Introduction

Axially chiral allenes play an important role in synthetic chemistry due to their unique chemical reactivity and inherent axial chirality1,2,3,4,5. These features drive advancements in asymmetric synthesis and facilitate the development of chiral catalysts, materials, and biologically active compounds6,7,8. Among these, axially chiral allenes bearing organoboron groups are of particular importance as they enable the synthesis of a wide range of enantioenriched compounds through transformations that exploit both the boron group and the allene moiety9,10,11,12,13. Recognizing the potential of these valuable synthetic intermediates, several research groups have focused their efforts on developing methods for synthesizing axially chiral allenes with organoboron groups (Fig. 1a). However, the majority of research efforts have been centered on the preparation of axially chiral allenyl borons through transition metal-catalyzed enantioselective hydroboration of 1,3-enynes14,15,16,17. In contrast, strategies for accessing axially chiral homoallenyl borons remain largely unexplored. In 2020, Xu and co-workers developed the sole method for generating axially chiral homoallenyl borons via a copper-catalyzed enantioselective protoborylation of CF3-substituted 1,3-enynes. However, this approach was limited to the exclusive formation of CF3-substituted axially chiral homoallenyl mono-boronic esters18.

Fig. 1: Axially Chiral Allenes Containing Organoboron.
figure 1

a Synthesis of axially chiral allenes bearing organoboron group. b Previously known gem-diboron compounds and remaining challenge. c Synthesis and diversifications of axially chiral α-boryl-homoallenyl boronic esters (this work). d Evaluation of reaction conditions (See the Supplementary information for details). Bpin: (pinacolato)boryl; Me: methyl; Ph: phenyl; Ac: acetyl; THF: tetrahydrofuran; Ar: aryl group; PG: protecting group.

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gem-Diboron compounds have emerged as valuable intermediates in synthetic chemistry owing to their applicability in transition metal-catalyzed19,20,21,22,23,24,25 or transition metal-free26,27,28,29 carbon−carbon bond formation reactions. Consequently, significant progress has been made in the synthesis of gem-diboron compounds containing various substituents at the α-carbon, such as alkyl19,20,21, aryl30,31,32,33,34,35, alkenyl36,37,38,39,40,41, metal42,43,44,45,46, and heteroatom47,48,49,50 groups. Despite these substantial advancements, the synthesis of gem-diborons bearing allenyl groups at the α-carbon, particularly axially chiral ones, remains a formidable challenge (Fig. 1b). Herein, we report the method for synthesizing axially chiral α-boryl-homoallenyl borons through SN2’-addition of (gem-diborylalkyl)copper species, generated in situ by transmetalation of (gem-diborylalkyl)lithiums and copper(I) halide, to chiral propargylic carbonates (Fig. 1c). The developed reaction yields axially chiral α-boryl-homoallenyl borons, a new class of diboron compounds with excellent regio- and stereospecificity. We demonstrate the versatility of these compounds by subjecting them to various stereospecific transformations, affording a wide range of axially and centrally enantioenriched molecules, thereby highlighting the potential of axially chiral α-boryl-homoallenyl borons as valuable chiral building blocks.

Results and discussion

Synthesis of α-boryl-homoallenyl boronic esters

Recently, our group devised a highly efficient technique for isolating (diborylmethyl)lithium from diborylmethane using lithium diisopropylamide (LDA) as a base43. Considering that copper-mediated SN2’-selective addition of nucleophiles to propargyl electrophiles is well-established for producing various allenes10,11,12,51,52,53,54,55, we hypothesized that the generation of (diborylmethyl)copper species through the transmetalation of (diborylmethyl)lithium with copper(I) halide could facilitate SN2’-selective addition to propargyl electrophiles, resulting in α-boryl-homoallenyl borons.

After extensive optimization studies (Fig. 1d), we found that the reaction of phenyl-(1-phenylprop-2-yn-1-yl) carbonate (1a) with isolated (diborylmethyl)lithium (2a-Li) in the presence of 1.2 equivalents of MgBr2 and CuBr•SMe2 in THF at 0 °C afforded the corresponding α-boryl-homoallenyl boronic ester (3a) with an excellent yield (95 %) and a complete SN2’-selectivity (entry 1). It should be noted that the SN2-selective product 3a’ was not detected under these reaction conditions. Control experiments revealed that product 3a was not formed in the absence of either MgBr2 or CuBr•SMe2 (entries 2 and 3). These results suggest that (diborylmethyl)magnesium bromide is initially generated through the transmetalation of 2a-Li with MgBr2. The magnesium species then undergoes an additional transmetalation with CuBr•SMe2 to produce the (diborylmethyl)copper species56,57,58,59, which subsequently reacts with 1a to yield product 3a. The yield of 3a decreased when the leaving group of the propargyl electrophile was changed from phenyl carbonate to acetate (entry 4). The use of other copper(I) salts such as CuCl and CuBr proved to be less effective than CuBr•SMe2 (entries 5 and 6). No reaction occurred when Cu(OAc)2 was used instead of CuBr•SMe2 (entry 7). Furthermore, using a catalytic amount of copper resulted in a significantly reduced the yield of 3a (entry 8).

With the optimized conditions in hand, we synthesized a variety of α-boryl-homoallenyl boronic esters to demonstrate the versatility of the developed method (Fig. 2a). In most cases, the isolated yields were generally lower than the 1H-NMR yields due to the instability of the synthesized α-boryl-homoallenyl boronic esters. To obtain the desired products in high purity, a two-step chromatographic purification process was necessary. The crude mixture was first passed through a boric acid-capped silica (B-SiO2)60 column to remove the unreacted electrophile and other impurities, followed by a short silica gel (2.5 cm) column chromatography to isolate the products. Although this two-step purification process resulted in a decrease in the isolated yields, it was crucial for ensuring the high purity of the obtained α-boryl-homoallenyl boronic esters. It is worth noting that the crude α-boryl-homoallenyl boronic esters can be directly used for further transformations without isolation (vide infra), highlighting the practicality and efficiency of the developed method.

Fig. 2: Substrate scope of α-boryl-homoallenyl boronic esters.
figure 2

a Scope of racemic allenes. b Scope of chiral allenes. The reaction was performed on 0.20 mmol scale of 1. The yield of 3 was determined by 1H NMR using CH2Br2 as an internal standard. In all cases, the isolated yields were given in parentheses. Enantiomeric ratio (er) was determined by HPLC analysis. aRuns for 3 h. bRuns at room temperature.

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Despite the challenges associated with product isolation, our method enabled the synthesis of a wide range of α-boryl-homoallenyl boronic esters, demonstrating its broad applicability. Aryl-substituted propargyl carbonates bearing various substituents at different positions of the phenyl ring (C2, C3, or C4) underwent smooth SN2’-selective addition, affording the desired products (3b-3l) in good yields. Moreover, the reaction tolerated naphthyl and thiophene-containing propargyl carbonates, delivering the corresponding the products 3m and 3n, respectively. Aliphatic propargyl carbonates also proved to be suitable substrates, furnishing the desired products 3o and 3p in moderate yields. Furthermore, a cyclohexyl-substituted propargyl carbonate afforded the product 3q in moderate yield at room temperature. Alkyl substituted gem-diborylalkanes could also be employed as competent nucleophiles, providing access to the corresponding α-boryl-homoallenyl boronic esters 3r-3t. Unfortunately, the use of an internal propargyl carbonate as an electrophile did not provided the product 3u, showing a limitation of this protocol.

Next, we sought to develop a stereospecific SN2’-addition of in situ generated (diborylalkyl)copper species to enantioenriched propargyl carbonates to synthesize axially chiral α-boryl-homoallenyl boronic esters. Gratifyingly, when (S)-phenyl-(1-phenylprop-2-yn-1-yl) carbonate [(S)-1a, >99:1 er] and 2a-Li were treated with MgBr2 and CuBr•SMe2 under the reaction conditions, the desired axially chiral α-boryl-homoallenyl boronic ester (S)-3a was obtained in good yield with high stereospecificity (98:2 er, 96% es). The absolute stereochemistry of (S)−3a was determined by converting it to a known allenyl alcohol through a two-step sequence involving the protodeboronation of one of the Bpin groups, followed by the oxidation of the resulting homoallenyl mono-boronic ester. The specific rotation value of the obtained allenyl alcohol was then compared with the reported data (See the Supplementary information for details). To further demonstrate the potential of this method, we explored the scope of chiral propargyl carbonates (Fig. 2b). Chiral propargyl carbonates bearing various substitution patterns on the aryl group were well-tolerated, furnishing products (S)−3d, (S)-3j, and (S)-3l with high efficiency and excellent stereocontrol. A naphthyl-containing chiral propargyl carbonate was successfully incorporated, delivering (S)-3m in good yield and stereospecificity. When aliphatic substituted chiral propargyl carbonate, such as (R)-phenyl (5-phenylpent-1-yn-3-yl) carbonate, was reacted with 2a-Li under the reaction conditions, the product (S)-3o was obtained in good yield, albeit with moderate stereospecificity (58% es). Moreover, the reaction conditions proved compatible with in situ generated (gem-diborylethyl)copper species, providing (S)-3r with complete retention of stereochemistry.

Stereospecific 1,3-Dienylation with Aldehydes and N-H Aldimines

Enantioenriched cyclic boronic esters are important structural motifs found in a wide range of natural products and pharmaceutically relevant compounds (Fig. 3a)61,62. As a result, the development of efficient methods for their synthesis has been a subject of intense research in recent years. Thus, we directed our attention towards developing a reaction that would enable the addition of the axially chiral α-boryl-homoallenyl boronic ester (S)-3a to various aldehydes through a chemoselective and stereospecific process, yielding the corresponding enantioenriched 1,2-oxaborinin-3,5-dienes63,64,65,66. Due to the low yields obtained during the isolation of the axially chiral α-boryl-homoallenyl boronic esters, which was attributed to their partial decomposition during column chromatography, we developed a one-pot reaction by directly subjecting the crude (S)-3a to various aldehydes. We were pleased to find that the reaction of crude (S)-3a with benzaldehyde in toluene at room temperature afforded the corresponding enantioenriched 1,2-oxaborinin-3,5-diene (4a) with an excellent yield and stereospecificity. The observed stereochemical outcome of the 1,3-dienylation reaction can be rationalized by considering the Zimmerman–Traxler transition-state model (Fig. 3b)66,67, which proposes a cyclic six-membered ring transition state for the addition of allylmetal reagents to aldehydes. Although the addition of (S)-α-boryl-homoallenyl boronic esters (S)−3a to an aldehyde can potentially proceed through various transition states (See the Supplementary Information for details), we have selected four representative transition states (TS-1 to TS-4) to illustrate the key factors influencing the stereoselectivity. Among these representative transition states, TS-1 is the most favorable as it does not involve any apparent steric interactions. In contrast, TS-2 suffers from destabilizing gauche interactions between the pseudo-equatorially oriented Bpin group and the pinacol moiety on the boron group. Both TS-3 and TS-4 encounter unfavorable steric interactions between the pseudo-axially oriented phenyl group of benzaldehyde and the pinacol moiety on the boron group. Consequently, the reaction proceeds predominantly through TS-1, leading to the formation of the observed product 4 with high stereoselectivity.

Fig. 3: Axial-to-central chirality transfer of axially chiral α-boryl-homoallenyl boronic esters.
figure 3

a Selected examples of biologically active molecules containing enantioenriched cyclic boronic esters. b Transition-state analyses. c Scope of stereospecific addition of (S)-3 to aldehydes. The reaction was performed on 0.10 mmol scale of aldehyde. In all cases, the isolated yields were given. Enantiomeric ratio (er) was determined by HPLC analysis.

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The reactions of (S)−3a with various aromatic aldehydes bearing substituents at the para-, meta-, and ortho-positions of the arene ring afforded the corresponding products 4b-4g with excellent yields and stereospecificity (Fig. 3c). When 2-naphthaldehyde was subjected to the 1,3-dienylation conditions, the product 4h was successfully produced. Moreover, an aliphatic aldehyde such as hydrocinnamaldehyde was also a suitable substrate, yielding 4i efficiently. Axially chiral α-boryl-homoallenyl boronic esters (S)-3d, (S)-3j, and (S)-3m were readily reacted with benzaldehyde to give access to the products 4j-4l.

We next focused on developing a chemo- and stereospecific addition of crude axially chiral α-boryl-homoallenyl boronic esters to N-H aldimines. Enantioenriched 2-aminomethyl-1,3-dienes are valuable building blocks for synthesizing biologically active molecules; however, methods for their enantioselective synthesis are scarce. Although the addition of homoallenyl boronic esters to imines offers a promising approach to access these compounds, this transformation remains rarely investigated, and the few reported examples exhibit moderate enantioselectivity, limiting their practical utility67. To address this challenge, we sought to develop a highly chemo- and stereoselective variant of this reaction, enabling efficient access to enantioenriched 2-aminomethyl-1,3-dienes.

The reaction of (S)-3a with in-situ generated phenyl N-H aldimine from the corresponding aldehyde and ammonia in ethanol, followed by benzoyl protection to facilitate isolation, afforded the desired 2-aminomethyl-1,3-diene bearing a (Z)-vinyl Bpin group (5a) in excellent yield and stereospecificity (Fig. 4). Since no other stereoisomers were detected under the reaction conditions, this reaction was believed to proceed in the same manner as the reaction with aldehydes. Other in-situ generated N-H aldimines, derived from benzaldehyde derivatives, readily participated in the chemo- and stereospecific reaction with (S)−3a, affording 5b-5i in good yields with high stereospecificity. Cinnamaldehyde also smoothly underwent the reaction, giving 5j with moderate stereospecificity. The reaction of phenyl N-H aldimine with axially chiral α-boryl-homoallenyl boronic esters (S)−3d and (S)-3l delivered the products 5k and 5l, respectively.

Fig. 4: Scope of stereospecific addition of (S)-3 to N-H aldimines.
figure 4

The reaction was performed on 0.10 mmol scale of aldehyde. In all cases, the isolated yields were given. Enantiomeric ratio (er) was determined by HPLC analysis.

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Synthetic applications for the synthesis of centrally and axially chiral molecules

The obtained axially chiral α-boryl-homoallenyl boronic esters can be transformed into various axially chiral allenes and other chiral compounds through further modifications of the diboron unit (Fig. 5a–c). For example, oxidation of the diboron groups in (S)-3a or (S)-3r with 3-chloroperoxybenzoic acid (mCPBA) afforded the corresponding allenyl aldehyde 6 (96:4 er) or allenyl ketone 7 (97:3 er) while retaining axial chirality68. Chemoselective protodeboronation of (S)-3a yielded the axially mono-boron compound with excellent regioselectivity, which was further transformed into alkylboronic ester 8 (97:3 er) through a one-carbon homologation reaction with LiCH2Cl. Oxidation of the homoallenyl mono-boron compound with H2O2 gave the corresponding alcohol 9 (98:2 er)69, which underwent intramolecular bromocyclization in the presence of bromine to form 3-bromo-2-phenyl-2,5-dihydrofuran 10. Subsequent Pd-catalyzed cross-coupling of 10 with p-anisylboronic acid delivered the compound 11 (96:4 er).

Fig. 5: Diversification to access various enantioenriched molecules.
figure 5

a Synthesis of axially chiral allenyl aldehyde and ketone. b Regio- and chemoselective protodeboronation and subsequent one carbon homologation of (S)−3a. c Synthesis of enantioenriched 2,5-dihydrofuran through regio- and chemoselective protodeboronation, oxidation of Bpin, bromo cyclization and palladium-catalyzed cross-coupling. d Gram-scale synthesis of 4a and its further manipulations. e Synthesis of enantioenriched 1,4-aminoalcohol through oxidation of Bpin and reduction.

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To showcase the scalability and practical value of our methodology, we performed a gram-scale synthesis of compound 4a (Fig. 5d). Under the optimized reaction conditions, 2a-Li and (S)-1a were converted to (S)-3a, which subsequently underwent a 1,3-dienylation with 5 mmol of benzaldehyde to furnish 4a in 80% yield (1.05 g) with excellent enantioselectivity (98:2 er). The boron group of the enantioenriched product 4a can be transformed into other functionalities through further modifications. For example, Pd-catalyzed Suzuki- Miyaura cross-coupling of 4a with 4-iodoanisole yielded the product 12 in good yield with high stereoselectivities (98:2 er, 1: > 20 E/Z). Oxidation of the boron group of 4a resulted in the formation of hemiacetal, which could be further transformed into the corresponding alcohol 13 by treatment with NaBH4 in 84% yield over two steps with good stereoselectivity (98:2 er). The obtained 2-aminomethyl-1,3-diene 5a could also be transformed into other enantioenriched product. Oxidation of the Bpin group in 5a by treatment with sodium perborate generated the cyclic N,O-hemiaminal 5a’. Subsequent reduction of 5a’ with sodium borohydride afforded the enantioenriched 1,4-aminoalcohol 15 in 77% yield with 98:2 er.

In summary, we have developed the method for synthesizing axially chiral α-boryl-homoallenyl boronic esters through a regio- and stereoselective copper-mediated SN2’-type addition of (diborylalkyl)copper species to chiral propargyl electrophiles. The obtained axially chiral α-boryl-homoallenyl boronic esters exhibit high versatility, as they can be transformed into a wide range of axially chiral allenes and other chiral compounds through further modifications of the gem-diboron unit, highlighting their potential for diverse applications. Moreover, we have successfully achieved axial-to-central chirality transfer through the chemoselective and stereospecific addition of axially chiral α-boryl-homoallenyl boronic esters to aldehydes and N-H aldimines, yielding enantioenriched 1,2-oxaborinin-3,5-dienes and 2-aminomethyl-1,3-dienes. We anticipate that the developed methodologies will significantly expand the synthetic toolbox for constructing various chiral architectures. Our ongoing studies aim to develop transition metal-catalyzed chemo- and stereoselective transformations of racemic α-boryl-homoallenyl boronic esters.

Methods

General procedure for the synthesis of axially chiral α-boryl-homoallenyl boronic esters

In a nitrogen-filled glove-box, isolated gem-(diborylalkyl)lithium 2-Li (0.24 mmol, 1.2 equiv), anhydrous magnesium bromide (44.2 mg, 0.24 mmol, 1.2 equiv), copper(I) bromide-dimethyl sulfide complex (49.3 mg, 0.24 mmol, 1.2 equiv), and anhydrous THF (0.8 mL) were added to a 4.0 mL dram vial with a Teflon coated magnetic stir bar. The vial was sealed with a PTFE/silicone-lined septum cap and stirred for 30 min at room temperature. After removing from the glove box, the vial was cooled to 0 oC. To this mixture, propargyl carbonate 1 (0.2 mmol, 1.0 equiv) in anhydrous THF (0.4 mL) was slowly added at 0 oC and stirred at 0 oC for 2 h. The reaction mixture was diluted with CH2Cl2 (15 mL), quenched with saturated aqueous NH4Cl (15 mL) solution, and the aqueous layer was extracted with CH2Cl2 (15 mL x 3). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude mixture was passed through B-SiO2 (16 cm, 70 mL of n-hexane:CH2Cl2 = 1:2) to remove the remaining electrophile and other impurities. After washing that B-SiO2 with diethyl ether, the filtrate mixture which contains homoallenylic gem-diboronic ester was purified by short column chromatography on silica gel (2.5 cm, n-hexane:CH2Cl2 = 1:2) to afford the desired product.

General procedure for the chemoselective and stereospecific 1,3-dienylation of (S)−3 with aldehydes

In a nitrogen-filled glove-box, crude axially chiral α-boryl-homoallenyl boronic esters (S)−3 (synthesized by GP6 in 0.2 mmol scale) and anhydrous toluene (0.5 mL) were added to a 4.0 mL dram vial with a Teflon coated magnetic stir bar. The vial was sealed with a PTFE/silicone-lined septum cap and removed from the glove box. To this mixture, the corresponding aldehyde (0.1 mmol) was added and stirred at room temperature for 12 h. The reaction mixture was filtered through a pad of silica/MgSO4, washed with Et2O (50 mL), and concentrated under reduced pressure. The crude mixture was purified by column chromatography on silica gel to afford the desired product.

General procedure for the chemoselective and stereospecific 1,3-dienylation of (S)-3 with N-H aldimines

In a nitrogen-filled glove-box, corresponding aldehyde (0.1 mmol) and anhydrous THF (0.6 mL) were added to a 4.0 mL dram vial with a Teflon coated magnetic stir bar. The vial was sealed with a PTFE/silicone-lined septum cap and removed from the glove box. To this mixture, ammonia solution (2.0 M in EtOH, 0.06 mL, 0.12 mmol, 1.2 equiv) was added. After stirring at room temperature for 5 h, crude axially chiral α-boryl-homoallenyl boronic esters (S)-3 (synthesized by GP6 in 0.2 mmol scale) in anhydrous toluene (0.4 mL) was added. The reaction mixture was heated to 50 oC and stirred for 17 h. Upon completion, The solution was cooled to 0 oC. After adding triethylamine (27.9 μL, 0.2 mmol, 2.0 equiv) and benzoyl chloride (23.2 μL, 0.2 mmol, 2.0 equiv), the reaction mixture was heated to room temperature and stirred for 1 h. The reaction mixture was filtered through a pad of celite, washed with Et2O (50 mL), and concentrated under reduced pressure. The crude mixture was purified by column chromatography on silica gel to afford the desired product.