Copper-Catalyzed Asymmetric Addition of Tertiary Carbon

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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Copper-Catalyzed Asymmetric Addition of Tertiary Carbon Nucleophiles to 2H‑Azirines: Access to Chiral Aziridines with Vicinal Tetrasubstituted Stereocenters Haipeng Hu, Jinxiu Xu, Wen Liu, Shunxi Dong, Lili Lin,* and Xiaoming Feng* Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064, China

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S Supporting Information *

ABSTRACT: A catalytic asymmetric nucleophilic addition of tertiary carbon nucleophiles to 2H-azirines was established in the presence of the chiral N,N′-dioxide/CuII complex. Various chiral aziridines with vicinal tetrasubstituted stereocenters were obtained in high yields with excellent diastereoselectivities and enantioselectivities. Moreover, on the basis of the control experiments, X-ray structures of the products, and catalyst, a possible transition state was proposed to explain the stereoselectivity.

Scheme 1. Asymmetric Additions of Nucleophiles to 2HAzirines

Aziridines are useful building blocks for organic synthesis and may exhibit various biological properties such as antitumor and antibacterial activities, which make them attractive synthetic targets.1 Naturally, much attention has been drawn to introducing the aziridine structures into different molecular scaffolds.2 Since Somfai’s pioneering work in 2002,3 the strategy employing nucleophilic addition to the unsaturated nitrogen-containing heterocyclic compound, 2H-azirine,4,5 has been one of the most efficient methods to deliver aziridines.6 However, the catalytic asymmetric version of the strategy was not developed until recently. In 2016, we reported an asymmetric imine amidation of 2H-azirines with oxindoles by using a chiral N,N′-dioxide/ScIII complex catalyst (Scheme 1a).7a This was the first example of N1 of oxindole participating in a catalytic reaction instead of C3. The phenomenon was rationalized by the fact that the high steric repulsion of the C3 position prevented the carbon nucleophilic addition process which could conveniently synthesize chiral aziridines with vicinal tetrasubstituted stereocenters. Later, the heteroatomic additions were further developed: (1) Zhang’s group realized a highly efficient kinetic resolution of 2H-azirine via the nucleophilic addition of pyrazole to 2H-azirine by using chiral imidodiphosphoric acid,7b and (2) Nakamura’s group applied phosphite and thiol as nucleophiles to react with 2Hazirines in the presence of chiral Bis(imidazole)/ZnII complex and 8-quinolinesulfonamide catalysis, respectively.7c,d Despite these successful examples, the catalytic asymmetric variant of the carbon nucleophilic addition reaction is still rare due to the poor nucleophilicity or high steric repulsion. Recently, the Wang group made a breakthrough in the catalytic asymmetric reaction of carbon nucleophiles with 2H-azirines (Scheme 1b).7e The author used the classical N-heterocyclic carbene © XXXX American Chemical Society

Received: July 20, 2018

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DOI: 10.1021/acs.orglett.8b02274 Org. Lett. XXXX, XXX, XXX−XXX

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carbonic L4-RaPr2 (entries 3−5). Meanwhile, after the substituents of the amide group were changed from isopropyl to ethyl or adamantyl, a negative effect was observed (entry 3 vs entries 6 and 7). Enhancing the steric hindrance on the 4positions of phenyl ring improved the enantio- and diastereoselectivity (entry 3 vs entry 8). Finally, by adjusting the ratio of metal to ligand to 1:1.5 and lowering the reaction temperature to −40 °C, chiral aziridine 3aa could be isolated in 87% yield, 92% ee, and >19:1 dr through column chromatography (entry 9). With the optimized reaction conditions established, the substrate scope was then investigated. First, various β-keto amides 1 were probed by reacting with 2H-azirine 2a (Table 2). The inden-1-one-derived β-keto amides (1a−k) with

(NHC) as catalyst, which reversed the inherent polarity of the aldehyde by forming the Breslow intermediate, successfully achieving the catalytic enantioselective aza-Benzoin reaction of aldehydes with 2H-azirines. A wide range of chiral aziridines with a quaternary stereocenter were assembled. To date, however, construction of chiral aziridines with vicinal tetrasubstituted stereocenters proposed in our previous work through the asymmetric addition of tertiary carbon nucleophiles to 2H-azirines remains a challenge. Notably, vicinal tetrasubstituted stereocenters8 are also represented in pharmaceutically active molecules, and development of new catalytic methods for the construction of vicinal tetrasubstituted stereocenters is a goal in organic chemistry. Herein, we report the highly enantioselective tertiary carbon nucleophilic addition9 of β-keto amides10 to 2H-azirines by applying a chiral N,N′-dioxide/CuII complex11 catalytic system (Scheme 1c), and the chiral aziridines with vicinal tetrasubstituted stereocenters were obtained in high yields and enantioselectivities. In our preliminary screening, the addition of β-keto amide 1a to 2,3-diphenyl-2H-azirine 2a was selected as the model reaction to optimize the reaction conditions. The β-keto amide 1a could be completely converted to the corresponding product in the presence of chiral N,N′-dioxide/CuII complexes in CH2Cl2 at 0 °C for 2 days. The diastereomers 3aa and 3′aa could be separated by column chromatography. Encouraged by the results, the structure of chiral ligands was evaluated as shown in Table 1. For the chiral backbone, L-proline-derived L-PrPr2 and (s)-pipecolic acid derived L-PiPr2 delivered poorer results than L-ramipril-derived L-RaPr2 did (entry 3 vs entries 1 and 2). Ligand L-RaPr2, which has a three-carbonic linkage, was superior to that of two-carbonic L2-RaPr2 or four-

Table 2. Substrate Scope for the β-Keto Amidesa

Table 1. Optimization of the Reaction Conditionsa

entry

ligand

drb (3aa:3′aa)

yield (%)c (3aa/3′aa)

ee (%)d (3aa/3′aa)

1 2 3 4 5 6 7 8 9e

L-PrPr2 L-PiPr2 L-RaPr2 L2-RaPr2 L4-RaPr2 L-RaEt2 L-RaAd L-RaPr3 L-RaPr3

70:30 75:25 64:36 75:25 63:37 64:36 57:43 70:30 88:12

68/28 75/20 60/34 63/23 63/35 57/34 50/40 70/22 87/−

10/10 13/13 55/25 0/3 48/9 50/33 3/47 66/11 92/−

a

Unless otherwise noted, all reactions were performed with 1 (0.05 mmol), rac-2a (2.5 equiv), and Cu(OTf)2/L-RaPr3 (1:1.5, 10 mol %) in CH2Cl2 (0.2 mL) at −40 °C. bDetermined by 1H NMR. cIsolated yields of 3 which were based on the β-keto amides 1. dDetermined by HPLC on a chiral stationary phase. eThe reaction temperature was −30 °C. fThe reaction was performed at −40 °C for 110 h, then −30 °C for 10 h. gThe reaction temperature was −10 °C. ND = not detected.

different substituents (both electron-donating or electronwithdrawing groups at C4, C5, C6, or C7 positions) all reacted quite well with 2a to form the corresponding chiral aziridines (3aa−ka) in 65−90% yields with moderate to excellent enantioselectivities (60−94%) (entries 1−11). The β-keto amide 1l incorporating a naphthyl group was also tolerable,

a

All reactions were performed with 1a (0.05 mmol), rac-2a (2.5 equiv), and Cu(OTf)2/ligand (1:1, 10 mol %) in CH2Cl2 (0.2 mL) at 0 °C for 48 h. bDetermined by 1H NMR. cIsolated yields of 3aa and 3′aa which were based on the β-keto amides 1a. dDetermined by HPLC on a chiral stationary phase. eThe reaction was performed with Cu(OTf)2/L-RaPr3 (1:1.5, 10 mol %) at −40 °C for 48 h. B


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respectively, were also tolerated (entries 9 and 10). Then R2 was explored (entries 11−16). It was found that electronic properties showed little effect on the reaction. Excellent enantioselectivities and good yields were obtained for the desired products 3ck−co (86−92% ee, 78−85% yield) (entries 11−15). Moreover, 2H-azirine 2p, possessing a benzyl group on the 2-position, could also be converted to the corresponding aziridine (entry 16). The poor results for 3cp could be explained by the fact that the flexible skeleton led to less steric hindrance and consequently reduced chiral recognition. Similarly, the stereocontrol of 3-phenyl-2H-azirine (2q) was poor, and the corresponding product 3cq was assembled in 99% yield with 45:55 dr and 35% ee/5% ee (entry 17). Subsequently, the synthetic value of the reaction was investigated. A gram-scale synthesis of 3ca was carried out, and the optically active aziridine 3ca was generated in 83% yield (0.96 g), 90% ee (Scheme 2). Meanwhile, the product 3ca could be easily reduced to β-hydroxy-functionalized aziridine derivative 4 (90% ee, 72% yield, > 19:1 dr) in the presence of LiAlH4.

giving chiral aziridine in 73% yield with 94% ee (entry 12). Notably, β-keto ester 1m participated in the reaction to afford the corresponding product 3ma in 80% yield with 75% ee (entry 13). Additionally, β-keto amides 1n and 1o derived from cyclopentanone and cyclohexanone were also applicable (entries 14 and 15). The absolute configuration of the product 3ca was determined to be (1S,2S,3S) by X-ray crystallographic analysis. Next, various 2H-azirines were investigated by reacting them with 5-phenyl-substituted β-keto amide (1c) (Table 3). Table 3. Substrate Scope for the 2H-Azirinesa

Scheme 2. Scaled-up Version of the Reaction and Transformation of 3ca

a

Dr was determined by the 1H NMR of the crude product.

To explain the stereoselectivity of the catalytic reaction, control experiments were carried out. First, racemic 2H-azirine 2a (2.0 equiv) was applied to react with β-keto amide 1a under the standard reaction conditions (Scheme 3a). The 3aa and 3′aa were obtained in 45% and 4% yields with 86% and 15% ee. Meanwhile, the recovered (R)-2a was obtained in 50% yield with 68% ee. The results showed that (S)-2a reacted with higher stereoselectivity than (R)-2a and at a faster rate, leading to a kinetic resolution. Then, optically pure 2H-azirine (S)-2a and (R)-2a were applied to react with 1a under the standard

a

Unless otherwise noted, all reactions were performed with 1 (0.05 mmol), rac-2 (2.5 equiv), and Cu(OTf)2/L-RaPr3 (1:1.5, 10 mol %) in CH2Cl2 (0.2 mL) at 0 °C for the indicated time. bDetermined by 1 H NMR. cIsolated yields of 3 which were based on the β-keto amides 1. dDetermined by HPLC on a chiral stationary phase. e1a was used. f 20 mol % catalyst loading. gThe diastereomers could not be separated by column chromatography. hThe dr was determined by HPLC.

Scheme 3. Control Experiments

Delightfully, the electronic nature of the substituents on the 4-position of phenyl ring (R1) had little effect on both yields and enantioselecitivities (83−86% yield, 89−92% ee; 3cb−ce and 3af) (entries 2−6). Substrate 2g, having a methyl group on the 3-position, could react smoothly to generate the corresponding chiral aziridine 3cg in 81% yield with 92% ee by increasing the catalyst loading to 20 mol % (entry 7). The disubstituted 2H-azirine 2h was also a suitable substrate, offering the chiral aziridine 3ch in 80% yield with 83% ee by prolonging the reaction time (entry 8). Meanwhile, compounds 2i/2j bearing fused ring and naphthyl substituents, C


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Figure 1. Proposed transition state.

repulsion (TS-1 vs TS-2), thus delivering the corresponding (1S, 2S, 3S)-configured product 3ca which was in accordance with the observed experiment result. In summary, the first asymmetric tertiary carbon nucleophilic addition of β-keto amides to 2H-azirines has been realized by using a chiral N,N’-dioxide/CuII complex. This strategy provides a novel and highly efficient method for the synthesis of chiral aziridines in good yields and excellent ee values under mild conditions. A possible transition state was proposed to explain the origin of the stereoselectivity. Meanwhile, the chemistry of 2H-azirine in organic synthesis was enriched. Further studies of the 2H-azirines and aziridines are underway.

conditions (Scheme 3b,c). The substrate 1a could be completely transformed to the corresponding product in both cases. The enantioselectivities of 3aa, 3′aa, and the recovered 2a were all maintained in Scheme 3b, indicating that no racemization process existed. The high reactivity of the (R)2a under the standard reaction conditions derived from the low selectivity of the kinetic resolution. In combination with the X-ray structures of 3ca and 3′ca (see the Supporting Information), we could draw a conclusion that the diastereoselectivity derived from the C−C bondforming event. Moreover, the X-ray structure of the catalyst was obtained in a THF/hexane/pyridine system, which showed that the four oxygen atoms of the chiral ligand and two nitrogen atoms of two pyridines coordinated to the metal, forming a rigid octahedral complex. Based on the above information, a possible catalytic transition-state model was proposed in Figure 1. The enolate of the β-keto amide 3c coordinated to the Cu(II) in a bidentate fashion through the oxygens of the dicarbonyl groups, forming a rigid octahedral complex. In all cases, the βketo amide 3c specifically attacked 2H-azirine 1a from the back side relative to the substituent on the 2-positon of 2H-azirine because of the reduced steric bulk. The Si-face of β-keto amide chelated with CuII/L-RaPr3 was disfavored for the steric repulsion between the aromatic ring of chiral ligand and the adamantyl substituent of the substrate 3c (TS-2, TS-3). The (S)-2a reacted at a faster rate than (R)-2a for the less steric

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b02274. Experimental procedures, full spectroscopic data for all new compounds, and 1H and 13C NMR and HPLC spectra (PDF) Accession Codes

CCDC 1843563, 1843566, and 1843598 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/ D


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2005. (b) Trost, B. M.; Jiang, C. Synthesis 2006, 369. (c) Wang, B.; Tu, Y. Q. Acc. Chem. Res. 2011, 44, 1207. (d) Trost, B. M.; Osipov, M. Angew. Chem., Int. Ed. 2013, 52, 9176. (9) (a) Córdova, A. Acc. Chem. Res. 2004, 37, 102. (b) Shi, Y. B.; Wang, Q. L.; Gao, Sh. H. Org. Chem. Front. 2018, 5, 1049. (c) Berkessel, A.; Gröger, H. Nucleophilic Addition to C N Double Bonds. Asymmetric Organocatalysis: From Biomimetic Concepts to Applications in Asymmetric Synthesis; Wiley-VCH Verlag: Weinheim, 2005; Chapter 5, pp 130−244. (10) Selected recent examples for the enantioselective reaction of βketo amides and β-keto esters in our group: (a) Lian, X. J.; Lin, L. L.; Fu, K.; Ma, B. W.; Liu, X. H.; Feng, X. M. Chem. Sci. 2017, 8, 1238. (b) Guo, j.; Lin, L. L.; Liu, Y. B.; Li, X. Q.; Liu, X. H.; Feng, X. M. Org. Lett. 2016, 18, 5540. (11) For selected examples using chiral N,N′-dioxide ligands, see: (a) Liu, X. H.; Lin, L. L.; Feng, X. M. Acc. Chem. Res. 2011, 44, 574. (b) Feng, X. M.; Liu, X. H. In Scandium: Compounds, Productions and Applications; Greene, V. A., Ed.; Nova Science: New York, 2011; pp 1−48. (c) Zheng, K.; Lin, L. L.; Feng, X. M. Huaxue Xuebao 2012, 70, 1785. (d) Liu, X. H.; Lin, L. L.; Feng, X. M. Org. Chem. Front. 2014, 1, 298. (e) Liu, X. H.; Zheng, H. F.; Xia, Y.; Lin, L. L.; Feng, X. M. Acc. Chem. Res. 2017, 50, 2621. (f) Liu, X. H.; Dong, S. X.; Lin, L. L.; Feng, X. M. Chin. J. Chem. 2018, 36, 791.

data_request/cif, or by emailing [email protected]. uk, or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Xiaoming Feng: 0000-0003-4507-0478 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We acknowledge the National Natural Science Foundation of China (Nos. 21432006 and 21572136) for financial support. REFERENCES

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Copper-Catalyzed Asymmetric Addition of Tertiary Carbon

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