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.

Resolution of Vaulted Biaryl Ligands via Borate Esters of Quinine and Quinidine.

Given the sudden and unexplained rise in the cost of (+)- and (-)-sparteine, an alternative method for the resolution of vaulted biaryls has been developed. This method involves the reaction of a racemic vaulted biaryl ligand with one equivalent of BH3·SMe2 and one equivalent of either quinine or quinidine. A precipitate then forms from the resulting mixture of diastereomeric borates as a result of differential solubilities. Hydrolysis of the precipitate then liberates the (S)-ligand in the case of quinine and the (R)-ligand in the case of quinidine, both with >99% ee. This method has been applied to 16 different vaulted biaryl ligands, including 10 whose preparation is described here for the first time. In addition, proof of principle has been demonstrated for the dynamic thermodynamic resolution of the vaulted biaryl ligands with this method in combination with a nonchiral copper(II) complex that can racemize the ligand.

Catalytic Asymmetric Epoxidation of Aldehydes with Two VANOL-Derived Chiral Borate Catalysts.

A highly diastereo- and enantioselective method for the epoxidation of aldehydes with α-diazoacetamides has been developed with two different borate ester catalysts of VANOL. Both catalytic systems are general for aromatic, aliphatic, and acetylenic aldehydes, giving high yields and inductions for nearly all cases. One borate ester catalyst has two molecules of VANOL and the other only one VANOL. Catalysts generated from BINOL and VAPOL are ineffective catalysts. An application is shown for access to the side-chain of taxol.

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.

Catalyst-Controlled Multicomponent Aziridination of Chiral Aldehydes.

A highly diastereoselective and enantioselective method for the multicomponent aziridination of chiral aldehydes has been developed with BOROX catalysts of the VANOL (3,3'-diphenyl-2,2'-bi-1-naphthol) and VAPOL (2,2'-diphenyl-(4-biphenanthrol)) ligands. Very high to perfect catalyst control is observed with most all substrates examined including aldehydes with chiral centers in the α- and ß-positions. High catalyst control was also observed for a number of chiral heterocyclic aldehydes allowing for the preparation of epoxy aziridines, bis(aziridines) and ethylene diaziridines. Application of this reaction in the synthesis of ß3 -homo-d-alloisoleucine and ß3 -homo-l-isoleucine is reported.

Multicomponent Catalytic Asymmetric Synthesis of trans-Aziridines.

A multicomponent trans-aziridination of aldehydes, amines, and diazo compounds with BOROX catalysts is developed. The optimal protocol is slightly different for aryl aldehydes than for aliphatic aldehydes. The key to the success with aryl aldehydes was allowing the catalyst, aldehyde, and amine to react for 20 min before addition of the diazo compound. A variety of 11 different electron-poor and electron-rich aryl aldehydes were screened to give trans-aziridines in 73-90% yield with 82-99% ee and trans/cis selectivities of 19:1 to >99:1. The optimal protocol for the trans-aziridination of aliphatic aldehydes did not require prereaction of the catalyst, aldehyde, and amine, and instead, the diazo compound could be added directly. The scope of the reaction is limited to unbranched aliphatic aldehydes and was tolerant of a number of functional groups including ethers, esters, epoxides, carbamates, and phthalimides. A total of 10 aliphatic aldehydes were examined and found to give trans-aziridines in 60-88% yield with 60-98% ee and trans/cis selectivities of 6:1 to >99:1. Alkenyl aldehydes did not react, but an alkynyl aldehyde gave a 71% yield and 95% ee of an aziridine that was found to be the cis- and not the trans-diastereomer. The aryl and aliphatic aldehydes both gave the trans-aziridines with the same absolute configuration with the same catalyst; however, in those cases where cis-aziridines were formed, the configuration was opposite for those formed from aryl versus aliphatic aldehydes.

Enantioselective Palladium-Catalyzed Carbonylative Carbocyclization of Enallenes via Cross-Dehydrogenative Coupling with Terminal Alkynes: Efficient Construction of α-Chirality of Ketones.

An enantioselective PdII /Brønsted acid-catalyzed carbonylative carbocyclization of enallenes ending with a cross-dehydrogenative coupling (CDC) with a terminal alkyne was developed. VAPOL phosphoric acid was found as the best co-catalyst among the examined 28 chiral acids, for inducing the enantioselectivity of α-chiral ketones. As a result, a number of chiral cyclopentenones were easily synthesized in good to excellent enantiomeric ratio with good yields.

Self-Assembly of a Library of Polyborate Chiral Anions for Asymmetric Catalytic Quinoline Reduction.

The 'template' polyborate BOROX catalysts are shown to mediate the asymmetric transfer hydrogenation of 2-quinolines. The rapid and simple generation of a large family of BOROX catalysts with significantly altered asymmetric pockets is described. A transition state model that explains the enantioselectivity is proposed.

Catalytic asymmetric α-Iminol rearrangement: new chiral platforms.

A series of 19 different asymmetric catalysts were screened in an effort to identify the first chiral catalyst for the rearrangement of α-hydroxy imines to α-amino ketones involving a 1,2-carbon shift. Although aluminate complexes of VAPOL, VANOL, and 7,7'-(t)Bu2VANOL were quite effective catalysts giving up to 88% ee, the ne plus ultra catalyst for this reaction was found to be a zirconium complex of VANOL which gives 97 to >99% ee for the majority of the substrates examined. An X-ray diffraction study of the catalyst reveals that the zirconium exists as a homoleptic complex with three VANOL ligands and two protonated N-methyl imidazoles.

Transition state analysis of enantioselective Brønsted base catalysis by chiral cyclopropenimines.

Experimental (13)C kinetic isotope effects have been used to interrogate the rate-limiting step of the Michael addition of glycinate imines to benzyl acrylate catalyzed by a chiral 2,3-bis(dicyclohexylamino) cyclopropenimine catalyst. The reaction is found to proceed via rate-limiting carbon-carbon bond formation. The origins of enantioselectivity and a key noncovalent CH···O interaction responsible for transition state organization are identified on the basis of density functional theory calculations and probed using experimental labeling studies. The resulting high-resolution experimental picture of the enantioselectivity-determining transition state is expected to guide new catalyst design and reaction development.

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.

ß-amino esters from the reductive ring opening of aziridine-2-carboxylates.

A general study is undertaken to examine the scope of the reductive ring opening of aziridine-2-carboxylates with samarium diiodide. The competition between C-C and C-N bond cleavage is examined as a function of the nature of the N-substituent of the aziridine, the nature of the substituent in the 3-position of the aziridine, and whether the substituent in the 3-position is in a cis or trans relationship with the carboxylate in the 2-position. The desired C-N bond cleavage leads to ß-amino esters that are the predominant products for most aziridines with an N-activating group. However, C-C cleavage products are observed with an aryl group in the 3-position; this can be particularly pronounced with cis-aziridines where a nearly equal mixture of the two is observed. Exclusive formation of the C-N cleavage product is observed for all aziridines with the strongly N-activating p-toluene sulfonate group. Similarly high selectivity is observed for the 2-trimethylsilylethyl sulfonate group (SES), which is easier to remove. The utility of these methods is illustrated in the synthesis of protected forms of (R)-ß(3)-DOPA and L-DOPA from the same aziridine, the former by SmI2-mediated reductive opening at C-2 and the latter by palladium-mediated reductive opening at C-3.

Three-component asymmetric catalytic Ugi reaction--concinnity from diversity by substrate-mediated catalyst assembly.

The first chiral catalyst for the three-component Ugi reaction was identified as a result of a screen of a large set of different BOROX catalysts. The BOROX catalysts were assembled in situ from a chiral biaryl ligand, an amine, water, BH3·SMe2, and an alcohol or phenol. The catalyst screen included 13 different ligands, 12 amines, and 47 alcohols or phenols. The optimal catalyst system (LAP 8-5-47) provided α-amino amides from an aldehyde, a secondary amine, and an isonitrile with excellent asymmetric induction. The catalytically active species is proposed to be an ion pair that consists of the chiral boroxinate anion and an iminium cation.

Enantioselective biomimetic total syntheses of kuwanons I and J and brosimones A and B.

The first enantioselective total syntheses of prenylflavonoid Diels-Alder natural products (-)-kuwanon I, (+)-kuwanon J, (-)-brosimone A, and (-)-brosimone B have been accomplished from a common intermediate based on a concise synthetic strategy. Key elements of the synthesis include a biosynthesis-inspired asymmetric Diels-Alder cycloaddition mediated by a chiral ligand/boron Lewis acid, as well as a process involving regioselective Schenck ene reaction, reduction, and dehydration to realize a biomimetic dehydrogenation for generation of the required diene precursor. Furthermore, a remarkable tandem inter-/intramolecular asymmetric Diels-Alder cycloaddition process was applied for the synthesis of (-)-brosimone A.

Synthesis of [m.n]cyclophanes: regiochemistry transfer from vinyl halides to cyclophanes via Fischer carbene complexes.

The double benzannulation of bis-carbene complexes of chromium with α,ω-diynes generates [m.n]cyclophanes in which all three rings are generated in a single reaction. This triple annulation process is very flexible allowing for the construction of symmetrical [n.n]cyclophanes and unsymmetrical [m.n]cyclophanes as well as isomers in which the two benzene rings are both meta bridged or both para bridged, and isomers that contain both meta and para bridges. The connectivity patterns of the bridges in the cyclophanes can be controlled by regioselectivity transfer from the bis-vinyl carbene complexes in which the substitution pattern of the vinyl groups in the carbene complexes dictate the connectivity pattern in the [m.n]cyclophanes. This synthesis of [n.n]cyclophanes is quite flexible with regard to ring size and can be used with tether lengths ranging from n=2 to n=16 and thus to ring sizes with up to 40 member rings. The only limitation to regioselectivity transfer from the carbene complexes to the [m.n]cyclophanes was found in the synthesis of para,para-cyclophanes with four carbon tethers for which the loss of fidelity occurred with the unexpected formation of meta,para-cyclophanes.

Vaulted biaryls in catalysis: A structure-activity relationship guided tour of the immanent domain of the VANOL ligand.

The active site in the BOROX catalyst is a chiral polyborate anion (boroxinate) that is assembled in situ from three equivalents of B(OPh)3 and one of the VANOL ligand by a molecule of substrate. The substrates are bound to the boroxinate by H bonds to oxygen atoms O1-O3. The effects of introducing substituents at each position of the naphthalene core of the VANOL ligand are systematically investigated in an aziridination reaction. Substituents in the 4,4'- and 8,8'-positions have a negative effect on catalyst performance, whereas, substituents in the 7- and 7'-positions have the biggest impact in a positive direction.

Isotope effects and mechanism of the asymmetric BOROX Brønsted acid catalyzed aziridination reaction.

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.

Employing a chiroptical sensor for the absolute stereochemical determination of α-amino and α-hydroxyphosphonates.

The absolute stereochemistry of the α-amino and α-hydroxyphosphonates is determined using a chiroptical sensor. The induced helicity of the host-guest complex is correlated to the chirality of the guest molecule via a simple binding model. The relative size of the substituents dictates the predominant helical population, leading to an easy circular dichroic readout.

A Lewis Acid-Controlled Enantiodivergent Epoxidation of Aldehydes.

Two epoxidation catalysts, one of which consists of two VANOL ligands and an aluminum and the other that consists of two VANOL ligands and a boron, were compared. Both catalysts are highly effective in the catalytic asymmetric epoxidation of a variety of aromatic and aliphatic aldehydes with diazoacetamides, giving high yields and excellent asymmetric inductions. The aluminum catalyst is effective at 0 °C and the boron catalyst at -40 °C. Although both the aluminum and boron catalysts of (R)-VANOL give very high asymmetric inductions (up to 99% ee), they give opposite enantiomers of the epoxide. The mechanism, rate- and enantioselectivity-determining step, and origin of enantiodivergence are evaluated using density functional theory calculations.

Simultaneous synthesis of both rings of chromenes via a benzannulation/o-quinone methide formation/electrocyclization cascade.

A new route to the chromene ring system has been developed which involves the reaction of an α,ß-unsaturated Fischer carbene complex of chromium with a propargyl ether bearing an alkenyl group on the propargylic carbon. This transformation involves a cascade of reactions that begins with a benzannulation reaction and is followed by the formation of an o-quinone methide, and finally results in the emergence of a chromene upon an electrocyclization. This reaction was extended to provide access by employing an aryl carbene complex. This constitutes the first synthesis of chromenes in which both rings of the chromene system are generated in a single step and is highlighted in the synthesis of lapachenole and vitamin E.