Synthesis of α-aminoboronic acids

Abstract

This review describes available methods for the preparation of α-aminoboronic acids in their racemic or in their enantiopure form. Both, highly stereoselective syntheses and asymmetric procedures leading to the stereocontrolled generation of α-aminoboronic acid derivatives are included. The preparation of acyclic, carbocyclic and azacyclic α-aminoboronic acid derivatives is covered. Within each section, the different synthetic approaches have been classified according to the key bond which is formed to complete the α-aminoboronic acid skeleton.

---

Patricia Andrés

Patricia Andrés graduated in Chemistry from the University of Zaragoza in 2011, and completed her Master's Thesis in Organic Chemistry one year later. She is currently a PhD student in the group of Prof. C. Cativiela at the same university. Her research focuses on the development of synthetic methodologies for the preparation of α-aminoboronic acids.

Gema Ballano

Gema Ballano received her PhD in Chemistry in 2006 from the University of Zaragoza under the supervision of Prof. C. Cativiela. She conducted postdoctoral research in the laboratories of Prof. C. Toniolo at the University of Padova (Italy). In 2012, she joined Rolabo Outsourcing S.L. (Zaragoza) and works in collaboration with the University of Zaragoza. Her research interests include the synthesis of non-proteinogenic amino acids and their incorporation into peptides.

M. Isabel Calaza

M. Isabel Calaza obtained her PhD in Chemistry from the University of Santiago de Compostela in 2000. She conducted postdoctoral research in the group of Prof. P. Knochel at the Ludwig Maximilians University of Munich. In 2004, she joined the Medicinal Chemistry Department at AstraZeneca R&D Mölndal. In 2007, she moved to the University of Zaragoza where she is an Assistant Professor. Her research interests include the synthesis of proline analogues for structural analysis and α-aminoboronic acids.

Carlos Cativiela

Carlos Cativiela is Full Professor of Organic Chemistry at the University of Zaragoza since 1996. His scientific activity started in the field of asymmetric synthesis and is oriented to the synthesis of non-proteinogenic amino acids in enantiomerically pure form. He has developed different methodologies for the synthesis of a wide variety of enantiopure non-coded constrained amino acids either by enantio-/diastereoselective syntheses or by chromatographic resolution procedures. Current research interests involve the incorporation of such amino acids into peptides of structural, medical or agrochemical interest. He is the author of more than 400 papers and several review articles on the synthesis of amino acids.

---

1. Introduction

In the last few decades important biomedical applications¹ have been established for compounds containing α-aminoboronic acids in their structure (Fig. 1). Most developments aimed at the use of α-aminoboronic acids in the area of protease inhibition.¹ In this context, the discovery of bortezomib (Fig. 1) represented a very significant advance and it presently constitutes an important treatment for multiple myeloma and mantle cell lymphoma. The α-aminoboronic acid residue in bortezomib, L-boroleucine,² is key for its proteasome-inhibitory activity.³ It forms tetrahedral adducts with the hydroxyl groups of threonine residues at the catalytic sites of 20S proteasome that block the enzymatic activity. Such adducts are considered transition state analogues for deacylation reactions that occur during proteasome-dependent proteolysis. The clinical efficacy of bortezomib encouraged further studies for its optimal delivery to tumours,⁴ as well as the development of new analogues,⁵ such as orally active ixazomib^5a (Ninlaro® has recently been granted approval by FDA) and delanzomib,^5b,c which preserve the key α-aminoboronic residue (Fig. 1).

Fig. 1 Proteasome inhibitors that contain an α-aminoboronic acid in their structure.

The analogous mechanism of inhibition in serine proteases has led to a wide range of compounds with pharmacologically relevant properties (Fig. 2).^1,6–9 Among the targeted enzymes¹ are thrombin, dipeptidyl peptidases (DPPs),⁶ β-lactamases,⁷ penicillin-binding proteins (PBPs), HCV NS3/4A protease, enteropeptidase, and mycosin-1 protease.^8,9 In this context, the most significant advances have been achieved in the development of compounds with anticancer, antiviral, and antibacterial activities, which are in various phases of clinical trials (Fig. 2).

Fig. 2 Boron-based serine protease inhibitors that exhibit pharmacologically relevant properties.

The increasing interest in α-aminoboronic acids is also linked to their utility as building blocks¹⁰ and their potential use in sensing applications.¹¹ In fact, boroglycine constitutes the key recognition part of a fluorescent tracer (Fig. 3) for binding assays that are aimed at the identification of inhibitors of PBPs and β-lactamases.^11a Besides, boronic acid analogues of L- and D-1-naphthylalanine,^11b and their bisboronic acid derivatives (Fig. 3),^11c are being examined as carbohydrate sensors, due to their significant fluorescent property changes upon sugar binding, and their water solubility.

Fig. 3 α-Aminoboronic acid-based investigational fluorescent sensors.

The enormous potential of α-aminoboronic acids has stimulated a great deal of innovation on synthetic methods for their preparation.¹² The difficulties associated with their isolation, which are due to the reactivity of the C–B bond, constitute a major synthetic issue.^12b The electron-deficient nature of the boron atom in its trivalent form enables it to form a three-membered ring adduct with the nitrogen atom. Such an adduct is subsequently protonated at carbon with concomitant C–B bond cleavage. For this reason, the preparation of suitable protected α-aminoboronic acid derivatives is assumed.

Herein, we wish to illustrate the progress of synthetic methods utilized for the construction of α-aminoboronic acid derivatives. Specifically, the preparation of acyclic, carbocyclic and azacyclic α-aminoboronic acid derivatives is covered. The different synthetic approaches, within each section, have been classified according to the bond which is formed to complete the α-aminoboronic acid skeleton.

2. Synthesis of acyclic α-aminoboronic acids

2.1. Formation of the C–B bond

2.1.1. Addition of α-amino organometallic compounds to boron-containing electrophiles. Synthetic routes towards acyclic α-aminoboronic acids that involve the borylation of α-amino metalated species are scarce in the literature.^13,14 In 2000, Priestley and Decicco¹³ described the preparation of acyclic (Scheme 1) and carbocyclic (vide infra) α-aminoboronic acid esters by the reaction of metalated isocyanides with trialkyl borate esters. Regrettably, the boronic analogue of α-aminoisobutyric acid (3, Scheme 1) was obtained in very low yield by reaction of the metalated isocyanide with triisopropyl borate, followed by acid hydrolysis. Such a low yield was attributed to the instability of the resulting α-isocyanoboronic ester under basic reaction conditions.

Scheme 1

More recently, Srebnik and Shibli¹⁴ reported the use of aminoboranes and aminocyanoboranes (4, Scheme 2) as precursors for the preparation of α-aminoboronic esters 5. The borane and cyanoborane groups inductively facilitate the selective α-deprotonation of the tertiary amines. The resulting lithiated complexes reacted readily with the boron-containing electrophile and furnished racemic α-alkylaminoboronic acid esters 5 in good yields.

Scheme 2

2.1.2. Addition of nucleophilic boron reagents to imines. By contrast, nucleophilic borylations¹⁵ of imines have emerged as very efficient approaches for the preparation of highly enantioenriched α-aminoboronic acid derivatives. In this context, the stereocontrol has been either achieved by the presence of a chiral auxiliary at the aldimine, or employing chiral catalysts with achiral substrates.
2.1.2.1. Substrate-controlled approach. In 2008, Ellman et al. reported the first stereoselective borylation of chiral sulfinylimines 6 (Scheme 3),^16a on the basis of preceding studies of diboration of racemic N-aryl aldimines.^16b Ellman's procedure involved in situ generation of a copper(I) boryl complex 7 (Scheme 3) by the treatment of bis(pinacolate)diboron (B₂Pin₂) with (1,3-dicyclohexylimidazol-2-ylidene)copper(I) tert-butoxide, also named as Sadighi's catalyst. The reaction of the active catalytic species (7) with sulfinylimines 6 proceeded at room temperature with good yield and high diastereoselectivity for a wide range of substrates (Scheme 3). The transformation was also achieved at 0 °C albeit with higher catalyst loading. The stereoselectivity observed was consistent with coordination of 7 from the least hindered face of the aldimine. Selective removal of the N-sulfinyl group under acidic conditions enabled the production of highly enantioenriched α-aminoboronic ester derivatives.

Scheme 3

The same catalyst was applied by Li et al. to the asymmetric borylation of imine 9 that bears a chiral N-phosphinyl auxiliary (Scheme 4).¹⁷ This group anchored onto the aldimine displayed good asymmetric induction in the borylation reaction and facilitated the isolation of the desired product by avoiding conventional purification methods (group-assisted purification concept). Thus, diastereomerically pure 10 was obtained by washing the crude reaction mixture with hexanes, and the chiral N-phosphinyl auxiliary was readily recovered after the subsequent deprotection step.

Scheme 4

In recent work, the reactivity of copper(I) boryl complexes supported by different N-heterocyclic carbene (NHC) ligands is described.^18,19 Benzimidazole-^18a and triazine-^18b based N-heterocyclic carbene (NHC) precursors (12 and 13 respectively, Scheme 5) lead to copper(I) boryl complexes that proved quite efficient catalysts for borylations of chiral sulfinylimines 6 (Scheme 5, entries 1–8). Remarkably, these reactions took place in a one-pot procedure without the need of a glove box as it was required with Sadighi's catalyst (Scheme 3).^16a

Scheme 5

In addition to this, Ellman et al.¹⁹ developed an air- and moisture-stable copper(II) catalytic system for the borylation of 6 (Scheme 5, conditions C). It is worth noting that not only sulfinylimines (Scheme 5, entries 9–12), but also ketimines (Scheme 6) reacted readily to provide access to α-sulfinamido boronate esters in good yields and with high stereoselectivities. The stereocontrol achieved with the catalytic system CuSO₄/PCy₃·HBF₄ was shown to be dependent on the nature of the phosphorus ligand, the ligand to copper ratio and the solvent mixture. It was found that the use of benzylamine as an additive was not essential for the phosphine salt selected but it proved beneficial for the borylation of challenging substrates such as 17 (Scheme 6).

Scheme 6

Alternatively, the addition of boron to N-tert-butanesulfinyl aldimines and ketimines 20 was possible in the absence of a transition metal complex as a catalyst (Scheme 7).²⁰ In this procedure, it was the in situ generated methoxide anion which was responsible to activate the diboron reagent and to promote the addition in the presence of an N-heterocyclic carbene as a ligand. The sp² boron atom in the adduct gains a nucleophilic character whereas the one that interacts with methoxide anion loses electron density because of the lack of electron donation from the oxygen atoms of its pinacolate moiety.²¹ Specifically, the use of carbene precursor 12 (Scheme 5), with a benzimidazole core, allowed the reaction to be performed without requiring an inert atmosphere.

Scheme 7

2.1.2.2. Reagent-controlled approach. The first catalytic enantioselective approach for the synthesis of α-aminoboronic esters was reported by Fernández et al., who conducted nucleophilic boron addition to tosylaldimines 22 in the presence of chiral phosphines as ligands (Scheme 8).²² The use of such phosphines proved to be essential for enantiofacial differentiation in the course of the reaction, even though aliphatic tosylaldimines gave low enantioselectivities (entries 7 and 8).

Scheme 8

Later, enantioselective copper-catalyzed boryl additions to N-benzoyl²³ and N-tert-butoxycarbonyl (N-Boc)^10e aldimines were accomplished (Scheme 9). On one hand, the asymmetric addition of B₂Pin₂ to N-benzoyl aldimines (entry 1) involved the use of NHC–Cu complexes in situ-generated by the treatment of 27 with sodium tert-butoxide and copper chloride.²³ The reaction proceed smoothly and gave excellent yields and high enantioselectivities for a broad scope of 4-substituted benzaldimines regardless of their electronic nature. However, some erosion in enantioselectivity was observed for sterically hindered 2- or 3-substituted benzaldimines. Alkyl aldimines were also effective under the reaction conditions but they were generated in situ by the treatment of α-tosylamine precursors with a base, in order to avoid their decomposition.

Scheme 9

On the other hand, Liao et al.^10e reported a highly enantioselective copper(I)-catalyzed boryl addition to N-Boc aldimines (Scheme 9, entries 2 and 3) by using chiral sulfoxide-dialkylphosphine 28 as a ligand. Remarkably, both enantiomers of α-aminoboronic esters 29 were obtained through a counteranion switch in the cationic copper(I) catalyst that was in situ-generated. The boryl copper species generated from precatalyst 28-Cu-OtBu underwent addition from the Si-face of the imine and afforded the (S)-products (entry 2). Conversely, the cationic copper complex with a larger anion, (28-Cu)⁺ BARF⁻, induced the opposite absolute configuration of 29 (entry 3). It was reasoned by the authors that the pinacolboryl moiety approaches the cationic copper complex from the back side of the BARF anion. As a consequence of this, the boryl-copper species underwent addition from the Re-face of the imine due to its coordination trans to the tert-butylsulfinyl group. The reaction gave high enantioselectivities for a broad scope of benzaldimines. Only low enantioselectivities were observed for ortho-substituted aryl aldimines when NaBARF was used as an additive and for alkyl aldimines with both catalytic systems.

In a related work, Morken and Hong²⁴ showed the diboration of in situ-generated silyl imines with B₂Pin₂ in the presence of a Pt–phosphonite catalyst made, in turn, from 32 (Scheme 10). The resulting diboration adducts 33 were directly acylated, thus providing straightforward access to N-acyl α-aminoboronic esters 34 or peptide derivatives such as 35.

Scheme 10

2.1.3. Hydroboration of enamides. It is only very recently that Tang et al. described the first enantioselective synthesis of α-amino tertiary boronic esters by rhodium-catalyzed hydroboration of α-arylenamides (Scheme 11).^10d The treatment of the latter with B₂Pin₂ in the presence of a rhodium complex, generated from phosphorous-chiral ligand 37, yielded α-aminoboronic esters 38 in good yields and excellent enantioselectivities. The regiocontrol achieved was shown to be due to the presence of a carbonyl directing group in the starting substrates. Under optimized conditions of solvent, base and ligand, the hydroboration was broad in scope, particularly regarding the electronic properties and the substitution pattern of the aryl group (Ar) in 36. Experimental studies supported the hydroboration reaction pathway and allowed to discard the tautomerization of 36 followed by diboration of the resultant acyl imine as an alternative mechanism. The catalytic cycle of the hydroboration involved oxidative addition of bis(pinacolate)diboron to the rhodium complex, reaction with the N–H of 36 to yield boryl rhodium hydride species, olefin insertion to the Rh–H bond, and reductive elimination.

Scheme 11

2.1.4. C(sp³)–H borylation reactions. The direct C(sp³)–H borylation α to a N atom certainly is a straightforward approach for synthesizing α-aminoboronic acid derivatives (Scheme 12). This type of C–B bond assembly has been recently achieved by using a diboron reagent in the presence of different heterogeneous catalytic systems.²⁵ The combination of [Rh(OMe)(cod)]₂ with silica-supported triarylphosphanes (A and B, Scheme 12) gave mono(phosphane)–metal complexes that enabled the selective borylation of N-adjacent C(sp³)–H bonds of amides and ureas 39 under quite mild reaction conditions.^25a,c According to the authors, the tryptycene-type cage structure featured by triarylphosphanes A and B and their immobilization proved critical factors for borylation activity. Such structural features resulted in an efficient isolation of each phosphane center, thus allowing the selective 1 : 1 metal-phosphane coordination.

Scheme 12

Furthermore, Sawamura et al.^25b described the catalytic application of a polystyrene-phosphane covalently bound hybrid (C, Scheme 12) for Rh-catalyzed N-adjacent C(sp³)–H borylations. In this case, the three-fold cross-linking increases the density of the polymer around the phosphane core, thus achieving 1 : 1 metal-phosphane ligation, and generates a ligand steric effect moderate enough to ensure catalytic performance.

These procedures gave access to boroglycine and borophenylglycine derivatives (Scheme 12) in good yields based on boron. The required excess of substrate against the boron reagent constitutes an undesirable feature if the activation of more laborious substrates is pursued. However, the applicability of the methodology for the preparation of additional acyclic α-aminoboronic acid derivatives has not yet been explored.

2.2. Formation of the C–N bond

2.2.1. S_N2-like nucleophilic displacements. A great deal of research has been devoted to the preparation of α-aminoboronic acid derivatives by reaction of (α-haloalkyl)boronic esters with nitrogen-based nucleophiles. This strategy was initiated by Matteson for the synthesis of α-aminomethylboronic esters (boroglycinates)²⁶ and further developed for the preparation of α-alkyl, α-alkenyl, and α-arylaminoboronic acid derivatives in racemic or enantioenriched form (Scheme 13).^12e,27

Scheme 13

The displacement of iodide from α-iodomethylboronate ester 41 by nitrogen-based nucleophiles was first reported in 1968 (Scheme 14).²⁶ Secondary amines reacted readily with 41 and furnished α-aminoboronic acids that were isolated as catechol ester derivatives. In addition, deprotonated amides provided compounds such as phthalimidomethaneboronic acid 43.

Scheme 14

Besides, tertiary amines²⁸ and lithiohexamethyldisilazane^29–31 reacted with α-halomethylboronic esters 44 and produced stable quaternary ammonium boronate salts 45 and silylated aminoboronic esters 46, respectively (Scheme 15). The latter were used as intermediates for the preparation of formamido-,²⁹ acylamino-,³⁰ and sulfonamidemethylboronic esters.³¹

Scheme 15

More recently, nucleophilic substitutions of α-halomethylboronic esters equipped with a tetracoordinated boron center have been described (Scheme 16).³² According to the authors, substitutions of trifluoroborate 51 by alkylamines follow a pure S_N2 mechanism.^32a By contrast, the nucleophilic displacement of the halide in a substrate with sp² hybridization at the boron atom involves the generation of an intermediate “ate” complex that undergoes migration of the nitrogen to the neighboring carbon atom (Scheme 17).^12e,27

Scheme 16

Scheme 17

The mechanism via an “ate”-type intermediate is at the base of Matteson's homologation methodology (Scheme 17), which involves the one-carbon chain extension of a sp²-boronic ester.^12e,27 Such a procedure has been a standard method for the synthesis of racemic^12e,27,33,34 and enantioenriched α-alkyl-, α-alkenyl- and α-arylaminoboronic acid derivatives.^{7a,10a,11c,12e,27,33,35} Specifically, addition of (dichloromethyl)lithium to a pinanediol boronic ester 55 (Scheme 17) places the group on the less hindered face of the chiral director. Rearrangement of the resulting “ate”-complex produces (α-chloroalkyl)boronic ester 56 in high diastereomeric purity.^12e Subsequent treatment of 56 with lithiohexamethyldisilazane furnishes the N-silylated derivative with inversion of the configuration. The experimental conditions for this chain-extending process have been optimized.³⁶ It was found that the presence of zinc chloride in the mixture enhances the stereoselectivity attained during the migration step (generally formed in ∼90–95% if the only cation is lithium and ≥99% if zinc chloride is used).^12e,36 This effect was attributed to the ability of the Lewis acid to act as a promoter of the rearrangement and as a scavenger of the chlorine ion that might cause epimerization at the α-carbon of 56. In addition, the use of diethyl ether as a solvent, instead of tetrahydrofuran, ensured reproducibility on a large-scale manufacturing process.³⁶

As already mentioned, the isolation of N-silylated derivatives is usually eluded and N-acyl (Scheme 18, entries 1–6), N-sulfonyl (Scheme 18, entry 14), and α-aminoboronic esters bearing tertiary amino groups (Scheme 18, entries 7–13) are produced.^{7a,10a,11c,12e,27,33,35} Alternatively, bis(trimethylsilyl)amino boronic esters 57 (Scheme 17) have been desilylated and reacted immediately for the preparation of peptidyl derivatives.³⁷ Mattesson's homologation proceeded with high diastereoselectivity for a broad scope of pinanediol boronic esters 55 (Scheme 18), generated, in turn, from aryl- and alkyl-Grignard reagents. Among others, the process gave access to boroalanine, boroleucine, borovaline, borophenylalanine and boroserine derivatives.

Scheme 18

Interestingly, (α-azidoalkyl)-^7a,38 (entry 6, Scheme 18) and (α-hydroxyalkyl)amino boronic esters^35m,39 (Scheme 19) proved useful intermediates for the preparation of bioactive molecules, such as α-(triazolyl)amino boronic acids,^7a α-amino cyclic boronates 60,^35m and α-(2-thiazolidinyl)amino boronic acids 63.³⁹

Scheme 19

In addition to aryl- and alkylboronic esters, Mattesson's homologation has been applied to α-alkenylboronic esters^34b,40 such as 64⁴⁰ (Scheme 20). Subsequent desilylation and acylation gave α-(acetamido)allylboronate 65 that, in turn, underwent radical addition of methanethiol to give boromethionine derivative 66.

Scheme 20

On the other hand, the hydroboration of allyl bromide furnished an haloalkyl-substituted boronate that proved a convenient precursor for azidoalkyl-substituted 67 (Scheme 21).^41,42 This substrate gave access to boroornithine^41a and boroarginine^41b derivatives when subjected to Matteson's homologation.

Scheme 21

Interestingly, the preparation of boroarginine- and borolysine-containing peptides⁴² has often involved the incorporation of a haloalkyl-substituted α-aminoboronic acid precursor in the peptide chain, followed by the side-chain transformations needed. Due to their utility as synthetic intermediates, a few haloalkyl-substituted α-aminoboronic esters have been isolated in diastereomerically pure form by transesterification of racemic precursors 70 with chiral pinanediols under selective crystallization conditions (Scheme 22).⁴³

Scheme 22

The synthetic versatility of chiral (α-haloalkyl)boronic esters (56, Scheme 17) stimulated the development of additional methods for their preparation.^12e,44–46 The preparative pathways include the reaction of dichloromethylboronic esters of C₂-symmetrical chiral diols with organometallic reagents (Scheme 23),^12e,45 and enantioselective hydrogenations of 1-chloro-1-alkenylboronic esters (Scheme 24).⁴⁶ Matteson reported the use of dichloromethylboronic esters of C₂ symmetric diols for chiral induction in the synthesis of (α-chloroalkyl)boronic esters.^12e,44 This methodology was applied by Mantri et al. to the preparation of 74 (Scheme 23), which is a precursor of boroornithine.⁴⁵ A high asymmetric induction (>99% dr) was achieved during the reaction of 72 with the dioxolane Grignard at a reaction temperature readily practicable for large scale synthesis. The resulting compound was transesterified to pinanediol ester due to good stability for projected boropeptide chemistry. The treatment of (α-chloroalkyl)boronic ester 73 with lithium bis(trimethylsilyl)amide (LHMDS) produced an amine that underwent deprotection in dry ethereal hydrogen chloride solution to generate hydrochloride salt 74. It should be noted that pinanediol (dichloromethyl)boronate was also used as a means of expanding the variety of side-chains to be incorporated during the synthesis of (α-chloroalkyl)boronic esters.⁴⁷ However, the resulting diastereomeric “ate”-complexes show quite different levels of stereocontrol during the subsequent migration step, thus leading to poor diastereomeric ratios of (α-chloroalkyl)boronic esters.^12e

Scheme 23

Scheme 24

The route towards (α-chloroalkyl)boronic esters 78 (Scheme 24) based on the asymmetric catalytic hydrogenation of 1-chloro-1-alkenylboronates 76 was reported by Časar et al. in 2012.^46a,b A range of substrates 76 were hydrogenated in the presence of a P⁁N ligand-based iridium catalyst. The stereoelectronic features of the chiral ligand and the substrate concentration were found to have a significant influence in the reaction outcome. Under optimized conditions, the transformation occurred without significant dehalogenation for all substrates. Excellent conversions and good enantioselectivities were obtained, albeit higher catalyst loadings were required to achieve full conversions for substrates bearing bulky alkyl moieties or aryl substituents. In a later report, the same authors found that 1-bromo-1-alkenylboronic appear to be less reactive towards hydrogenation with a number of iridium–P⁁N complexes.^46c In spite of this, the study demonstrated that high chemoselectivities and enantioselectivities of up to 73% ee, along with full conversions could be obtained for hydrogenation of acyclic alkyl substituted derivatives.

In addition to the aforementioned methods, a few strategies that provide access to racemic (α-haloalkyl)boronic esters have been reported.^48–50 Methods available include chlorination of α-alkoxyboronic esters generated, in turn, by borylation of α-alkoxyorganolithium reagents,⁴⁸ cleavage of a carbon–zirconium bond in boron–zirconium gem-bimetallic species with N-halosuccinimides (vide infra),⁴⁹ and the preparation of (α-haloalkyl)boronic esters under conditions amenable to the introduction of side chains as electrophiles (Scheme 25).⁵⁰ In the latter case, alkyl bromides and methyl acrylate were allowed to react with the stabilized anion of (phenylthio)methylboronate 80. The resulting (α-phenylthioalkyl)boronic esters 81 were converted to the corresponding sulfonium salts by alkylation with excess methyl iodide. Such salts in the presence of sodium iodide produced α-iodo derivatives 82. The latter gave access to α-aminoboronic esters 83 by conventional methods. In some cases racemic pinacol boronic esters were transesterified to (+)-pinanediol esters, and enantiomerically pure isomers could be separated by chromatography. This strategy proved particularly valuable with side chains that contain functionalities which are sensitive to basic conditions, thus being complementary to those procedures that involve the use of Grignard reagents. Among others, the methodology provided access to the boronic analogues of aspartic and glutamic acid.

Scheme 25

2.2.2. Allylic aminations. In 2009 Carboni et al. studied Mitsunobu reactions of (3-hydroxy-buten-1-yl)boronic acid ester 84 with various nucleophiles, and found that the boronic ester moiety governed the regio- and stereochemical course of the amination.⁵¹ Specifically, the use of N-tosylpropargylamine as the nucleophile gave access to α-aminoboronic ester 85 (Scheme 26). On the basis of the regio- and stereoselectivity observed a plausible reaction mechanism was proposed. It involved in situ generation of the leaving group, as in the classical Mitsunobu reaction, the formation of a borate by addition of the nucleophile to the boron atom, and 1,2-migration of the nitrogenated group in an S_N2′ manner. The formation of a single isomer (E) was rationalized through a transition state that places the migrating substituent in anti to the leaving group and arranges for the least possible allylic 1,3-strain.

Scheme 26

The allylic amination of alkenylboronic esters 86 catalyzed by chiral iridium complexes was later investigated by the same group (Scheme 27).⁵² In this case, the nature of the boronic ester directed the regioselectivity of the process. The use of trifluoroborates 86 led to α-aminoboronate 87 as the only product, while pinacol boronic esters preferentially gave the linear allylic amine. The inversion of regioselectivity was attributed to the electronic effect of the trifluoroborate group on the (π-allyl)Ir intermediate. Under optimized conditions of the solvent and base, the allylic amination was broad in scope for cyclic amines, but only suited to acyclic amines endowed with a small cone angle, such as benzylethylamine. Unfortunately, no data were provided by the authors regarding the enantiomeric excess of allylic substitution products due to the lack of a suitable analytical method.

Scheme 27

2.2.3. Electrophilic aminations. Sbrenik and Zheng⁴⁹ reported the preparation of α-aminoboronic ester 90, in the racemic form, by electrophilic amination of boron–zirconium gem-bimetallic species 89 (Scheme 28). This species was generated through the regioselective hydrozirconation of alkenylboronic ester 88 by using Schwartz's reagent. Subsequent selective cleavage of the carbon–zirconium bond with O-mesitylsulfonyl hydroxylamine (MSH)⁵³ as the electrophilic aminating reagent provided α-aminoboronic ester 90 in a reasonable yield.

Scheme 28

2.2.4. [3,3]-Sigmatropic rearrangements. Pietruszka et al.⁵⁴ investigated [3,3]-sigmatropic rearrangements of trichloro- and trifluoroacetimidates 91 as an entry to enantiopure α-aminoboronic acid derivatives 92 (Scheme 29). However, it was found that the rearrangement required a very high temperature to occur and led to 92 as mixtures of diastereoisomers that were determined to be close to 60 : 40 in all cases. Unfortunately, the separation of diastereoisomers was unsuccessful and, therefore, no further attempts to pursue the approach were made by the authors.

Scheme 29

More recently, Carboni's group carried out the synthesis of allylic α-aminoboronic esters 96via a [3,3]-sigmatropic cyanate–isocyanate rearrangement of racemic carbamate 93 (Scheme 30).⁵⁵ Dehydration of 93 with triphenylphosphine, carbon tetrabromide and triethylamine gave cyanate 94, which underwent [3,3]-sigmatropic rearrangement at room temperature. The resulting allyl isocyanate 95 was transformed in situ by reaction with a variety of nucleophiles. It was suggested that the rearrangement occurs through a cyclic transition state of six centers with the boronate and methyl groups in pseudoequatorial positions, which helps to explain the detection of a single geometric isomer of E configuration.

Scheme 30

2.2.5. Curtius rearrangement of α-borylcarboxylic acids. Yudin et al. reported an attractive boroalkyl group migration that provides access to α-aminoboronic acid derivatives (Scheme 31).⁵⁶ The procedure^56a,b involved the preparation of α-borylisocyanates 98via Curtius rearrangement of α-borylcarboxylic acids 97.⁵⁷ The thermal decomposition of the intermediate carboxylic azides worked well with aryl- or alkyl-substituted precursors (entries 1–7) and with α,α-disubstituted analogues (entry 8). In addition, α-borylcarboxylic acid 100 was used for the stereochemical investigation of the migratory process that it was found to occur with complete retention of the configuration. The resulting α-borylisocyanates 98 have enabled the synthesis of α-aminoboronic acid derivatives 99 by reaction with amine and alcohol nucleophiles at the isocyanate group.

Scheme 31

In addition, the deoxygenation of isocyanates 102 (Scheme 32) furnished isocyanides 103 that enabled the preparation of boropeptides through a multicomponent approach.^56c

Scheme 32

3. Synthesis of carbocyclic α-aminoboronic acids

As mentioned in Section 2.1.1, Priestley and Decicco¹³ reported the preparation of carbocyclic α-aminoboronic acid esters through borylation of α-amino metalated species. Specifically, three- and six-membered carbocyclic α-aminoboronates 107 (Scheme 33) were obtained through a three-step sequence that involved the addition of metalated isocyanides to triisopropyl borate, esterification of the boronic acids isolated after the hydrolytic work-up, and acid-catalyzed hydrolysis of isocyanides 106.

Scheme 33

4. Synthesis of azacyclic α-aminoboronic acids

4.1. Formation of the C–B bond

4.1.1. Addition of α-amino organometallic compounds to boron-containing electrophiles. The ease of the lithiation of N-Boc-pyrrolidine 108 has been applied to the preparation of boroproline both in racemic⁵⁸ and enantioenriched forms⁵⁹ (Scheme 34). Treatment of 108 with sec-butyllithium in the presence of tetramethylethylenediamine (TMEDA) generated α-anionic species that efficiently reacted with trimethyl borate.^58a The resulting boroprolinate was hydrolysed during the work-up to give 109 in high yield. Diastereochemically pure 111a was produced through a sequence⁶⁰ that involved esterification of the racemic precursor 109 with (+)-pinanediol, deprotection of the amine functionality under acidic conditions, and sequential selective crystallizations of the resulting amine hydrochloride (Scheme 34). The absolute configuration of the new stereogenic center was assigned as R on the basis of X-ray diffraction analysis of 111a. Scale-up of the overall process engaged several modifications for the α-metalation step, such as avoidance of TMEDA as an additive, and improvements for recycling the chiral auxiliary that is employed as a resolving agent.^58b

Scheme 34

Alternatively, highly enantioselective syntheses of N-Boc protected boroproline have been accomplished by asymmetric directed α-metalations of 108 (Scheme 34).⁵⁹ Specifically, (−)-sparteine-mediated lithiation of 108 and subsequent treatment with triisopropyl borate yielded (S)-configured boroproline 109b with 90% ee.^59a In contrast, the use of diamine 112 for the generation of the chiral lithium–carbanion pair furnished (R)-configured boroproline 109a with 95% ee.^59b

More recently, Lai et al. described the preparation of the cis stereoisomer of 4-hydroxy-l-boroproline 115 (Scheme 35) for designing dipeptidyl peptidase IV inhibitors for the treatment of type II diabetes.⁶¹ The lithiation of pyrrolidinol 113 required the use of an additional equivalent of sec-butyllithium and to raise the temperature to −46 °C for two hours. After treatment with triisopropyl borate and hydrolytic work-up the crude mixture was esterified with (+)-pinanediol. Diastereochemically pure 115 was isolated in 35% yield by crystallization of the diastereoisomeric mixture. The stereochemistry and regiochemistry of the process were unambiguously assigned by 2D NMR of cyclic dipeptide derivatives.

Scheme 35

4.1.2. C(sp³)–H borylation reactions. Rh-catalyzed N-adjacent C(sp³)–H borylation through heterogeneous approaches were also applicable to the preparation of racemic α-aminoboronic ester derivatives with azacyclic structure (Scheme 36).²⁵ The catalytic species generated from silica-supported phosphane ligands^25a,c enabled the selective borylation of amides and ureas 116 (entries 1 and 2, respectively) under mild reaction conditions. The selectivity for ring borylation was not limited to the use of N-acyl groups as catalyst directing groups, but also to N-heterocyclic groups. In fact, pyridine worked well as a directing group for catalysts generated from silica-,^25a,c or polystyrene-supported^25b phosphane ligands and azacyclic α-aminoboronic esters were obtained from saturated cyclic amines with different ring sizes (entries 3–7).

Scheme 36

4.2. Formation of the C–N bond

4.2.1. Two-component cyclizations. In 2011, Walsh et al. reported the synthesis of boron-substituted aziridines 119 by the treatment of BPin-substituted allylic alcohols 118 with N-aminophthalimide as the nitrogen source in the presence of di(acetoxyiodo)benzene (Scheme 37).⁶² The nitrene, which is generated by the action of this oxidant, produced BPin-substituted aziridines 119 in good yields with high levels of diastereoselectivity. The nature of the solvent, the presence of a base, and the order of addition of reagents were found to have a significant influence on the reaction outcome. The syn relative stereochemistry between the aziridine ring and the hydroxyl group was confirmed by X-ray diffraction analysis of 119 (R¹ = iPr, R² = 4-MeO-Ph). The chemoselectivity attained with dyene 120 suggested the reactions being accelerated and directed by the allylic hydroxyl group.

Scheme 37

4.2.2. Intramolecular C–N cyclization. In 1990, the procedure developed by Matteson for the synthesis of α-aminoboronic acids was applied to the synthesis of racemic boroproline derivatives (Scheme 38).⁶³ The pyrrolidine ring was assembled by intramolecular C–N cyclization of a halogen-substituted α-aminoboronic ester. The latter was obtained by the treatment of 122 with LHMDS. The cyclization reaction took place by distillation of the crude N-silylated α-aminoboronic ester intermediate.

Scheme 38

This type of chain-extension methodology was later applied by Matteson and Lu to the asymmetric synthesis of 131, which is an analogue of kainic acid having cyano and boronic acid moieties in place of the two carboxylic acid groups (Scheme 39).⁶⁴ The cyanomethyl and bis(trimethylsilyl)amino substituents were sequentially incorporated into pinanediol boronate 125. According to the authors, all of the boronic ester intermediates were produced in high diastereomeric purity, with the exception of 126. In this case, reaction of 125 with (dichloromethyl)lithium gave better yield when conducted without zinc chloride. The major isomer of the diastereomeric mixture (dr ∼ 10 : 1) was obtained by crystallization. The deprotection of the oxygen group in 128 involved the generation of a formate ester that was subsequently treated with potassium thiocyanate. The resulting hydroxyl group was mesylated under standard conditions. The pyrrolidine ring formation took place rapidly by the treatment of 129 with lithium diisopropylamide.

Scheme 39

More recently, Sun et al. reported^18b the asymmetric synthesis of 14h by copper(I)-catalyzed borylation of a chiral sulfinylimine precursor (Section 2.1.2.1, Scheme 5). The tolerance of this methodology to the presence of a chloride group in the starting sulfinylimine was further exploited for the preparation of the cyclic derivative (Scheme 40). Thus, the treatment of 14h with base led to intramolecular cyclization and gave 132 in high diastereomeric purity. Removal of the N-protecting group gave boroproline ester 111a.

Scheme 40

4.3. Intramolecular C–C bond formation

4.3.1. Ring-closing metathesis. In 2004, Carboni et al. reported ruthenium catalyzed ring-closing metathesis as the key step for the synthesis of cyclic α-aminoboronic esters 134, in racemic form (Scheme 41).⁶⁵ The Grubbs catalyst was found to be effective for six- and seven-membered ring formation from N-Boc- or N-tosylaminoboronates 133 (entries 2–5). In addition, substrates with 1,1-disubstituted double bonds gave moderate yields of cyclic α-aminoboronic esters, such as 134f, in the presence of second-generation Grubbs catalysts. Instead, five-membered ring-closing proved difficult due to the instability of the products in the presence of either catalyst, and only a moderate yield of 134a (entry 1) was obtained with catalyst C. Deprotection and hydrogenation of the double bond in 134b gave access to the boronic acid analogue of pipecolic acid.

Scheme 41

4.3.2. Tandem carbene addition/cyclopropanation. The same group⁶⁶ explored the preparation of strained bicyclic α-aminoboronic esters by reaction of 1,6- and 1,7-enynes 85 and 137 (Scheme 42) with trimethylsilyldiazomethane in the presence of a ruthenium catalyst. The carbene addition/cyclopropanation sequence took place under mild conditions and furnished racemic 136 and 138 in good yields. The major isomer exhibited a cis configuration of the vinyl and ester group along with high Z-stereoselectivity for the created alkenyl chain.

Scheme 42

4.4. Synthesis from aromatic heterocycles

In 1993, Kelly et al. reported an efficient route for the preparation of multigram quantities of racemic N-Boc protected boroproline 109 (Scheme 43), that was resolved as previously described (Scheme 34 in Section 4.1.1).⁶⁰ The synthetic procedure involved the lithiation–borylation–reduction of N-Boc protected pyrrole 139.^58a,60,67 Treatment of the latter with lithium tetramethylpiperidide (LTMP) generated the α-anion that reacted with triethylborate. Hydrolytic work-up produced free boronic acid 140 that was readily hydrogenated by using Pt/C as a catalyst.

Scheme 43

5. Concluding remarks

In this review we have tried to provide a general perspective of methodologies for the preparation of α-aminoboronic acid derivatives in either racemic or enantiopure form. A variety of valuable protocols have been established depending upon the acyclic, carbocyclic and azacyclic nature of the targeted structures. Among the implemented methods, the most widely-applied for the preparation of acyclic α-aminoboronic acids, Matteson's methodology, relied on the highly stereoselective chain-extension of a chiral boronic ester, followed by the addition of a nitrogen-nucleophile to the electrophilic boron atom, and stereospecific 1,2-migration of the amino function. This methodology, wherein the selection of the chiral director sets up the final stereochemistry, gave efficient access to a broad scope of highly enantioenriched α-aminoboronic acids. More recently, nucleophilic borylations of aldimines and rearrangements of chiral boronates of α-borylcarboxylic acids have delivered noteworthy contributions for the preparation of this type of compounds. On the other hand, the preparation of azacyclic analogues has largely addressed the isolation of boroproline in enantiomerically pure form, as it is part of serine protease inhibitors with important pharmacological properties. Best results were accomplished through highly enantioselective lithiation–borylation of a pyrrolidine precursor, intramolecular cyclization of α-aminoboronic esters generated by borylation of a chiral aldimine, and chemical resolution processes.

There is no doubt that the results achieved will encourage further investigations focusing on the refinement of the processes in an effort to improve the enantiomeric purity of the resulting α-aminoboronic acids. In some cases, the optical purity and absolute configuration of the final compound has not been established largely due to the limitations for their separation and analysis.

Acknowledgements

Financial support from Ministerio de Economía y Competitividad (CTQ2010-17436, CTQ2013-40855-R; FPI fellowship to P. A.) and Gobierno de Aragón – Fondo Social Europeo (research group E40) is gratefully acknowledged.

Notes and references

1. (a) R. Smoum, A. Rubinstein, V. M. Dembitsky and M. Srebnik, Chem. Rev., 2012, 112, 4156–4220; (b) B. C. Das, P. Thapa, R. Karki, C. Schinke, S. Das, S. Kambhampati, S. K. Banerjee, P. Van Veldhuizen, A. Verma, L. M. Weiss and T. Evans, Future Med. Chem., 2013, 5, 653–676.
2. The prefix “boro” in L-boroleucine, also abbreviated as L-boroLeu, indicates that the carboxyl group of the amino acid residue is replaced by B(OH)₂.
3. (a) M. Groll, C. R. Berkers, H. L. Ploegh and H. Ovaa, Structure, 2006, 14, 451–456; (b) D. Chen, M. Frezza, S. Schmitt, J. Kanwar and Q. P. Dou, Curr. Cancer Drug Targets, 2011, 11, 239–253.
4. J. D. Ashley, J. F. Stefanick, V. A. Schroeder, M. A. Suckow, T. Kiziltepe and B. Bilgicer, J. Med. Chem., 2014, 57, 5282–5292.
5. (a) M. Gentile, M. Offidani, E. Vigna, L. Corvatta, A. G. Recchia, L. Morabito, F. Morabito and S. Gentili, Expert Opin. Invest. Drugs, 2015, 24, 1287–1298; (b) E. Gallerani, M. Zucchetti, D. Brunelli, E. Marangon, C. Noberasco, D. Hess, A. Delmonte, G. Martinelli, S. Böhm, C. Driessen, F. De Braud, S. Marsoni, R. Cereda, F. Sala, M. D'Incalci and C. Sessa, Eur. J. Cancer, 2013, 49, 290–296; (c) R. C. Roemmele and M. A. Christie, Org. Process Res. Dev., 2013, 17, 422–426.
6. S. E. Poplawski, J. H. Lai, Y. Li, Z. Jin, Y. Liu, W. Wu, Y. Wu, Y. Zhou, J. L. Sudmeier, D. G. Sanford and W. W. Bachovchin, J. Med. Chem., 2013, 56, 3467–3477.
7. (a) E. Caselli, C. Romagnoli, R. Vahabi, M. A. Taracila, R. A. Bonomo and F. Prati, J. Med. Chem., 2015, 58, 5445–5458; (b) S. J. Hecker, K. R. Reddy, M. Totrov, G. C. Hirst, O. Lomovskaya, D. C. Griffith, P. King, R. Tsivkovski, D. Sun, M. Sabet, Z. Tarazi, M. C. Clifton, K. Atkins, A. Raymond, K. T. Potts, J. Abendroth, S. H. Boyer, J. S. Loutit, E. E. Morgan, S. Durso and M. N. Dudley, J. Med. Chem., 2015, 58, 3682–3692; (c) S. G. Kurz, S. Hazra, C. R. Bethel, C. Romagnoli, E. Caselli, F. Prati, J. S. Blanchard and R. A. Bonomo, ACS Infect. Dis., 2015, 1, 234–242.
8. M. S. Frasinyuk, S. Kwiatkowski, J. M. Wagner, T. J. Evans, R. W. Reed, K. V. Korotkov and D. S. Watt, Bioorg. Med. Chem. Lett., 2014, 24, 3546–3548.
9. For α-aminoboronic-containing peptidomimetics with antimicrobial activity see: O. V. Gozhina, J. S. Svendsen and T. Lejon, J. Pept. Sci., 2014, 20, 20–24.
10. (a) T. Ohmura, T. Awano and M. Suginome, J. Am. Chem. Soc., 2010, 132, 13191–13193; (b) T. Awano, T. Ohmura and M. Suginome, J. Am. Chem. Soc., 2011, 133, 20738–20741; (c) A. W. Buesking and J. A. Ellman, Chem. Sci., 2014, 5, 1983–1987; (d) N. Hu, G. Zhao, Y. Zhang, X. Liu, G. Li and W. Tang, J. Am. Chem. Soc., 2015, 137, 6746–6749; (e) D. Wang, P. Cao, B. Wang, T. Jia, Y. Lou, M. Wang and J. Liao, Org. Lett., 2015, 17, 2420–2423; (f) G. A. Molander, J. Org. Chem., 2015, 80, 7837–7848; (g) C. Romagnoli, E. Caselli and F. Prati, Eur. J. Org. Chem., 2015, 1075–1083.
11. (a) S. R. Inglis, M. Strieker, A. M. Rydzik, A. Dessen and C. J. Schofield, Anal. Biochem., 2012, 420, 41–47; (b) S. Jin, C. Zhu, M. Li and B. Wang, Bioorg. Med. Chem. Lett., 2009, 19, 1596–1599; (c) S. Jin, C. Zhu, Y. Cheng, M. Li and B. Wang, Bioorg. Med. Chem., 2010, 18, 1449–1455.
12. For previous reviews in the subject see: (a) V. M. Dembitsky and M. Srebnik, Tetrahedron, 2003, 59, 579–593; (b) V. M. Dembitsky and M. Srebnik, in Amino Acids, Peptides and Proteins in Organic Chemistry. Modified Amino Acids, Organocatalysis and Enzymes, ed. A. B. Hughes, Wiley-VCH, Weinheim, 2009, vol. 2, pp. 145–187; (c) I. Georgiou, G. Ilyashenko and A. Whiting, Acc. Chem. Res., 2009, 42, 756–768; (d) S. Touchet, F. Carreaux, B. Carboni, A. Bouillon and J.-L. Boucher, Chem. Soc. Rev., 2011, 40, 3895–3914; (e) D. S. Matteson, J. Org. Chem., 2013, 78, 10009–10023.
13. E. S. Priestley and C. P. Decicco, Org. Lett., 2000, 2, 3095–3097.
14. A. Shibli and M. Srebnik, Eur. J. Inorg. Chem., 2006, 1686–1689.
15. J. Cid, H. Gulyás, J. J. Carbó and E. Fernández, Chem. Soc. Rev., 2012, 41, 3558–3570.
16. (a) M. A. Beenen, C. An and J. A. Ellman, J. Am. Chem. Soc., 2008, 130, 6910–6911; (b) G. Mann, K. D. John and R. T. Baker, Org. Lett., 2000, 2, 2105–2108.
17. J.-B. Xie, J. Luo, T. R. Winn, D. B. Cordes and G. Li, Beilstein J. Org. Chem., 2014, 10, 746–751.
18. (a) K. Wen, H. Wang, J. Chen, H. Zhang, X. Cui, C. Wei, E. Fan and Z. Sun, J. Org. Chem., 2013, 78, 3405–3409; (b) J. Chen, L.-Y. Chen, Y. Zheng and Z. Sun, RSC Adv., 2014, 4, 21131–21133.
19. A. W. Buesking, V. Bacauanu, I. Cai and J. A. Ellman, J. Org. Chem., 2014, 79, 3671–3677.
20. K. Wen, J. Chen, F. Gao, P. S. Bhadury, E. Fan and Z. Sun, Org. Biomol. Chem., 2013, 11, 6350–6356.
21. H. Gulyás, A. Bonet, C. Pubill-Ulldemolins, C. Solé, J. Cid and E. Fernández, Pure Appl. Chem., 2012, 84, 2219–2231.
22. C. Solé, H. Gulyás and E. Fernández, Chem. Commun., 2012, 48, 3769–3771.
23. S.-S. Zhang, Y.-S. Zhao, P. Tian and G.-Q. Lin, Synlett, 2013, 437–442.
24. K. Hong and J. P. Morken, J. Am. Chem. Soc., 2013, 135, 9252–9254.
25. (a) S. Kawamorita, T. Miyazaki, T. Iwai, H. Ohmiya and M. Sawamura, J. Am. Chem. Soc., 2012, 134, 12924–12927; (b) T. Iwai, T. Harada, K. Hara and M. Sawamura, Angew. Chem., Int. Ed., 2013, 52, 12322–12326; (c) T. Iwai, R. Murakami, T. Harada, S. Kawamorita and M. Sawamura, Adv. Synth. Catal., 2014, 356, 1563–1570.
26. D. S. Matteson and T.-C. Cheng, J. Org. Chem., 1968, 33, 3055–3060.
27. D. S. Matteson, K. M. Sadhu and G. E. Lienhard, J. Am. Chem. Soc., 1981, 103, 5241–5242.
28. (a) D. S. Matteson and D. Majumdar, J. Organomet. Chem., 1979, 170, 259–264; (b) V. J. Reddy, J. Muriithi and M. V. R. Reddy, J. Mol. Catal. A: Chem., 2007, 271, 86–88.
29. J. P. G. Versleijen, P. M. Faber, H. H. Bodewes, A. H. Braker, D. van Leusen and A. M. van Leusen, Tetrahedron Lett., 1995, 36, 2109–2112.
30. (a) K. Amssoms, S. L. Oza, E. Ravaschino, A. Yamani, A.-M. Lambeir, P. Rajan, G. Bal, J. B. Rodriguez, A. H. Fairlamb, K. Augustyns and A. Haemers, Bioorg. Med. Chem. Lett., 2002, 12, 2553–2556; (b) R. Smoum, A. Rubinstein and M. Srebnik, Bioorg. Chem., 2003, 31, 464–474; (c) G. A. Molander and M.-A. Hiebel, Org. Lett., 2010, 12, 4876–4879; (d) A. Zervosen, A. Bouillez, A. Herman, A. Amoroso, B. Joris, E. Sauvage, P. Charlier and A. Luxen, Bioorg. Med. Chem., 2012, 20, 3915–3924.
31. (a) Q. Tan, A. M. Ogawa, R. E. Painter, Y.-W. Park, K. Young and F. P. DiNinno, Bioorg. Med. Chem. Lett., 2010, 20, 2622–2624; (b) O. Eidam, C. Romagnoli, E. Caselli, K. Babaoglu, D. T. Pohlhaus, J. Karpiak, R. Bonnet, B. K. Shoichet and F. Prati, J. Med. Chem., 2010, 53, 7852–7863.
32. (a) G. A. Molander and J. Ham, Org. Lett., 2006, 8, 2031–2034; (b) S. Adachi, A. B. Cognetta 3rd, M. J. Niphakis, Z. He, A. Zajdlik, J. D. St. Denis, C. C. G. Scully, B. F. Cravatt and A. K. Yudin, Chem. Commun., 2015, 51, 3608–3611.
33. (a) D. S. Matteson and K. M. Sadhu, Organometallics, 1984, 3, 614–618; (b) C. A. Kettner and A. B. Shenvi, J. Biol. Chem., 1984, 259, 15106–15114; (c) D. H. Kinder and J. A. Katzenellenbogen, J. Med. Chem., 1985, 28, 1917–1925; (d) P. K. Jadhav and H.-W. Man, J. Org. Chem., 1996, 61, 7951–7954; (e) D. S. Matteson, R. P. Singh, C. H. Sutton, J. D. Verheyden and J.-H. Lu, Heteroat. Chem., 1997, 8, 487–494.
34. For racemic α-aminoboronic acid derivatives obtained by Matteson's procedure see: (a) K. Duncan, W. S. Faraci, D. S. Matteson and C. T. Walsh, Biochemistry, 1989, 28, 3541–3549; (b) A. Schlapbach and R. W. Hoffmann, Eur. J. Org. Chem., 2001, 323–328.
35. For enantioenriched α-aminoboronic acid derivatives obtained by Matteson's procedure see: (a) R. Martin and J. B. Jones, Tetrahedron Lett., 1995, 36, 8399–8402; (b) V. Martichonok and J. B. Jones, J. Am. Chem. Soc., 1996, 118, 950–958; (c) E. S. Priestley, I. De Lucca, B. Ghavimi, S. Erickson-Viitanen and C. P. Decicco, Bioorg. Med. Chem. Lett., 2002, 12, 3199–3202; (d) K. K. Hansen, B. Grosch, S. Greiveldinger-Poenaru and P. A. Bartlett, J. Org. Chem., 2003, 68, 8465–8470; (e) F. Morandi, E. Caselli, S. Morandi, P. J. Focia, J. Blazquez, B. K. Shoichet and F. Prati, J. Am. Chem. Soc., 2003, 125, 685–695; (f) S. Morandi, E. Caselli, A. Forni, M. Bucciarelli, G. Torre and F. Prati, Tetrahedron: Asymmetry, 2005, 16, 2918–2926; (g) J. M. Thomson, A. M. Distler, F. Prati and R. A. Bonomo, J. Biol. Chem., 2006, 281, 26734–26744; (h) S. Morandi, F. Morandi, E. Caselli, B. K. Shoichet and F. Prati, Bioorg. Med. Chem., 2008, 16, 1195–1205; (i) A. S. Ivanov, A. A. Zhalnina and S. V. Shishkov, Tetrahedron, 2009, 65, 7105–7108; (j) H. Nakamura, M. Watanabe, H. S. Ban, W. Nabeyama and A. Asai, Bioorg. Med. Chem. Lett., 2009, 19, 3220–3224; (k) T. Watanabe, I. Momose, M. Abe, H. Abe, R. Sawa, Y. Umezawa, D. Ikeda, Y. Takahashi and Y. Akamatsu, Bioorg. Med. Chem. Lett., 2009, 19, 2343–2345; (l) L. Dzhekieva, M. Rocaboy, F. Kerff, P. Charlier, E. Sauvage and R. F. Pratt, Biochemistry, 2010, 49, 6411–6419; (m) X. Li, Y.-K. Zhang, Y. Liu, C. Z. Ding, Q. Li, Y. Zhou, J. J. Plattner, S. J. Baker, X. Qian, D. Fan, L. Liao, Z.-J. Ni, G. V. White, J. E. Mordaunt, L. X. Lazarides, M. J. Slater, R. L. Jarvest, P. Thommes, M. Ellis, C. M. Edge, J. A. Hubbard, D. Somers, P. Rowland, P. Nassau, B. McDowell, T. J. Skarzynski, W. M. Kazmierski, R. M. Grimes, L. L. Wright, G. K. Smith, W. Zou, J. Wright and L. E. Pennicott, Bioorg. Med. Chem. Lett., 2010, 20, 3550–3556; (n) S. M. Drawz, M. Taracila, E. Caselli, F. Prati and R. A. Bonomo, Protein Sci., 2011, 20, 941–958; (o) E. C. Y. Woon, A. Zervosen, E. Sauvage, K. J. Simmons, M. Zivec, S. R. Inglis, C. W. G. Fishwick, S. Gobec, P. Charlier, A. Luxen and C. J. Schofield, ACS Med. Chem. Lett., 2011, 2, 219–223; (p) M. Iqbal, P. A. M. McLaughlin, D. Dunn, S. Mallya, J. Husten, M. A. Ator and S. Chatterjee, Bioorg. Med. Chem., 2012, 20, 2362–2368; (q) J. Weski, M. Meltzer, L. Spaan, T. Mönig, J. Oeljeklaus, P. Hauske, L. Vouilleme, R. Volkmer, P. Boisguerin, D. Boyd, R. Huber, M. Kaiser and M. Ehrmann, ChemBioChem, 2012, 13, 402–408; (r) M. B. Kostova, D. M. Rosen, Y. Chen, R. C. Mease and S. R. Denmeade, J. Med. Chem., 2013, 56, 4224–4235.
36. (a) D. S. Matteson, P. K. Jesthi and K. M. Sadhu, Organometallics, 1984, 3, 1284–1288; (b) I. F. Pickersgill, J. E. Bishop, C. Koellner, J.-M. Gomez, A. Geiser, R. Hett, V. Ammoscato, S. Munk, Y. Lo, F.-T. Chiu and V. R. Kulkarni, US Pat. Appl., US 20050240047, 2005.
37. (a) V. Martichonok and J. B. Jones, Bioorg. Med. Chem., 1997, 5, 679–684; (b) K. R. Shreder, M. S. Wong, S. Corral, Z. Yu, D. T. Winn, M. Wu, Y. Hu, T. Nomanbhoy, S. Alemayehu, S. R. Fuller, J. S. Rosenblum and J. W. Kozarich, Bioorg. Med. Chem. Lett., 2005, 15, 4256–4260.
38. (a) R. P. Singh and D. S. Matteson, J. Org. Chem., 2000, 65, 6650–6653; (b) D. S. Matteson, D. Maliakal and L. Fabry-Asztalos, J. Organomet. Chem., 2008, 693, 2258–2262.
39. L. Dzhekieva, S. A. Adediran and R. F. Pratt, Biochemistry, 2014, 53, 6530–6538.
40. D. S. Matteson, T. J. Michnick, R. D. Willett and C. D. Patterson, Organometallics, 1989, 8, 726–729.
41. (a) C. Lebarbier, F. Carreaux and B. Carboni, Synthesis, 1996, 1371–1374; (b) C. Lebarbier, F. Carreaux, B. Carboni and J. L. Boucher, Bioorg. Med. Chem. Lett., 1998, 8, 2573–2576.
42. (a) C. Kettner, L. Mersinger and R. Knabb, J. Biol. Chem., 1990, 265, 18289–18297; (b) G. De Nanteuil, P. Gloanec, C. Lila, B. Portevin, A. Boudon, A. Rupin and T. J. Verbeuren, Bioorg. Med. Chem., 1995, 3, 1019–1024; (c) J. Wityak, R. A. Earl, M. M. Abelman, Y. B. Bethel, B. N. Fisher, G. S. Kauffman, C. A. Kettner, P. Ma, J. L. McMillan, L. J. Mersinger, J. Pesti, M. E. Pierce, F. W. Rankin, R. J. Chorvat and P. N. Confalone, J. Org. Chem., 1995, 60, 3717–3722; (d) R. A. Galemmo Jr., J. M. Fevig, D. J. Carini, J. Cacciola, B. L. Wells, G. L. Hillyer, J. Buriak Jr., K. A. Rossi, P. F. W. Stouten, R. S. Alexander, R. Hilmer, L. Bostrom, M. M. Abelman, S.-L. Lee, P. C. Weber, C. A. Kettner, R. M. Knabb and R. R. Wexler, Bioorg. Med. Chem. Lett., 1996, 6, 2913–2918; (e) Z. Yin, S. J. Patel, W.-L. Wang, G. Wang, W.-L. Chan, K. R. R. Rao, J. Alam, D. A. Jeyaraj, X. Ngew, V. Patel, D. Beer, S. P. Lim, S. G. Vasudevan and T. H. Keller, Bioorg. Med. Chem. Lett., 2006, 16, 36–39; (f) B. A. Katz, J. Finer-Moore, R. Mortezaei, D. H. Rich and R. M. Stroud, Biochemistry, 1995, 34, 8264–8280.
43. C. S. Brosz, J. C. Calabrese, C. A. Kettner and C. A. Teleha, Tetrahedron: Asymmetry, 1997, 8, 1435–1440.
44. (a) D. S. Matteson, Tetrahedron, 1998, 54, 10555–10607; (b) S. P. Thomas, R. M. French, V. Jheengut and V. K. Aggarwal, Chem. Rec., 2009, 9, 24–39.
45. P. Mantri, D. E. Duffy and C. A. Kettner, J. Org. Chem., 1996, 61, 5690–5692.
46. (a) I. G. Smilović, E. Casas-Arcé, S. J. Roseblade, U. Nettekoven, A. Zanotti-Gerosa, M. Kovačevič and Z. Časar, Angew. Chem., Int. Ed., 2012, 51, 1014–1018; (b) I. G. Smilović and Z. Časar, Chim. Oggi, 2013, 31, 20–25; (c) S. J. Roseblade, I. G. Smilović and Z. Časar, Tetrahedron, 2014, 70, 2654–2660.
47. (a) S. Elgendy, G. Claeson, V. V. Kakkar, D. Green, G. Patel, C. A. Goodwin, J. A. Baban, M. F. Scully and J. Deadman, Tetrahedron, 1994, 50, 3803–3812; (b) S.-L. Lee, R. Alexander, A. Smallwood, R. Trievel, L. Mersinger, P. C. Weber and C. Kettner, Biochemistry, 1997, 36, 13180–13186; (c) A. V. Purandare, H. Wan, N. Laing, K. Benbatoul, W. Vaccaro and M. A. Poss, Bioorg. Med. Chem. Lett., 2004, 14, 4701–4704; (d) Y. Zhu, X. Zhao, X. Zhu, G. Wu, Y. Li, Y. Ma, Y. Yuan, J. Yang, Y. Hu, L. Ai and Q. Gao, J. Med. Chem., 2009, 52, 4192–4199; (e) S. Venkatraman, W. Wu, A. Prongay, V. Girijavallabhan and F. G. Njoroge, Bioorg. Med. Chem. Lett., 2009, 19, 180–183; (f) Y. Zhu, G. Wu, X. Zhu, Y. Ma, X. Zhao, Y. Li, Y. Yuan, J. Yang, S. Yu, F. Shao and M. Lei, J. Med. Chem., 2010, 53, 8619–8626.
48. L. Carmès, F. Carreaux, B. Carboni and J. Mortier, Tetrahedron Lett., 1998, 39, 555–556.
49. B. Zheng and M. Srebnik, Tetrahedron Lett., 1994, 35, 1145–1148.
50. S. Jagannathan, T. P. Forsyth and C. A. Kettner, J. Org. Chem., 2001, 66, 6375–6380.
51. F. Berrée, N. Gernigon, A. Hercouet, C. H. Lin and B. Carboni, Eur. J. Org. Chem., 2009, 329–333.
52. S. Touchet, F. Carreaux, G. A. Molander, B. Carboni and A. Bouillon, Adv. Synth. Catal., 2011, 353, 3391–3396.
53. B. Zheng, L. Deloux, S. Pereira, E. Skrzypczak-Jankun, B. V. Cheesman, M. Sabat and M. Srebnik, Appl. Organomet. Chem., 1996, 10, 267–278.
54. J. Pietruszka, N. Schöne, W. Frey and L. Grundl, Chem. – Eur. J., 2008, 14, 5178–5197.
55. S. Touchet, A. Macé, T. Roisnel, F. Carreaux, A. Bouillon and B. Carboni, Org. Lett., 2013, 15, 2712–2715.
56. (a) Z. He, A. Zajdlik, J. D. St. Denis, N. Assem and A. K. Yudin, J. Am. Chem. Soc., 2012, 134, 9926–9929; (b) A. Zajdlik, Z. He, J. D. St. Denis and A. K. Yudin, Synthesis, 2014, 445–454; (c) A. Zajdlik, Z. Wang, J. L. Hickey, A. Aman, A. D. Schimmer and A. K. Yudin, Angew. Chem., Int. Ed., 2013, 52, 8411–8415; (d) Z. He, A. Zajdlik and A. K. Yudin, Acc. Chem. Res., 2014, 47, 1029–1040.
57. For the synthesis of α-borylcarboxylic acids see: Z. He and A. K. Yudin, J. Am. Chem. Soc., 2011, 133, 13770–13773.
58. (a) S. J. Coutts, T. A. Kelly, R. J. Snow, C. A. Kennedy, R. W. Barton, J. Adams, D. A. Krolikowski, D. M. Freeman, S. J. Campbell, J. F. Ksiazek and W. W. Bachovchin, J. Med. Chem., 1996, 39, 2087–2094; (b) F. S. Gibson, A. K. Singh, M. C. Soumeillant, P. S. Manchand, M. Humora and D. R. Kronenthal, Org. Process Res. Dev., 2002, 6, 814–816.
59. (a) A. S. Batsanov, C. Grosjean, T. Schütz and A. Whiting, J. Org. Chem., 2007, 72, 6276–6279; (b) M. Ronsheim, N. Diep, Y. Kalyan, G. Lawton, P. Wang and M. Ouellette, PCT Int. Appl., WO2010107809, 2010.
60. T. A. Kelly, V. U. Fuchs, C. W. Perry and R. J. Snow, Tetrahedron, 1993, 49, 1009–1016.
61. W. Wu, Y. Liu, L. J. Milo Jr., Y. Shu, P. Zhao, Y. Li, I. Woznica, G. Yu, D. G. Sanford, Y. Zhou, S. E. Poplawski, B. A. Connolly, J. L. Sudmeier, W. W. Bachovchin and J. H. Lai, Bioorg. Med. Chem. Lett., 2012, 22, 5536–5540.
62. J. Hernández-Toribio, M. M. Hussain, K. Cheng, P. J. Carroll and P. J. Walsh, Org. Lett., 2011, 13, 6094–6097.
63. W. W. Bachovchin, A. G. Plaut, G. R. Flentke, M. Lynch and C. A. Kettner, J. Biol. Chem., 1990, 265, 3738–3743.
64. D. S. Matteson and J. Lu, Tetrahedron: Asymmetry, 1998, 9, 2423–2436.
65. A. Hercouet, C. Baudet and B. Carboni, Tetrahedron Lett., 2004, 45, 8749–8751.
66. C. Vovard-Le Bray, H. Klein, P. H. Dixneuf, A. Macé, F. Berrée, B. Carboni and S. Dérien, Adv. Synth. Catal., 2012, 354, 1919–1925.
67. C. Gao, B. J. Lavey, C.-H. L. Lo, A. Datta, P. Wentworth Jr. and K. D. Janda, J. Am. Chem. Soc., 1998, 120, 2211–2217.

---