The author’s work on (α-haloalkyl)boronic esters as reagents for asymmetric synthesis is reviewed. Diastereomeric ratios exceeding 1000 can be achieved with this chemistry, and ratios around 100 are commonplace. The method allows sequential installation of a series of stereocenters and tolerates a wide variety of suitably protected functional substituents. (α-Amidoalkyl)boronic acids include biochemically significant serine protease inhibitors, one of which is the clinically successful proteasome inhibitor bortezomib, used for treatment of multiple myeloma and mantle cell lymphoma.

Boronic esters in asymmetric synthesis.

Chiral acetals in asymmetric synthesis

α-Halo boronic esters in asymmetric synthesis

Structurally, boronic acids are trivalent boron-containing organic compounds that possess one alkyl substituent (i.e., a C–B bond) and two hydroxyl groups to fill the remaining valences on the boron atom (Figure 1.1). With only six valence electrons and a consequent deficiency of two electrons, the sp2-hybridized boron atom possesses a vacant p orbital. This low-energy orbital is orthogonal to the three substituents, which are oriented in a trigonal planar geometry. Unlike carboxylic acids, their carbon analogues, boronic acids are not found in nature. These abiotic compounds are derived synthetically from primary sources of boron such as boric acid, which is made by the acidification of borax with carbon dioxide. Borate esters, the main precursors for boronic acid derivatives, are made by simple dehydration of boric acid with alcohols. The first preparation and isolation of a boronic acid was reported by Frankland in 1860 [1]. By treating diethylzinc with triethylborate, the highly air-sensitive triethylborane was obtained, and its slow oxidation in ambient air eventually provided ethylboronic acid. Boronic acids are the products of the second oxidation of boranes. Their stability to atmospheric oxidation is considerably superior to that of borinic acids, which result from the first oxidation of boranes. The product of a third oxidation of boranes, boric acid, is a very stable and a relatively benign compound to humans (Section 1.2.2.3). Their unique properties as mild organic Lewis acids and their mitigated reactivity profile, coupled with their stability and ease of handling, makes boronic acids a particularly attractive class of synthetic intermediates. Moreover, because of their low toxicity and their ultimate degradation into the environmentally friendly boric acid, boronic acids can be regarded as “green” compounds. They are solids that tend to exist as mixtures of oligomeric anhydrides, in particular the cyclic six-membered boroxines (Figure 1.1). For this reason and other considerations outlined below, the corresponding boronic esters are often preferred as synthetic intermediates. Although other classes of organoboron compounds have found tremendous utility in organic

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Structure, Properties, and Preparation of Boronic Acid Derivatives. Overview of Their Reactions and Applications

The creation of quaternary stereogenic centers with high enantioselectivity is challenging, in part, because of the high steric repulsion between the substituents on the carbon center that is generated during construction. Nevertheless, significant progress has been made towards this goal in recent years, even in conformationally flexible acyclic systems. However, whilst in many cases high e.r. values have been achieved, the selectivities are invariably substrate-dependent. We have approached this problem from a different perspective and considered the possibility of employing stereospecific homologations of tertiary boronic esters 1. Such boronic esters can be easily prepared from the corresponding secondary alcohols with very high e.r. values by using the methodology developed by our group, or alternatively, by borylation of allylic carbonates/Michael acceptors reported by Hoveyda and co-workers (Scheme 1). However, whilst the homologation reaction

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Enantioselective construction of quaternary stereogenic centers from tertiary boronic esters: methodology and applications.

A stereospecific convergent coupling of nucleophilic and electrophilic chiral carbons

(S,S)-Diisopropylethanediol (S) 6, (S,S)-DIPED] boronic esters 1? (S)-3, (S)-9, 11 with (dichloromethyl)lithium yield the chain extended (αR)-(α-chloroalkyl)boronic esters (S)-2, (1R,2R)-24, (1R,2S)-24, (R)-27, respectively in 98% diastereoisomeric excess. The major (αR) isomers with Grignard reagents yield the products of displacement of chloride by alkyl (S)-3, (1R,2R)-25, (1R,2S)-25, (S)-9. The enantiomers have been made from (R,R)-DIPED. Contrakinetic (S,S)-DIPED (αS)-(α-chloroalkyl)boronate (S)-7 has been prepared indirectly and found to undergo a different major reaction with methylmagnesium bromide which leads to B-methyl-1,4,2-dioxaborinane 10. Thus, in the two-step formation of a new chiral center, the minor isomer is twice discriminated against. The utility of this new chemistry has been demonstrated with the asymmetric synthesis of each of the four stereoisomers of 4-methyl-3-heptanol (26) in very high purity. Diastereoselectivities measured at 350:1 to 1000:1 per chiral center have been achieved

Asymmetric synthesis of the four stereoisomers of 4-methyl-3-heptanol via boronic esters : sequential double stereodifferentiation leads to very high purity

Asymmetric Synthesis of the Four Stereoisomers of 4‐Methyl‐3‐heptanol via Boronic Esters: Sequential Double Stereodifferentiation Leads to Very High Purity.

Prana B. Tripathy

Papers

A stereospecific convergent coupling of nucleophilic and electrophilic chiral carbons

Asymmetric synthesis of the four stereoisomers of 4-methyl-3-heptanol via boronic esters : sequential double stereodifferentiation leads to very high purity

Asymmetric Synthesis of the Four Stereoisomers of 4‐Methyl‐3‐heptanol via Boronic Esters: Sequential Double Stereodifferentiation Leads to Very High Purity.

A Stereospecific Convergent Coupling of Nucleophilic and Electrophilic Chiral Carbons.