Conspectus Developing new methods that enable the synthesis of new and complex molecules with complete control of their 3-D shape is central to the advancement of synthetic chemistry with ...applications spanning from medicine to materials. Our approach consists of the iterative combination of small building blocks through the use of boron chemistry to essentially “grow” molecules. This approach, which we term assembly-line synthesis (ALS), resembles the way that nature assembles natural products (e.g., the polyketide synthase machinery) and has the advantage that many structural variations can be easily introduced and the products can be evaluated in structural or biological contexts. Chiral boronic esters have been recognized as valuable building blocks due to their unique chemical properties. They are both chemically and configurationally stable, and they can be prepared with very high levels of enantioselectivity. Additionally they undergo a broad array of transformations that lead to the stereocontrolled formation of C–C and C–X (X = heteroatom) bonds. This versatility makes boronic acids ideal building blocks for iterative molecular assembly. A powerful reaction platform for chemical diversification using chiral boronic esters is their homologation using lithium carbenoids via 1,2-metalate rearrangement. In the 1980s, Matteson described the use of boronic esters bearing a chiral diol in a two-step homologation process with dichloromethyl lithium and Grignard reagents (substrate-controlled approach). We have focused on reagent control and have found that Hoppe’s chiral lithiated carbamates can be used as carbenoid equivalents in conjunction with achiral boronic esters. This reagent-controlled process offers many advantages due to the easy access of both the chiral lithiated carbamates and stable boronic esters. The carbamates can be derived from primary or secondary alcohols, and a broad range of functionalized boronic esters and boranes can be employed. Multiple homologations can be carried out in a one-pot sequence thereby streamlining the process to a single operation. This methodology has enabled the synthesis of many molecules containing multiple contiguous stereogenic centers with exquisite 3-D control. In this Account, we trace our own studies to establish the lithiation–borylation methodology and describe selected synthetic applications.
This Minireview highlights advances in the Suzuki–Miyaura cross‐coupling of secondary boron reagents for the creation of CC bonds with control of stereochemistry. It also includes ...non‐transition‐metal coupling of secondary and tertiary boronic esters to electron‐rich aromatics.
Just couple it: In the past decade, highly efficient protocols have been developed to allow the stereospecific arylation of chiral organoborons. This Minireview documents the rapid development of this area, thus providing a clear overview of the various processes available together with mechanisms, as well as their scope and limitations.
While radical additions to π-bonds are well established, additions to σ-bonds are far less explored. We have found that electron deficient radicals derived from alkyl iodides under visible light ...irradiation add to the central strained bond of bicyclobutyl (BCB)-boronate complexes and lead to 1,3-alkyl disubstituted cyclobutyl boronic esters in high yields, with full stereospecificity and high levels of stereoselectivity. Novel cyclobutyl-substituted structures, including peptide and steroid boronic ester derivatives can be accessed. Additionally, although the use of electron-rich alkyl iodides as radical precursors was found to be ineffective, an alternative route involving alkylsulfonylation of the BCB-boronate followed by reductive desulfonylation provided access to simple alkyl substituted cyclobutane products.
Vinyl boronates react with electron-deficient alkyl iodides in the presence of visible light to give boronic esters in which two new C–C bonds have been created. The reaction occurs by radical ...addition of an electron-deficient alkyl radical to the vinyl boronate followed by electron transfer with another molecule of alkyl iodide, continuing the chain, and triggering a 1,2-metalate rearrangement. In a number of cases, the use of a photoredox catalyst enhances yields significantly. The scope of the radical precursor includes α-iodo ketones, esters, nitriles, primary amides, α-fluorinated halo-acetates and perfluoroalkyl iodides.
Photoredox‐catalyzed methylcyclobutanations of alkylboronic esters are described. The reactions proceed through single‐electron transfer induced deboronative radical addition to an electron‐deficient ...alkene followed by single‐electron reduction and polar 4‐exo‐tet cyclization with a pendant alkyl halide. Key to the success of the methodology was the use of easily oxidizable arylboronate complexes. Structurally diverse cyclobutanes are shown to be conveniently prepared from readily available alkylboronic esters and a range of haloalkyl alkenes. The mild reactions display excellent functional group tolerance, and the radical addition‐polar cyclization cascade also enables the synthesis of 3‐, 5‐, 6‐, and 7‐membered rings.
Arylboronate complexes formed from alkylboronic esters and phenyllithium were found to undergo facile single‐electron oxidation to form alkyl radicals. The novel use of these complexes as radical precursors enabled the development of a photoredox‐catalyzed cyclobutane synthesis proceeding through a radical‐polar crossover mechanism.
An operationally simple deaminative borylation reaction of primary alkylamines has been developed. The formation of electron-donor–acceptor complexes between N-alkylpyridinium salts and ...bis(catecholato)diboron enables photoinduced single-electron transfer and fragmentation to carbon-centered radicals, which are subsequently borylated. The mild conditions allow a diverse range of readily available alkylamines to be efficiently converted into synthetically valuable alkylboronic esters under catalyst-free conditions.
The use of pyridinium‐activated primary amines as photoactive functional groups for deaminative generation of alkyl radicals under catalyst‐free conditions is described. By taking advantage of the ...visible light absorptivity of electron donor–acceptor complexes between Katritzky pyridinium salts and either Hantzsch ester or Et3N, photoinduced single‐electron transfer could be initiated in the absence of a photocatalyst. This general reactivity platform has been applied to deaminative alkylation (Giese), allylation, vinylation, alkynylation, thioetherification, and hydrodeamination reactions. The mild conditions are amenable to a diverse range of primary and secondary alkyl pyridiniums and demonstrate broad functional group tolerance.
Electron donor–acceptor complexes between pyridinium‐activated primary amines and Hantzsch ester or triethylamine undergo catalyst‐free photoinduced single‐electron transfer with visible light. Fragmentation leads to alkyl radicals that could be intercepted with a variety of acceptors. This deaminative radical generation was applied to catalyst‐free Giese, allylation, vinylation, alkynylation, thioetherification, and hydrodeamination reactions.
The reaction of bicyclo1.1.0butyl pinacol boronic ester (BCB‐Bpin) with nucleophiles has been studied. Unlike BCBs bearing electron‐withdrawing groups, which react with nucleophiles at the ...β‐position, BCB‐Bpin reacts with a diverse set of heteroatom (O, S, N)‐centred nucleophiles exclusively at the α‐position. Aliphatic alcohols, phenols, carboxylic acids, thiols and sulfonamides were found to be competent nucleophiles, providing ready access to α‐heteroatom‐substituted cyclobutyl boronic esters. In contrast, sterically hindered bis‐sulfonamides and related nucleophiles reacted with BCB‐Bpin at the β′‐position leading to cyclopropanes with high trans‐selectivity. The origin of selectivity is discussed.
Bicyclo1.1.0butyl boronic ester (BCB‐Bpin) reacts with a diverse range of heteroatom (O, S, N)‐centred nucleophiles, with exclusive α‐selectivity. In contrast, sterically hindered bis‐sulfonamides react at the β′‐position leading to cyclopropanes with high trans‐selectivity.
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