Ligand Conformational Flexibility Enables Enantioselective Tertiary C-B Bond Formation in the Phosphonate-Directed Catalytic Asymmetric Alkene Hydroboration.

Conformationally flexible ancillary ligands have been widely used in transition metal catalysis. However, the benefits of using flexible ligands are often not well understood. We performed density functional theory (DFT) and experimental studies to elucidate the mechanisms and the roles of conformationally flexible α,α,α',α'-tetraaryldioxolane-4,5-dimethanol (TADDOL)-derived ligands on the reactivity and selectivity in the Rh-catalyzed asymmetric hydroboration (CAHB) of alkenes. DFT calculations and deuterium labeling studies both indicated that the most favorable reaction pathway involves an unusual tertiary C-B bond reductive elimination to give high levels of regio- and enantioselectivities. Here, the asymmetric construction of the fully substituted carbon center is promoted by the flexibility of the TADDOL backbone, which leads to two ligand conformations with distinct steric environments in different steps of the catalytic cycle. A pseudo-chair ligand conformation is preferred in the rate-determining tertiary benzylic C-B reductive elimination. The less hindered steric environment with this conformation allows the benzylic group to bind to the Rh center in an η3 fashion, which stabilizes the C-B reductive elimination transition state. On the other hand, a pseudo-boat ligand conformation is involved in the selectivity-determining alkene migratory insertion step, where the more anisotropic steric environment leads to greater ligand-substrate steric interactions to control the π-facial selectivity. Thus, using a conformationally flexible ligand is beneficial for enhancing both reactivity and enantioselectivity by controlling ligand-substrate interactions in two different elementary steps.

Facile access to functionalized chiral secondary benzylic boronic esters via catalytic asymmetric hydroboration.

Allylic and homoallylic phosphonates bearing an aryl or heteroaryl substituent at the γ- or δ-position undergo rhodium-catalyzed asymmetric hydroboration by pinacolborane to give functionalized chiral secondary benzylic boronic esters in yields up to 86% and enantiomer ratios up to 99 : 1. Compared to minimally-functionalized terminal and 1,1-disubstituted vinyl arenes, there are relatively few reports of efficient catalytic asymmetric hydroboration (CAHB) of more highly functionalized internal alkenes. Phosphonate substrates bearing a variety of common heterocyclic ring systems, including furan, indole, pyrrole and thiophene derivatives, as well as those bearing basic nitrogen substituents (e.g., morpholine and pyrazine) are tolerated, although donor substituents positioned in close proximity of the alkene can influence the course of the reaction. Stereoisomeric (E)- and (Z)-substrates afford the same major enantiomer of the borated product. Deuterium-labelling studies reveal that rapid (Z)- to (E)-alkene isomerization accounts for the observed (E/Z)-stereoconvergence during CAHB. The synthetic utility of the chiral boronic ester products is illustrated by stereospecific C-B bond transformations including stereoretentive electrophile promoted 1,2-B-to-C migrations, stereoinvertive SE2 reactions of boron-ate complexes with electrophiles, and stereoretentive palladium- and rhodium-catalyzed cross-coupling protocols.

Ligand-Controlled Regiodivergent Enantioselective Rhodium-Catalyzed Alkene Hydroboration.

Regiocontrol in the rhodium-catalyzed boration of vinyl arenes is typically dominated by the presence of the conjugated aryl substituent. However, small differences in TADDOL-derived chiral monophosphite ligands can override this effect and direct rhodium-catalyzed hydroboration of ß-aryl and ß-heteroaryl methylidenes by pinacolborane to selectively produce either chiral primary or tertiary borated products. The regiodivergent behavior is coupled with enantiodivergent addition of the borane. The nature of the TADDOL backbone substituents and that of the phosphite moiety function synergistically to direct the sense and extent of regioselectivity and enantioinduction. Twenty substrates are shown to undergo each reaction mode with regioselectivity values reaching greater than 20:1 and enantiomer ratios reaching up to 98:2. A variety of subsequent transformations illustrate the potential utility of each product.

Phosphonate-Directed Catalytic Asymmetric Hydroboration: Delivery of Boron to the More Substituted Carbon, Leading to Chiral Tertiary Benzylic Boronic Esters.

Phosphonate-directed catalytic asymmetric hydroboration (CAHB) of ß-aryl/heteroaryl methylidenes and trisubstituted alkenes by pinacolborane enables facile access to functionalized, chiral tertiary benzylic boronic esters. Hydroboration is catalyzed by a chiral rhodium catalyst prepared in situ from a Rh(I)-precursor in combination with a simple TADDOL-derived chiral cyclic monophosphite in a 1:1 ratio. The regio- and stereochemistry arises from the combined effects of the relative disposition of the directing group to the alkene, the alkene substitution pattern, and the necessity of an aryl substituent attached to the alkene. A range of aryl and heteroaryl substituents can be accommodated, and for several chiral substrates, the reactions are efficiently catalyst-controlled enabling the choice of diastereomeric products as desired. Stereospecific transformations of the chiral boronic ester afford chiral phosphonates bearing a quaternary carbon stereocenter. The synthetic utility of the products is further demonstrated by α-oxidation of the phosphonate leading to hydroxy- and oxo-phosphonates; the latter readily undergo elimination/substitution reactions to unmask the phosphonate functionality with the formation of aldehydes, alcohols, esters, amides, acids and ketones.

Enantioselective γ-borylation of unsaturated amides and stereoretentive Suzuki-Miyaura cross-coupling.

The rhodium-catalyzed, directed catalytic asymmetric hydroboration of γ,δ-unsaturated amides affords a direct route to chiral acyclic secondary γ-borylated carbonyl derivatives in high enantiomeric purity. In contrast to a similar ß-borylated amide derivative, the γ-borylated amide undergoes Suzuki-Miyaura cross-coupling with stereoretention. The utility of the boronic ester products is further illustrated by other stereospecific C-B bond transformations leading to γ-amino acid derivatives, 1,4-amino alcohols, and 5-substituted-γ-lactone and γ-lactam ring systems.

Remarkably Facile Borane-Promoted, Rhodium-Catalyzed Asymmetric Hydrogenation of Tri- and Tetrasubstituted Alkenes.

Oxime-directed catalytic asymmetric hydroboration is diverted to catalytic asymmetric hydrogenation (CAH) upon the addition of a proton source, such as MeOH, or by running the reaction under a hydrogen atmosphere. A borane (e.g., pinacolborane) is required to promote CAH. Tri- and tetrasubstituted alkenes, including the challenging all-alkyl tetrasubstituted alkenes, undergo CAH with enantiomer ratios (er) as high as 99:1. The mild reaction conditions, i.e., ambient temperature, moderate reaction times, and the need for only a slight excess of H2, contrast those used in most state-of-the-art catalysts for related substrates.

Synthesis of Chiral Tertiary Boronic Esters: Phosphonate-Directed Catalytic Asymmetric Hydroboration of Trisubstituted Alkenes.

Highly enantioselective rhodium-catalyzed hydroboration of allylic phosphonates by pinacolborane affords chiral tertiary boronic esters. The ß-borylated phosphonates are readily converted to chiral ß- and γ-hydroxyphosphonates and aminophosphonates and to phosphonates bearing a quaternary carbon stereocenter. The utility of the latter is illustrated by the synthesis of (S)-(+)-bakuchiol methyl ether.

Ruthenium-Catalyzed Amination of Secondary Alcohols using Borrowing Hydrogen Methodology.

A new ruthenium complex catalyzes the amination of primary and secondary alcohols and the regioselective mono- and sequential diamination of diols via the borrowing hydrogen pathway. Several variations on new intra- and intermolecular cyclizations of aminoalcohols, diols and diamines lead to heterocyclic ring systems.

Synthesis of Chiral Tertiary Boronic Esters by Oxime-Directed Catalytic Asymmetric Hydroboration.

Chiral boronic esters are useful intermediates in asymmetric synthesis. We have previously shown that carbonyl-directed catalytic asymmetric hydroboration (CAHB) is an efficient approach to the synthesis of functionalized primary and secondary chiral boronic esters. We now report that the oxime-directed CAHB of alkyl-substituted methylidene and trisubstituted alkene substrates by pinacolborane (pinBH) affords oxime-containing chiral tertiary boronic esters with yields up to 87% and enantiomeric ratios up to 96:4 e.r. The utility of the method is demonstrated by the formation of chiral diols and O-substituted hydroxylamines, the generation of quaternary carbon stereocenters through carbon-carbon coupling reactions, and the preparation of chiral 3,4,4-trisubstituted isoxazolines.

Surprisingly Facile C-H Activation in the Course of Oxime-Directed Catalytic Asymmetric Hydroboration.

Deuterium-labeling studies carried out in conjunction with investigations into the directed catalytic asymmetric hydroboration of unsaturated oxime ethers reveal a surprisingly facile ortho-metallation or σ-bond metathesis pathway that that diverts the expected course of CAHB to a tandem C-H activation/hydroboration reaction pathway.

Enantioselective desymmetrization via carbonyl-directed catalytic asymmetric hydroboration and Suzuki-Miyaura cross-coupling.

The rhodium-catalyzed enantioselective desymmetrization of symmetric γ,δ-unsaturated amides via carbonyl-directed catalytic asymmetric hydroboration (directed CAHB) affords chiral secondary organoboronates with up to 98% ee. The chiral γ-borylated products undergo palladium-catalyzed Suzuki-Miyaura cross-coupling via the trifluoroborate salt with stereoretention.

Mechanistic Insights into Carbonyl-Directed Rhodium-Catalyzed Hydroboration: ab Initio Study of a Cyclic γ,δ-Unsaturated Amide.

A two-point binding mechanism for the cationic rhodium(I)-catalyzed carbonyl-directed catalytic asymmetric hydroboration of a cyclic γ,δ-unsaturated amide is investigated using density functional theory. Geometry optimizations and harmonic frequency calculations for the model reaction are carried out using the basis set 6-31+G** for C, O, P, B, N, and H and LANL2DZ for Rh atoms. The Gibbs free energy of each species in THF solvent is obtained based on the single-point energy computed using the PCM model at the ECP28MWB/6-311+G(d,p) level plus the thermal correction to Gibbs free energy by deducting translational entropy contribution. The Rh-catalyzed reaction cycle involves the following sequence of events: (1) chelation of the cyclic γ,δ-unsaturated amide via alkene and carbonyl complexation in a model active catalytic species, [Rh(L2)2S2]+, (2) oxidative addition of pinacol borane (pinBH), (3) migratory insertion of the alkene double bond into Rh-H (preferred pathway) or Rh-B bond, (4) isomerization of the resulting intermediate, and finally, (5) reductive elimination to form the B-C or H-C bond with regeneration of the catalyst. Free energy profiles for potential pathways leading to the major γ-borylated product are computed and discussed in detail. The potential pathways considered include (1) pathways proceeding via migratory insertion into the Rh-H bond (pathways I, I-1, and I-2), (2) a potential pathway proceeding via migratory insertion into the Rh-B bond (pathway II), and two potential competing routes to a ß-borylated byproduct (pathway III). The results find that the Rh-H migratory insertion pathway I-2, followed in sequence by an unanticipated isomerization via amide rotation and reductive elimination, is the most favorable reaction pathway. A secondary consequence of amide rotation is access to a competing ß-hydride elimination pathway. The pathways computed in this study are supported by and help explain related experimental results.

γ-Selective directed catalytic asymmetric hydroboration of 1,1-disubstituted alkenes.

Directed catalytic asymmetric hydroborations of 1,1-disubstituted alkenes afford γ-dioxaborato amides and esters in high enantiomeric purity (90-95% ee).

Two-stage optimization of a supramolecular catalyst for catalytic asymmetric hydroboration.

Systematic changes, first to the structure of the catalyst scaffold and then to the ligating groups, are used to fine tune supramolecular catalysts to achieve high regioselectivity (95-98%) and high enantioselectivity (94-97% ee) across a series of meta-substituted styrenes varying in electronic character.

Ligand scaffold optimization of a supramolecular hydrogenation catalyst: Analyzing the influence of key structural subunits on reactivity and selectivity.

Results are reported for the catalytic asymmetric hydrogenation of two prototypical substrates with a series of more than 150 closely related supramolecular catalysts differing in only their ligand/catalyst scaffold. These modular catalysts are constructed from four subunits and vary widely in their reactivity (no reaction to quantitative yield) and enantioselectivity (racemic to 96% ee). Analysis of the ligand/catalyst scaffold optimization data reveals how each subunit contributes to the effectiveness of the modular supramolecular catalyst. The results suggest that a balance between key elements of rigidity and flexibility is required for the successful catalysts and, moreover, that this balance is required to enable effective fine-tuning via catalyst scaffold optimization.

Catalytic asymmetric hydroboration of ß,γ-unsaturated Weinreb amides: striking influence of the borane.

Subtle differences in the structure of the borane strongly influence the catalytic efficiency and level of enantioselectivity in the catalytic asymmetric hydroboration of ß,γ-unsaturated Weinreb amides.

Remarkable levels of enantioswitching in catalytic asymmetric hydroboration.

TADDOL-derived phosphites and phosphoramidites are effective ligands for rhodium-catalyzed asymmetric hydroborations of ß,γ-unsaturated amides, achieving up to 99% ee. However, the sense of stereoinduction, R or S, is surprisingly dependent on rather subtle features of the ligand. For example, catalysts employing a TADDOL phenylphosphite and those using the closely related N-methylaniline-derived phosphoramidite of the same configuration give opposite enantiomers of the product. Those derived from optical antipodes give the same product with virtually the same enantioselectivity as illustrated above. The different stereochemical outcomes may reflect fundamental differences in catalyst structure, reactivity, or reaction mechanism.

Amide-directed catalytic asymmetric hydroboration of trisubstituted alkenes.

Rhodium-catalyzed hydroborations of trisubstituted alkenes are generally slow and often suffer from competing alkene isomerization. In contrast, the trisubstituted alkene moieties contained within the framework of a beta,gamma-unsaturated amide undergo facile reaction, perhaps facilitated by carbonyl directing effects and two-point binding of the substrate to the rhodium catalyst. Stereoisomeric substrates, for example, (E)- and (Z)-3, cleanly give rise to diastereomeric products, and thus the rhodium-catalyzed reaction is stereospecific. In addition, simple TADDOL-derived phenyl monophosphite ligands in combination with Rh(nbd)(2)BF(4) afford highly enantioselective catalysts (seven examples, 91-98% ee). These catalysts provide an alternative methodology to prepare Felkin or anti-Felkin acetate-aldol products and related derivatives that are obtainable from the intermediate chiral organoboranes.

Oligo(vinylidene fluoride) Langmuir-Blodgett films studied by spectroscopic ellipsometry and the density functional theory.

Thin films of amphiphilic vinylidene fluoride oligomers prepared by Langmuir-Blodgett deposition on silicone substrates were investigated by comparing experimental and theoretical mid-infrared (IR) spectra. The experimental spectra were obtained using infrared spectroscopic ellipsometry. Theoretical spectra were calculated using density functional theory. Excellent correspondence of major IR bands in both data sets shows that the molecular backbone is oriented with the long axis normal to the substrate plane. This is in contrast to poly(vinylidene fluoride) LB films, in which the polymer chains are parallel to the substrate.

Biotinyl-methyl 4-(amidomethyl)benzoate is a competitive inhibitor of human biotinidase.

Posttranslational modification of histones by biotinylation can be catalyzed by both biotinidase (BTD) and holocarboxylase synthetase. Biotinylation of histones is an important epigenetic mechanism to regulate gene expression, DNA repair, and chromatin remodeling. The role of BTD in histone biotinylation is somewhat ambiguous, given that BTD also catalyzes removal of the biotin tag from histones. Here, we sought to develop BTD inhibitors for future studies of the role of BTD in altering chromatin structure. We adopted an existing colorimetric BTD assay for use in a novel 96-well plate format to permit high-throughput screening of potential inhibitors. Biotin analogs were chemically synthesized and tested for their ability to inhibit human BTD. Seven of these compounds inhibited BTD by 26-80%. Biotinyl-methyl 4-(amidomethyl)benzoate had the largest effect on BTD, causing an 80% inhibition at 1 mM concentration. Enzyme kinetics studies were conducted to determine V(max), K(m) and K(i) for the seven inhibitors; kinetics were consistent with the hypothesis that biotinyl-methyl 4-(amidomethyl)benzoate and the other compounds acted by competitive inhibition of BTD. Finally, biotinyl-methyl 4-(amidomethyl)benzoate did not affect biotin transport in human cells, suggesting specificity in regard to biotin-related processes.