Catalytic asymmetric synthesis of meta benzene isosteres.

Although aromatic rings are common elements in pharmaceutically active compounds, the presence of these motifs brings several liabilities with respect to the developability of a drug1. Nonoptimal potency, metabolic stability, solubility and lipophilicity in pharmaceutical compounds can be improved by replacing aromatic rings with non-aromatic isosteric motifs2. Moreover, whereas aromatic rings are planar and lack three-dimensionality, the binding pockets of most pharmaceutical targets are chiral. Thus, the stereochemical configuration of the isosteric replacements may offer an added opportunity to improve the affinity of derived ligands for target receptors. A notable impediment to this approach is the lack of simple and scalable catalytic enantioselective syntheses of candidate isosteres from readily available precursors. Here we present a previously unknown palladium-catalysed reaction that converts hydrocarbon-derived precursors to chiral boron-containing nortricyclanes and we show that the shape of these nortricyclanes makes them plausible isosteres for meta disubstituted aromatic rings. With chiral catalysts, the Pd-catalysed reaction can be accomplished in an enantioselective fashion and subsequent transformation of the boron group provides access to a broad array of structures. We also show that the incorporation of nortricyclanes into pharmaceutical motifs can result in improved biophysical properties along with stereochemistry-dependent activity. We anticipate that these features, coupled with the simple, inexpensive synthesis of the functionalized nortricyclane scaffold, will render this platform a useful foundation for the assembly of new biologically active agents.

Stereospecific Phosphination and Thioetherification of Organoboronic Esters.

Alkyllithium-activated organoboronic esters are found to undergo stereospecific phosphination with copper chloride and chlorophosphines. They also react with thiolsulfonate electrophiles under copper catalysis. These reactions enable stereospecific phosphination and thiolation of organoboronic esters, which are further applied in preparation of chiral ligands and biologically active molecules.

Site-Selective Activation and Stereospecific Functionalization of Bis(boronic Esters) Derived from 2-Alkenes: Construction of Propionates and Other 1,2-Difunctional Motifs.

Non-directed regioselective activation of bis(boronic esters), followed by functionalization, is reported. A bulky activator is shown to selectively activate the less hindered boronic ester enabling it to undergo stereospecific cross-coupling to a variety of electrophiles. This steric-based regioselectivity provides a simple and efficient method to prepare highly functionalized, enantiomerically enriched products starting from simple alkenes.

Substrate Plasticity Enables Group-Selective Transmetalation: Catalytic Stereospecific Cross-Couplings of Tertiary Boronic Esters.

Activation of enantiomerically enriched tertiary alkylboronic esters with adamantyllithium generated in situ enables stereoretentive boron-to-copper transmetalation. The resulting alkylcopper species can undergo cross-coupling reactions with an array of electrophiles to furnish synthetically useful compounds bearing quaternary stereocenters. DFT calculations of the transmetalation process provide insights for reactivity and selectivity.

Stereospecific Transformations of Alkylboronic Esters Enabled by Direct Boron-to-Zinc Transmetalation.

Chiral secondary organoboronic esters, when activated with t-butyllithium, are shown to undergo efficient stereoretentive transmetalation with either zinc acetate or zinc chloride. This reaction provides chiral secondary alkylzinc reagents that are configurationally stable under practical experimental conditions. The organozinc compounds were found to engage in stereospecific reactions with difluorocarbene, catalytic cross-couplings with palladium-based catalysts, and trifluoromethylation with a copper(III) complex. Mechanistic and computational studies shed light on the inner workings of the transmetalation event.

Enantioselective Construction of Carbocyclic and Heterocyclic Tertiary Boronic Esters by Conjunctive Cross-Coupling Reaction.

Synthesis of stereodefined carbocyclic and heterocyclic tertiary boronic esters is accomplished by performing a conjunctive cross-coupling reaction on preformed cyclic boron ate complexes. Boronates bearing spirocyclic and aryl bicyclic skeletons can be synthesized enantioselectively using a chiral PHOX-ligated Pd catalyst with achiral starting material, while substrates bearing continuous stereogenic centers can be generated diastereoselectively. A variety of aryl and alkenyl electrophiles are incorporated.

Desymmetrization of Vicinal Bis(boronic) Esters by Enantioselective Suzuki-Miyaura Cross-Coupling Reaction.

The development of an enantioselective catalytic Suzuki-Miyaura reaction that applies to meso 1,2-diborylcycloalkanes is described. This reaction provides a modular route to enantiomerically enriched substituted carbocycles and heterocycles that retain a synthetically versatile boronic ester. With appropriately constructed substrates, compounds bearing additional stereogenic centers and fully substituted carbon atoms can be generated in a straightforward fashion. Preliminary mechanistic experiments suggest that substrate activation arises from the cooperative effect of vicinal boronic esters during the transmetalation step.

Palladium-Catalyzed Conjunctive Cross-Coupling with Electronically Asymmetric Ligands.

Palladium-catalyzed conjunctive cross-coupling can be accomplished with the use of chiral phosphine-oxazoline based ligand structures. Of note, the reaction can be conducted on Grignard-based boron ate complexes and operates without the use of halide-scavenging additives, which are required for other catalyst systems.

Copper-Catalyzed Stereospecific Transformations of Alkylboronic Esters.

Copper-catalyzed stereospecific cross-couplings of boronic esters are reported. Boron "ate" complexes derived from pinacol boronic esters and tert-butyl lithium undergo stereospecific transmetalation to copper cyanide, followed by coupling with alkynyl bromides, allyl halides, propargylic halides, ß-haloenones, hydroxylamine esters, and acyl chlorides. Through this simple transformation, commercially available inexpensive compounds can be employed to convert primary and secondary alkylboronic esters to a wide array of synthetically useful compounds.

Copper-Catalyzed Coupling of Alkyl Vicinal Bis(boronic Esters) to an Array of Electrophiles.

A neighboring boronate group in the substrate provides a dramatic rate acceleration in transmetalation to copper and thereby enables organoboronic esters to participate in unprecedented site-selective cross-couplings. This cross-coupling operates under practical experimental conditions and allows for coupling between vicinal bis(boronic esters) and allyl, alkynyl, and propargyl electrophiles as well as a simple proton. Because the reactive substrates are vicinal bis(boronic esters), the cross-coupling described herein provides an expedient new method for the construction of boron-containing reaction products from alkenes. Mechanistic experiments suggest that chelated cyclic ate complexes may play a role in the transmetalation.

Enantioselective Synthesis of Tertiary ß-Boryl Amides by Conjunctive Cross-Coupling of Alkenyl Boronates and Carbamoyl Chlorides.

Synthesis of versatile ß tert-boryl amides is accomplished by conjunctive cross-coupling of α-substituted alkenyl boron "ate" complexes and carbamoyl chloride electrophiles. This reaction can be accomplished in an enantioselective fashion using a palladium catalyst in combination with MandyPhos. The addition of water results in enhanced chemoselectivity for the conjunctive coupling product relative to the Suzuki-Miyaura cross-coupling product. Transformations of the reaction products were examined as well as application to the synthesis of (+)-adalinine.

Stereocontrolled Pericyclic and Radical Cycloaddition Reactions of Readily Accessible Chiral Alkenyl Diazaborolidines.

In this paper is described an easily synthesized chiral diazaborolidine that is inexpensive, stable, and provides excellent stereoselection across a number of reaction classes. These versatile compounds possess utility in four different classes of cycloaddition reactions, offering good yield and stereoselectivity. X-ray structure analysis provides insight about the origin of stereocontrol.

Enantiomerically Enriched α-Borylzinc Reagents by Nickel-Catalyzed Carbozincation of Vinylboronic Esters.

In this paper is described a synthesis of enantiomerically enriched, configurationally stable organozinc reagents by catalytic enantioselective carbozincation of a vinylboronic ester. This process furnishes enantiomerically enriched α-borylzinc intermediates that are shown to undergo stereospecific reactions, producing enantioenriched secondary boronic ester products. The properties of the intermediate α-borylzinc reagent are probed and the synthetic utility of the products is demonstrated by application to the synthesis of (-)-aphanorphine and (-)-enterolactone.

Asymmetric synthesis from terminal alkenes by cascades of diboration and cross-coupling.

Terminal, monosubstituted alkenes are ideal prospective starting materials for organic synthesis because they are manufactured on very large scales and can be functionalized via a broad range of chemical transformations. Alkenes also have the attractive feature of being stable in the presence of many acids, bases, oxidants and reductants. In spite of these attributes, relatively few catalytic enantioselective transformations have been developed that transform aliphatic α-olefins into chiral products with an enantiomeric excess greater then 90 per cent. With the exception of site-controlled isotactic polymerization of α-olefins, none of these catalytic enantioselective processes results in chain-extending carbon-carbon bond formation to the terminal carbon. Here we describe a strategy that directly addresses this gap in synthetic methodology, and present a single-flask, catalytic enantioselective conversion of terminal alkenes into a number of chiral products. These reactions are facilitated by a neighbouring functional group that accelerates palladium-catalysed cross-coupling of 1,2-bis(boronates) relative to non-functionalized alkyl boronate analogues. In tandem with enantioselective diboration, this reactivity feature transforms alkene starting materials into a diverse array of chiral products. We note that the tandem diboration/cross-coupling reaction generally provides products in high yield and high selectivity (>95:5 enantiomer ratio), uses low loadings (1-2 mol per cent) of commercially available catalysts and reagents, offers an expansive substrate scope, and can address a broad range of alcohol and amine synthesis targets, many of which cannot be easily addressed with current technology.

Recent Advances in Radical Addition to Alkenylboron Compounds.

The addition of carbon-centered radicals to alkenylboron compounds provides a useful method for the construction of organoboron reagents which are versatile reagents in chemical synthesis. While the first examples of this type or process appeared 70 years ago, until recently, attention to this type of reaction has been limited. A number of examples of this reactivity have been demonstrated recently, and strategies are emerging that allow for tuning the reagent structure in order to modulate reactivity. This review surveys recent advances in this class of reaction.

Reactions of organoboron compounds enabled by catalyst-promoted metalate shifts.

This tutorial review describes recent developments in catalytic reaction design that involve catalyst-promoted 1,2-metalate shifts as a critical part of the reaction mechanism. Issues pertaining to catalysis, stereoselectivity, and reaction mechanism are discussed.

Catalytic Enantioselective Synthesis of anti-Vicinal Silylboronates by Conjunctive Cross-Coupling.

Chiral 1,2-bimetallic reagents are useful motifs in synthetic chemistry. Although syn-1,2-bimetallic compounds can be prepared by alkene dimetallation, anti-1,2-bimetallics are still rare. The stereospecific 1,2-metallate shift that occurs during conjunctive cross-coupling is shown to enable a practical and modular approach to the catalytic synthesis of enantioenriched anti-1,2-borosilanes. In addition to reaction development, the synthetic utility of anti-1,2-borosilanes was investigated, including applications to the synthesis of anti-1,2-diols and anti-1,2-amino alcohols.

Diastereo- and Enantioselective 1,4-Difunctionalization of Borylenynes by Catalytic Conjunctive Cross-Coupling.

Enantioselective conjunctive cross-coupling of enyne-derived boronate complexes occurs with 1,4 addition of the electrophile and migrating group across the π system. This reaction pathway furnishes α-boryl allenes as the reaction product. In the presence of a chiral catalyst, both the central and axial chirality of the product can be controlled during product formation.

Catalytic Conjunctive Coupling of Carboxylic Acid Derivatives with 9-BBN-Derived Ate Complexes.

ß-Boryl carbonyl compounds are produced by a Ni-catalyzed cross-coupling of vinylboron "ate" complexes and acid chloride or acid anhydride electrophiles. The reactions are efficient, being complete in as little as two minutes, and can be applied to a broad range of substrates.