Efficient catalytic enantioselective Nazarov cyclizations of divinyl ketoesters

Abstract

An efficient catalytic enantioselective Nazarov cyclization of divinyl ketoesters was developed using a chiral BOX/Cu(II) complex, which provides facile access to a variety of optically active multi-substituted cyclopent-2-enone esters in 78–95% yields with 78–90% ee.

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Multi-substituted five membered carbocyclic skeletons are widely found in natural products and other biologically active compounds.¹ Nazarov cyclization reaction^2–4 represents one of the most effective methods for the construction of five membered carbocyclic rings, and it has been applied in the total synthesis of many useful natural products.⁵ However, in the asymmetric catalytic Nazarov reaction, which has attracted increasing attention from chemists, it is quite difficult to achieve high enantioselectivity. Only a few successful examples have been reported.^6–9 In 2004, Trauner et al. developed the first highly efficient scandium–pybox catalyzed asymmetric Nazarov reactions of divinyl ketones bearing an oxygen at the α-position of the vinyl nucleophile (Type A, Fig. 1).^6b In 2013, Rawal et al. documented the Cr(III)/salen promoted enantioselective Nazarov cyclizations of dienones (Type A, Fig. 1), giving rise to cyclopentenoids in 80 − 96% ee.^6f In 2010, an elegant bifunctional thiourea promoted organocatalytic asymmetric Nazarov cyclization of diketoesters (Type B, Fig. 1) was realized by Tius et al., affording the α-hydroxycyclopentenones in 42–95% yields with 80–97% ee.^7a In the same year, our group reported a highly regio-, diastereo-, and enantioselective Nazarov reaction of alkoxy divinyl ketoesters (Type C, Fig. 1) catalyzed by a chiral trisoxazoline/copper(II) system.⁸

Fig. 1 Representative substrate types used in Nazarov reaction.

On the other hand, for acyclic divinyl ketoesters (Type D, Fig. 1) as substrates,^10d,e the racemic studies on the Nazarov cyclization¹⁰ have achieved important breakthrough in recent years; however, successful examples of an asymmetric version are still limited. In 2003, Aggarwal et al. developed the first asymmetric Nazarov cyclization promoted by stoichiometric or semi-stoichiometric chiral Cu(II)–pybox complexes, achieving up to 88% enantiomeric excess (eqn (1), Scheme 1).^9a Togni et al. reported a chiral tridentate phosphine Pigiphos/Ni(II) catalyzed process of divinyl ketoesters containing an activated trimethoxyphenyl (TMP) group or a 4-methoxyphenyl (PMP) group, affording the products in 32–97% yields with 45–88% ee after 4–15 days (eqn (2), Scheme 1).^9b Despite these great efforts, challenging problems, such as reactivity, stereoselectivity and substrate scope generality in this process, have not been well resolved yet. Recently, we have developed an efficient catalytic enantioselective Nazarov cyclization of divinyl ketoesters, which provides facile access to the optically active multi-substituted cyclopent-2-enones in high yields with good to excellent ee values (eqn (3), Scheme 1). In this communication, we wish to report the preliminary results.

Scheme 1 Asymmetric Nazarov cyclization of divinyl ketoesters (Type D).

Initially, the enantioselective Nazarov cyclization of substrate 1a was carried out with 20 mol% of copper complex in a chloroform solution at 40 °C. The pyridyl bisoxazolines were documented as effective chiral ligands in the asymmetric Nazarov reactions.^6b,e,9a,c However, as to substrate 1a,¹¹ with L1 the reaction could not occur (entry 1, Table 1). Then we tried to use BOX ligand L2, and found that the cyclization proceeded smoothly producing 2a in 86% yield with 51% ee (entry 2). Changing the solvent to 1,2-dichloroethane (DCE) led to a better level of enantioselectivity (61% ee, entry 3). Next, we turned to investigate a series of BOX ligands bearing various chiral backbones.¹² With the L-Ala derived BOX ligand L3, the product 2a was obtained in 84% yield with 47% ee (entry 4). A more hindered ⁱPr group was beneficial to the enantioselectivity (67% ee, entry 5). However, on continuing to increase the hindrance, L5 led to a dramatic drop of the enantioselectivity (23% ee entry 6). Meanwhile, when the L-Phe derived BOX ligand L6 was employed, 2a was produced in 93% yield with 58% ee (entry 7). Under optimal conditions, we finally found that chiral ligand L7 could promote the reaction very efficiently, affording 2a in 92% yield with 90% ee after 10 h (entry 8), better than pybox/Cu(SbF₆)₂ in both selectivity and catalyst loading. We also examined the counter ion effect of this reaction. As shown in entries 8–10, ClO₄⁻ proved to be the best one. However, when the catalyst loading was further reduced to 10 mmol%, the ee value dropped to 84% ee (entry 11). In order to raise the efficiency of this reaction system, additives were examined. Interestingly, 4 Å molecular sieves destroyed the reaction, while a trace amount of water could promote the reaction to give 92% yield and 90% ee (entry 12 vs. 13).¹³

Table 1 Reaction optimization^a

Entry	Metal salts	L	Solvent	Time (h)	Yield^b (%)	ee^c (%)
a Reactions were carried out with metal salts (0.04 mmol), ligand (0.04 mmol) and 1a (0.2 mmol) in solvent (4.0 mL) under an Ar atmosphere. b Isolated yield. c Determined by chiral HPLC. d The reaction was carried out with 10 mol% catalyst loading. e 4 Å molecular sieves were added. f H2O (0.12 mmol, 2.3 μL) was added.
1	Cu(ClO4)2·6H2O	L1	CHCl3	24	0	—
2	Cu(ClO4)2·6H2O	L2	CHCl3	17	86	51
3	Cu(ClO4)2·6H2O	L2	DCE	14	90	62
4	Cu(ClO4)2·6H2O	L3	DCE	12	84	47
5	Cu(ClO4)2·6H2O	L4	DCE	14	90	67
6	Cu(ClO4)2·6H2O	L5	DCE	16	95	23
7	Cu(ClO4)2·6H2O	L6	DCE	14	93	58
8	Cu(ClO4)2·6H2O	L7	DCE	10	92	90
9	Cu(SbF6)2	L7	DCE	8	94	89
10	Cu(OTf)2	L7	DCE	10	86	88
11^d	Cu(ClO4)2·6H2O	L7	DCE	14	91	84
12^d^,^e	Cu(ClO4)2·6H2O	L7	DCE	24	0	—
13^d^,^f	Cu(ClO4)2·6H2O	L7	DCE	24	92	90

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Under the optimized reaction conditions (entry 8, Table 1), we next investigated the substrate scope (Table 2). Divinyl ketoesters 1b–d bearing the R¹ group with –Br substituted at the para-, meta- and ortho- positions underwent cyclization with high enantioselectivity (85–88% ee) and a decline of the reactivity (entries 2–4). When R¹ was a 4-PhC₆H₅– group, 20% catalyst loading was required to produce the cyclization product 2e in 92% yield with 88% ee (entry 5). Cyclic enone products 2g and 2h bearing both 1- and 2-naphthyl groups could be easily accessed in 89% yield with 86% ee, and in 93% yield with 87% ee, respectively (entries 7 and 8). The catalyst system was even competent with electron deficient substrate 1f, affording the product 2f in 83% yield with 84% ee (entry 6). As to the electron-rich substrates 1i and 1j, the reactions proceeded very fast and were complete within 2 h at room temperature, giving the corresponding products 2i and 2j in high yields with good enantioselectivities (entries 9 and 10). Thus, the current catalyst system is tolerated for both electron rich and poor substrates. In addition, by changing the ester group from ethyl to methyl, both the reactivity and the enantioselectivity are maintained (entry 11). Moreover, for the 4-IC₆H₅ substituted divinyl ketoester 1l, a pleasing result of 87% yield with 90% ee was obtained (entry 12).

Table 2 Substrate scope^a

Entry	R^1; R^2; R^3; R^4	2	Time (h)	Yield^b (%)	ee^c (%)
a Reactions were carried out with Cu(ClO4)2·6H2O (0.02 mmol), L7 (0.02 mmol), 1 (0.2 mmol) and H2O (0.12 mmol) in DCE (4.0 mL) under an Ar atmosphere. b Isolated yield. c Determined by chiral HPLC. d The reaction was carried out with 20 mol% catalyst loading. e The absolute configuration of the major enantiomer is (1R,5S) by the comparison of the reported data.^9c f The reaction was carried out at rt.
1	Ph; Ph; Ph; Et	2a	24	92	90^e
2	4-BrC6H5; Ph; Ph; Et	2b	45	81	88
3	3-BrC6H5; Ph; Ph; Et	2c	55	80	85
4	2-BrC6H5; Ph; Ph; Et	2d	60	78	86
5	4-PhC6H5; Ph; Ph; Et	2e	22	92	84 (88)^d
6	4-CF3C6H5; Ph; Ph; Et	2f	72	83	84
7	1-Naphthyl; Ph; Ph; Et	2g	24	89	86
8	2-Naphthyl; Ph; Ph; Et	2h	24	93	87
9^f	Ph; 4-MeOC6H5; Ph; Et	2i	2	91	78
10^f	Ph; 4-MeOC6H5; 4-MeOC6H5; Et	2j	2	90	82
11	Ph; Ph; Ph; Me	2k	20	95	90
12	4-IC6H5; Ph; Ph; Me	2l	30	87	90

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Interestingly, when substrate 1a′ was employed with the current catalytic system, the absolute configuration of the major enantiomer reversed to (1S,5R), leading to the product 2a′ in 72% ee (Scheme 2). Thus, under the same catalyst system, both the enantiomers could be obtained in terms of changing the Z/E configuration of substrates.

Scheme 2 Control experiment of 1a′.

Fluorine-containing chiral cyclic ketoesters are potentially useful building blocks for the synthesis of natural products and medicines. Ma et al. reported an elegant copper-catalyzed tandem Nazarov cyclization–electrophilic fluorination reaction in the stereoselective synthesis of highly substituted indanones.¹⁴ We found that under mild reaction conditions, compound 2a was easily transferred to fluorine substituted ketoester 3a in 87% yield without loss of optical purity with stereospecific diastereoselectivity (Scheme 3).^7,9c

Scheme 3 Product transformation.

Conclusions

In conclusion, we have developed an efficient catalytic enantioselective Nazarov cyclization of divinyl ketoesters by a chiral BOX/Cu(II) complex, which provides facile access to the optically active cyclopent-2-enone esters with functional diversity in 78–95% yields with 78–90% ee. There are several remarkable features of the method, such as mild reaction conditions, high catalytic efficiency and simple procedure, that make the current reaction practically useful. A study on the application of this method to the total synthesis of natural products is ongoing in our lab.

Acknowledgements

We are grateful for the financial support from the National Natural Sciences Foundation of China (no. 21121062 and 21272250), and the Chinese Academy of Sciences. We thank Dr Xue-bing, Leng (SIOC) and Mr Jie, Sun (SIOC) for X-ray crystal analysis.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures and the characterization data of new compounds. See DOI: 10.1039/c5qo00099h

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