Asymmetric intramolecular reductive coupling of bisimines templated by chiral diborons

Abstract

An asymmetric intramolecular reductive coupling of bisimines has been accomplished for the first time under mild conditions with bis((+)-pinanediolato)diboron as the template, providing the unprecedented chiral dihydrophenanthrene-9,10-cis-diamines in high yields and excellent enantioselectivities. The chiral exocyclic cis-diamine products have served as effective chiral ligands for asymmetric catalysis. A DFT study highlights the crucial roles of the uncommon twisted-boat pathway (instead of the common chair type) and the steric effect in exclusively forming the cis-diamines and achieving high enantioselectivity. This reductive coupling protocol represents a significant expansion of the diboron-promoted [3,3]-sigmatropic rearrangement.

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Introduction

Chiral exocyclic vicinal cis-diamines¹ belong to a unique class of chiral vicinal diamines that are found in the structures of a number of biologically important natural products and therapeutic agents (Fig. 1a). For example, biotin,² containing a chiral cis-diamine substructure on a tetrahydrothiofuran ring, is involved in a wide range of metabolic processes as one of the B vitamins; edoxaban,³ a factor Xa inhibitor used as an anti-coagulant medication, possesses a chiral cyclohexane cis-diamine scaffold; saxitoxin,⁴ bearing a cis-diamine structure on a cyclic guanidine, is a neurotoxin that acts as a sodium channel blocker. In addition, enantiomerically pure exocyclic vicinal cis-diamines serve as conformationally rigid and sterically bulky backbones for transition-metal catalysts in asymmetric catalysis.⁵ However, despite the significant progress in the synthesis of chiral acyclic vicinal diamines⁶ and exocyclic trans-diamines,⁷ the construction of chiral exocyclic vicinal cis-diamines, mainly based on a cyclohexane skeleton, remains a significant challenge.⁸ The current reported methods suffered from either lengthy synthetic sequences^8d or low diastereo- and/or enantioselectivities.

Fig. 1 Chiral cis-diamines and their enantioselective syntheses by intramolecular asymmetric reductive coupling of bisimine. (a) The prevalence of chiral cis-diamines. (b) Intermolecular asymmetric reductive coupling of imines templated by chiral diborons. (c) This study on intramolecular asymmetric reductive coupling of imines.

We have recently developed an efficient method for the synthesis of chiral vicinal diamines through asymmetric intermolecular reductive homocoupling of imines templated by chiral diborons (Fig. 1b).⁹ The featured diboron-promoted [3,3]-sigmatropic rearrangement has enabled the single-step synthesis of chiral tetrahydro-bisisoquinolines, bis(cyclic amine)s, acyclic vicinal disubstituted diamines, and acyclic vicinal tetrasubstituted diamines in excellent yields, diastereoselectivities, and enantioselectivities. By using bisaldimines as starting materials, polymeric chiral diamines were synthesized in a highly stereoselective fashion with M_n ranging from 5000 to 14 000.^9d In contrast, efficient asymmetric intramolecular reductive coupling of bisimines has not been realized. Such transformation would lead to chiral exocyclic vicinal diamines in a step-economic fashion.

There are several challenges for such an unprecedented transformation: (1) chemoselectivity: how to inhibit the intermolecular polymerization and enforce the intramolecular cyclization? (2) Diastereoselectivity: would the intramolecular diboron-promoted [3,3]-sigmatropic rearrangement proceed through a chair-like six-membered transition state to form a trans-diamine or a cis-diamine? (3) Enantioselectivity: can a chiral exocyclic diamine be constructed in a single step from a readily available starting material? In this study, we have successfully addressed the above challenges by judicious selection of bisimine substrates and chiral diborons, and accomplished the first and asymmetric intramolecular reductive coupling of bisimines (Fig. 1c). The coupling protocol has enabled one-step synthesis of unprecedented dihydrophenanthrene-9,10-cis-diamines and provided excellent yields, exclusive cis selectivities, and almost perfect enantioselectivities, by employing chiral bis(pinanediolato)diboron as the template.

Results and discussion

At the outset of our study, the feasibility of intramolecular reductive coupling of bisimines was investigated with the hexane-1,6-diimine substrate (1a), which was in situ prepared from adipaldehyde and ammonia (Fig. 2a). Treatment of 1a with (Bpin)₂ at rt provided a mixture of polyamines without detection of intramolecular cyclization product 2a. We assumed that the intermolecular coupling was more favorable than the intramolecular coupling in the case of 1a. A structurally more rigid diimine 1b could be more suitable for intramolecular coupling. Thus, compound 1b was prepared in situ from [1,1′-biphenyl]-2,2′-dicarbaldehyde and ammonia and treated with (Bpin)₂ at rt. Indeed, a trace amount of the intramolecular coupling product 2b was formed according to LC-MS, and the major isolated product was 5-hydroxy-5H-dibenzo[c,e]azepin (2b′).¹⁰ These results showed that the intramolecular coupling of bisimine could be accomplished by inhibiting the polymerization process and other side reactions, including hydrolysis and formation of a stable dibenzo[c,e]azepin derivative, by employing substrates with increased rigidity and steric hindrance. Pleasingly, the efficiency of the intramolecular coupling was significantly enhanced when N-substituents were introduced into the substrate. Thus, 1c was treated with (Bpin)₂ under similar conditions, and the resulting cyclization cis-diamine product 2c was formed in 80% yield, whose relative configuration was confirmed by the X-ray crystal structure of its urea derivative 3c (Fig. 2b).¹¹ Notably, the unexpected formation of cis-diamine 2c was intriguing since no meso products were formed in our previous reports on various intermolecular reductive homocouplings of imines.⁹ Despite the symmetry of cis-diamine 2c, we proposed that a chiral cis-diamine would be constructed for the first time if an unsymmetrical bisimine based on the [1,1′-biphenyl]-2,2′-dicarbaldehyde skeleton was employed, and an effective chiral diboron template could be discovered. Hence, 3-methoxy-[1,1′-biphenyl]-2,2′-dicarbaldehyde (4a) was treated with MeNH₂·HCl and triethylamine in situ to form bisimine 5a, which was then treated with chiral diborons in THF at rt for 48 h (Fig. 2c). Encouragingly, the chiral diboron with four phenyl substituents DB1 provided 6a in 85% yield and 22% ee. This proof-of-concept result demonstrated the feasibility of forming 6a in high enantioselectivity by screening various chiral diborons. While DB2 with bromo substituents showed no reactivity, DB3 with six phenyl substituents led to 6a in 84% yield and 55% ee. Further modifications of substituents on the aryl groups in DB4-10 all provided good yields, but with moderate enantioselectivities. Finally, employment of chiral bis(pinanediolato)diboron DB11 led to the formation of 6a in 90% yield and 99% ee. Further solvent screening showed that the cyclization proceeded with similarly high enantioselectivities in various solvents, indicating the robustness of the transformation (see the ESI† for more details).

Fig. 2 Asymmetric intramolecular reductive coupling of bisimine 5a templated by various chiral diborons. (a) Attempts on diboron templated intramolecular reductive coupling of bisimines. (b) Formation of cis-diamine by diboron templated intramolecular reductive coupling. (c) The development of asymmetric intramolecular reductive coupling protocol.

The substrate scope of intramolecular reductive coupling was studied. As can be seen from Table 1, unsymmetrical [1,1′-biphenyl]-2,2′-bisimine substrates with various 3-substituents were employed, providing chiral dihydrophenanthrene-9,10-cis-diamines 6a–h in moderate to high yields. While most products 6d–g were formed in almost perfect enantioselectivities regardless of their electronic properties, the small-size fluoro-substituted product 6c was obtained in 56% ee, indicating that the size of the substituent might be influential to the enantioselectivity. In addition, product 6h with a dioxolane ring was less selective (75% ee). The presence of 3-substitution (ortho-substitution) appeared to be crucial for the enantioselectivity, as substrates with 4- or 5-methoxy substituents provided very low enantioselectivities (see the ESI† for more details).

Table 1 Asymmetric intramolecular reductive coupling of bisimine 5 templated by chiral diboron DB11^a

a Unless otherwise specified, the reactions were carried out at rt with 5a–aj (0.2 mmol, 1.0 equiv.), DB11 (0.2 mmol, 1.0 equiv.) in THF (10 mL) for 48 h. Isolated yields. The ee values were determined by chiral HPLC analysis.

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By fixing the upper aryl ring with a methoxy substituent at the 3′ position, the substitution effect on the lower aryl ring was studied. The excellent enantioselectivities (91–99% ee) obtained for 6i–u demonstrated that the reaction was compatible with various substituents at 3′, 4′, and 5′ positions regardless of their electronic properties. It was interesting that products 6o and 6p with ortho-substituents on both upper and lower rings were obtained in excellent ee's. The synthesis of product 6v with a thiophene ring was extremely enantioselective (99% ee). A substrate with a naphthalene upper ring was also compatible, forming 6w in 88% yield and 99% ee. Surprisingly, product 6x with a dioxolane ring at both 4′ and 5′ positions was afforded in a low ee (30%). Substrates with multiple substituents on the upper aryl ring were also suitable. While the optical purity of product 6y with ortho-fluoro substituent was inferior (47% ee), product 6z with ortho-bromo substituent was obtained in 99% ee. The intramolecular reductive coupling was not limited to N-methyl substituents. A substrate with N-ethyl substituents was also compatible, leading to 6ab in 36% yield and 71% ee. Finally, substrates with 3-aryl substituents were employed, forming a series of ortho-aryl dihydrophenanthrene-9,10-cis-diamines 6ac–aj in good yields (53–98%) and excellent enantioselectivities (95–99% ee).

The exclusive formation of uncommon cis-diamine products and excellent enantioselectivities from the intramolecular reductive coupling called for a plausible mechanistic rationale. To gain insights into the reaction mechanism and the origin of the enantioselectivity, a systematic DFT study (SMD M06-2X-D3/def2-TZVP//SMD M06-2X-D3/BS1 method mainly) was first conducted by using the chiral diboron agent DB11 and the bisimine substrate 5e (R=Br; Fig. 3).¹¹ Compared with our previous studies on the intermolecular coupling systems,^9a,c,11e our current computational results reveal a distinct feature for this intramolecular coupling of bisimines. This intramolecular coupling adopts uncommon twisted boat transition states during the [3,3]-sigmatropic rearrangement to afford the synthetically challenging chiral vicinal cis-diamines, due to the ring strain of the bisimine tether (Fig. 3b, S2 and S3†). In contrast, the previous intermolecular coupling systems follow the common chair-type pathway.^9a,c,11e A total of 16 conformers for the coupling transition states (TSs) (Tables S8 and S10, Fig. S2 and S3†) were located for 5e through our comprehensive conformational search, with eight of them yielding the major product (P) and the others yielding the enantiomer product (P_ent). As shown in Fig. 3a, the most favorable TS1F leading to the desired coupling product (P) was computed to be lower in free energy than that giving the minor product P_entviaTS1A_ent by 1.8 kcal mol⁻¹. This result qualitatively explains the observed stereochemistry. The similar free energy difference (ΔΔG^≠) is also supported by a few different common computational methods (Tables S9 and S11†).

Fig. 3 (a) Calculated Gibbs free energy profile of the reaction of DB11 with 5e (R=Br) at the SMD M06-2X-D3/BS1 (L1) and SMD M06-2X-D3/def2-TZVP//SMD M06-2X-D3/BS1 (L2) levels (see ref. 11a). (b) Computed structures and key geometric parameters (distances in Å and dihedrals in italics and degrees) of the three key coupling transition states with their relative Gibbs free energies. Unimportant H atoms were omitted for clarity. (c) The effect of R substituents on the relative Gibbs free energy (in kcal mol⁻¹) of the two key transition states to form the minor product with respect to their corresponding lowest-energy TS1F forms leading to the major product at the SMD M06-2X-D3/def2-TZVP//SMD M06-2X-D3/BS1 level. #TS1G_ent-H has the same geometry as TS1F-H.

Additional calculations were conducted to examine the size effect of R (F, Cl, Br or H) on the stereoselectivity (Fig. 3c, S4 and Tables S12–S17†). Likewise, the same favorable coupling TSs (TS1F-Cl and TS1A_ent-Cl) and free energy difference (ΔΔG^≠ ∼1.8 kcal mol⁻¹) for 5d (R=Cl) were also found. In contrast, 5c (R=F) adopts another and lower-energy conformer for the minor-coupling TS (TS1G_ent-F), which reduces the free energy difference between the two stereo-determining coupling TSs (ΔΔG^≠) to ∼0.9 kcal mol⁻¹ only. To examine the steric effect of R on the energetics of the three key coupling TSs, tBu was employed and found to further increase the free energy difference (ΔΔG^≠ ∼2.4–6.1 kcal mol⁻¹vs. 1.8–4.4 kcal mol⁻¹ for R=Br; Table S18†). Overall, these computational results are in qualitative agreement with the experimental observation, highlighting the essential role of the steric effect of the R substituent in controlling stereoselectivity (particularly for the TS1G_ent type TSs).

As shown in Fig. 3b and S4,† the major coupling TSs (TS1F, TS1F-Cl and TS1F-F) can avoid steric congestion between the halogen substituent and diboron as well as minimize H–H repulsion inside the diboron part (especially on the methylene bridge; see Fig. S6†). In contrast, the minor coupling TSs (e.g.TS1A_ent and TS1G_ent) suffer from more steric hindrance between R and the diboron as well as more severe H–H repulsion in the diboron part. Generally, such steric crowdedness slightly increases the dihedral angle along the biphenyl C–C single bond (diminishing delocalization) and decreases the dihedral angles of the boat-shaped [3,3]-sigmatropic rearrangement TS structure (Table S19†). The TS1G_ent and TS1F form TSs adopt the essentially same conformation except for the substituent positioned in different arene rings. For a very small substituent (R=F or H), the TS1G_ent form TSs are more energetically favorable to form the minor product than the TS1A_ent form TSs and lead to a smaller free energy difference with the TS1F form TSs. However, the TS1G_ent form TSs become unfavorable than the TS1A_ent and TS1F form TSs with a larger R (R=Cl or Br), since the R substituent has the closest contact with the diboron in the TS1G_ent form TSs and experiences more steric repulsion. In addition, the most favorable TS1F type TSs have a lesser B–B bond elongation than the other two minor-type TSs. Distortion/interaction analysis¹² further revealed that the TS1F type TSs have smaller distortion energy than the two types of minor TSs (ΔΔE_dist = 2.7–4.0 kcal mol⁻¹ for R=F and 3.3–9.1 kcal mol⁻¹ for R=Br; Table S20†), which plays a vital role in the stereoselectivity. Local distortion analysis¹³ on the 10-atom diboron core part also gave comparable relative distortion energies for these key TSs (ΔΔE_dist = 1.5–5.3 kcal mol⁻¹ for R=Br; Fig. S5†).

To demonstrate the practicality of this transformation, the reductive cyclization of 5e was performed in THF at rt for 48 h in the presence of DB11 at a 2.5 gram scale and product 6e was obtained in 92% yield and 99% ee as a single diastereomer (Scheme 1a). Treatment of 6e with triphosgene and TEA provided 7e, whose absolute stereochemistry was confirmed by its X-ray crystal structure. The yields from 5e to 6e were monitored by NMR studies, and the intramolecular reductive coupling was found to be a much slower process, in contrast to the previously reported intermolecular homocoupling of isoquinolines.^9a The chiral bromo-substituted product 7e was a versatile intermediate for further derivatization (Scheme 1b). The Suzuki–Miyaura coupling of 7e with phenylboronic acid or prop-1-en-2-ylboronic acid catalyzed by Pd/SPhos afforded products 7ac and 8a in 50% yield and 99% yield, respectively, without erosion of enantiomeric purities (99% ee). Moreover, the Suzuki–Miyaura coupling of 7e with 9-anthrylboronic acid proceeded with Pd(OAc)₂ and BIDIME as the catalyst system to give 7aj in 69% yields. A Buchwald–Hartwig coupling of 7e with aniline catalyzed by Pd/BIDIME delivered 8b in 93% yield. In addition, Sonogashira coupling of 7e with phenylacetylene led to 8c in 62% yield and 99% ee.

Scheme 1 Derivatization and catalytic applications of chiral cis-diamines. (a) Gram scale reaction and kinetic profile. (b) Transformation of coupling product. (c) Utility of chiral cis-diamine product in asymmetric transfer hydrogenation.

The conformationally rigid chiral cis-diamine products were suitable ligands for asymmetric catalysis. We envisioned that its η⁵ iridium complex could be suitable for asymmetric transfer hydrogenation.^9d,14 Therefore, iridium complexes 9a, 9ac, and 9aj were prepared and applied to the asymmetric transfer hydrogenation of trifluoroacetophenones 10a and 10b (Scheme 1c). All reductions were found to be enantioselective. Notably, the asymmetric transfer hydrogenation of 10b with catalyst 9ac provided 11b in 90% yield and 85% ee, demonstrating the effectiveness of these chiral cis-diamines as chiral ligands in asymmetric catalysis.

Conclusions

In summary, we have developed an asymmetric intramolecular reductive coupling of bisimines under mild conditions using chiral bis(pinanediolato)diboron as the template, providing the unprecedented chiral dihydrophenanthrene-9,10-cis-diamines in high yields and excellent enantioselectivities. Our systematic computational investigation has revealed the vital roles of a less common twisted-boat pathway (rather than the common chair pathway) and steric effect in exclusively forming the cis-diamines and achieving high enantioselectivity for this first intramolecular reductive coupling. The chiral exocyclic cis-diamine products are effective ligands for asymmetric catalytic reactions. This method signifies the broad scope of the diboron-promoted [3,3]-sigmatropic rearrangement and enriches the chemistry of chiral vicinal cis-diamines.

Data availability

The ESI† is available and includes full experimental details, synthesis protocols, characterization data, and spectroscopic details. CCDC 2428416 (compound 3c), 2428418 (compound 7a), and 2428420 (compound 7e) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge viahttps://www.ccdc.ca-m.ac.uk/data_request/cif, or by emailing E-mail: data_request@ccdc.cam.ac.uk, or by contacting the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

Author contributions

W. T., G. X. and H. Y. conceptualised the work. T. C., R. X. and H. Y. conducted experiments. H.-Y. W. and L. W. C. performed DFT calculations. The manuscript was written through contributions of all authors. W. T., L. W. C., J. S. and H. Y. supervised the work, secured funding, edited and finalised the manuscript.

Conflicts of interest

The authors declare no competing financial interest.

Acknowledgements

The work was supported by the National Key R&D Program of China (2021YFF0701600), NSFC (82188101, 22122104, and 22193023), the Youth Innovation Promotion Association, CAS, the Shenzhen Nobel Prize Scientists Laboratory Project (C17783101), the Guangdong Provincial Key Laboratory of Catalysis (2020B121201002) and the Science and Technology Commission of Shanghai Municipality (23ZR1476500). The authors thank the Center for Computational Science and Engineering of Southern University of Science and Technology and CHEM HPC at SUSTech for partly supporting this work.

Notes and references

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Footnotes

† Electronic supplementary information (ESI) available. CCDC 2428416, 2428418, 2428420. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d5sc03633j

‡ These authors contributed equally to this work.

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