Synthesis of cyclic chiral α-amino boronates by copper-catalyzed asymmetric dearomative borylation of indoles

A copper-catalyzed asymmetric dearomative borylation of indoles has been developed to furnish chiral α-amino boronate esters for the first time.

Abstract

A copper(i)-catalyzed dearomative borylation of N-alkoxycarbonyl protected indole-3-carboxylates has been developed. The boron addition in this reaction occurred regioselectively at the 2-position of indoles followed by diastereoselective protonation, affording the corresponding stable cyclic chiral α-amino boronates (2-borylindolines) in moderate to good yields with excellent diastereo- and enantioselectivities. The product 2c could be used as a versatile precursor to undergo subsequent stereoselective transformations, delivering highly functionalized 2,3,3-trisubstituted chiral indolines.

The importance of chiral α-amino boronic acid derivatives has been demonstrated in pharmaceutically useful protease inhibitors such as bortezomib,1 delanzomib,2 and ixazomib.3 In addition, their use in transition-metal-catalyzed stereospecific C–C bond forming reactions has also gained growing attention.4 Therefore, significant efforts have been devoted to the development of efficient methods to synthesize chiral α-amino boronate esters.5 Most methods rely on a diastereoselective synthesis involving a stoichiometric amount of chiral auxiliaries.6 The recently emerged transition-metal-catalyzed asymmetric borylations by Fernández, Morken, Lin, Liao, Miura, Tang, Parra and Tortosa, and our group also provide efficient methods to access a number of acyclic chiral α-amino boronate esters.7 In contrast, the direct catalytic asymmetric borylation towards cyclic chiral α-amino boronate esters remains elusive,8 although some of these molecules have shown promising bioactivities such as dipeptidyl peptidase-4 (DPP-4) inhibitors, e.g., talabostat and dutogliptin.9

Dearomatization reactions have emerged as powerful approaches to convert readily available planar aromatic compounds into a plethora of three dimensional, highly functionalized cyclic products.10 Among them, dearomative borylation involving N-heteroarenes has gained increasing attention recently as it can provide saturated or partially saturated borylated N-heterocycles that are important building blocks for the synthesis of natural and bioactive compounds. Pioneered by Hill and Suginome,11 many systems including transition-metal catalysis and organocatalysis have been developed to achieve high chemo- and regioselectivity in this area.12 The successes of most aforementioned reactions are probably due to the formation of stable N–B bonds.11b In stark contrast, only a few examples of asymmetric transformations have been documented. In 2015, the Ito group reported a copper-catalyzed asymmetric protoboration of 2-substituted indoles, delivering 3-borylindolines with high regio-, diastereo-, and enantioselectivity (Fig. 1a).13 Subsequently, they developed one-pot sequential dearomative reduction/asymmetric borylation of pyridines and quinolines.14 The reaction produced C3 borylated chiral piperidine derivatives with high diastereo- and enantioselectivity (Fig. 1a). Tang and coworkers recently reported chiral diboron templated dearomative reductive coupling of isoquinolines involving a diastereoselective concerted [3,3]-sigma rearrangement along with the formation of two N–B bonds (Fig. 1b).15 It is quite surprising that the direct asymmetric boryl addition to the carbon adjacent to the nitrogen of N-heteroarenes remains elusive although numerous examples have been shown with carbon nucleophiles.16 The lack of research probably arises from the instability of the product.14a However, the asymmetric nucleophilic addition of a boryl group at N-adjacent carbon could offer a straightforward method that leads to cyclic chiral α-amino boronate esters. Particularly, asymmetric dearomative borylation of the 2-position of 3-substituted indoles could also furnish potentially useful chiral 2,3-disubstituted indolines that may serve as key building blocks in drug discovery and natural product synthesis. In this communication, we disclose a copper(i)-catalyzed asymmetric dearomative borylation of N-alkoxycarbonyl protected indole-3-carboxylates by way of a borylcopper(i) species (Fig. 1c).17 The boron addition takes place regioselectively at the 2-position followed by diastereoselective protonation, affording a series of indoline-based cyclic chiral α-amino boronate esters (2-borylindolines) with high diastereo- and enantioselectivity. Stereospecific transformations of the C–B bond of chiral 2-borylindoline have also been demonstrated.

Fig. 1. Recent advances in asymmetric dearomative borylation of N-heteroarenes.

To test our hypothesis, we began our reaction with an indole substrate with different combinations of substituents at 1 and 3 positions. The initial results showed that in the presence of dppe/CuCl (10 mol%), NaOtBu (10 mol%) and tBuOH (2.0 equiv.), the reaction of N-alkoxycarbonyl methyl indole-3-carboxylates with bis(pinacolato)diboron (B₂pin₂) in THF at room temperature for 18 hours gave a significant amount of isolable cis-2-borylindoline whereas the other diastereomer was not stable towards purification.18 Particularly, the N-Boc methyl indole-3-carboxylate 1a gave the cis-isomer preferentially. With 1a in hand, we then turned our attention to the asymmetric version of this reaction. The reaction of 1a with B₂pin₂ in the presence of 10 mol% of the axially chiral ligand (S)-BINAP (L1) or bulky (R)-DTBM-SEGPHOS (L2) only gave a trace amount of the product (Table 1, entries 1 and 2). Fortunately, when the electron-rich ligand (R,R)-DuPhos (L3) was used, an appreciable amount of cis-product 2a was obtained with an excellent ee value (92%) albeit with almost no dia-stereoselectivity (45 : 55) (Table 1, entry 3). Encouraged by this, several electron-rich bidentate phosphines were investigated. For example, the use of (R,R)-Me-BPE resulted in a product with elevated diastereoselectivity (80 : 20) but decreased enantioselectivity (80%) compared to L3 (Table 1, entry 4). Gratifyingly, when the bulky electron-rich ligand (R,R)-QuinoxP* (L5) was used, the reaction proceeded smoothly, affording cis-2-borylindoline 2a in 90% yield with good stereoselectivity (86% ee, 92 : 8 d.r.; Table 1, entry 5). The size of R in the ester moiety also played an important role in controlling the stereoselectivity. For example, when R was ethyl (2b), an enhanced stereoselectivity was observed (91% ee, >98 : 2 d.r.; Table 1, entry 6). With the use of a substrate with R = iPr, the corresponding 2-borylindoline 2c could be obtained with 94% ee and good diastereoselectivity (94 : 6 d.r.; Table 1, entry 7). Further increasing the size of R such as tBu (2d) led to a diminished ee value (81%) and yield (72%) whereas good diastereoselectivity (97 : 3 d.r.; Table 1, entry 8) was maintained. Although the other applied alcohols such as MeOH, EtOH or iPrOH gave products with excellent enantiomeric excesses (96–97%), only moderate d.r. values (50 : 50–70 : 30) were achieved. When the reaction of 2c was carried out at 0 °C, the product was obtained with a slightly enhanced stereoselectivity (95% ee, 95 : 5 d.r.; Table 1, entry 12).

Table 1. Optimization of the reaction conditions for the asymmetric dearomative borylation ^a .

Entry	Ligand	1: R	Yield b (%)	d.r. c	ee d (%)
1	L1	1a: Me	Trace	n.d.	n.d.
2	L2	1a: Me	Trace	n.d.	n.d.
3	L3	1a: Me	44	45 : 55	92
4	L4	1a: Me	60	80 : 20	80
5	L5	1a: Me	90	92 : 8	86
6	L5	1b: Et	86	>98 : 2	91
7	L5	1c: iPr	93	94 : 6	94
8	L5	1d: tBu	72	97 : 3	81
9 e	L5	1c: iPr	46	50 : 50	96
10 f	L5	1c: iPr	55	63 : 37	97
11 g	L5	1c: iPr	56	70 : 30	97
12 h	L5	1c: iPr	85	95 : 5	95

^aUnless otherwise noted, all the reactions were carried out with 1 (0.2 mmol), L (0.02 mol), CuCl (0.02 mmol), NaOMe (0.02 mmol), alcohol (0.4 mmol), and B₂pin₂ (0.3 mmol) in toluene (1 mL) at 25 °C for 16 h.

^bThe yield of isolated cis-product 2.

^cThe diastereoselective ratio (cis/trans) was determined by ¹H NMR of crude reaction mixtures.

^dThe enantiomeric excess was determined by HPLC on a chiral IE column.

^eMeOH was used instead of tBuOH.

^fEtOH was used instead of tBuOH.

^g iPrOH was used instead of tBuOH.

^hThe reaction was carried out at 0 °C for 18 h.

With the optimized reaction conditions (Table 1, entry 12) in hand,19 we then explored the substrate scope of this reaction as illustrated in Fig. 2. Generally, the N-protecting group affected enantioselectivity significantly, with less influence on diastereoselectivity. For example, the smaller groups MeOCO and Cbz provided inferior results (78% and 68% ee, respectively; Fig. 2e and f) compared to the substrate with bulkier Boc (86% ee; Fig. 2a). The size of the ester at the 3-position of indole also played a pivotal role in chiral induction. The reaction of the substrate with R = iPr (1c) afforded corresponding cis-2-borylindoline (2c) with a superior ee value (95%) compared to those with R = Me (2a, 86% ee), Et (2b, 93% ee) and tBu (2d, 91% ee). In most cases, the reaction of N-Boc isopropyl indole-3-carboxylate 1 resulted in good yields (81–93%) with uniformly excellent stereoselectivities (92–96% ee, ≥94 : 6 d.r.). The use of an electron-withdrawing group such as F or cyano at the 5-position in 1 afforded a decreased yield (67% and 50%, respectively) and stereoselectivity (2k: 93% ee, 85 : 15 d.r.; 2m: 85% ee, 71 : 29 d.r.). Interestingly, when 7-bromo indole 1t was employed, the reaction gave trans-product 3t predominantly (cis/trans = 16 : 84) with 78% ee. The destruction of coplanarity of Boc and indole caused by steric repulsion between bromo and Boc may give rise to reversed diastereoselectivity. The proton might approach the copper O-bound enolate intermediate from the opposite side of Boc's tBu group that would be in the trans position of the boryl group, thereby leading to trans-2-borylindoline 3t as the major product. 2-Methylindole (1u) failed to yield any product (2u or 3u). The reaction of 3-cyano indole 1v could also give a cis-product in good yield with reasonable stereoselectivity (2v: 92 : 8 d.r., 73% ee). However, when the EWG was formyl or acetyl, only a labile trans-product was observed (3w and 3x). The absolute configuration of 2s was determined to be 2R, 3R by X-ray analysis.20 The configurations of the other products were provisionally assigned as the same by analogy. Because the proton at the 3 position of product 2 is relatively acidic, we tested the stability of its stereochemistry. The results of control experiments clearly show that no isomerization was observed when 2c was subjected to reaction conditions at 40 °C for 18 hours or in its CDCl₃ solution at room temperature for 24 hours (see the ESI† for more information).

Fig. 2. Substrate scope of reaction. Unless otherwise noted, all the reactions were carried out with 1 (0.2 mmol), (R,R)-QuinoxP* (0.02 mol), CuCl (0.02 mmol), NaOMe (0.02 mmol), tBuOH (0.4 mmol), and B₂pin₂ (0.3 mmol) in toluene (1 mL) at 0 °C for 18 h. The d.r. values (cis/trans) were determined by ¹H NMR of crude reaction mixtures. The enantiomeric excesses were determined by chiral HPLC. ^aThe d.r. value was determined by GC of crude reaction mixtures. ^bThe reaction time was 48 hours.

To demonstrate the practicality of our method, a gram-scale reaction and synthetic applications of 2c were performed as illustrated in Fig. 3. Firstly, the current method could be amendable to the gram-scale with reduced catalyst loading (2.5 mol%) and elevated temperature. The reaction of 1c (1.21 grams, 4.0 mmol) at room temperature for 18 hours gave corresponding 2-borylindoline 2c (1.64 grams, 3.8 mmol) in 95% yield with excellent stereoselectivity (97 : 3 d.r. and 96% ee). The acidity of the C3 proton allows further functionalization at this position. The deprotonation of 2c with LDA at –78 °C in THF followed by the addition of electrophiles afforded 2,3,3-trisubstituted 2-borylindolines 4 in good yields with good stereoselectivities.21 The C–B bond in 4a could be transformed to a C–O bond in the presence of NaBO₃. After benzoylation, the corresponding indolin-2-yl benzoate 5 was obtained in 60% overall yield (2 steps) with 95% ee. The C–B bond in 4a could also undergo stereospecific C–C bond forming reactions. For example, the reaction of 4a with vinylMgBr followed by the sequential addition of methanolic solution of I₂ and NaOMe could provide 2-vinylindoline 6 in 98% yield with 95% ee.22 In addition, the arylation of 4a with furyl-2-lithium followed by the addition of NBS was able to produce 2-(2-furyl)-indoline 7 in 40% yield with 95% ee.23

Fig. 3. Gram-scale synthesis and transformations of 2-borylindoline 2c.

The plausible reaction mechanism for the current copper(i)-catalyzed dearomative borylation of 3-substituted indoles is depicted in Fig. 4. Because the borylation only worked for indole with an EWG at its 3-position, the reaction should proceed in a similar way to the copper-catalyzed conjugate boration of α,β-unsaturated carbonyl compounds.24 The reaction of LCu-OtBu (A) with B₂pin₂ would generate active species borylcopper(i) B. The coordination of complex B to the C2–C3 π bond of indole 1c followed by the subsequent syn-addition of the Cu–B bond to the C2–C3 π bond would give C-bound enolate D. The protolytic cleavage of the copper–carbon bond of D by tBuOH would result in trans-product 3c, which is not consistent with the experimental outcome. To release large steric congestion between the Bpin group and LCu, D would isomerize into O-bound enolate E.25 To avoid the steric repulsion between the Bpin group and bulky tBuOH, the protonation of E would take place from the opposite side of Bpin to liberate cis-product 2c and A for the next catalytic cycle.

Fig. 4. Plausible reaction pathway of the current dearomative borylation.

Conclusions

In conclusion, we have developed a copper-catalyzed asymmetric dearomative borylation of N-alkoxycarbonyl protected indole-3-carboxylates under mild reaction conditions, providing a straightforward method to achieve cyclic chiral α-amino boronate esters with high diastereo- and enantioselectivity. The obtained products could undergo subsequent stereoselective transformations, affording highly functionalized 2,3,3-trisubstituted chiral indolines. This method provides not only a route to cyclic chiral α-amino boronate esters but also a series of versatile chiral precursors for chiral indoline synthesis. The further application of chiral 2-borylindolines and the development of other dearomative process are currently underway in our laboratory.

Conflicts of interest

There are no conflicts to declare.