Highly enantioselective Michael reaction employing cycloheptanone and cyclooctanone as nucleophiles

Abstract

An organocatalytic Michael reaction of cycloheptanone and cyclooctanone with nitrodienes and nitroolefins catalyzed by a hydroquinine-based primary amine catalyst has been accomplished. The corresponding Michael adducts were obtained in good yields (up to 88%) with good to excellent diastereoselectivities (up to >100 : 1) and enantioselectivities (up to >99% ee). The absolute configuration of the Michael product was assigned by TDDFT simulation of the ECD spectrum. And the Michael products can be readily converted into analogues of cycloalkano[b] fused pyrrolidines.

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Introduction

Over the past decade, chemists have witnessed a rapid development in organocatalysis, a powerful and attractive field involving the synthesis of chiral building blocks, natural products, and biologically active compounds using inexpensive and environmentally benign organocatalysts under mild conditions. Numerous elegant enantiocontrol organocatalytic methodologies have been developed.¹ The Michael reaction has been widely used to build valuable carbon–carbon bonds in modern organic chemistry.² Accordingly, the asymmetric organocatalytic Michael reaction has attracted considerable attention, and significant progress has been widely made over the past 10 years with a diverse combination of Michael donors and acceptors.³ Specifically, the asymmetric organocatalytic Michael addition of carbonyl compounds to nitroalkenes has stimulated extensive interest because the chiral adducts (γ-nitrocarbonyl compounds) serve as key precursors of various key complex organic targets.⁴

Therefore, much effort has been directed to determine new transformations to prepare these powerful intermediates.⁵ To date, poor enantioselectivity has been achieved in most cases when cycloheptanone or cyclooctanone serves as the Michael donor.⁶ Recently, Wang reported one example of secondary amine catalysed asymmetric Michael addition of cycloheptanone with nitroolefin, giving excellent enantioselectivity.^6e However, numerous biologically active compounds, both naturally occurring and artificial, contain complex seven- and eight-membered carbocycles in their core structures, such as cycloalkano[b]fused pyrrolidines (Fig. 1)⁷ and α-methylene butyrolactones.⁸ Consequently, the development of an efficient organocatalytic method for the Michael reaction of cycloheptanone and cyclooctanone with electrophiles with high enantioselectivity remains challenging and indispensable.

Fig. 1 Examples of biologically active compounds containing seven- and eight-membered carbocycles.

Results and discussion

We initiated our study using catalyst 3 for the Michael reaction of cycloheptanone 1a with nitrodiene 2a (Scheme 1).⁹Table 1 shows that the secondary amine catalysts L-prolinol 3a, L-proline 3b, Jørgensen-Hayashi catalyst 3c, and MacMillan catalyst 3d were almost completely inactive (entries 1 to 4) for the Michael transformation. The multifunctional Xu catalysts 3e and 3f led to moderate catalytic activity (10% and 52% yield) and good enantioselectivity (70% ee and 67% ee) (entries 5 and 6). The chiral primary amine catalyst 3g and the chiral primary amine-thiourea bifunctional catalyst 3h could not promote the reaction (entries 7 and 8). By contrast, higher selectivity was obtained using the Cinchona alkaloid-based primary amine catalysts 3i, 3j, 3k, 3l, and 3m,¹⁰ which promoted the formation of 5a with high diastereoselectivity (9 : 1 dr to 29 : 1 dr) and enantioselectivity (67% ee to 88% ee), although low yields (11% to 19%) were obtained (entries 9 to 13). The loadings of catalysts 3i, 3k, and 3m were then verified, and the results showed that the yield increased with increasing catalyst loading. The yield and enantioselectivity increased from 19% and 86% ee to 73% and 89% ee, respectively, when the loading amount of catalyst 3m increased from 20 mol% to 50 mol% (entries 13 to 18). Additionally, increasing the reaction temperature led to higher yield but lower selectivity (entry 19 vs. entry 17). Notably, xylene and PhCO₂H were found to be the comparatively suitable solvent and additive, respectively, among a series of organic solvents and acids (see the ESI†).¹¹ Thus, an efficient catalyst 3m/PhCO₂H/xylene system was developed for the highly enantioselective Michael reaction.

Scheme 1 The catalysts used in this study.

Table 1 Catalyst screening and reaction optimization^a

Entry	Catalyst	T (°C)	Yield^d (%)	dr^e (anti : syn)	ee^e (%) (anti)
a Unless otherwise stated, the reaction was conducted by stirring in xylene (0.5 ml) using 1a (0.5 mmol) and 2a (0.13 mmol) with 20 mol% catalyst 3 and 20 mol% PhCO2H 4a at room temperature. b 30 mol% catalyst 3 and 30 mol% PhCO2H 4a were used. c 50 mol% catalyst 3 and 50 mol% PhCO2H 4a were used. d Isolated yield. e Determined by HPLC analysis on a Chiralcel AS-H. f The opposite configuration.
1	3a	25	5<	n.d.	n.d.
2	3b	25	Trace	n.d.	n.d.
3	3c	25	Trace	n.d.	n.d.
4	3d	25	Trace	n.d.	n.d.
5	3e	25	10	4 : 1	70
6	3f	25	52	3 : 1	67
7	3g	25	Trace	n.d.	n.d.
8	3h	25	Trace	n.d.	n.d.
9	3i	25	16	24 : 1	85^f
10	3j	25	12	9 : 1	69^f
11	3k	25	11	29 : 1	88
12	3l	25	12	9 : 1	67
13	3m	25	19	13 : 1	86
14^b	3i	25	23	8 : 1	83^f
15^b	3k	25	25	8 : 1	89
16^b	3m	25	37	11 : 1	88
17^c	3k	25	48	6 : 1	90
18^c	3m	25	73	7 : 1	89
19^c	3k	50	70	4 : 1	83

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The scope of the reaction with respect to nitrodiene was explored using the established optimized reaction conditions (Table 2). With cycloheptanone 1a, aryl and alkyl substituents were well tolerated on nitrodiene reactants and provided the respective Michael product 5a–l with moderate to high yields (60% to 88%), diastereoselectivities (2 : 1 to 9 : 1 dr), and enantioselectivities (78% to 91% ee) (entries 1 to 12). Apparently, electron-donating and electron-withdrawing substituents on the aromatic ring of the nitrodienes had limited effect on yield and selectivity (entries 1 to 9). Accordingly, the nitrodiene scope was further explored using cyclooctanone 1b as the substrate (entries 13 to 18). In this case, various nitrodiene derivatives with different substitution patterns on the aromatic ring all provided the expected products 5m to 5q with excellent levels of diastereoselectivity (23 : 1 to 99 : 1 dr) and enantioselectivity (91% to 94% ee) (entries 13 to 17). Notably, alkyl-substituted nitrodiene could also be used as a reaction partner, and the product 5r was obtained in 83% yield with 99 : 1 dr and 99% ee (entry 18). Compared with the previous results with 1a, the use of 1b as the substrate generally led to enhanced diastereoselectivities and enantioselectivities.

Table 2 Substrate scope of nitrodienes in Michael reaction^a

Entry	n/1	R^1	Product	Yield^c (%)	dr^d (anti : syn)	ee^d (%) (anti)
a Unless otherwise stated, the reaction was conducted by stirring in xylene (0.5 ml) using 1 (0.5 mmol) and 2 (0.13 mmol) with 30 mol% catalyst 3m and 30 mol% PhCO2H 4a at room temperature. In the case of racemic samples, 50 mol% pyrrolidine and 50 mol% PhCO2H 4a were used. b 50 mol% catalyst 3m and 50 mol% PhCO2H 4a were used. c Isolated yield. d Determined by HPLC analysis.
1	1/1a	C6H5	5a	73	7 : 1	89
2	1/1a	4-MeC6H4	5b	72	8 : 1	90
3	1/1a	4-MeOC6H4	5c	67	7 : 1	87
4	1/1a	4-FC6H4	5d	80	7 : 1	89
5	1/1a	4-ClC6H4	5e	75	6 : 1	90
6	1/1a	4-BrC6H4	5f	62	6 : 1	88
7	1/1a	3-FC6H4	5g	78	7 : 1	86
8	1/1a	3-ClC6H4	5h	75	6 : 1	91
9	1/1a	3-BrC6H4	5i	60	6 : 1	86
10	1/1a	Pr	5j	84	8 : 1	80
11	1/1a	iPr	5k	78	9 : 1	83
12	1/1a	CO2Et	5l	88	2 : 1	78
13	2/1b	C6H5	5m	45	23 : 1	92
14	2/1b	4-MeC6H4	5n	41	47 : 1	93
15	2/1b	4-FC6H4	5o	23	99 : 1	91
16	2/1b	4-ClC6H4	5p	37	99 : 1	92
17	2/1b	4-BrC6H4	5q	23	26 : 1	94
18	2/1b	iPr	5r	83	99 : 1	99

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The macrocyclic ketones 1c and 1d could also readily participate in the Michael transformation as nucleophiles, which resulted in the additional products 5s and 5t with high ee values of 98% and 94% and dr values of 83 : 1 and 10 : 1, respectively. Acyclic ketone 1e also served as a suitable carbon nucleophile for the Michael reaction, and afforded the corresponding adduct 5u with good results in terms of yield (67%), diastereoselectivity (9 : 1 dr), and enantioselectivity (96% ee).

With the above success, the reaction scope was further extended to nitroolefins. As illustrated in Table 3, the reaction of cycloheptanone 1a or cyclooctanone 1b with nitroolefins were performed under the above optimal reaction conditions. The reactions proceeded smoothly in moderate to high yields (up to 84% yield), high to excellent diastereoselectivities (up to >100 : 1 dr) and good to excellent enantioselectivities (up to >99 ee) (entries 1 to 15). It is noteworthy that reactions between 1b and nitroolefins gave better results than those nitrodienes that were used as the nucleophiles (Table 3, entries 9 to 15 vs.Table 2, entries 13 to 18), and reactions between 1a and nitroolefins obtained better diastereoselectivities than those between 1a and nitrodienes (Table 3, entries 1 to 8 vs.Table 2, entries 1 to 9). The reactions of β-disubstituted nitroalkenes including β-methyl nitroalkene (Table 3, entries 16 and 17) reacted successfully to give the corresponding products 7p and 7q in good to high diastereoselectivities with high to excellent enantioselectivities (Scheme 2).

Table 3 Substrate scope of nitroolefins in Michael reaction^a

Entry	n/1	R^2	R^3	Product	Yield^c (%)	dr^d (anti : syn)	ee^d (%) (anti)
a Unless otherwise stated, the reaction was conducted by stirring in xylene (0.5 ml) using 1 (0.5 mmol) and 6 (0.13 mmol) with 30 mol% catalyst 3m and 30 mol% PhCO2H 4a at room temperature. In the case of racemic samples, 50 mol% pyrrolidine and 50 mol% PhCO2H 4a were used. b 50 mol% catalyst 3m and 50 mol% PhCO2H 4a were used. c Isolated yield. d Determined by HPLC analysis.
1	1/1a	C6H5	H	7a	70	19 : 1	89
2	1/1a	4-MeC6H4	H	7b	69	30 : 1	84
3	1/1a	4-MeOC6H4	H	7c	84	20 : 1	90
4	1/1a	4-FC6H4	H	7d	76	38 : 1	92
5	1/1a	4-ClC6H4	H	7e	79	24 : 1	87
6	1/1a	4-BrC6H4	H	7f	79	38 : 1	83
7	1/1a	3-MeOC6H4	H	7g	75	22 : 1	81
8	1/1a	3-BrC6H4	H	7h	50	57 : 1	86
9	2/1b	C6H5	H	7i	67	86 : 1	99
10	2/1b	4-MeC6H4	H	7j	60	59 : 1	95
11	2/1b	4-MeOC6H4	H	7k	57	>100 : 1	99
12	2/1b	4-FC6H4	H	7l	39	43 : 1	99
13	2/1b	4-BrC6H4	H	7m	54	26 : 1	99
14	2/1b	3-ClC6H4	H	7n	58	>100 : 1	>99
15	2/1b	3-BrC6H4	H	7o	50	16 : 1	98
16	1/1a	C6H5	Me	7p	34	3 : 1	93
17	2/1b	C6H5	Me	7q	38	8 : 1	99

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Scheme 2 Further investigation of the substrate scope.

The absolute configuration (AC) of the Michael product 5a was determined to be S, S by comparing the experimental CD spectrum with the results of time-dependent density functional theory (TDDFT) calculations of electronic circular dichroism (ECD) spectra.^11,12 As shown in Fig. 2 (Fig. S6, ESI†), in the selected data in the 200–390 nm UV region, the experimental CD spectrum is consistent with the calculated data of 1-SS. Then, a transition state model was proposed (Scheme 3). Nitrodiene 2a was activated well through the hydrogen-bonding interaction between the protonated bridgehead nitrogen atom of 3m and the nitro group of 2a. Therefore, the enamine formed from 3m and 1a attacked the activated 2a from the S_i face to afford the major stereoisomer of Michael adduct 5a with the configuration of (S, S).

Fig. 2 Experimental (dotted trace) and calculated ECD spectra (full trace) of the Michael product 5a.

Scheme 3 Proposed transition state for the reaction.

The enantioselective Michael reaction can be performed successfully on the gram-scale to obtain 2.09 g of 5a (73% yield) with the same diastereoselectivity and enantioselectivity under modified conditions (Scheme 4). The synthetic utility of this Michael reaction was also demonstrated in the synthesis of chiral cycloalkano[b]fused pyrrolidine 9a (Scheme 4).¹³ The transformation involves the Zn/HCl-mediated reductive cyclization of adduct 5a to obtain imine 8a in 95% yield. A reduction of imine 8a with NaBH₄ followed by Bn protection resulted in 9a with good overall yield and without racemization.

Scheme 4 Enantioselective gram-scale synthesis of 5a, and derivatization of Michael adduct 5a to cycloalkano[b]fused pyrrolidine 9a.¹¹

Conclusions

In summary, an organocatalytic enantioselective Michael reaction of nucleophiles, cycloheptanone or cyclooctanone, with nitrodienes and nitroolefins catalyzed by hydroquinine-based primary amine catalysts has been established. The corresponding adducts were obtained in good yields (up to 88%) with good to excellent diastereoselectivities (up to >100 : 1 dr) and good to excellent enantioselectivities (up to >99% ee). The product can be readily converted into analogs of cycloalkano[b] fused pyrrolidines, which further enhances the utility of this transformation for the synthesis of potentially valuable chiral molecules.

Experimental section

General information

The ¹H NMR and ¹³C NMR spectra were recorded in deuterated solvents and are reported in ppm relative to tetramethylsilane. GC-MS experiments were performed on a GC system with a mass selective detector. HRMS data were measured using a TOF mass spectrometer. Column chromatography and flash chromatography experiments were performed on silica gel (200–300 mesh) eluting with ethyl ether and petroleum ether. TLC experiments were carried out on glass-backed silica plates. In each case, the enantiomeric ratio was determined on a chiral column in comparison with authentic racemates by chiral HPLC. Chemicals were used without purification as commercially available. Nitrodienes¹⁴ and organocatalysts 3d,¹⁵3e–3f,¹⁶3h,¹⁷3i–3l,¹⁸3m¹⁹ were synthesized according to literature.

Typical experimental procedure for the Michael reaction

Xylene (0.5 mL) was added to a mixture of cycloheptanone 1a or cyclooctanone 1b (0.5 mmol) with nitrodienes 2 or nitroolefins 6 (0.126 mmol) in the presence of a 30 mol% or 50 mol% catalyst 3m and 30 mol% or 50 mol% PhCO₂H 4a at room temperature with vigorous stirring. The reaction conversion was monitored by GC-MS. After three days, the reaction mixture was extracted with DCM, washed with water, dried and concentrated. The residue was purified by flash chromatography on silica gel (ether/petroleum ether = 1 : 4 to 1 : 2 as an eluent) to give the slightly white solid of the Michael addition products 5a–5i, 5m–5q, 7a–7b, 7e–7f, 7i–7k, 7n–7q, the slightly yellow liquid products 5j–5l, 5r, 7g and colorless oil 7c, 7l. The enantiomeric excesses (% ee) were determined by HPLC analysis using chiral stationary phases.

Acknowledgements

This work was supported by the NSFC (21202149), the Zhejiang Natural Science Foundation (Y4110348), the Foundation of Zhejiang Education Committee (Y201225109), the Foundation of Zhejiang Key Course of Chemical Engineering and Technology, and the Foundation of Zhejiang Key Laboratory of Green Pesticides and Cleaner Production Technology.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures, characterization, NMR spectra and HPLC spectra. See DOI: 10.1039/c4nj01206b

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