Cobalt-catalyzed enantioselective reductive addition of ketimine with cyclopropyl chloride to construct chiral amino esters bearing cyclopropyl fragments

Abstract

Chiral amino acid derivatives containing cyclopropyl fragments are high-value drug candidates, but their synthesis is still challenging. We herein report an efficient construction of chiral α-tertiary amino acid derivatives containing cyclopropane fragments, which has been achieved via a cobalt-catalyzed asymmetric reductive addition of α-iminoesters with cyclopropyl chloride. This strategy enables the formation of these valuable motifs with broad functional group tolerance under mild conditions with good yields and excellent enantioselectivities.

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Introduction

Since the discovery of (+)-trans-chrysanthemic acid by Staudinger and Ruzicka in 1924,¹ the development of cyclopropyl-containing natural products and pharmaceutical molecules has gained significant attention in the realm of medicinal chemistry.² In the meantime, a large number of cyclopropyl-containing natural products have been isolated from various sources.³ Therefore, notable progress has been achieved for the construction of cyclopropane and its application in the total synthesis of cyclopropyl-containing natural products and drug molecules.⁴ In particular, cyclopropyl group embedded α-amino acid derivatives represent an attractive class of substructure motifs in a broad spectrum of biologically active small molecules (Scheme 1a).⁵ The existence of the cyclopropyl group in pharmaceuticals would enhance drug efficacy, increase metabolic stability, and increase lipid solubility.⁶ Given the value and importance of the cyclopropane fragment, considerable efforts have been devoted to developing the highly effective and enantioselective synthesis of cyclopropyl-containing compounds.⁷ Among various known synthetic methods, the direct introduction of pre-existing cyclopropyl rings is an attractive strategy via transition metal-catalyzed cross-coupling by utilizing cyclopropyl nucleophiles or cyclopropyl electrophiles.⁸ Notably, reductive cross-coupling between two electrophiles could circumvent the use of unstable organometallic reagents and has garnered increasing interest recently.^9–14 In 2020, Rousseaux¹⁵ and Weix¹⁶ (Scheme 1b) disclosed nickel-catalyzed decarboxylative reductive coupling using cyclopropyl redox-active esters and aryl halides as electrophilic reagents to obtain the corresponding cyclopropyl arylation products. In sharp contrast, leveraging the cyclopropanyl-containing electrophiles in enantioselective transformations remains elusive.

Scheme 1 Examples of chiral α-cyclopropane amino acids and the synthesis of cyclopropyl compounds.

Recently, our group has disclosed the Earth-abundant cobalt-catalyzed asymmetric aza-Barbier reaction of α-amino esters with organoelectrophiles as addition fragments to construct α,α-disubstituted amino esters with exceptional enantioselectivities.¹⁷ This enantioselective reductive addition protocol could circumvent the use of organometallic reagents, thus enabling a broad substrate scope, especially for those functionalities that are not compatible with organometallic reagents. Based on our group's continuing research interest in asymmetric catalysis,^17,18 we herein report our recent progress in cobalt-catalyzed asymmetric reductive addition of ketimines¹⁹ with the use of cyclopropyl chloride as the coupling component, thus allowing the expedient construction of chiral amino acid derivatives bearing this pre-existing cyclopropyl ring with excellent enantioselectivities (Scheme 1c).

Our study began with the use of α-imino ester 1a as a model substrate and cyclopropyl chloride 2a as the coupling component to test the feasibility of this asymmetric reductive addition protocol as shown in Table 1.

Table 1 Optimization of the reaction conditions^a

Entry	Ligand	Reductant	Temp. (°C)	Yield^d (%)	ee^e (%)
a Reaction conditions: 1a (0.1 mmol), 2a (0.15 mmol, 1.5 equiv.), CoI2 (10 mol%), ligand (12 mol%), EtOH (0.1 mmol, 1.0 equiv.), reductant (0.2 mmol, 2.0 equiv.), MeCN (0.2 M) at temperature for 20 h. b Without EtOH. c 5 mol% CoI2 and 6 mol% ligand were used. d Yields determined by NMR using CH2Br2 as an internal standard. e ee values were determined by chiral HPLC. f Isolated yield.
1	L1	Mn	35	43	99
2	L1	Zn	35	30	99
3	L1	In	35	24	99
4^b	L1	Mn	35	16	99
5	L1	In	50	80	99
6	L1	In	80	84	97
7	L2	In	50	83 (78)	99
8	L3	In	50	57	97
9	L4	In	50	80	97
10	L5	In	50	69	99
11	L2	Mn	50	70	99
12^c	L2	In	50	70	99

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The desired amino ester product 3a could be obtained in 43% yield with 99% ee by the utilization of CoI₂ and NPN ligand L1 as a catalyst,²⁰ Mn as a reductant and EtOH as an additive in MeCN at 35 °C (Table 1, entry 1). Using zinc or indium as the terminal reductant resulted in yields of 30% and 24% respectively, albeit without affecting the enantioselectivity (Table 1, entries 2 and 3). When the ethanol additive was omitted, the reaction efficiency decreased significantly, leading to a lower yield (Table 1, entry 4). Although the yield was low with indium, the conversion rate of ketimine 1a was also relatively low (see the ESI† for details). Increasing the reaction temperature to 50 °C with In as the reductant resulted in a dramatic improvement in the yield (80%, 99% ee), while on increasing the reaction temperature to 80 °C, the yield was improved but the enantioselectivity slightly decreased to 97% ee (Table 1, entries 5 and 6). The screening of chiral ligands was subsequently executed under the aforementioned conditions. Changing the isobutyl group on the chiral oxazoline moiety to other groups such as sec-butyl (L2), tert-butyl (L3), isopropyl (L4), and phenyl (L5) all led to high enantioselectivity (Table 1, entries 7–10). In particular, the employment of the isobutyl substituted NPN ligand L2 further improved the yield to 83% (78% isolated yield) with 99% ee (Table 1, entry 7). These conditions were determined to be optimal. However, replacing the reductant with manganese powder or reducing the catalyst loading led to a decrease in the yield (Table 1, entries 11 and 12).

With the optimized conditions in hand, we investigated the substrate scope for the enantioselective reductive addition of ketimines to construct chiral amino acids containing cyclopropane fragments (Scheme 2). The reaction efficiency varied with different ester groups on the imine substrate, including methyl (3b), ethyl (3a), and isopropyl (3k), affording the corresponding products in 78–90% yields with excellent 99% ee. The scope of the aryl groups on imines was also examined, with high yields and enantioselectivities observed for various substituents, such as naphthalene (3c), pepper rings (3d), and halogens like chlorine (3e) and fluorine (3f) on the benzene ring. These substituents had no adverse effects on the reaction yield or enantioselectivity. For heterocyclic-substituted imines like thiophene, product 3g was obtained in 55% yield with 99% ee. Evaluation of the substitution pattern of the aromatic ring on the nitrogen atom moiety revealed that both electron-rich substitution (3h) and steric hindrance (3i) would not affect the yield and enantioselectivity. Furthermore, when the phenyl group was replaced with a methyl group, the reaction still obtained the product (3j) in 46% yield with 99% ee.

Scheme 2 Substrate scope. Reaction conditions: 1 (0.1 mmol), 2 (0.15 mmol, 1.5 equiv.), CoI₂ (10 mol%), L2 (12 mol%), R²OH (0.1 mmol, 1.0 equiv.), In (0.2 mmol, 2.0 equiv.), MeCN (0.2 M) at 50 °C for 20 h. ^a Extend the reaction time to 40 hours.

Next, we explored the applicability of cyclopropyl chloride electrophiles to afford amino esters with excellent enantioselectivities (3k–3t). For substrates with large sterically hindered substituents on the benzene ring, including tert-butyl (3l) and phenyl (3m), the reaction yield and enantioselectivity were not significantly affected. Encouragingly, both electron-donating groups (–OR) and electron-withdrawing halogen atoms (–Cl) were successfully incorporated into the substrate, leading to the corresponding products in excellent yields with outstanding enantioselectivities (3n, 3o, 3q). Additionally, naphthalene and thiophene groups did not adversely affect the reaction's efficiency or enantioselectivity (3p, 3t). Finally, the introduction of functional groups at the ortho (–Cl) and meta (–OⁱPr) positions of aryl groups maintained the expected enantioselectivity, although steric hindrance reduced the reaction yield (3r, 3s). The absolute configuration of 3k was determined as R configuration which was confirmed by X-ray diffraction analysis.

To further showcase the potential synthetic utility of the reductive addition protocol for constructing chiral amino acids containing cyclopropane fragments, we performed the following synthetic application (Scheme 3). Firstly, we scaled up the reaction to 3.0 mmol using cyclopropyl chloride 2a and ketimine 1b as substrates under the standard conditions. The desired product 3k was obtained on a gram scale with 86% isolated yield and 99% ee (Scheme 3a). Subsequently, we carried out a series of derivatization experiments. For the chiral product 3b, we used CAN to remove the PMP group, successfully obtaining compound 4 in 95% yield with 99% ee. Following this, the methyl ester was hydrolyzed using LiOH to obtain amino acid 5 in 96% yield. Moreover, treating 3k with LiAlH₄ allowed us to efficiently obtain amino alcohol 6 in 94% yield without compromising the enantioselectivity. Subsequently, alcohol 6 was cyclized using the Mitsunobu reaction, resulting in the bicyclic product 7 in 77% yield with 95% ee (Scheme 3b).

Scheme 3 Synthetic application.

On the basis of the previous research on the Co-catalyzed reductive addition of ketimine, we proposed the following plausible mechanism (Scheme 4). First, the reaction is initiated by the generation of the LCo(I) species utilizing In as the reductant. The active LCo(I) species coordinates with imine substrate 1a to afford the Co(I) species int A, which immediately undergoes a SET process with cyclopropyl chloride 2a to produce int B and the cyclopropyl radical. The cyclopropyl radical could combine with Co(II) of int B to generate the Co(III) species int C, followed by reduction to give int D. A subsequent enantioselective migratory insertion to the C=N double bond of int D generates int E (path a), which finally releases product 3a and regenerates int A by protonation, ligand exchange and a reduction process. Alternatively, the cyclopropyl radical could also undergo enantioselective radical addition to the C=N double bond of int B to generate the Co(III) species int C′ followed by reduction with In to afford int E (path b), which could release product 3a and regenerate int A in the same way as mentioned above.

Scheme 4 Proposed mechanism.

Conclusions

In conclusion, we disclose a cobalt-catalyzed asymmetric reductive addition reaction of cyclopropyl chloride with α-imino esters under mild conditions, enabling the efficient construction of chiral α-tertiary amino acid derivatives containing cyclopropane fragments. This method exhibits excellent enantioselectivity, good functional group tolerance, broad substrate scope and ease of scale-up. Further exploration of this reductive addition is currently ongoing in our group.

Author contributions

Jiangtao Hu and Tingting Xia performed most experiments. Hongrui Feng provided assistance in the experiment. Xianqing Wu and Jingping Qu guided the process of the experiment. Yifeng Chen conceived the idea and supervised the research. Tingting Xia and Yifeng Chen co-wrote the manuscript with feedback from all authors.

Data availability

The data supporting this article have been included as part of the ESI.†

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work was supported by the National Natural Science Foundation of China (22171079, 22371071, 92356301), Sinopec Seeding Program (C0607-0876), Shanghai Municipal Science and Technology Major Project (Grant No.2018SHZDZX03), the Program of Introducing Talents of Discipline to Universities (B16017), Shanghai Sailing Program (23YF1408800) and the Fundamental Research Funds for the Central Universities. The authors thank the Analysis and Testing Center of East China University of Science and Technology for help with NMR and HRMS analysis.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. CCDC 2355497. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d4qo01474j

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