Visible‐Light‐Driven Strain‐Increase Ring Contraction Allows the Synthesis of Cyclobutyl Boronic Esters

There are a limited number of ring‐contraction methodologies which convert readily available five‐membered rings into strained four‐membered rings. Here we report a photo‐induced radical‐mediated ring contraction of five‐membered‐ring alkenyl boronate complexes into cyclobutanes. The process involves the addition of an electrophilic radical to the electron‐rich alkenyl boronate complex, leading to an α‐boryl radical. Upon one‐electron oxidation, ring‐contractive 1,2‐metalate rearrangement occurs to give a cyclobutyl boronic ester. A range of radical precursors and vinyl boronates can be employed, and chiral cyclobutanes can be accessed with high levels of stereocontrol. The process was extended to the preparation of benzofused cyclobutenes and the versatility of the boronic ester was demonstrated by conversion to other functional groups.     

Enantioselective installation of adjacent tertiary benzylic stereocentres using lithiation–borylation–protodeboronation methodology. Application to the synthesis of bifluranol and fluorohexestrol

1,2-Diaryl ethanes bearing 1,2-stereogenic centres show interesting biological activity but their stereocontrolled synthesis has not been reported forcing a reliance of methods involving diastereomer and enantiomer separation. We have found that this class of molecules can be prepared with very high stereocontrol using lithiation–borylation methodology. The reaction of an enantioenriched benzylic lithiated carbamate with an enantioenriched benzylic secondary pinacol boronic ester gave a tertiary boronic ester with complete diastereo- and enantiocontrol. It was essential to use MgBr₂/MeOH after formation of the boronate complex, both to promote the 1,2-migration and to trap any lithiated carbamate/benzylic anion that formed from fragmentation of the ate complex, anions that would otherwise racemise and re-form the boronate complex eroding both er and dr of the product. When the benzylic lithiated carbamate and benzylic secondary pinacol boronic ester were too hindered, boronate complex did not even form. In these cases, it was found that the use of the less hindered neopentyl boronic esters enabled successful homologation to take place even for the most hindered reaction partners, with high stereocontrol and without the need for additives. Protodeboronation of the product boronic esters with TBAF gave the target 1,2-diaryl ethanes bearing 1,2-stereogenic centres. The methodology was applied to the stereocontrolled synthesis of bifluranol and fluorohexestrol in just 7 and 5 steps, respectively.     

Probing the Lewis Acidity of Boronic Acids through Interactions with Arene Substituents

Boronic acids are Lewis acids that exist in equilibrium with boronate forms in aqueous solution. Here we experimentally and computationally investigated the Lewis acidity of 2,6-diarylphenylboronic acids; specially designed phenylboronic acids that possess two flanking aromatic rings with tunable aromatic character. Hammett analysis of 2,6-diarylphenylboronic acids reveals that their Lewis acidity remains unchanged upon the introduction of EWG/EDG at the distant para position of the flanking aromatic rings. Structural and computational studies demonstrate that polar-π interactions and solvation effects contribute to the stabilization of boronic acids and boronate forms by aromatic rings. Our physical-organic chemistry work highlights that boronic acids and boronates can be stabilized by aromatic systems, leading to an important molecular knowledge for rational design and development of boronic acid-based catalysts and inhibitors of biomedically important proteins.     

Catalytic Borylative Opening of Propargyl Cyclopropane,Epoxide, Aziridine,and Oxetane Substrates: Ligand Controlled Synthesis of Allenyl Boronates and Alkenyl Diboronates

A new copper‐catalyzed reaction for the stereo‐ and regioselective synthesis of alkenyl diboronates and allenyl boronates is presented. In this process propargyl derivatives of strained three/four‐membered rings were employed as substrates and B₂pin₂ was used as the boronate source. Selective formation of the alkenyl diboronate versus the allenyl boronate products was controlled by the choice of phosphine ligand.     

Catalytic Borylative Opening of Propargyl Cyclopropane,Epoxide, Aziridine,and Oxetane Substrates: Ligand Controlled Synthesis of Allenyl Boronates and Alkenyl Diboronates

A new copper‐catalyzed reaction for the stereo‐ and regioselective synthesis of alkenyl diboronates and allenyl boronates is presented. In this process propargyl derivatives of strained three/four‐membered rings were employed as substrates and B₂pin₂ was used as the boronate source. Selective formation of the alkenyl diboronate versus the allenyl boronate products was controlled by the choice of phosphine ligand.     

Enantiospecific Trifluoromethyl‐Radical‐Induced Three‐Component Coupling of Boronic Esters with Furans

In the presence of trifluoromethylsulfonium reagents, boronate complexes derived from 2‐lithio furan and non‐racemic secondary and tertiary alkyl or aryl boronic esters undergo deborylative three‐component coupling to give the corresponding 2,5‐disubstituted furans with excellent levels of enantiospecificity. The process proceeds via the reaction of boronate complexes with a trifluoromethyl radical, which triggers 1,2‐metallate rearrangement upon single‐electron oxidation. Alternative electrophiles can also be used in place of trifluoromethylsulfonium reagents to effect similar three‐component coupling reactions.     

Visible-Light-Promoted Reaction of N-Hydroxyphthalimide Esters with Vinyl Boronic Pinacol Ester

A novel and easy-to-execute light-driven protocol for the preparation of alkyl boronic acid pinacol esters from vinyl boronate using N-hydroxyphthalimide esters as the potential precursor is described. In this photochemical protocol, the N-hydroxyphthalimide ester's fragmentation generates C-centered radicals, which undergo a radical Michael addition to vinyl boronic pinacol ester furnishing the desired products. A good substrate scope having various functionalities is presented and good to high yields are obtained.     

Synthesis of a (β-acetamido-α-acetoxyethyl)boronic ester via azido boronic esters

(Azidomethyl)boronic esters of 1,2-dicyclohexyl-1,2-ethanediol (“DICHED”) and pinanediol have been prepared from the corresponding (bromomethyl)boronic esters. Conversion to (2-azido-1-chloro- or bromoethyl)boronic esters by reaction with a (dihalomethyl)lithium followed. Attempted displacement of halide from DICHED (2-azido-1-haloethyl)boronates with alkoxides failed. Reaction of either pinanediol or DICHED (2-azido-1-chloromethyl)boronate with sodium acetate in acetic acid yielded the 1-acetoxy derivative as a ∼1:1 mixture of diastereomers, indicating probable involvement of an α-boryl carbocation intermediate. Hydrogenation of the pinanediol azido boronic ester over platinum in a solution of hydrogen chloride in dioxane was accompanied by deacetylation to form the impure (2-amino-1-hydroxyethyl)boronic ester hydrochloride. Attempted purification of this material resulted in deboronation to ethanolamine. Acetylation yielded pinanediol (2-acetamido-1-acetoxyethyl)boronate.     

Preparation of α-oxygenated ketones by the dioxygenation of alkenyl boronic acids

Two in two: Dioxygenation of alkenyl boronic acids has been achieved with N-hydroxyphthalimide. The two-step process involves etherification of an alkenyl boronic acid with N-hydroxyphthalimide followed by a [3,3] rearrangement. The dioxygenated product can then be hydrolyzed to form either the corresponding α-hydroxy ketone or the α-benzoyloxy ketone.     

On the mechanism and origin of the stereoselectivity in iodo-deboronation and chloro-deboronation of hindered alkenyl boronate esters using either ICl-NaOMe or ICl-pyridine

Conversion of hindered alkenyl boronate esters into the corresponding iodoalkene, or alkenyl chloride can be carried out stereoselectively using ICl. In the presence of NaOMe, direct reaction of ICl is favoured yielding the E-iodoalkene, however, the reaction with ICl followed by NaOMe can be used to give different major alkenyl iodide and chloride products, depending upon reaction temperature, ICl source and alkenyl boronate stereoelectronics.     

Regioselectivity of 1,3‐Dipolar Cycloadditions of Benzonitrile Oxide to Alkenyl Boronic Esters: An Experimental and Computational Study

1,3‐Dipolar cycloaddition reactions of benzonitrile oxide to monosubstituted or 1,1‐disubstituted alkenyl boronic ester gave only 2‐isoxazolines, bearing the boronic ester group at the 5‐position of the ring. On the other hand, the cycloaddition reactions of benzonitrile oxide with trans‐1,2‐disubstituted alkenyl boronic esters produced 2‐isoxazolines, bearing the boronic ester group at the 4‐position of the ring. We used quantum mechanical calculations to investigate two regioisomeric channels that were associated with the formation of 2‐isoxazolines, bearing the boronic ester group at the 4‐position or 5‐position. The study revealed that the experimental results agreed well with the parameters based on the transition state energies in gas or solvent phase. The study also informed that all the cycloaddition reactions proceed in a spontaneous and exergonic fashion.     

Asymmetric synthesis of 1-acyl-3,4-disubstituted pyrrolidine-2-boronic acid derivatives

An analogue of N-acetylkainic acid having a cyano group and a boronic acid group in place of the two carboxyl groups has been synthesized with high stereocontrol via a series of chain extensions of pinanediol [(trityloxy)methyl]boronate with (dihalomethyl)lithium followed by appropriate nucleophilic substitution of the resulting chloro or bromo boronic ester. Substituents were introduced in the order isopropenyl, cyanomethyl, and bis(trimethylsilyl)amino. The last of these was converted to acetamido, the hydroxyl function was unmasked and mesylated, and the pyrrolidine ring was closed. Attempts to carry out further chain extension on the boronic ester resulted in low yields, evidently the highly polar amido substituent interferes with the (dichloromethyl)lithium insertion process.     

Catalytic (2 + 2)-cycloaddition reactions of silyl enol ethers. A convenient and stereoselective method for cyclobutane ring formation

An efficient catalytic (2 + 2)-cycloaddition reaction leading to the formation of cyclobutane rings has been devised. The process transforms silyl enol ethers and alpha,beta-unsaturated esters into polysubstituted cyclobutanes with a high degree of trans-stereoselectivity. Both the rate and stereoselectivity of the process can be controlled by the choice of the ester group and silyl substituents. The results of stereochemical studies show that the cycloaddition step in this reaction proceeds in a nonstereospecific manner and, thus, by a pathway involving sequential nucleophilic additions via a short-lived zwitterionic intermediate.     

Diols and anions can control the formation of an exciplex between a pyridinium boronic acid with an aryl group connected via a propylene linker

The exciplex formation between a pyridinium boronic acid and phenyl group connected via a propylene linker can be monitored using fluorescence. Addition of pinacol affords a cyclic boronate ester with enhanced Lewis acidity that increases the strength of its cation-π stacking interaction causing a four-fold fluorescence enhancement.     

Stereospecific 1,2-Migrations of Boronate Complexes Induced by Electrophiles

The stereospecific 1,2-migration of boronate complexes is one of the most representative reactions in boron chemistry. This process has been used extensively to develop powerful methods for asymmetric synthesis, with applications spanning from pharmaceuticals to natural products. Typically, 1,2-migration of boronate complexes is driven by displacement of an α-leaving group, oxidation of an α-boryl radical, or electrophilic activation of an alkenyl boronate complex. The aim of this article is to summarize the recent advances in the rapidly expanding field of electrophile-induced stereospecific 1,2-migration of groups from boron to sp² and sp³ carbon centers. It will be shown that three different conceptual approaches can be utilized to enable the 1,2-migration of boronate complexes: stereospecific Zweifel-type reactions, catalytic conjunctive coupling reactions, and transition metal-free sp²–sp³ couplings. A discussion of the reaction scope, mechanistic insights, and synthetic applications of the work described is also presented.     

Stereospecific Conversion of Boronic Esters into Enones using Methoxyallene: Application in the Total Synthesis of 10-Deoxymethynolide

Enones are widely utilized linchpin functional groups in chemical synthesis and molecular biology. We herein report the direct conversion of boronic esters into enones using commercially available methoxyallene as a three-carbon building block. Following boronate complex formation by reaction of the boronic ester with lithiated-methoxyallene, protonation triggers a stereospecific 1,2-migration before oxidation generates the enone. The protocol shows broad substrate scope and complete enantiospecificity is observed with chiral migrating groups. In addition, various electrophiles could be used to induce 1,2-migration and give a much broader range of α-functionalized enones. Finally, the methodology was applied to a 14-step synthesis of the enone-containing polyketide 10-deoxymethynolide.     

Chemoselective Boronic Ester Synthesis by Controlled Speciation

Control of boronic acid solution speciation is presented as a new strategy for the chemoselective synthesis of boronic esters. Manipulation of the solution equilibria within a cross‐coupling milieu enables the formal homologation of aryl and alkenyl boronic acid pinacol esters. The generation of a new, reactive boronic ester in the presence of an active palladium catalyst also facilitates streamlined iterative catalytic C? C bond formation and provides a method for the controlled oligomerization of sp²‐hybridized boronic esters.     

Enantiospecific Synthesis of ortho‐Substituted 1,1‐Diarylalkanes by a 1,2‐Metalate Rearrangement/anti‐SN2′ Elimination/Rearomatizing Allylic Suzuki–Miyaura Reaction Sequence

The one‐pot sequential coupling of benzylamines, boronic esters, and aryl iodides has been investigated. In the presence of an N‐activator, the boronate complex formed from an ortho‐lithiated benzylamine and a boronic ester undergoes stereospecific 1,2‐metalate rearrangement/anti‐S_N2′ elimination to form a dearomatized tertiary boronic ester. Treatment with an aryl iodide under palladium catalysis leads to rearomatizing γ‐selective allylic Suzuki–Miyaura cross‐coupling to generate 1,1‐diarylalkanes. When enantioenriched α‐substituted benzylamines are employed, the corresponding 1,1‐diarylalkanes are formed with high stereospecificity.     

Stereospecific 1,2‐Migrations of Boronate Complexes Induced by Electrophiles

The stereospecific 1,2‐migration of boronate complexes is one of the most representative reactions in boron chemistry. This process has been used extensively to develop powerful methods for asymmetric synthesis, with applications spanning from pharmaceuticals to natural products. Typically, 1,2‐migration of boronate complexes is driven by displacement of an α‐leaving group, oxidation of an α‐boryl radical, or electrophilic activation of an alkenyl boronate complex. The aim of this article is to summarize the recent advances in the rapidly expanding field of electrophile‐induced stereospecific 1,2‐migration of groups from boron to sp² and sp³ carbon centers. It will be shown that three different conceptual approaches can be utilized to enable the 1,2‐migration of boronate complexes: stereospecific Zweifel‐type reactions, catalytic conjunctive coupling reactions, and transition metal‐free sp²–sp³ couplings. A discussion of the reaction scope, mechanistic insights, and synthetic applications of the work described is also presented.     

Synthesis,characterization, and star polymer assembly of boronic acid end‐functionalized polycaprolactone

Boronic acid end‐functionalized polycaprolactone (PCL) polymers were synthesized by ring‐opening polymerization using a pinacol boronate ester‐containing (Bpin) initiator. The polymerization provides access to boron‐terminated polymers (i.e. Bpin‐PCL‐OH) with narrow molecular weight distributions (PDI = 1.09). Postsynthetic manipulation of the polymer's terminal hydroxyl group by copper‐catalyzed azide‐alkyne cycloaddition chemistry provides a series of bis end‐functionalized polymers with significant structural diversity at the termini. Deprotection of the boronate ester end group was accomplished with an acidic solid phase DOWEX resin. The boronate ester deprotection methodology does not result in hydrolysis of the polymeric backbone. The boronic acid‐tipped polymers were converted into star polymer assemblies using thermal dehydration and ligand‐facilitated trimerization. Thermal dehydration of (HO)₂B‐PCL‐OAc to the corresponding boroxine‐based star polymer assembly was inefficient and lead to degradation products. Ligand‐facilitated trimerization using either pyridine or 7‐azaindole as the Lewis base was efficient and mild. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2010