Enantio‐ and Regioselective Cascade Hydroboration of Methylenecyclopropanes for Facile Access to Chiral 1,3‐ and 1,4‐Bis(boronates)

Abstract Chiral 1, n‐bis(boronate) plays a crucial role in organic synthesis and medicinal chemistry. However, their catalytic and asymmetric synthesis has long posed a challenge in terms of operability and accessibility from readily available substrates. The recent discovery of the C═C bond formation through β‐C elimination of methylenecyclopropanes (MCP) has provided an exciting opportunity to enhance molecular complexity. In this study, the catalyzed asymmetric cascade hydroboration of MCP is developed. By employing different ligands, various homoallylic boronate intermediate are obtained through the hydroboration ring opening process. Subsequently, the cascade hydroboration with HBpin or B2pin2 resulted in the synthesis of enantioenriched chiral 1,3‐ and 1,4‐bis(boronates) in high yields, accompanied by excellent chemo‐ and enantioselectivities. The selective transformation of these two distinct C─B bonds also demonstrated their application potential in organic synthesis.


Introduction
Chiral 1,n-bis(boronate) compounds, known for their potential in the asymmetric construction of complex structures through selective and multiple conversions of two C-B bonds, [1] are recognized as highly versatile and valuable synthetic modules in chemical biology, material science and organic synthesis. [2]To date, transition metal-catalyzed hydroboration, diboration, hydrogenation and cross-coupling reactions have been developed for the synthesis of chiral geminal [3] and vicinal diboronates. [4]However, the efficient and straightforward approaches for preparation of chiral 1,3-and 1,4-bis(boronate) compounds are very limited, and only a few advancements have been made (Scheme 1A).Based on lithiation-borylation methodology, [5] Aggarwal and DOI: 10.1002/advs.202400096co-workers realized sparteine-ligated lithiated carbamate-promoted asymmetric homologation of optically pure 1,2-bis(boronic esters) and double homologation of diborylmethane to generate chiral 1,3-bis(boronic esters). [6]Besides, dienes were applied into the synthesis of such structures. [7]7a-c] Other alternative methods include asymmetric hydroboration/boration of designed unsaturated substrates that require prior attachment of borane groups. [8]Indeed, there is still a strong desire for the development of a practical method that is capable of constructing 1,3-or 1,4-diboronates from readily accessible starting materials, providing a more efficient and accessible route to these valuable chiral compounds in an enantio-and regioselective manner.Methylenecyclopropanes (MCPs), a type of highly versatile reagent commonly used in organic synthesis, can undergo various switchable reaction patterns through C─C bond cleavage facilitated by transition metals (Scheme 1B). [9]For example, the insertion of transition metals into proximal C2─C3 single bond or the distal C3─C4 single bond results in the formation of characteristic metallacyclobutane species. [10]While the addition of transition metal complexes to the exo C═C bond happened, the redox-neutral -C elimination occurs, leading to the generation of various ring-opening structures and the formation of new C═C bond. [11]The newly formed double bond in MCPs has the potential for further transformation, especially in asymmetric version.Nevertheless, the merger of ring-opening process and the cascade enantioselective hydrofunctionalization of MCPs, which could lead to the synthesis of complex chiral molecules with high enantioselectivity is very rare.Recently, we reported the Cu/DTBM-SegPhos-catalyzed cascade hydroamination reaction of MCPs and chiral 1,4-diamines were obtained with high efficiency. [12]n the other hand, copper-catalyzed asymmetric hydroboration of unsaturated bonds has emerged as a powerful tool for the construction of chiral organoborons, due to the mild reaction conditions, high efficiency, and the advantage of using low-cost of Cu catalysts. [13]In 2019, Engle and co-workers reported a copper-catalyzed hydroboration of benzylidenecyclopropanes with B 2 pin 2 , affording access to cyclopropylboronic esters and alkenylboronates in one step granted by BINAP and DPPE. [14]Very recently, the cobalt-catalyzed dihydroboration of arylidenecyclopropanes was disclosed by Ge group. [15]The 1,4diboronate was obtained via a homoallylic boronate intermediate and the 1,3-diboronate was derived from a diene intermediate, both in racemic form.
Based on our ongoing interests in developing asymmetric hydrofunctionalization reactions of unsaturated bonds, particularly those involving P-containing species addition reactions and cascade reactions catalyzed by transition metals, [12,16] we have made further progress in understanding the characteristic reaction patterns of MCPs.Specifically, we have discovered that the characteristic reaction pattern of MCPs involves a process of -C elimination followed by a sequential cascade hydroamination of the newly formed double bond, facilitated by Cu-H species.This discovery inspired us to explore the possibility of employing chiral copper catalyst with HBpin or B 2 Pin 2 reagents, which may enable a new type of cascade reaction of MCPs (Scheme 1C).In our investigation, we envisioned that the first hydroboration of MCPs with HBpin involves the regioselective migratory insertion of L*Cu-H and subsequent -C elimination, leading to the formation of a homoallylic boronate intermediate I.This intermedi-ate then undergoes a cascade hydroboration of the double bond, resulting in the formation of a chiral 1,4-bis(boronate) compound.The switch to the construction of chiral 1,3-bis(boronate) compounds by asymmetric hydroboration of intermediate I with B 2 pin 2 is appealing, but there are several challenges that need to be addressed to achieve the high chemo-, enantio-and regioselectivity.For instance, the suppression of over-hydroboration of intermediate I in the ring-opening process to ensure the regioselective of cascade hydroboration is necessary.Besides, controlling the highly selective formation of (E)-intermediate I via -C elimination is crucial for the cascade hydroboration with L*Cu-Bpin species.In response to this scenario, herein, we disclose a copper-catalyzed asymmetric ring-opening cascade hydroboration of MCPs driven by C─C bond cleavage, presenting a highly enantio-and regioselective access to structurally diverse and synthetically versatile chiral 1,3-and 1,4-bis(boronates).
In comparison to Cu(OAc) 2 , the use of CuCl maintained the ee value, but caused a slight drop in yield (entry 9).Besides, no increase in yield was observed by raising the reaction temperature (entry 10).
Having optimized reaction conditions in hand, a scope study of various MCP derivatives was conducted and outlined in Table 2. Generally, a range of substituents, including both electron-donating and electron-withdrawing groups at the para-, meta-, and ortho-positions on the aryl group of MCPs, were welltolerated, affording corresponding products in good to excellent yields (46−97% yields) with 90−98% ee.Notably, products 4d, 4e, 4i, and 4k were generated with >99% ees.Additionally, substrates containing other aromatic rings, such as aryl, naphthalene, and benzofuran, were also compatible in this transformation and delivered products 4n, 4o, 4p, and 4q in good yields and high level of enantioselectivies.MCPs with two or three substitutes on aryl ring could be dihydroborated to products 4r and 4s smoothly.The attempt to employ aliphatic substituted MCP was unsuccessful (see Supporting Information).Furthermore, the absolute configuration of 4a was unambiguously determined to be S by comparing with the literature. [17]ext, our attention turned toward the formation of chiral 1,3-bis(boronates), where a cascade asymmetric hydroboration of intermediate I with B 2 pin 2 was designed.To prevent overhydroboration of intermediate I during the ring-opening process of MCP, modification of reaction conditions was conducted (see Table S1, Supporting Information).Under the CuBr/L8-catalyzed condition, the int-I was obtained in 71% yield but with E/Z ratio a) Unless otherwise noted, the reaction conditions were conducted with 1 (0.1 mmol, 1.0 equiv), 2 (0.22 mmol, 2.2 equiv), Cu(OAc) 2 (5 mol %), L8 (6 mol %), tBuOK (20 mol %) in toluene 0.5 mL, rt, 36 h.Isolated yields of compounds 4; b) reacted at 40 °C for 48 h; c) 10 mol % catalyst was used and reacted for 60 h.
Table 3. Substrate scope of MCPs in synthesis of chiral 1,3-bis(boronates).a) a) Unless otherwise noted, the reaction conditions were conducted with 1 (0.12 mmol, 1.2 equiv), 2 (0.1 mmol, 1.0 equiv), CuBr (2.5 mol %), L17 (12 mol %), tBuOK (20 mol %) in toluene 0.4 mL, rt, 36 h.Then, the prepared mixture of CuBr/L10 (1/1.1, 10 mol %), tBuOK (20 mol %) in THF 0.8 mL was added, followed by the addition of 5 (0.12 mmol, 1.2 equiv). of 78/22 and no observation of over-hydroborated product.Unlike the protocol that reacted with HBpin, the formation of E/Z isomers with different configurations would complicate the construction of carbon chirality of C─B bond from addition of Cu-Bpin species to the double bond in a one-pot sequential protocol.It becomes crucial to control and obtain the highly selective (E)-int-I to ensure the next controlling of the C-B bond formation.After extensive optimization, it was found that Cu precursors, solvent and base were not the crucial factors in achieving E/Z selectivity (see Tables S1 and S2, Supporting Information).Then, various ligands were screened using CuBr as the precursor, tBuOK as the base, and toluene as the solvent.In Scheme 2, P-stereogenic ligands L5 and L10 could slightly increase the E/Z ratio of int-I, and similar results were also observed for axial ligands L13 and L14, in which isomers of int-I were obtained with E/Z ratio of 90/10 and 89/11 respectively.Monodentate lig-and L12 was also capable of facilitating the ring-opening process, but with poor selectivity.To our delight, the use of L17 enabled the generation of nearly pure (E)-int-I with an E/Z ratio of 99/1 in 87% yield.This finding provided a highly selective approach for the desired (E)-int-I.The use of THF as solvent dropped the yield to 58% while maintaining the high E/Z selectivity.The DFT calculation was conducted, and it was shown that the larger bite angle of L17, which allows a larger catalyst pocket, was considered as a major factor for the high selectivity (see Supporting Information).Subsequently, efforts toward the optimization of asymmetric hydroboration of (E)-int-I with B 2 pin 2 were made.Of note, the failure of L17 as ligand in the cascade transformation guarantees the construction of chirality (see Table S3, Supporting Information).By successfully combining the optimized reaction conditions for each step, a sequential one-pot process was achieved, in which intermediate (E)-int-I was prepared without isolated and directly subjected to the CuBr/L10 catalytic condition, leading to a generation of chiral 1,3-bis(boronate) 6a in 87% yield with 90% ee (see Table S3, Supporting Information).
With optimized reaction conditions in hands, we next focused on examining the generality of this sequential cascade protocol.As described in Table 3, various MCPs bearing with different substitutes (Me, tBu, Ph, OMe, OCF 3 , F, and Br) at orth-, meta-or para-position of the phenyl group were efficiently transformed into desired products with moderate to good yields (41-82%) and high levels of enantio-controlling (74-91% ees).Additionally, fused ring substrates (7j and 7k) and benzofuran ring (7l) were tolerated.Multi-substituted MCPs with 3,4-diF and 3,4,5-triOMe also afforded products 7m and 7n in good yields and enantioselectivities. Finally, the absolute configuration of 7a was determined to be S by comparison with the literature. [18]o further demonstrate the practical utility of this approach, cascade Cu-catalyzed dihydroboration reactions on a larger scale were performed.The product 3a was obtained in 92% yield and 96% ee in the gram-scale synthetic experiments.MCP 1a at 1.2 mmol scale in the one-pot protocol was transformed to 6a with no loss of enantioselectivity (Scheme 3a).Furthermore, we also conducted the synthetic transformations of these structurally diverse and synthetically versatile chiral 1,3-and 1,4-bis(boronates).Optically pure five-membered rings, such as tetrahydrofuran, pyrrolidine, and tetrahydrothiophene, could be easily synthesized through several convenient transformations of 3a. [19]Particularly, the presence of two C-B bonds provides extensive opportunities for modular manipulations.For instance, chiral phosphate 8 with a hydroxyl group could be furnished, and chiral 1,4-and 1,3-diphosphate 9 and 12 were modularly synthesized with good enantiocontrolling from 3a and 6a respectively.Moreover, the involvement of 3a and 6a in Pd-catalyzed Suzuki−Miyaura crosscouplings and sequential oxidation reaction led to the synthesis of chiral butanols 10, 11 with different substitutes, and chiral propanol 13 (Scheme 3b).
Several experiments were conducted to gain insights of mechanism of this cascade reaction.the int-I obtained with an E/Z ratio of 78/22, and pure (E)-int-I, were subjected to the standard conditions, product 4a was observed in 82% yield, and 93% yield with similar enantioselectivities respectively.Besides, diene 13 was prepared and subjected to Cu-catalyzed cascade hydroboration, under catalyzed by Cu(OAc) 2 /L8, a mixture of allylboronate 14 (34% yield) and 1,4-boronate 3a (44% yield) were produced with moderate regioselectivity (Scheme 4a).Furthermore, as shown in Scheme 4b, the int-I with E/Z ratio of 78/22 was subjected to the standard conditions and product 7a was observed in 38% yield, and 91% yield, which demonstrate the (Z)-int-I delayed the cascade transformation.Also, only trace amount of 7a was observed when (Z)-int-I was employed in standard condition.Additionally, when CuBr/L17 was used as the catalyst, only the formation of allylboronate 14 was observed.This observation suggests a distinct reaction pathway which exclude the possibility of diene as intermediate in comparison to the Co-catalyzed hydroboration of MCPs. [15]ased on the previous reports on Cu-catalyzed hydroboration and considering the control experiments above, [3a,12,20] we proposed a plausible mechanism for the hydroboration where HBpin or B 2 pin 2 were involved (Figure 1

Conclusion
In this work, we have disclosed an efficient, straightforward, and versatile cascade hydroboration protocol of MCPs, which involves a ring-opening hydroboration procedure through -C elimination, followed by a cascade hydroboration using different type of boron reagents.This methodology allows the facile access to a range of chiral 1,4-and 1,3-bis(boronates) in a highly chemoand enantioselective manner.The modularity of diversifying two C-B bonds of products to obtain various optically pure 1,3-and 1,4-diphosphnates, butanol, and propanol with different substitutes highlights the practicality of this novel and easily operated protocol.We anticipate that this protocol will inspire further exploration of its potential applications in asymmetric catalysis and organic synthesis.
).The reaction is initiated by Cu-H species B, which is generated through the reaction of Cu-alkoxide A with pinacolborane.Cu-H species B then adds to the exo-double bond of MCP, leading to the formation of complex C. The subsequent -C elimination of complex C releases complex D, which undergoes reductive elimination to form intermediate E and liberate Cu-H species B. Notably, the use of L17 enables the selective formation of trans-intermediate D', and then affords trans-intermediate E'.Intermediate E then proceeds through the cascade hydroboration II procedure with HBpin, providing chiral 1,4-bis(boronate).Alternatively, as shown in cascade hyroboration III, chiral nucleophile Cu-Bpin H, formed through transmetalation between Cu-alkoxide G and B 2 pin 2, coordinates and adds to double bond of intermediate E'.Then, the protonation of alkyl-Cu intermediate I via MeOH produces chiral 1,3bis(boronate) and regenerates Cu-alkoxide G.

Table 1 .
Optimization of the reaction conditions.