Axially chiral α-boryl-homoallenyl boronic esters as versatile toolbox for accessing centrally and axially chiral molecules

ABSTRACT Axially chiral allenes bearing organoboron groups are highly sought-after building blocks in organic synthesis due to their potential for generating a wide range of axially and

centrally chiral molecules. However, the existing methods for preparing axially chiral allenes containing boron group are primarily limited to the synthesis of allenyl boronic esters, and

strategies for accessing axially chiral homoallenyl boronic esters are still scarce. Here, we report the general method for synthesizing axially chiral α-boryl-homoallenyl boronic esters

through a highly regio- and stereoselective copper-mediated SN2’-addition of newly prepared (diborylalkyl)copper species to chiral propargyl electrophiles. The reaction conditions were

optimized to achieve high yields and excellent stereospecificity. The obtained products were successfully transformed into various axially chiral allenes and other chiral molecules by

transforming diboron units. The potential for axial-to-central chirality transfer of axially chiral α-boryl-homoallenyl boronic esters is also demonstrated through the stereospecific

addition to aldehydes and N-H aldimines, yielding enantioenriched 1,2-oxaborinin-3,5-dienes and 2-aminomethyl-1,3-dienes. SIMILAR CONTENT BEING VIEWED BY OTHERS ENANTIOSELECTIVE CONSTRUCTION

OF C-B AXIALLY CHIRAL ALKENYLBORONS BY NICKEL-CATALYZED RADICAL RELAYED REDUCTIVE COUPLING Article Open access 30 November 2024 SYNTHESIS OF AXIALLY CHIRAL ALKENYLBORONATES THROUGH COMBINED

COPPER- AND PALLADIUM-CATALYSED ATROPOSELECTIVE ARYLBORATION OF ALKYNES Article 05 January 2023 NI-CATALYSED ASSEMBLY OF AXIALLY CHIRAL ALKENES FROM ALKYNYL TETRACOORDINATE BORONS VIA

1,3-METALLATE SHIFT Article 05 January 2024 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. _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. 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. 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. 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 (_m_CPBA) 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). 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. DATA AVAILABILITY Experimental procedures, characterization of the compounds are available in the Supplementary

Information. Crystallographic data for the compound 5A is available in the Supplementary Information and from the Cambridge Crystallographic Data Centre (CCDC) under the reference number

2360524. The data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/. Data supporting the findings of this manuscript are also available from the authors upon request

REFERENCES * Alcaide, B., Almendros, P. & Aragoncillo, C. Exploiting [2+2] cycloaddition chemistry: achievements with allenes. _Chem. Soc. Rev._ 39, 783–816 (2010). Article  CAS  PubMed

  Google Scholar  * Krause, N. & Winter, C. Gold-Catalyzed Nucleophilic Cyclization of Functionalized Allenes: A Powerful Access to Carbo- and Heterocycles. _Chem. Rev._ 111, 1994–2009

(2011). Article  CAS  PubMed  Google Scholar  * Ye, J. & Ma, S. Palladium-Catalyzed Cyclization Reactions of Allenes in the Presence of Unsaturated Carbon-Carbon Bonds. _Acc. Chem. Res._

47, 989–1000 (2014). Article  CAS  PubMed  Google Scholar  * Neff, R. K. & Frantz, D. E. Recent applications of chiral allenes in axial-to-central chirality transfer reactions.

_Tetrahedron_ 71, 7–18 (2015). Article  CAS  Google Scholar  * Alonso, J. M., Quirós, M. T. & Muñoz, M. P. Chirality transfer in metal-catalysed intermolecular addition reactions

involving allenes. _Org. Chem. Front._ 3, 1186–1204 (2016). Article  CAS  Google Scholar  * Hoffmann-Röder, A. & Krause, N. Synthesis and Properties of Allenic Natural Products and

Pharmaceuticals. _Angew. Chem., Int. Ed._ 43, 1196–1216 (2004). Article  Google Scholar  * Rivera-Fuentes, P. & Diederich, F. Allenes in Molecular Materials. _Angew. Chem., Int. Ed._ 51,

2818–2828 (2012). Article  CAS  Google Scholar  * Yu, S. & Ma, S. Allenes in Catalytic Asymmetric Synthesis and Natural Product Syntheses. _Angew. Chem., Int. Ed._ 51, 3074–3112 (2012).

Article  CAS  Google Scholar  * Shimizu, M., Kurahashi, T., Kitagawa, H. & Hiyama, T. gem-Silylborylation of an sp Carbon:  Novel Synthesis of 1-Boryl-1-silylallenes. _Org. Lett._ 5,

225–227 (2003). Article  CAS  PubMed  Google Scholar  * Ito, H., Sasaki, Y. & Sawamura, M. Copper(I)-Catalyzed Substitution of Propargylic Carbonates with Diboron: Selective Synthesis of

Multisubstituted Allenylboronates. _J. Am. Chem. Soc._ 130, 15774–15775 (2008). Article  CAS  PubMed  Google Scholar  * Chen, M. & Roush, W. R. Enantioselective Synthesis of anti- and

syn-Homopropargyl Alcohols via Chiral Brønsted Acid Catalyzed Asymmetric Allenylboration Reactions. _J. Am. Chem. Soc._ 134, 10947–10952 (2012). Article  CAS  PubMed  PubMed Central  Google

Scholar  * Wang, B. et al. Cu-Catalyzed SN2′ Substitution of Propargylic Phosphates with Vinylarene-Derived Chiral Nucleophiles: Synthesis of Chiral Allenes. _Org. Lett._ 21, 3913–3917

(2019). Article  CAS  PubMed  Google Scholar  * Manna, S., Das, K. K., Aich, D. & Panda, S. Synthesis and Reactivity of Allenylboron Compounds. _Adv. Synth. Cat._ 363, 2444–2463 (2021).

Article  CAS  Google Scholar  * Matsumoto, Y., Naito, M., Uozumi, Y. & Hayashi, T. Axially chiral allenylboranes: catalytic asymmetric synthesis by palladium-catalysed hydroboration of

but-1-en-3-ynes and their reaction with an aldehyde. _J. Chem. Soc., Chem. Commun_. 1993, 1468−1469. * Gao, D.-W. et al. Catalytic, Enantioselective Synthesis of Allenyl Boronates. _ACS

Catal._ 8, 3650–3654 (2018). Article  CAS  PubMed  PubMed Central  Google Scholar  * Huang, Y., del Pozo, J., Torker, S. & Hoveyda, A. H. Enantioselective Synthesis of Trisubstituted

Allenyl–B(pin) Compounds by Phosphine–Cu-Catalyzed 1,3-Enyne Hydroboration. Insights Regarding Stereochemical Integrity of Cu–Allenyl Intermediates. _J. Am. Chem. Soc._ 140, 2643–2655

(2018). Article  CAS  PubMed  PubMed Central  Google Scholar  * Sang, H. L., Yu, S. & Ge, S. Copper-catalyzed asymmetric hydroboration of 1,3-enynes with pinacolborane to access chiral

allenylboronates. _Org. Chem. Front._ 5, 1284–1287 (2018). Article  CAS  Google Scholar  * Yang, C. et al. Catalytic Asymmetric Conjugate Protosilylation and Protoborylation of

2-Trifluoromethyl Enynes for Synthesis of Functionalized Allenes. _Org. Lett._ 22, 1360–1367 (2020). Article  CAS  PubMed  Google Scholar  * Miralles, N., Maza, R. J. & Fernández, E.

Synthesis and Reactivity of 1,1-Diborylalkanes towards C–C Bond Formation and Related Mechanisms. _Adv. Synth. Cat._ 360, 1306–1327 (2018). Article  CAS  Google Scholar  * Nallagonda, R.,

Padala, K. & Masarwa, A. gem-Diborylalkanes: recent advances in their preparation, transformation and application. _Org. Biomol. Chem._ 16, 1050–1064 (2018). Article  CAS  PubMed  Google

Scholar  * Wu, C. & Wang, J. Geminal bis(boron) compounds: Their preparation and synthetic applications. _Tetrahedron Lett._ 59, 2128–2140 (2018). Article  CAS  Google Scholar  * Corro,

M., Salvado, O., González, S., Dominguez-Molano, P. & Fernández, E. Reactivity Trends with Borylalkyl Copper(I) Species. _Eur. J. Inorg. Chem._ 2021, 2802–2813 (2021). Article  CAS 

Google Scholar  * Lee, Y., Han, S. & Cho, S. H. Catalytic Chemo- and Enantioselective Transformations of gem-Diborylalkanes and (Diborylmethyl)metallic Species. _Acc. Chem. Res._ 54,

3917–3929 (2021). Article  CAS  PubMed  Google Scholar  * Zhang, C., Hu, W. & Morken, J. P. α-Boryl Organometallic Reagents in Catalytic Asymmetric Synthesis. _ACS Catal._ 11,

10660–10680 (2021). Article  CAS  PubMed  PubMed Central  Google Scholar  * Paul, S., Das, K. K., Aich, D., Manna, S. & Panda, S. Recent developments in the asymmetric synthesis and

functionalization of symmetrical and unsymmetrical gem-diborylalkanes. _Org. Chem. Front._ 9, 838–852 (2022). Article  CAS  Google Scholar  * Kim, K. D. & Lee, J. H. Development of

Transition-Metal-Free Carbon–Carbon and Carbon-Boron Bond-Forming Reactions by Utilizing 1,1-Bis[(Pinacolato)Boryl]Alkanes. _Bull. Kor. Chem. Soc._ 39, 5–7 (2018). Article  ADS  CAS  Google

Scholar  * Cuenca, A. B. & Fernández, E. Boron-Wittig olefination with gem-bis(boryl)alkanes. _Chem. Soc. Rev._ 50, 72–86 (2021). Article  CAS  PubMed  Google Scholar  * Jo, W., Lee, J.

H. & Cho, S. H. Advances in transition metal-free deborylative transformations of gem-diborylalkanes. _Chem. Commun._ 57, 4346–4353 (2021). Article  CAS  Google Scholar  * Salvado, O.

& Fernández, E. A modular olefination reaction between aldehydes and diborylsilylmethide lithium salts. _Chem. Commun._ 57, 6300–6303 (2021). Article  CAS  Google Scholar  * Abu Ali, H.,

Goldberg, I., Kaufmann, D., Burmeister, C. & Srebnik, M. Novel C1-Bridged Bisboronate Derivatives by Insertion of Diazoalkanes into Bis(pinacolato)diborane(4). _Organometallics_ 21,

1870–1876 (2002). Article  Google Scholar  * Cho, S. H. & Hartwig, J. F. Iridium-catalyzed diborylation of benzylic C–H bonds directed by a hydrosilyl group: synthesis of

1,1-benzyldiboronate esters. _Chem. Sci._ 5, 694–698 (2014). Article  CAS  Google Scholar  * Wommack, A. J. & Kingsbury, J. S. On the scope of the Pt-catalyzed Srebnik diborylation of

diazoalkanes. An efficient approach to chiral tertiary boronic esters and alcohols via B-stabilized carbanions. _Tetrahedron Lett._ 55, 3163–3166 (2014). Article  CAS  Google Scholar  *

Palmer, W. N., Obligacion, J. V., Pappas, I. & Chirik, P. J. Cobalt-Catalyzed Benzylic Borylation: Enabling Polyborylation and Functionalization of Remote, Unactivated C(sp3)–H Bonds.

_J. Am. Chem. Soc._ 138, 766–769 (2016). Article  CAS  PubMed  Google Scholar  * Palmer, W. N., Zarate, C. & Chirik, P. J. Benzyltriboronates: Building Blocks for Diastereoselective

Carbon–Carbon Bond Formation. _J. Am. Chem. Soc._ 139, 2589–2592 (2017). Article  CAS  PubMed  PubMed Central  Google Scholar  * Lee, H., Lee, Y. & Cho, S. H. Palladium-Catalyzed

Chemoselective Negishi Cross-Coupling of Bis[(pinacolato)boryl]methylzinc Halides with Aryl (Pseudo)Halides. _Org. Lett._ 21, 5912–5916 (2019). Article  CAS  PubMed  Google Scholar  * Miura,

T., Nakahashi, J. & Murakami, M. Enantioselective Synthesis of (_E_)-δ-Boryl-Substituted anti-Homoallylic Alcohols Using Palladium and a Chiral Phosphoric Acid. _Angew. Chem., Int. Ed._

56, 6989–6993 (2017). Article  CAS  Google Scholar  * Miura, T. et al. Enantioselective Synthesis of anti-1,2-Oxaborinan-3-enes from Aldehydes and 1,1-Di(boryl)alk-3-enes Using Ruthenium

and Chiral Phosphoric Acid Catalysts. _J. Am. Chem. Soc._ 139, 10903–10908 (2017). Article  CAS  PubMed  Google Scholar  * Park, J., Choi, S., Lee, Y. & Cho, S. H. Chemo- and

Stereoselective Crotylation of Aldehydes and Cyclic Aldimines with Allylic gem-Diboronate Ester. _Org. Lett._ 19, 4054–4057 (2017). Article  CAS  PubMed  Google Scholar  * Gao, S., Chen, J.

& Chen, M. (Z)-α-Boryl-crotylboron reagents via Z-selective alkene isomerization and application to stereoselective syntheses of (E)-α-boryl-syn-homoallylic alcohols. _Chem. Sci._ 10,

3637–3642 (2019). Article  CAS  PubMed  PubMed Central  Google Scholar  * Gao, S., Duan, M., Shao, Q., Houk, K. N. & Chen, M. Development of α,α-Disubstituted Crotylboronate Reagents and

Stereoselective Crotylation via Brønsted or Lewis Acid Catalysis. _J. Am. Chem. Soc._ 142, 18355–18368 (2020). Article  CAS  PubMed  Google Scholar  * Green, J. C., Zanghi, J. M. &

Meek, S. J. Diastereo- and Enantioselective Synthesis of Homoallylic Amines Bearing Quaternary Carbon Centers. _J. Am. Chem. Soc._ 142, 1704–1709 (2020). Article  CAS  PubMed  PubMed Central

  Google Scholar  * La Cascia, E., Cuenca, A. B. & Fernández, E. Opportune gem-Silylborylation of Carbonyl Compounds: A Modular and Stereocontrolled Entry to Tetrasubstituted Olefins.

_Chem. Eur. J._ 22, 18737–18741 (2016). Article  PubMed  Google Scholar  * Lee, Y., Park, J. & Cho, S. H. Generation and Application of (Diborylmethyl)zinc(II) Species: Access to

Enantioenriched gem-Diborylalkanes by an Asymmetric Allylic Substitution. _Angew. Chem., Int. Ed._ 57, 12930–12934 (2018). Article  CAS  Google Scholar  * Kim, J. & Cho, S. H. Access to

Enantioenriched Benzylic 1,1-Silylboronate Esters by Palladium-Catalyzed Enantiotopic-Group Selective Suzuki–Miyaura Coupling of (Diborylmethyl)silanes with Aryl Iodides. _ACS Catal._ 9,

230–235 (2019). Article  CAS  Google Scholar  * Kim, J., Lee, E. & Cho, S. H. Chemoselective Palladium-Catalyzed Suzuki-Miyaura Cross-Coupling of (Diborylmethyl)silanes with Alkenyl

Bromides. _Asian J. Org. Chem._ 8, 1664–1667 (2019). Article  CAS  Google Scholar  * Shin, M. et al. Facile Synthesis of α-Boryl-Substituted Allylboronate Esters Using Stable

Bis[(pinacolato)boryl]methylzinc Reagents. _Org. Lett._ 22, 2476–2480 (2020). Article  CAS  PubMed  Google Scholar  * Han, S., Lee, Y., Jung, Y. & Cho, S. H. Stereoselective Access to

Tetra- and Tri-Substituted Fluoro- and Chloro-Borylalkenes via Boron-Wittig Reaction. _Angew. Chem., Int. Ed._ 61, e202210532 (2022). Article  CAS  Google Scholar  * Hwang, C., Lee, Y., Kim,

M., Seo, Y. & Cho, S. H. Diborylmethyl Group as a Transformable Building Block for the Diversification of Nitrogen-Containing Molecules. _Angew. Chem., Int. Ed._ 61, e202209079 (2022).

Article  ADS  CAS  Google Scholar  * Hu, J. et al. Photocatalyzed Borylcyclopropanation of Alkenes with a (Diborylmethyl)iodide Reagent. _Angew. Chem., Int. Ed._ 62, e202305175 (2023).

Article  CAS  Google Scholar  * Fang, T., Wang, L., Wu, M., Qi, X. & Liu, C. Diborodichloromethane as Versatile Reagent for Chemodivergent Synthesis of gem-Diborylalkanes. _Angew. Chem.,

Int. Ed._ 62, e202315227 (2024). Google Scholar  * Rona, P. & Crabbe, P. A novel allene synthesis. _J. Am. Chem. Soc._ 90, 4733–4734 (1968). Article  CAS  Google Scholar  * Marshall, J.

A. & Pinney, K. G. Stereoselective synthesis of 2,5-dihydrofurans by sequential SN2’ cleavage of alkynyloxiranes and silver(I)-catalyzed cyclization of the allenylcarbinol products. _J.

Org. Chem._ 58, 7180–7184 (1993). Article  CAS  Google Scholar  * Ohmiya, H., Yokobori, U., Makida, Y. & Sawamura, M. General Approach to Allenes through Copper-Catalyzed γ-Selective

and Stereospecific Coupling between Propargylic Phosphates and Alkylboranes. _Org. Lett._ 13, 6312–6315 (2011). Article  CAS  PubMed  Google Scholar  * Uehling, M. R., Marionni, S. T. &

Lalic, G. Asymmetric Synthesis of Trisubstituted Allenes: Copper-Catalyzed Alkylation and Arylation of Propargylic Phosphates. _Org. Lett._ 14, 362–365 (2012). Article  CAS  PubMed  Google

Scholar  * Skotnitzki, J. et al. Regio- and diastereoselective reactions of chiral secondary alkylcopper reagents with propargylic phosphates: preparation of chiral allenes. _Chem. Sci._ 11,

5328–5332 (2020). Article  CAS  PubMed  PubMed Central  Google Scholar  * Harutyunyan, S. R., den Hartog, T., Geurts, K., Minnaard, A. J. & Feringa, B. L. Catalytic Asymmetric Conjugate

Addition and Allylic Alkylation with Grignard Reagents. _Chem. Rev._ 108, 2824–2852 (2008). Article  CAS  PubMed  Google Scholar  * Davies, R. P. The structures of lithium and magnesium

organocuprates and related species. _Coord. Chem. Rev._ 255, 1226–1251 (2011). Article  CAS  Google Scholar  * Müller, D. S. & Marek, I. Copper mediated carbometalation reactions. _Chem.

Soc. Rev._ 45, 4552–4566 (2016). Article  PubMed  PubMed Central  Google Scholar  * Ziegler, D. S., Wei, B. & Knochel, P. Improving the Halogen–Magnesium Exchange by using New

Turbo-Grignard Reagents. _Chem. Eur. J._ 25, 2695–2703 (2019). Article  CAS  PubMed  Google Scholar  * Scaggs, W. R. & Snaddon, T. N. Enantioselective α-Allylation of Acyclic Esters

Using B(pin)-Substituted Electrophiles: Independent Regulation of Stereocontrol Elements through Cooperative Pd/Lewis Base Catalysis. _Chem. Eur. J._ 24, 14378–14381 (2018). Article  CAS 

PubMed  Google Scholar  * Luci, G., Mattioli, F., Falcone, M. & Di Paolo, A. Pharmacokinetics of Non-β-Lactam β-Lactamase Inhibitors. _Antibiotics_ 10, 769 (2021). Article  CAS  PubMed 

PubMed Central  Google Scholar  * Das, B. C. et al. Boron-Containing heterocycles as promising pharmacological agents. _Bioorg. Med. Chem._ 63, 116748 (2022). Article  CAS  PubMed  Google

Scholar  * Gridnev, I., Kanai, G., Miyaura, N. & Suzuki, A. Synthesis of pinacol esters of 2,3-alkadienylboronic acid via the copper(I) mediated coupling reaction of Knochel’s

(dialkoxyboryl)methylzinc reagents with propargylic tosylates. _J. Organomet. Chem._ 481, C4–C7 (1994). Article  CAS  Google Scholar  * Zheng, B. & Srebnik, M. Use of gem-Borazirconocene

Alkanes in the Regioselective Synthesis of.alpha.-Allenic Boronic Esters and Conversion of the Latter to Dienes and Trienes. _J. Org. Chem._ 60, 486–487 (1995). Article  CAS  Google Scholar

  * Soundararajan, R., Li, G. & Brown, H. C. Chiral Synthesis via Organoboranes. 44. Racemic and Diastereo- and Enantioselective Homoallenylboration Using Dialkyl

2,3-Butadien-1-ylboronate Reagents. Another Novel Application of the Tandem Homologation−Allylboration Strategy. _J. Org. Chem._ 61, 100–104 (1996). Article  CAS  Google Scholar  * Huang, Y.

et al. Asymmetric Synthesis of 1,3-Butadienyl-2-carbinols by the Homoallenylboration of Aldehydes with a Chiral Phosphoric Acid Catalyst. _Angew. Chem., Int. Ed._ 54, 7299–7302 (2015).

Article  CAS  Google Scholar  * Ma, W.-W., Yang, C., Xie, Q. & Xu, Y.-H. Dienylation of N-benzoylhydrazones with CF3-substituted homoallenylboronates in water. _Org. Biomol. Chem._ 20,

1386–1390 (2022). Article  CAS  PubMed  Google Scholar  * Alonso, J. M. & Almendros, P. Highlighting the Rich Chemistry of the Allenone Moiety. _Adv. Synth. Cat._ 365, 1332–1384 (2023).

Article  CAS  Google Scholar  * Alonso, J. M. & Almendros, P. Deciphering the Chameleonic Chemistry of Allenols: Breaking the Taboo of a Onetime Esoteric Functionality. _Chem. Rev._ 121,

4193–4252 (2021). Article  CAS  PubMed  PubMed Central  Google Scholar  Download references ACKNOWLEDGEMENTS This work is dedicated to Professor Sang-gi Lee (Ewha Womans University) on his

honourable retirement. This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) [NRF-2022R1A2C3004731 and RS-2023-00219859]. This

research was also supported by the Bio&Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (MSIT) [RS-2023-00274113]. This

work was supported in part by the Glocal University 30 Project (Research Center for Molecular Catalysis, POSTECH). S.H. Cho thanks Korea Toray Science Foundation for the financial support.

We thank Vom Kang and Dr. Jinrok Oh (POSTECH) for assistance with X-ray structure analysis. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Chemistry, Pohang University of

Science and Technology (POSTECH), Pohang, 37673, Republic of Korea Yonghoon Jin, Junseok Lee, Woohyun Jo, Jeongwoo Yu & Seung Hwan Cho * Institute for Convergence Research and Education

in Advanced Technology (I-CREATE), Yonsei University, Seoul, 03722, Republic of Korea Seung Hwan Cho Authors * Yonghoon Jin View author publications You can also search for this author

inPubMed Google Scholar * Junseok Lee View author publications You can also search for this author inPubMed Google Scholar * Woohyun Jo View author publications You can also search for this

author inPubMed Google Scholar * Jeongwoo Yu View author publications You can also search for this author inPubMed Google Scholar * Seung Hwan Cho View author publications You can also

search for this author inPubMed Google Scholar CONTRIBUTIONS Y. J., W.J. and S.C. conceived and designed the project. Y.J. and S.C. wrote the manuscript. Y.J., J.L., W.J. and J.Y. carried

out the experiments. S.C. organized the research. All authors analysed the data, discussed the results and commented on the manuscript. CORRESPONDING AUTHOR Correspondence to Seung Hwan Cho.

ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing interests. PEER REVIEW PEER REVIEW INFORMATION _Nature Communications_ thanks Elena Fernández, and the other,

anonymous, reviewers for their contribution to the peer review of this work. A peer review file is available. ADDITIONAL INFORMATION PUBLISHER’S NOTE Springer Nature remains neutral with

regard to jurisdictional claims in published maps and institutional affiliations. SUPPLEMENTARY INFORMATION SUPPLEMENTARY INFORMATION TRANSPARENT PEER REVIEW FILE RIGHTS AND PERMISSIONS OPEN

ACCESS This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, 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 licence, and indicate if you

modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in

this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative

Commons licence 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 licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/. Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Jin, Y., Lee, J., Jo, W. _et al._ Axially chiral

α-boryl-homoallenyl boronic esters as versatile toolbox for accessing centrally and axially chiral molecules. _Nat Commun_ 15, 9239 (2024). https://doi.org/10.1038/s41467-024-53606-6

Download citation * Received: 05 June 2024 * Accepted: 14 October 2024 * Published: 25 October 2024 * DOI: https://doi.org/10.1038/s41467-024-53606-6 SHARE THIS ARTICLE Anyone you share the

following link with will be able to read this content: Get shareable link Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided by the Springer

Nature SharedIt content-sharing initiative