Dinuclear Ni₂–Schiff base complex-catalyzed asymmetric 1,4-addition of β-keto esters to nitroethylene toward γ^2,2-amino acid synthesis

Abstract

A homodinuclear Ni₂–Schiff base 1 complex (1–10 mol%) promoted the catalytic asymmetric 1,4-addition reactions of β-keto esters and an N-Boc oxindole to nitroethylene, giving products in 98–75% ee.

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Catalytic asymmetric 1,4-additions of carbon nucleophiles are highly useful synthetic transformations for the construction of quaternary carbon stereocenters.^1,2 Over recent years, there has been tremendous progress in both metal catalysis and organocatalysis for the asymmetric 1,4-additions of β-keto esters and related compounds.² β-Substituted nitroalkenes are most often used as acceptors, giving β-substituted γ-nitro esters with α-quaternary carbon stereocenters.³ The use of a β-unsubstituted acceptor (nitroethylene), however, is much less common,^4,5 possibly due to potential difficulties of enantiocontrol and competitive polymerization of nitroethylene. Gellman et al. and Wennermers et al. independently reported highly enantioselective organocatalytic asymmetric 1,4-additions of aldehydes to nitroethylene and their applications to γ²-amino acid synthesis,⁴ but α,α-disubstituted aldehydes were not utilized as donors. Barbas was the first to successfully construct a quaternary carbon stereocenter viacatalytic asymmetric 1,4-addition of an N-Boc oxindole to nitroethylene.⁵ Because γ²-amino acids are potentially useful building blocks for folder research and the synthesis of biologically active compounds,^6,7 further studies to expand the scope of donors, especially for the synthesis of adducts with a quaternary stereocenter adjacent to a carbonyl group γ^2,2,^8,9 are highly desirable. To address this issue, we herein report the utility of a homodinuclear Ni₂–Schiff base 1 complex (Fig. 1). Ni₂–1 (1–10 mol%) promoted the reactions of β-keto esters to nitroethylene, affording products in 98–75% ee.

Fig. 1 Structures of dinucleating Schiff base 1 and homodinuclear M₂–Schiff base 1 complexes.

As part of our ongoing studies of bifunctional Lewis acid/Brønsted base catalysis in collaboration with Shibasaki,¹⁰ one of authors (S.M.) and Shibasaki recently reported the utility of dinuclear Schiff base complexes.^11–15 Among them, homodinuclear Co₂–1^12a,b and Mn₂–1^12c complexes were suitable for 1,4-additions with β-substituted nitroalkenes. Thus, we first applied Co₂–1 and Mn₂–1 complexes for the reaction of β-keto ester 2a and nitroethylene. Both of these complexes, however, gave an unsatisfactory yield and enantioselectivity (Table 1, entries 1 and 2, less than 30% NMR yield and 67% ee). Among the homodinuclear^12,13 and heterodinuclear¹⁴Schiff base complexes screened, the Ni₂–1catalyst¹³ afforded promising results. The reaction of β-keto ester 2a with 1.2 equiv. of nitroethylene in THF at 0 °C gave product 3a in 75% yield and 97% ee (entry 3). Among the solvents screened (entry 3–8), AcOEt was the best in terms of yield and enantioselectivity (entry 8, 96% yield and 98% ee). We then tried to reduce catalyst loading in entries 9–12. With 2.5 mol% catalyst, reactivity was decreased at 0 °C and the reaction did not complete after 48 h (entry 10). Raising the reaction temperature to 40 °C drastically improved the reactivity and the reaction completed within 5 h with high enantioselectivity (entry 12, 93% ee).

Table 1 Optimization of reaction conditions^a

Entry	M	x	Solvent ^b	Temp/°C	Time/h	% Yield^c	% ee
a 1.2 equiv. of nitroethylene (in toluene) were used. b Reactions were run in solvent/toluene = 10 ∶ 1, because nitroethylene stored in toluene was used. c Yield was determined by ^1H NMR analysis of the crude reaction mixture.
1	Co(OAc)	10	THF	0	25	<30	67
2	Mn(OAc)	10	THF	0	25	<20	67
3	Ni	10	THF	0	25	75	97
4	Ni	10	Toluene	0	25	94	68
5	Ni	10	CH2Cl2	0	25	>95	92
6	Ni	10	CHCl3	0	25	>95	90
7	Ni	10	CH3CN	0	25	78	78
8	Ni	10	AcOEt	0	25	95	98
9	Ni	5	AcOEt	0	23	91	96
10	Ni	2.5	AcOEt	0	48	83	89
11	Ni	2.5	AcOEt	rt	48	87	92
12	Ni	2.5	AcOEt	40	5	>95	93

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The substrate scope and limitations of the reaction are summarized in Table 2.¹⁶ Because the reactivity of β-keto esters 2 depends on the structure, the reaction conditions, such as catalyst loading and reaction time, were optimized for each β-keto ester. The best results for each substrate are summarized in Table 2. Indanone-derived β-keto esters 2b–2d showed good reactivity, and products 3b–3d were obtained in 92–90% yield and 98–94% ee after 4.5 to 10 h using 2.5 mol% of Ni₂–1 (entries 2, 4–5). In entry 3, the reaction was performed with 1 mol% Ni₂–1catalyst, but both the reactivity and enantioselectivity decreased (18 h, 84% yield, 87% ee). The reactivity of β-keto esters 2e and 2f with a six-membered ring was lower than that of β-keto ester 2a, and 10 mol% of Ni₂–1 was required to obtain products 3e and 3f in 98–73% yield and 91–75% ee after 24 h (entries 6 and 7). The reactivity of acyclic β-keto esters 2g and 2h was much lower than that of cyclic β-keto esters, and products 3g and 3h were obtained in only 35–51% yield even using 10 mol% of the catalyst (entries 8–9, 82–85% ee). We are speculating that the modest to poor reactivity in entries 7–10 is due to poor nucleophilicity of Ni–enolates. The Ni₂–1catalyst was also applicable to N-Boc oxindole 2i, giving product 3i in 99% yield and 80% ee after 24 h. To demonstrate the synthetic utility of the reaction, transformation of the products was performed (Scheme 1). Reduction of 3c with RANEY® Ni under H₂ (1 atm) in the presence of Boc₂O gave γ^2,2-amino ester 4c in 72% yield. Reduction of 3a with Pd/C under H₂ (1 atm) in MeOH gave bicyclic amino ester, which was isolated after Boc-protection in 82% yield (5a, 2 steps).

Scheme 1 Transformation of 1,4-adducts.

Table 2 Catalytic asymmetric 1,4-addition of β-keto esters 2 to nitroethylene^a

Entry	2	cat. (x mol%)	Time/h	% Yield^b	% ee^c
a The reactions were run with 1.2 equiv. of nitroethylene (in toluene). b Isolated yield after purification by silica gel column chromatography. c Determined by HPLC analysis.
1		2.5	5	92	93
2		2.5	4.5	92	97
3		1	18	84	87
4		2.5	5	90	98
5		2.5	10	90	94
6		10	18	98	91
7		10	24	73	75
8		10	120	35	85
9		10	126	51	82
10		10	24	99	80

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In the present reaction, we assume that the two Ni centers function cooperatively as observed in other related reactions using Ni₂–1.¹³ The postulated reaction mechanism is summarized in Fig. 2. One of the Ni–O bonds in the outer O₂O₂ cavity is speculated to work as a Brønsted base to generate Ni–enolate in situ.¹⁷ The other Ni in the inner N₂O₂ cavity functions as a Lewis acid to control the position of nitroethylene, similar to conventional metal–salen Lewis acid catalysis. The C–C bond-formation via the transition state (TS in Fig. 2), followed by protonation, affords product and regenerates the Ni₂–1catalyst.

Fig. 2 Postulated catalytic cycle of Ni₂–1-catalyzed 1,4-addition of β-keto esters to nitroethylene.

In summary, we developed a homodinuclear Ni₂–Schiff base-catalyzed enantioselective 1,4-addition of β-keto esters to nitroethylene. The reaction proceeded with 1–10 mol% catalyst, and products bearing a quaternary carbon stereocenter adjacent to an ester were obtained in 98–75% ee and 99–35% yield (TON = up to 84). Further studies to improve the poor reactivity for acyclic β-keto esters through ligand modification are ongoing.

This work was supported by Takeda Science Foundation, Inoue Science Research Award from Inoue Science Foundation, and Grant-in-Aid for Young Scientists (A) from JSPS. We thank Prof. M. Shibasaki at Institute of Microbial Chemistry, Tokyo and Prof. M. Kanai at the University of Tokyo for their generous supports, fruitful discussion, and unrestricted access to analytical facilities.

Notes and references

1. Recent reviews on catalytic asymmetric construction of quaternary carbon stereocenters: (a) J. Christoffers and A. Baro, Adv. Synth. Catal., 2005, 347, 1473; (b) B. M. Trost and C. Jiang, Synthesis, 2006, 369; (c) P. G. Cozzi, R. Hilgraf and N. Zimmermann, Eur. J. Org. Chem., 2007, 5969.
2. General reviews on asymmetric 1,4-addition to electron-deficient alkenes with metal catalysis: (a) J. Christoffers, G. Koripelly, A. Rosiak and M. Rössle, Synthesis, 2007, 1279; With organocatalysis: (b) S. B. Tsogoeva, Eur. J. Org. Chem., 2007, 1701.
3. A review on asymmetric 1,4-addition to nitroalkenes: O. M. Berner, L. Tedeschi and D. Enders, Eur. J. Org. Chem., 2002, 1877.
4. (a) Y. Chi, L. Guo, N. A. Kopf and S. H. Gellman, J. Am. Chem. Soc., 2008, 130, 5608; (b) M. Wiesner, J. D. Revell, S. Tonazzi and H. Wennemers, J. Am. Chem. Soc., 2008, 130, 5610.
5. T. Bui, S. Syed and C. F. Barbas, III, J. Am. Chem. Soc., 2009, 131, 8758.
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7. A general review on asymmetric synthesis of γ-amino acids: M. Ordóñez and C. Cativiela, Tetrahedron: Asymmetry, 2007, 18, 3.
8. For diastereoselective 1,4-addition of a chiral enamino ester derived from a cyclic β-keto ester and chiral amine to nitroethylene, see: J. d'Angelo, C. Cavé, D. Desmaële, A. Gassama, C. Thominiaux and C. Riche, Heterocycles, 1998, 47, 725.
9. For alternative highly enantioselective catalytic asymmetric approaches to γ^2,2-amino acids with α-quaternary carbon stereocenters via ring-opening reactions of aziridines and cyclic sulfamidates with β-keto esters, see: (a) T. A. Moss, D. R. Fenwick and D. J. Dixon, J. Am. Chem. Soc., 2008, 130, 10076; (b) M. W. Paixão, M. Nielsen, C. B. Jacobsen and K. A. Jørgensen, Org. Biomol. Chem., 2008, 6, 3467; (c) T. A. Moss, B. Alonso, D. R. Fenwick and D. J. Dixon, Angew. Chem., Int. Ed., 2010, 49, 568.
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11. For a general review on bimetallic Schiff base catalysts: R. M. Haak, S. J. Wezenberg and A. W. Kleij, Chem. Commun., 2010, 46, 2713.
12. Co₂–1catalyst for 1,4-addition of β-keto esters to β-substituted nitroalkenes: (a) M. Furutachi, Z. Chen, S. Matsunaga and M. Shibasaki, Molecules, 2010, 15, 532; (b) Z. Chen, M. Furutachi, Y. Kato, S. Matsunaga and M. Shibasaki, Angew. Chem., Int. Ed., 2009, 48, 2218. Mn₂–1catalyst for 1,4-addition of N-Boc oxindoles to β-substituted nitroalkenes: (c) Y. Kato, M. Furutachi, Z. Chen, H. Mitsunuma, S. Matsunaga and M. Shibasaki, J. Am. Chem. Soc., 2009, 131, 9168.
13. Ni₂–1catalyst: (a) Z. Chen, H. Morimoto, S. Matsunaga and M. Shibasaki, J. Am. Chem. Soc., 2008, 130, 2170; (b) Y. Xu, G. Lu, S. Matsunaga and M. Shibasaki, Angew. Chem., Int. Ed., 2009, 48, 3353; (c) S. Mouri, Z. Chen, S. Matsunaga and M. Shibasaki, Chem. Commun., 2009, 5138; (d) S. Mouri, Z. Chen, H. Mitsunuma, M. Furutachi, S. Matsunaga and M. Shibasaki, J. Am. Chem. Soc., 2010, 132, 1255; For the use of Ni₂–1catalyst in 1,4-addition to β-substituted nitroalkenes with other donors: (e) N. E. Shepherd, H. Tanabe, Y. Xu, S. Matsunaga and M. Shibasaki, J. Am. Chem. Soc., 2010, 132, 3666; (f) Y. Xu, S. Matsunaga and M. Shibasaki, Org. Lett., 2010, 12, 3246.
14. Heterobimetallic transition metal/rare earth metal Schiff base catalysts: (a) S. Handa, V. Gnanadesikan, S. Matsunaga and M. Shibasaki, J. Am. Chem. Soc., 2007, 129, 4900; (b) S. Handa, K. Nagawa, Y. Sohtome, S. Matsunaga and M. Shibasaki, Angew. Chem., Int. Ed., 2008, 47, 3230; (c) H. Mihara, Y. Xu, N. E. Shepherd, S. Matsunaga and M. Shibasaki, J. Am. Chem. Soc., 2009, 131, 8384; (d) S. Handa, V. Gnanadesikan, S. Matsunaga and M. Shibasaki, J. Am. Chem. Soc., 2010, 132, 4925.
15. For selected examples of related bifunctional bimetallic Schiff base complexes in asymmetric catalysis from other groups, see: (a) V. Annamalai, E. F. DiMauro, P. J. Carroll and M. C. Kozlowski, J. Org. Chem., 2003, 68, 1973 and references therein; (b) M. Yang, C. Zhu, F. Yuan, Y. Huang and Y. Pan, Org. Lett., 2005, 7, 1927; (c) J. Gao, F. R. Woolley and R. A. Zingaro, Org. Biomol. Chem., 2005, 3, 2126; (d) W. Li, S. S. Thakur, S.-W. Chen, C.-K. Shin, R. B. Kawthekar and G.-J. Kim, Tetrahedron Lett., 2006, 47, 3453; (e) C. Mazet and E. N. Jacobsen, Angew. Chem., Int. Ed., 2008, 47, 1762; (f) J. Park, K. Lang, K. A. Abboud and S. Hong, J. Am. Chem. Soc., 2008, 130, 16484; (g) W. Hirahata, R. M. Thomas, E. B. Lobkovsky and G. W. Coates, J. Am. Chem. Soc., 2008, 130, 17658; (h) B. Wu, J. C. Gallucci, J. R. Parquette and T. V. RajanBabu, Angew. Chem., Int. Ed., 2009, 48, 1126; For related early studies with dinuclear Ni₂–Schiff base complexes as epoxidation catalysts, see also: (i) T. Oda, R. Irie, T. Katsuki and H. Okawa, Synlett, 1992, 641; For other examples, see ref. 11.
16. The absolute configuration of 3b was determined by comparing with the reported data in ref. 9c after conversion into known γ^2,2-amino ester. See ESI†.
17. ¹H NMR analysis of the bimetallic Ni₂–1 complex does not show any peaks, suggesting that at least one of Ni metal centers has non-planar coordination mode. Based on the molecular model, we assume that the outer Ni center has cis-β configuration due to strain of the bimetallic complex. In other words, one of the Ni–O bonds of the outer Ni center is speculated to be in apical position. Thus, the weak Ni–O bond would work as a Brønsted base to deprotonate β-keto esters to give the Ni–enolate intermediate. Detailed mechanistic studies to clarify the role of two Ni metal centers are ongoing. For the utility of cis-β metal complexes of salens in asymmetric catalysis, see a review: T. Katsuki, Chem. Soc. Rev., 2004, 33, 437.

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Footnote

† Electronic supplementary information (ESI) available: General experimental information, spectral data of new compounds, and copies of NMR spectral data. See DOI: 10.1039/c0cc02152k

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