Enantioselective synthesis of α-aminoboronates by NiH-catalysed asymmetric hydroamidation of alkenyl boronates

Chiral α-aminoboronic acids and their derivatives are generally useful as bioactive compounds and some have been approved as therapeutic agents. Here we report a NiH-catalysed asymmetric hydroamidation process that with a simple amino alcohol ligand can easily produce a wide range of highly enantioenriched α-aminoboronates from alkenyl boronates and dioxazolones under mild conditions. The reaction is proposed to proceed by an enantioselective hydrometallation followed by an inner-sphere nitrenoid transfer and C–N bond forming sequence. The synthetic utility of this transformation was demonstrated by the efficient synthesis of a current pharmaceutical agent, Vaborbactam.

Enantioenriched α-aminoboronic acids and their derivatives are privileged structural elements commonly encountered in materials science and drug discovery (Fig. 1a) 1-3 . They have also been used as synthetically useful chiral building blocks in cross-coupling chemistry 4,5 . As a result, the development of catalytic synthetic methods to efficiently and selectively prepare molecules containing such high-value motifs from simple starting materials, has been the subject of intense research. In addition to traditional chiral auxiliary approaches [6][7][8] , a number of catalytic asymmetric methods have been developed for the synthesis of α-aminoboronic acids, including borylation of aromatic aldimines [9][10][11] , hydroboration of enamides 12,13 and hydrogenation [14][15][16][17] (Fig. 1b). As an alternative, a robust CuH-catalysed hydroamination [18][19][20][21][22][23][24][25][26][27][28][29][30][31] of easily available alkenylBdan (dan, naphthalene-1,8-diaminato) substrates was recently disclosed by Hirano and Miura 29 . Subsequently, a more efficient CuH-cascade hydroboration/hydroamination catalysis using readily available alkynes as starting materials was reported by Liu and Engle 31 . Despite the elegant nature of hydroamination reactions, a further four step sequence is needed to convert the obtained tertiary amines bearing an adjacent Bdan substituent to the desired αaminoboronic acid pharmacophores and this has dramatically reduced the synthetic efficiency of the process. Consequently, the development of a complementary hydroamidation approach which could directly produce the pharmacophores -enantioenriched amides with an adjacent Bpin or B(OH) 2 group, is highly desirable.
In this work, we describe a highly enantioselective Ni-catalysed hydroamidation process enabled by a simple chiral amino alcohol ligand under exceptionally mild conditions. A wide variety of enantioenriched α-aminoboronates, a biologically active pharmacophore, were directly obtained in high yields with excellent enantioselectivities. The utility of this protocol is illustrated by the synthesis of Vaborbactam in three steps.

Reaction design and optimisation
Our initial studies focused on the enantioselective hydro-amidation of a pinacol-protected alkenylboronate (1a) using 3-phenyl-1,4,2-dioxazol-5one (2a) as an amidating reagent (Fig. 2). We found that NiCl 2 •6H 2 O and the chiral amino alcohol ligand (L*) with triethoxysilane could afford the desired hydroamidation product (3a) in 71% isolated yield with 95% ee (entry 1). Other nickel sources such as NiCl 2 •dme (dme = dimethoxyethane) led to lower yields and ee (entry 2). Other ligands (L1-L6) also gave significantly lower yields and ee (entries 3-8). Dimethoxy(methyl) silane was shown to be a less effective silane (entry 9). Addition of a catalytic amount of an iodide salt was found to improve the yield (entry 10) and LiI was proved to be the best additive (entry 11). Currently, the exact role of LiI is still under investigation. Inclusion of an extra proton source improved both the yield and the ee (entry 12), but alcohol was less effective than H 2 O (entry 13). Through DFT calculation, Chang, Seo and coworkers have demonstrated that the transmetalation between Ni-enamido complex and hydrosilane is thermodynamically unfavorable, and the addition of H 2 O could provide thermodynamic driving force for this step by an irreversible Si-O bond formation 60 . Similarly, with other solvents, the reaction proceeded less efficiently (entry 14). Notably, the E,Z-configuration of alkenyl boronates has a significant effect on the ee of the products. For example, a diminished ee was observed when (Z)-1a was used (entry 15). Notably, the reaction is insensitive to air (entry 16) and moisture (entry 17).

Application
The preparative utility of this process was highlighted by a 5 mmol scale experiment (Fig. 5a). Product 3a was obtained without notable erosion of the yield or the enantioselectivity (cf. Fig. 2, entry 1, 71% yield, 95% ee). As shown in Fig. 5b, the desired hydroamidation product (3a) could also be obtained directly from alkyne through a one-pot reaction sequence without isolating the hydroboration intermediate (1a). The synthetic utility was further demonstrated by a three-step synthesis of Vaborbactam, a β-lactamase inhibitor (Fig. 5c) 70 . The key hydroamidation of the alkenyl boronate (6), obtained through Zr-catalysed hydroboration, generated the α-aminoboronate product (7) in moderate yield (50%) with high diastereoselectivity (97:3 dr). The synthesis of target compound, Vaborbactam was completed by HClmediated deprotection.

Mechanistic investigation
A series of experiments were carried out to gain insight into the reaction mechanism. A linear correlation between the ee value of the ligand L* and that of the product 3a was observed (Fig. 6a), an observation that is consistent with the monomeric nature of the active catalyst. Since H 2 O 38 and hydrosilane could both act as a hydride source, an isotopic labelling experiment was carried out using D 2 O (Fig. 6b, top). No deuterium incorporation was observed in the product (3a), eliminating the possibility of a protic reagent as the hydride source. To gain insight into the hydrometallation process, the reaction of a deuterium labeled olefin (1b-D) was evaluated (Fig. 6b, bottom). Diastereomerically pure 3b-D was obtained from this reaction, indicating that syn-hydronickellation is involved in the enantio-determining step. This conclusion is also consistent with the observation that the E,Z-configuration of alkenyl boronates has a significant effect on the ee of the products (cf. Fig. 2, entry 1 vs.  entry 15).
To further understand the subsequent amidation process, we treated dioxazolone (2a) with triphenylphosphine (PPh 3 ) under standard conditions (Fig. 6c) 60 . A nitrene transfer to the phosphine adduct, imidophosphorane was obtained, suggesting that the formation of a nickel-nitrenoid species could be one possible pathway for amidation process.
In conclusion, we are reporting development of a NiH-catalysed enantioselective hydroamidation procedure which enables the facile synthesis of a variety of enantioenriched α-aminoboronates with high potential in medicinal chemistry. With a simple chiral amino alcohol ligand as the source of chirality, a broad range of both alkenyl boronates and dioxazolone partners are suitable for this transformation. This mild and straightforward hydroamidation process has been applied to the efficient synthesis of a pharmaceutical agent.

General procedure (A) for NiH-catalysed asymmetric hydroamidation of alkenyl boronates
In a nitrogen-filled glove box, to an oven-dried 8 mL screw-cap vial equipped with a magnetic stir bar was added NiCl 2 ·6H 2 O (4.8 mg, 10 mol%), L* (8.0 mg, 12 mol%), LiI (13.4 mg, 0.10 mmol, 0.50 equiv), 1,4,2-dioxazol-5-one (0.30 mmol, 1.5 equiv) (if the olefin is a solid, it was also added at this time), and anhydrous DMA (1.0 mL, 0.20 M). The mixture was stirred for 10 min at rt, at which time alkenyl boronate (0.20 mmol, 1.0 equiv) (if the 1,4,2-dioxazol-5-one is a liquid, it was added at this time), H 2 O (1.8 μL, 0.10 mmol, 0.50 equiv), and (EtO) 3 SiH (92 μL, 0.50 mmol, 2.5 equiv) were added to the resulting mixture in this order. The tube was sealed with a teflon-lined screw cap, removed from the glove box and the reaction was stirred at 25°C water bath for up to 20 h (the mixture was stirred at 800 rpm). After the reaction was complete, the reaction was quenched upon the addition of H 2 O, and the mixture was extracted with Et 2 O. The organic layer was concentrated to give the crude product. n-Dodecane (20 μL) was added as an internal standard for GC analysis. The product was purified by flash column chromatography (petroleum ether/EtOAc) for each substrate. The yields reported are the average of at least two experiments, unless otherwise indicated. The enantiomeric excesses (% ee) were determined by HPLC analysis using chiral stationary phases.

Data availability
The authors declare that the main data supporting the findings of this study, including experimental procedures and compound characterization, are available within the article and its Supplementary information files, and also are available from the corresponding authors.  Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ licenses/by/4.0/.