# Synthesis of Chiral δ-Aminoboronic Esters by Enantioselective Hydrogenation of 1,2-Azaborines

Jiangpeng Liu, Yuping Dai, Devon Robinson, Bo Li, Karinne Miqueu, Shih-yuan Liu

► To cite this version:

Jiangpeng Liu, Yuping Dai, Devon Robinson, Bo Li, Karinne Miqueu, et al.. Synthesis of Chiral δ-Aminoboronic Esters by Enantioselective Hydrogenation of 1,2-Azaborines. Angewandte Chemie International Edition, 2025, 64 (24), pp.e202504419. 10.1002/anie.202504419. hal-05150812

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# Synthesis of Chiral δ-Aminoboronic Esters by Enantioselective Hydrogenation of 1,2-Azaborines

Jiangpeng Liu,[a] Yuping Dai,[b] Devon Robinson,[a] Bo Li,[a] Karinne Miqueu,[b]* and Shih-Yuan Liu[a,b]*

Supporting information for this article is given via a link at the end of the document.

**Abstract:** We describe herein an iridium-catalyzed highly diastereo- and enantioselective hydrogenation of 1,2-azaborines accessing δ-aminoboronic esters of potential biological importance. This method represents the first enantioselective hydrogenation of boron-containing heteroarene and features a diverse substitution pattern and wide scope. The synthetic utility of our method was demonstrated by the synthesis of (–)-Phenibut and the formal synthesis of (+)-3-PPP and Fluvirucinine A₁.

## Introduction

Boron-containing molecules have emerged as a new class of compounds acquiring increasing pharmaceutical significance in the past decade due to their unique bioactivities.[1] Particularly, aminoboronic acid derivatives currently play a significant role in drug discovery, attributed to their capacity to function as natural amino acid bioisosteres through reversible covalent interaction with hydroxyl group and non-covalent hydrogen bonding interaction in biomolecules.[1a,1e] Since the approval of the first boron-containing compound Bortezomib[2] as an anti-cancer medication by the FDA in 2003, several aminoboronic acids[3] have been investigated in drug discovery campaigns (Figure 1).

<figure><img src="image_2.png" /><figcaption>**Figure 1.** Representative bioactive aminoboronic acids.</figcaption></figure>

With the growing interest in aminoboronic acid as a pharmacophore in medicinal chemistry, the development of new methodologies accessing chiral functionalized aminoboronic acids has become increasingly attractive to organic chemists. While various catalytic systems have been successfully devised for synthesizing chiral α-,[4] β-,[4b,5] and γ-aminoboronic acid derivatives,[6] the preparation of δ-aminoboronic acids has remained

<footnote>[a] J. Liu, D. Robinson, Dr. B. Li, Prof. Dr. S.-Y. Liu*
Department of Chemistry
Boston College
2609 Beacon Street, Merkert Chemistry Center, Chestnut Hill, MA 02467, USA
E-mail: shihyuan.liu@bc.edu</footnote>

<footnote>[b] Dr. Y. Dai, Dr. K. Miqueu*
E2S UPPA/CNRS, Institut des Sciences Analytiques et de Physico-Chimie pour l'Environnement et les Matériaux IPREM UMR 5254
Université de Pau et des Pays de l'Adour, 64053 Pau Cedex 09, France
Email: karinne.miqueu@univ-pau.fr</footnote>
underdeveloped with a scarcity of precedents. The early synthesis of simple δ-aminoboronic acids was reported by Vaultier and co-workers,[7] involving a hydroboration, azidation and hydrogenative reduction sequence. In 2013, Ramachandran *et al.* accomplished the stereoselective synthesis of δ-aminoboronic esters,[8] employing allylation and hydroboration as key steps (Scheme 1a). This synthetic approach necessitated functional group manipulations, stoichiometric amounts of chiral reagents, and relied on hydroboration of the terminal alkene to incorporate the boron moiety, restricting the scope due to challenges associated with the regio- and stereoselective control for the more challenging internal alkene substrates.[6c,9] In addition to the hydroboration strategy, sporadic instances of δ-aminoboronic esters synthesized in a catalytic and enantioselective manner have been reported. In 2009, Hoveyda *et al.* achieved the catalytic and enantioselective diboration of terminal alkynes with a single example of δ-aminoboronic esters presented in their scope.[10] Recently, nickel-catalyzed C(sp³)-C(sp³) cross-coupling showcased the capability to generate α-stereogenic δ-aminoboronic esters through an α-boryl nickel-alkyl intermediate (Scheme 1b).[11] During the preparation of our manuscript, Su *et al.* reported a copper-catalyzed 1,4-borylamination of arylidenecyclopropanes, achieving high levels of regioselectivity and enantioselectivity that is however limited to a single substitution pattern.[12] Thus, the continued development of a modular, catalytic and stereoselective synthesis of diverse δ-aminoboronic esters remains of significant interest to both synthetic and medicinal chemistry community.

<figure><img src="image_3.png" /></figure>
1,2-Azaborine, a BN/CC isostere of benzene, has become an attractive molecule possessing unique properties with emerging application in material science[13] and biomedical research.[14] We have expanded the utility of readily available 1,2-azaborine to organic synthesis as a 4C+1N+1B synthon through dearomative processes, specifically [4+2] cycloaddition and photoisomerization,[15] by leveraging the selective C(sp²) functionalization toolkit.[16,17] We envisioned that functionalized 1,2-azaborines could serve as precursors to δ-aminoboronic esters via hydrogenation chemistry, enabling the efficient construction of a diverse library of chiral δ-aminoboronic esters for future drug discovery efforts. Over the past decade, significant progress has been achieved in the catalytic enantioselective hydrogenation of (hetero)arenes.[18] However, boron-containing arenes have remained an elusive class of substrates in the field. The ability of boron to modulate reactivity and enable downstream functionalization presents both challenges and unique opportunities in enantioselective synthesis.

Additionally, achieving a high level of enantioselectivity in the hydrogenation of monocyclic (hetero)arenes is inherently more difficult[18a,18d] due to arguably higher aromaticity and reduced steric differentiation. Herein, we demonstrate an iridium-catalyzed enantioselective hydrogenation of C3 and/or C5 functionalized 1,2-azaborines followed by B-N bond functionalization, providing a general access to enantioenriched δ-aminoboronic esters with broad scope and diverse substitution pattern (Scheme 1d). We also demonstrate the synthetic applicability of our method in the synthesis of (–) Phenibut and the formal synthesis of (+)-3-PPP and Fluvirucinine A1.

## Results and Discussion

To test the feasibility of the proposed transformation, we initially subjected **1aa** to Pd/C high-pressure hydrogenation conditions. Subsequent B–N bond functionalization[15a,15c] with benzoyl chloride and pinacol resulted in the observation of the desired δ-aminoboronic ester **2a**. Encouraged by this validation, we set about identifying suitable homogenous transition metal catalysts. The initial screening of a diverse array of ligands with a ruthenium catalyst system proved fruitless. Considering the electronic similarity with 1,2-azaborines, we then decided to systematically investigate catalytic systems that have been developed for the enantioselective hydrogenation of indoles[19] and pyrroles.[20] C3-*n*-propyl 1,2-azaborines with varying substituents on boron and nitrogen were subjected to screening with various catalytic systems (see the Supporting Information, Table S1), where BN substituents may substantially alter electronic properties and steric environment of 1,2-azaborines. We determined that Ru/PhTRAP ([Ru]/L2)[19c] and commercially available Ir-ThrePHOX ([Ir]-L1)[19d] catalysts exhibited promising enantioselectivity.
<figure><img src="image_4.png" /><figcaption>**Table 1.** Survey of reaction conditions.[a]</figcaption></figure>

[a] Reactions were performed on a 0.10 mmol scale. See SI for further optimization results and detailed procedures. [b] Yields were determined by ¹H NMR analysis of an unpurified reaction mixture with 2-methoxynaphthalene as the internal standard. Isolated yield is shown in parentheses. [c] Enantiomeric excesses were determined by chiral HPLC analysis. [d] Ru(2-methylallyl)₂(COD) was pre-mixed with L2 and 0.5 equiv. of Et₃N was added to the reaction mixture. [e] Under 500 psi hydrogen pressure. [f] With 2 mol% catalyst and 0.30 mmol 1af.

The results of surveying different combinations of catalysts and BN substituents are summarized in Table 1 and reveal that the hydrogenation of 1,2-azaborine **1af** bearing B-(-)-menthoxy ((-)-Men) group in CH₂Cl₂ with [Ir]-L1 (5 mol%) affords desired δ-aminoboronic ester in 89% NMR yield and 97% ee (Table 1, entry 6). The presence of menthoxy group is crucial to both high yield and enantioselectivity. The secondary menthoxy group is less sterically encumbered than the *t*-Amyl and adamantyl groups, presumably allowing for higher reactivity (entry 6 vs. entries 2 and 3). Additionally, the menthoxy group imparts suitable steric environment along the extended space, resulting in improved differentiation of prochiral faces by the chiral catalyst (entry 6 vs. entries 1 and 4). Notably, both enantiomers of menthoxy group lead to the same stereochemical outcome in the desired product, with only a minimal match/mismatch effect observed (entries 6 vs. 5), consistent with a predominantly ligand-controlled process. We also assessed the performance of the [Ru]/L2 and other iridium catalysts with structurally different P-N ligands, all of which were found to be inferior to [Ir]-L1 (entry 7 vs. entries 8-12). Hydrogenation also proceeds in toluene or under lower hydrogen pressure with a slightly lower yield while maintaining high enantioselectivity (entries 13 and 14). Further optimization showed that the catalyst loading can be lowered to 2 mol% with 78% isolated yield and 98% ee obtained (entry 15).
With the optimized conditions in hand, we first evaluated the scope of C3-alkyl substituted 1,2-azaborines using 3 mol% catalyst loading for consistency, given the slightly lower conversion observed for certain substrates (Table 2). In all cases, the desired δ-aminoboronic esters were obtained in good yield with high to excellent enantioselectivity. Substrates with ethyl, *n*-propyl, *n*-butyl and *i*-butyl group at the C3-position (entries **2a**, **2ca**, **2d**, **2e**) afforded the product with excellent ee. However, the C3-methyl substituted substrate only resulted in moderate ee (entry **2b**) presumably due to a smaller steric bias. The hydrogenated intermediate could also be trapped by 3,5-dinitrobenzoyl chloride, yielding **2cb**, and suitable crystals were obtained for X-ray crystallographic analysis. Regarding functional group compatibility, the benzyl-protected alcohol (entry **2g**) and ester (entry **2i**) remained intact after hydrogenation. Additionally, the alkyl chloride (entry **2f**) and acetal (entry **2h**) groups could also be tolerated. The absolute configuration of the product was assigned based on the X-ray crystallographic analysis of **2cb**.

Subsequently, we expanded the C3 scope to aryl substituents, where the menthoxy group resulted in almost no hydrogenation, presumably due to steric hindrance, and was therefore replaced by the smaller methoxy group (Table 3). With the [Ir]-L1 catalyst, substrates bearing phenyl (entry **4a**), para- and meta-methoxyphenyl (entries **4b**, **4c**) gave the desired product with good yield and excellent ee. The hydrogenation to furnish **4c** was carried out on a 1.2 mmol scale, demonstrating the scalability of this transformation. The hydrogenation of a C3-naphthyl substituted substate (entry **4d**) proceeded with a diminished ee. Aryls bearing electron-withdrawing substituents (entries **4e** and **4f**) exhibited a decelerated hydrogenation rate, requiring higher catalyst loading for complete conversion. Although full conversion of hydrogenation was achieved in most cases shown in Table 3, the lower yields were attributed to loss during the isolation of the labile benzylic boronic esters.

<figure><img src="image_5.png" /><figcaption>**Table 2.** Scope of C3-alkyl substituted 1,2-azaborine.[a]</figcaption></figure>

[a] Reactions were performed on a 0.30 mmol scale. All yields refer to isolated products. Enantiomeric excess was determined by chiral HPLC analysis. [b] 3,5-Dinitrobenzoyl chloride was used instead of benzoyl chloride.
<figure><img src="image_6.png" /><figcaption>**Table 3.** Scope of C3-aryl substituted 1,2-azaborine.[a]</figcaption></figure>

[a] Reactions were performed on a 0.30 mmol scale. All yields refer to isolated products. Enantiomeric excesses were determined by chiral HPLC analysis. [b] With 3 mol% catalyst. [c] With 10 mol% catalyst.

We further explored the hydrogenation of C3/C5-disubstituted 1,2-azaborines (Table 4) to simultaneously construct two stereogenic centers. Gratifyingly, good diastereo- and excellent enantioselectivity were achieved with a range of substituents (entries **6a–6f**). An increased dr was observed for the bulkier *n*-propyl group *versus* the methyl group (entry **6a** vs. entry **6b**). The single crystal X-ray diffraction analysis of product **6d** revealed the same absolute configuration at α-stereogenic center as **2cb** (Table 2), and the *cis* configuration is consistent with a substrate-controlled process during the second hydrogenation. We were pleased to find that the versatile Bpin group at the C5 position (entry **6e**) could also be tolerated with minimal deborylation observed. For the hydrogenation to yield compound **6f**, an amine intermediate **6f'** was detected by high-resolution mass spectrometry and ¹H NMR analysis when a lower catalyst loading was applied (see the Supporting Information); no other regio-isomers were detected. This observation is consistent with a stepwise hydrogenation that proceeds through successive 1,2-additions for C3,C5-disubstituted substrates, and the double bond adjacent to boron is engaging in the hydrogenation first in the enantiodetermining step.
<figure><img src="image_7.png" /><figcaption>**Table 4.** Scope of C3,C5-disubstituted 1,2-azaborine.[a]</figcaption></figure>

[a] Reactions were performed on a 0.30 mmol scale, and catalyst loadings are specified in parentheses. All yields refer to isolated products including all diastereomers. Enantiomeric excesses were determined by chiral HPLC analysis. Diastereomeric ratios were determined by ¹H NMR analysis of an unpurified reaction mixture.

We extended our investigation to also include C5-aryl-substituted 1,2-azaborines. After a brief examination of iridium catalysts, we determined that the use of [Ir]-L4 led to slightly improved enantioselectivity compared to [Ir]-L1. 1,2-Azaborines bearing phenyl, *p*-tolyl, 4-fluorophenyl and 4-chlorophenyl furnished the corresponding δ-aminoboronic esters (8aa, 8ab, 8b–8d) in excellent yield and ee. These compounds can serve as potential synthetic precursors of γ-aminobutyric acids (e.g., phenibut, Tolibut, 4-FluoroPhenibut, and Baclofen) which represent an important class of bioactive molecules.[21,22]
<figure><img src="image_8.png" /><figcaption>**Table 5.** Scope of C5-aryl substituted 1,2-azaborine.[a]</figcaption></figure>

[a] Reactions were performed on a 0.30 mmol scale. All yields refer to isolated products. Enantiomeric excesses were determined by chiral HPLC analysis. BzCl: benzoyl chloride; CbzCl: benzyl chloroformate. [b] With 4 mol% catalyst.

The chiral δ-aminoboronic esters products are synthetically versatile intermediates capable of undergoing various stereospecific transformations[23] leading to valuable biologically active molecular scaffolds. We showcase the synthetic utility of our method in the synthesis of (−) Phenibut and the formal synthesis of (+)-3-PPP and Fluvirucinine A₁ (Scheme 2). The oxidation of **8ab** with H₂O₂ gave the 1,4-amino alcohol **9**. Subsequent TEMPO-catalyzed oxidation,[24] followed by hydrogenative deprotection, yielded the anxiolytic agent (−)-Phenibut (Scheme 2a).[21] The absolute configuration of the product was assigned by comparing the optical rotation of (−)-Phenibut to literature values.[22] Additionally, the boryl group in **4c** can undergo homologation[25] and oxidation to provide 1,5-amino alcohol **11** (Scheme 2b), which was converted to the mesylate. Sequential reduction of the secondary amide[26] and cyclization resulted in piperidine **12**, a known precursor to (+)-3-PPP.[27] Lastly, under standard hydrogenation condition, the *ent*-**2ca** could be obtained in 89% yield and 94% ee using *ent*-[Ir]-**L1** (Scheme 2c). The Zweifel olefination protocol[29] allowed the installation of the vinyl group, and subsequent hydrolysis of the benzoyl group gave the key intermediate **14** toward Fluvirucinine A₁.[30,31]
<figure><img src="image_9.png" /><figcaption>**Scheme 2.** Synthetic applications.</figcaption></figure>

We performed Density Functional Theory (DFT) calculations at B3LYP-D3(BJ)/SDD+f(Ir), 6-31G** (other atoms) level of theory to identify 1,2-azaborine (*B*-menthoxy group) π-complexes with the [Ir]-L1 catalyst and determine their relative stability. The resulting π-alkene·Ir(III)-dihydrogen-dihydride complexes[32] associated with the C3-C4 double bond of the 1,2-azaborine are presumed to be key intermediates formed prior the stereochemistry-determining migratory insertion step. This docking analysis simplifies the computational effort as it avoids the need to calculate the entire reaction profile for a relatively large system. The C3-C4 double bond of the functionalized 1,2-azaborine can coordinate to the metal center in either *cis* or *trans* position relative to phosphorus atom. In addition, the Ir-catalyst can approach the 1,2-azaborine moiety from "top face" or "bottom face". Eight isomers were located on the Potential Energy Surface (PES), with relative energies ranging from 1 to 23.6 kcal/mol. The two lowest isomers for each of the faces (top and bottom, respectively), are presented in Figure 2, and the other remaining complexes are shown in the Supporting Information. It is noteworthy that bottom-face approach leads to the experimentally observed enantiomer of the δ-aminoboronic ester.

Analysis of the relative Gibbs free energies of these key alkene·Ir(III)-dihydrogen-dihydride intermediates indicates that the C3-C4 double bond of the functionalized 1,2-azaborine preferentially approaches the Ir center
trans to the PCy₂ ligand, and that the favored environment around the metal center has H₂ positioned toward the oxazolyl phenyl group. The global minimum corresponds to the bottom-face approach of the [Ir]-L1 catalyst to the C3-C4 double bond of the 1,2-azaborine, with an energy difference of 5.8 kcal/mol compared to the complex with the top-face coordination mode. The illustrated lowest-energy complex (bottom approach) minimizes the steric repulsions between the 1,2-azaborine substrate and the chiral ligand and is consistent with the experimentally observed stereochemistry. Analysis of the geometrical features of the two π-complexes (top vs. bottom approach) reveals that the C3-C4 double bond is asymmetrically coordinated to the Ir center in both cases, with shorter Ir-C3 distances compared to Ir-C4, and stronger coordination in the bottom-face approach (Ir-C3bot: 2.544 Å, Ir-C4bot: 2.719 Å) than the top-face approach (Ir-C3top: 2.564 Å, Ir-C4top: 2.785 Å). The reduced steric interaction between the 1,2-azaborine substrate and the [Ir]-L1 catalyst results in shorter bonds and should account for the preference for bottom-face coordination.

<figure><img src="image_10.png" /><figcaption>**Figure 2.** Optimized geometries for the two key alkene·Ir(III)-dihydrogen-dihydride complexes, with [Ir]-L1 catalyst and 1,2-azaborine bearing menthoxy group. [Ir]-L1 catalyst approaches the alkene from the bottom (left) and the top face (right), respectively. Relative Gibbs free energies in kcal/mol. Distances in Å. Select hydrogen atoms are omitted for clarity.</figcaption></figure>

**Conclusion**

In summary, we have developed an iridium-catalyzed diastereo- and enantioselective hydrogenation of 1,2-azaborines for the preparation of enantioenriched δ-aminoboronic esters. This reaction exhibited good functional group tolerance, a broad scope, and diverse substitution patterns. The synthetic utility of our method was demonstrated through the synthesis of (–)-Phenibut and formal syntheses of (+)-3-PPP and Fluvirucinine A₁. Computational docking analysis of geometrically optimized π-alkene·Ir(III)-dihydrogen-dihydride complexes associated with the C3-C4 double bond of the 1,2-azaborine reveal preferential binding of the Ir-metal to the bottom face of the 1,2-azaborine substrate, which is consistent with the experimentally observed stereochemistry of the δ-aminoboronic ester products.

**Supporting Information**

The authors have cited additional references within the Supporting Information.
Deposition numbers CCDC 2384173 (for **6d**) and CCDC 2384174 (for **2cb**) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

## Acknowledgements

Research reported in this publication was supported by the National Institute of General Medical Sciences of the National Institutes of Health (NIGMS) under Award Number R35GM153328. We also acknowledge the NIH-S10 (award: S10OD026910), the NSF-MRI (award: CHE-2117246) for the support of Boston College's NMR facilities, and the NIH-S10 (award: S10OD030360) for the support of Boston College's X-ray facilities. The "Direction du Numérique" of the Université de Pau et des Pays de l'Adour and the Mésocentre de Calcul Intensif Aquitain (MCIA) are acknowledged for the support of computational facilities. We thank Dr. Xinyu Yang for assistance in the preparation of BN heterocyclic building blocks and Dr. Duo-Sheng Wang and Dr. Wei Shang Lo for their helpful suggestions regarding experimental setups.

**Keywords:** enantioselective hydrogenation • iridium catalysis • boron-nitrogen heterocycle • aminoboronic ester

[1] a) S. Touchet, F. Carreaux, B. Carboni, A. Bouillon, J.-L. Boucher, *Chem. Soc. Rev.* **2011**, *40*, 3895-3914. b) S. J. Baker, J. W. Tomsho, S. J. Benkovic, *Chem. Soc. Rev.* **2011**, *40*, 4279-4285. c) R. Smoum, A. Rubinstein, V. M. Dembitsky, M. Srebnik, *Chem. Rev.* **2012**, *112*, 4156-4220. d) A. Adamczyk-Woźniak, K. M. Borys, A. Sporzyński, *Chem. Rev.* **2015**, *115*, 5224-5247. e) D. B. Diaz, A. K. Yudin, *Nat. Chem.* **2017**, *9*, 731-742. f) G. F. S. Fernandes, W. A. Denny, J. L. Dos Santos, *Eur. J. Med. Chem.* **2019**, *179*, 791-804. g) S. Song, P. Gao, L. Sun, D. Kang, J. Kongsted, V. Poongavanam, P. Zhan, X. Liu, *Acta Pharm. Sin. B* **2021**, *11*, 3035-3059. h) B. C. Das, N. K. Nandwana, S. Das, V. Nandwana, M. A. Shareef, Y. Das, M. Saito, L. M. Weiss, F. Almaguel, N. S. Hosmane, T. Evans, *Molecules* **2022**, *27*, 2615. i) R. J. Grams, W. L. Santos, I. R. Scorei, A. Abad-García, C. A. Rosenblum, A. Bita, H. Cerecetto, C. Viñas, M. A. Soriano-Ursúa, *Chem. Rev.* **2024**, *124*, 2441-2511.

[2] J. Adams, *The Oncologist* **2002**, *7*, 9-16.

[3] a) A. M. O'Farrell, A. van Vliet, K. Abou Farha, J. M. Cherrington, D. A. Campbell, X. Li, D. Hanway, J. Li, H.-P. Guler, *Clin. Ther.* **2007**, *29*, 1692-1705. b) A. S. Gorovoy, O. Gozhina, J.-S. Svendsen, G. V. Tetz, A. Domorad, V. V. Tetz, T. Lejon, *J. Pept. Sci.* **2013**, *19*, 613-618. c) A. Gzik, J. Chrzanowski, R. Blaszczyk, B. Borek, J. Olczak, A. Golebiowski, M. M. Grzybowski, P. Pomper, N. C. Güner-Chalimoniuk, K. Lisiecki, D. Kusmirek, WO 2022137156 A1, **2022**.

[4] For an overview, see: a) P. Andrés, G. Ballano, M. I. Calaza, C. Cativiela, *Chem. Soc. Rev.* **2016**, *45*, 2291-2307. b) A. Šterman, I. Sosič, S. Gobec, Z. Časar, *Org. Chem. Front.* **2019**, *6*, 2991-2998. c) W. Ming, H. S. Soor, X. Liu, A. Trofimova, A. K. Yudin, T. B. Marder, *Chem. Soc. Rev.* **2021**, *50*, 12151-12188.

[5] X. Li, D. G. Hall, *J. Am. Chem. Soc.* **2020**, *142*, 9063-9069.

[6] a) A. D. J. Calow, A. S. Batsanov, A. Pujol, C. Solé, E. Fernández, A. Whiting, *Org. Lett.* **2013**, *15*, 4810-4813. b) L. Jiang, P. Cao, M. Wang, B. Chen, B. Wang, J. Liao, *Angew. Chem. Int. Ed.* **2016**, *55*, 13854-13858. c) Y. Xi, J. F. Hartwig, *J. Am. Chem. Soc.* **2016**, *138*, 6703-6706. d) S. Zhang, J. del Pozo, F. Romiti, Y. Mu, S. Torker, A. H. Hoveyda, *Science* **2019**, *364*, 45-51. e) T. Wang, M. Wang, Y. Zheng, Q. Chen, Y. Zhao, Z. Shi, *Chem* **2023**, *9*, 130-142.

[7] a) J. M. Jego, B. Carboni, M. Vaultier, *J. Organomet. Chem.* **1992**, *435*, 1-8. b) S. Collet, P. Bauchat, R. Danion-Bougot, D. Danion, *Tetrahedron: Asymmetry* **1998**, *9*, 2121-2131.

[8] P. V. Ramachandran, W. Mitsuhashi, D. Biswas, D. R. Nicponski, *Tetrahedron Lett.* **2013**, *54*, 4830-4833.

[9] a) A. Dicko, M. Montury, M. Baboulene, *Synth. Commun.* **1988**, *18*, 459-463. b) Y. Xi, J. F. Hartwig, *J. Am. Chem. Soc.* **2016**, *138*, 6703-6706. c) H. Zhao, Q. Gao, Y. Zhang, P. Zhang, S. Xu, *Org. Lett.* **2020**, *22*, 2861-2866.

[10] Y. Lee, H. Jang, A. H. Hoveyda, *J. Am. Chem. Soc.* **2009**, *131*, 18234-18235.

[11] a) S. Bera, R. Mao, X. Hu, *Nat. Chem.* **2021**, *13*, 270-277. b) C. Sun, Y. Li, G. Yin, *Angew. Chem. Int. Ed.* **2022**, *61*, e202209076. c) Z. Li, H. Shi, X. Chen, L. Peng, Y. Li, G. Yin, *J. Am. Chem. Soc.* **2023**, *145*, 13603-13614.

[12] Y.-S. Zhu, Y.-L. Guo, Y.-Y. Zhu, B. Su, *J. Am. Chem. Soc.* **2024**, *146*, 32283-32291.
[13] For select examples involving monocyclic 1,2-azaborines, see: a) A. J. V. Marwitz, J. T. Jenkins, L. N. Zakharov, S.-Y. Liu, *Angew. Chem. Int. Ed.* **2010**, *49*, 7444–7447. b) T. Taniguchi, S. Yamaguchi, *Organometallics* **2010**, *29*, 5732–5735. c) A. J. V. Marwitz, A. N. Lamm, L. N. Zakharov, M. Vasiliu, D. A. Dixon, S.-Y. Liu, *Chem. Sci.* **2012**, *3*, 825–829. d) A. W. Baggett, F. Guo, B. Li, S.-Y. Liu, F. Jäkle, *Angew. Chem. Int. Ed.* **2015**, *54*, 11191–11195. e) H. Braunschweig, M. A. Celik, F. Hupp, I. Krummenacher, L. Mailänder, *Angew. Chem. Int. Ed.* **2015**, *54*, 6347–6351. f) W.-M. Wan, A. W. Baggett, F. Cheng, H. Lin, S.-Y. Liu, F. Jäkle, *Chem. Commun.* **2016**, *52*, 13616–13619. g) M. Chen, K. S. Unikela, R. Ramalakshmi, B. Li, C. Darrigan, A. Chrostowska, S.-Y. Liu, *Angew. Chem. Int. Ed.* **2021**, *60*, 1556–1560.

[14] a) D. H. Knack, J. L. Marshall, G. P. Harlow, A. Dudzik, M. Szaleniec, S.-Y. Liu, J. Heider, *Angew. Chem. Int. Ed.* **2013**, *52*, 2599–2601. b) H. Lee, M. Fischer, B. K. Shoichet, S.-Y. Liu, *J. Am. Chem. Soc.* **2016**, *138*, 12021–12024. c) P. Zhao, D. O. Nettleton, R. G. Karki, F. J. Zécri, S.-Y. Liu, *ChemMedChem* **2017**, *12*, 358–361. d) Y. Liu, S.-Y. Liu, *Org. Biomol. Chem.* **2019**, *17*, 7002–7006.

[15] a) R. J. Burford, B. Li, M. Vasiliu, D. A. Dixon, S.-Y. Liu, *Angew. Chem. Int. Ed.* **2015**, *54*, 7823–7827. b) K. Edel, X. Yang, J. S. A. Ishibashi, A. N. Lamm, C. Maichle-Mössmer, Z. X. Giustra, S.-Y. Liu, H. F. Bettinger, *Angew. Chem. Int. Ed.* **2018**, *57*, 5296–5300. c) Z. X. Giustra, X. Yang, M. Chen, H. F. Bettinger, S.-Y. Liu, *Angew. Chem. Int. Ed.* **2019**, *58*, 18918–18922. d) T. Ozaki, S. K. Bentley, N. Rybansky, B. Li, S.-Y. Liu, *J. Am. Chem. Soc.* **2024**, *146*, 24748–24753. e) T. Ozaki, S.-Y. Liu, *Chem. Eur. J.* **2024**, *30*, e202402544.

[16] For an overview, see: C. R. McConnell, S.-Y. Liu, *Chem. Soc. Rev.* **2019**, *48*, 3436–3453.

[17] a) A. W. Baggett, M. Vasiliu, B. Li, D. A. Dixon, S.-Y. Liu, *J. Am. Chem. Soc.* **2015**, *137*, 5536–5541. b) A. N. Brown, B. Li, S.-Y. Liu, *J. Am. Chem. Soc.* **2015**, *137*, 8932–8935. c) C. R. McConnell, F. Haeffner, A. W. Baggett, S.-Y. Liu, *J. Am. Chem. Soc.* **2019**, *141*, 9072–9078.

[18] For an overview, see: a) D.-S. Wang, Q.-A. Chen, S.-M. Lu, Y.-G. Zhou, *Chem. Rev.* **2012**, *112*, 2557–2590. b) Z. X. Giustra, J. S. A. Ishibashi, S.-Y. Liu, *Coord. Chem. Rev.* **2016**, *314*, 134–181. c) M. P. Wiesenfeldt, Z. Nairoukh, T. Dalton, F. Glorius, *Angew. Chem. Int. Ed.* **2019**, *58*, 10460–10476. d) A. N. Kim, B. M. Stoltz, *ACS Catal.* **2020**, *10*, 13834–13851.

[19] For selected examples, see: a) R. Kuwano, K. Sato, T. Kurokawa, D. Karube, Y. Ito, *J. Am. Chem. Soc.* **2000**, *122*, 7614–7615. b) R. Kuwano, K. Kaneda, T. Ito, K. Sato, T. Kurokawa, Y. Ito, *Org. Lett.* **2004**, *6*, 2213–2215. c) R. Kuwano, M. Kashiwabara, *Org. Lett.* **2006**, *8*, 2653–2655. d) A. Baeza, A. Pfaltz, *Chem. Eur. J.* **2010**, *16*, 2036–2039. e) D.-S. Wang, Q.-A. Chen, W. Li, C.-B. Yu, Y.-G. Zhou, X. Zhang, *J. Am. Chem. Soc.* **2010**, *132*, 8909–8911. f) A. M. Maj, I. Suisse, C. Méliet, F. Agbossou-Niedercorn, *Tetrahedron: Asymmetry* **2010**, *21*, 2010–2014. g) Y. Duan, L. Li, M.-W. Chen, C.-B. Yu, H.-J. Fan, Y.-G. Zhou, *J. Am. Chem. Soc.* **2014**, *136*, 7688–7700. h) T. Touge, T. Arai, *J. Am. Chem. Soc.* **2016**, *138*, 11299–11305. i) Y. Ge, Z. Wang, Z. Han, K. Ding, *Chem. Eur. J.* **2020**, *26*, 15482–15486. j) F. Zhang, H. S. Sasmal, C. G. Daniliuc, F. Glorius, *J. Am. Chem. Soc.* **2023**, *145*, 15695–15701.

[20] a) R. Kuwano, M. Kashiwabara, M. Ohsumi, H. Kusano, *J. Am. Chem. Soc.* **2008**, *130*, 808–809. b) D.-S. Wang, Z.-S. Ye, Q.-A. Chen, Y.-G. Zhou, C.-B. Yu, H.-J. Fan, Y. Duan, *J. Am. Chem. Soc.* **2011**, *133*, 8866–8869. c) K. Tian, G. Liu, X.-Q. Dong, *Chin. Chem. Lett.* **2022**, *33*, 5092–5095.

[21] I. Lapin, *CNS Drug Rev.* **2001**, *7*, 471–481.

[22] N. Langlois, N. Dahuron, H.-S. Wang, *Tetrahedron* **1996**, *52*, 15117–15126.

[23] For an overview, see: C. Sandford, V. K. Aggarwal, *Chem. Commun.* **2017**, *53*, 5481–5494.

[24] M. Zhao, J. Li, E. Mano, Z. Song, D. M. Tschaen, E. J. J. Grabowski, P. J. Reider, *J. Org. Chem.* **1999**, *64*, 2564–2566.

[25] K. Mathew. Sadhu, D. S. Matteson, *Organometallics* **1985**, *4*, 1687–1689.

[26] D. J. A. Schedler, A. G. Godfrey, B. Ganem, *Tetrahedron Lett.* **1993**, *34*, 5035–5038.

[27] a) S. B. Hellewell, W. D. Bowen, *Brain Res.* **1990**, *527*, 244–253. b) S. B. Hellewell, A. Bruce, G. Feinstein, J. Orringer, W. Williams, W. D. Bowen, *Eur. J. Pharmacol.: Mol. Pharmacol. Sect.* **1994**, *268*, 9–18.

[28] a) L. Zhou, D. W. Tay, J. Chen, G. Y. C. Leung, Y.-Y. Yeung, *Chem. Commun.* **2013**, *49*, 4412–4414. b) S.-J. Zhang, W.-W. Sun, Q.-Y. Yu, P. Cao, X.-P. Dong, B. Wu, *Tetrahedron Lett.* **2017**, *58*, 606–609.

[29] R. P. Sonawane, V. Jheengut, C. Rabalakos, R. Larouche-Gauthier, H. K. Scott, V. K. Aggarwal, *Angew. Chem. Int. Ed.* **2011**, *50*, 3760–3763.

[30] N. Naruse, O. Tenmyo, K. Kawano, K. Tomita, N. Ohgusa, T. Miyaki, M. Konishi, T. Oki, *J. Antibiot.* **1991**, *44*, 733–740.

[31] B. Liang, E. Negishi, *Org. Lett.* **2008**, *10*, 193–195.

[32] a) T. L. Church, T. Rasmussen, P. G. Andersson, *Organometallics* **2010**, *29*, 6769–6781. b) Y. Ge, Z. Wang, Z. Han, K. Ding, *Chem. Eur. J.* **2020**, *26*, 15482–15486.
Entry for the Table of Contents

<figure><img src="image_11.png" /></figure>

* First enantioselective hydrogenation of boron-containing heteroarene

* Broad scope, diverse substitution pattern and good stereoselectivity

* Ready access to pharmaceutically relevant building blocks

1,2-Azaborines serve as building blocks to enantiomerically enriched delta-aminoboronic esters through the development of the first enantioselective hydrogenation of a boron-containing heteroarene.