The utility of this method for the synthesis of VAPOL derivatives is demonstrated in the synthesis of (S)-7,7'-dimethyl-VAPOL.

Synthesis and Characterization of Chiral Diphosphine Platinum(II) VANOL and VAPOL Complexes

Reaction of (dppe)PtCO3 with S-VANOL or S-VAPOL yielded (dppe)Pt(S-VANOL) and (dppe)Pt(S-VAPOL), respectively. NMR data indicate that the VANOL ligand in the former complex adopts a C2-symmetric O,O‘-bound form, while the VAPOL ligand binds to the metal in a C,O-binding mode that partially disrupts the ligand aromaticity. When matched complexes of S-VANOL and S-VAPOL were synthesized with (S,S-chiraphos)PtCO3, both complexes adopt the symmetric O,O‘-mode. Mismatched complexes with (R,R-chiraphos)PtCO3 have both ligands adopting the C,O-binding mode; however, the S-VANOL complex could not be isolated. Competition experiments between S-VANOL and S-VAPOL for the (S,S-chiraphos)Pt2+ fragment indicate that VANOL is the thermodynamically preferred ligand.

Active Site Design in a Chemzyme: Development of a Highly Asymmetric and Remarkably Temperature-Independent Catalyst for the Imino Aldol Reaction.

Unusually robust: A remarkably temperature-independent catalyst has been developed for the imino aldol reaction of imines derived from ortho-aminophenols. This catalyst is prepared from two equivalents of the VAPOL ligand and a zirconium tetraalkoxide. From a consideration of likely intermediates in the catalytic cycle it was deduced that a methyl substituent ortho to the phenol (R1 ) should enhance induction. This resulted in asymmetric inductions in excess of 98 % ee at room temperature as well as at 100°C. TMS=trimethylsilyl.