Organocatalytic asymmetric [4 + 2] formal cycloadditions of cyclohexenylidenemalononitriles and enals to construct chiral bicyclo[2.2.2]octanes

Abstract

A highly regio- and stereoselective [4 + 2] formal cycloaddition process of cyclohexenylidenemalononitriles and α,β-unsaturated aldehydes has been developed by the catalysis of a chiral secondary amine, affording a range of bridged bicyclo[2.2.2]octane architectures with high molecular complexity (up to 98% ee, >19:1 d.r.).

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There has been continuing interest in the chemistry of functionalized bridged bicyclo[2.2.2]octanes that exist in a vast array of natural products and drug candidates as outlined in Fig. 1.¹ Since such skeletons have vital applications in the total syntheses of natural products,² developing concise methods to access diversely structured bicyclo[2.2.2]octanes have always triggered much attention in organic chemistry.³ Among them, the [4 + 2] cycloaddition reactions of cyclohexadienes with olefinic dienophiles have provides one of the most straightforward protocols to access these skeletons.⁴ In particular, the in situ generated cross-conjugated dienamine species between 2-cyclohexenones and an amine catalyst, pioneered by Barbas and co-workers,⁵ could perform as HOMO-raised dienes in [4 + 2] cycloadditions with various electron-deficient dienophiles, furnishing bicyclo[2.2.2]octanes in a highly enantioenriched manner (Scheme 1).⁶ However, such catalytic strategy still suffer from relatively narrow substrate scope, and highly reactive dienophiles are generally required.

Fig. 1 Selected natural products containing bicyclo[2.2.2]octane core.

Scheme 1 Organocatalytic asymmetric [4 + 2]-type cycloadditions to access bicyclo[2.2.2]octane frameworks.

The iminium-promoted direct γ-regioselective vinylogous additions of alkylidenemalononitriles to α,β-unsaturated carbonyl compounds have been well established in our previous work.⁷ Inspired by this success, we envisaged that the analogous cyclohexenylidenemalononitriles might act as γ′-regioselective vinylogous donors in the reactions with iminium-activated α,β-unsaturated aldehydes, thus a sequential intramolecular δ-regioselective 1,6-addition⁸ via cascade enamine catalysis would efficiently afford chiral bicyclo[2.2.2]octanes with densely adored substitutions (Scheme 1).⁹

The initial attempts to the potential [4 + 2]-type cycloaddition of cyclohexenylidenemalononitrile 2a and crotonaldehyde 3a by the well-established iminium catalysis of α,α-diphenylprolinol-O-TMS ether 1a ¹⁰ (Table 1) and benzoic acid (BA) were unfortunately unsuccessful at ambient temperature in diverse solvents (Table 1, entry 1). Replacing benzoic acid with basic N,N-diisopropylethylamine (DIPEA) also resulted in no reactions in a spectrum of solvents (entry 2). To our delight, it was found that the desired reaction proceeded very smoothly catalyzed by amine 1a and DIPEA by using MeCN as the solvent. A multifunctional bicyclo[2.2.2]octane 4a was isolated in 87% yield after 12 h and with excellent stereoselectivity (entry 3, 93% ee, >19:1 d.r.). It should be noted that almost no reaction occurred in the absence of DIPEA, indicating that DIPEA is important to the activation of nucleophile 2a. Subsequently, a few chiral secondary amine catalysts were investigated (entries 4–7), and the studies revealed that α,α-diphenylprolinol-O-TES ether 1b was the best choice in term of yield and enantioselectivity. Nevertheless, the reaction of 2a and cinnamaldehyde 3b bearing a β-phenyl group occurred more slowly under the above optimized catalytic conditions, and a significantly decreased enantioselectivity was detected (entry 8). Consequently, we further screened the reaction of donor 2a and cinnamaldehyde 3b with diverse amine catalysts (entries 9–12), and 1a was found to give better enantiocontrol (entry 9). Interestingly, benzoic acid was found to be a superior additive for iminium catalysis, and phenyl substituted bicyclic product 4b was obtained in a high yield after 12 h and with remarkable enantioselectivity (entry 13). It should be noted that acetonitrile was still crucial for the reaction, as almost no conversion was observed in other solvents (entry 14).

Table 1 Screening studies on the [4 + 2] formal cycloadditions of cyclohexenylidenemalononitrile 2a with α,β-unsaturated aldehydes 3^a

Entry	1	3	Additives	Solvents	Time (h)	Yield^b (%)	Ee^c (%)
a Reactions were performed with vinylogous donor 2a (0.1 mmol), α,β-unsaturated aldehyde 3 (0.15 mmol), amine 1 (0.02 mmol), and additive (0.02 mmol) in 1.0 mL of solvent at rt.b Isolated yield.c Determined by chiral HPLC analysis after reduction to the corresponding alcohol with NaBH(OAc)3; d.r. > 19:1 by ^1H NMR analysis.d Toluene, CHCl3, MeCN or THF were screened.e Toluene, CHCl3 or THF were screened.
1	1a	3a	BA	Solvent^d	12	—	—
2	1a	3a	DIPEA	Solvent^e	12	—	—
3	1a	3a	DIPEA	MeCN	12	4a, 87	93
4	1b	3a	DIPEA	MeCN	12	4a, 84	97
5	1c	3a	DIPEA	MeCN	12	4a, 72	96
6	1d	3a	DIPEA	MeCN	12	4a, 84	95
7	1e	3a	DIPEA	MeCN	12	4a, 79	95
8	1b	3b	DIPEA	MeCN	24	4b, 68	84
9	1a	3b	DIPEA	MeCN	24	4b, 75	90
10	1c	3b	DIPEA	MeCN	24	4b, 68	5
11	1d	3b	DIPEA	MeCN	24	4b, 61	42
12	1e	3b	DIPEA	MeCN	24	4b, 75	86
13	1a	3b	BA	MeCN	12	4b, 90	98
14	1a	3b	BA	Solvent^e	12	—	—

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With the screened catalytic conditions in hand, the substrate scope and limitations for the [4 + 2] formal cycloadditions of a variety of cyclohexenylidenemalononitriles 2 and α,β-unsaturated aldehydes 3 were explored. The results are summarized in Table 2. At first, a few alkyl group substituted acroleins were tested under the catalysis of amine 1b and DIPEA in MeCN at ambient temperature. Both 2-pentenal and 2-hexenal smoothly delivered the desired bridged products with good results in reactions with donor 2a (Table 2, entries 2 and 3). Nevertheless, 4-methyl-2-pentenal, bearing a branched β-alkyl group, failed to produce the cycloadduct probably due to steric reason (entry 4). On the other hand, an array of α,β-unsaturated aldehydes with diverse aryl or heteroaryl groups were investigated in reactions with donor 2a under the catalysis of amine 1a and benzoic acid, generally affording the cycloadducts in high yields and with outstanding enantioselectivity (entries 5–13). In addition, enals substituted by a β-2-styryl or phenylethynyl group exhibited high α,β-regioselectivity, and the bicyclo[2.2.2]octanes 4m and 4n with more functional groups were obtained in good data (entries 14 and 15). Unfortunately, a complex reaction was observed when phenylpropiolaldehyde 5 was applied (entry 16). Moreover, a few cyclic α,α-dicyanodienes were prepared and tested in the reactions with cinnamaldehyde 3b. A δ-ethyl substrate 2b gave product 4o in similar stereocontrol (entry 17). Notably, δ-phenylethynyl-substituted donor 2c showed even higher reactivity, while the enantioselectivity was slightly decreased (entry 18). Inversely, the reaction of substrate 2d with δ′,δ′-dimethyl groups proceeded sluggishly, but good data could be produced after a longer time (entry 19). To our disappointment, the application of cyclopentylidenemalononitrile 2e to construct bicyclo[2.2.1] heptane architecture was not successful, and a complex mixture was generated (entry 20).

Table 2 [4 + 2] formal cycloadditions of cyclic α,α-dicyanodienes 2 with α,β-unsaturated aldehydes 3^a

Entry	2	R^2	Conditions	Time (h)	Yield^b (%)	Ee^c (%)
a Reactions were performed with vinylogous donor 2 (0.1 mmol), α,β-unsaturated aldehyde 3 (0.15 mmol) either in conditions A [amine 1b (0.02 mmol) DIPEA (0.02 mmol), in MeCN (1.0 mL)] or conditions B [amine 1a (0.02 mmol), benzoic acid (0.02 mmol), in MeCN (1.0 mL)] at rt.b Isolated yield.c Determined by chiral HPLC analysis after reduction to the corresponding alcohol with NaBH(OAc)3; d.r. > 19:1 by ^1H NMR analysis.d The absolute configuration of the alcohol of 4g was determined by X-ray analysis. The other products were assigned by analogy.
1	2a	Me	A	12	4a, 84	97
2	2a	Et	A	12	4c, 73	91
3	2a	nPr	A	16	4d, 76	93
4	2a	iPr	A	24	—	—
5	2a	Ph	B	12	4b, 90	98
6	2a	4-MeOPh	B	12	4e, 94	95
7	2a	4-MePh	B	12	4f, 83	95
8	2a	3-ClPh	B	12	4g, 91	94^d
9	2a	2-BrPh	B	12	4h, 87	94
10	2a	3,4-Cl2Ph	B	12	4i, 85	96
11	2a	4-NO2Ph	B	12	4j, 90	92
12	2a	2-Pyridinyl	B	12	4k, 94	84
13	2a	2-Furyl	B	12	4l, 93	94
14	2a	2-Styryl	B	18	4m, 79	92
15	2a	Phenylethynyl	B	18	4n, 83	94
16	2a	5	B	12	—	—
17	2b	Ph	B	16	4o, 84	91
18	2c	Ph	B	6	4p, 82	86
19	2d	Ph	B	36	4q, 78	92
20	2e	Ph	B	12	—	—

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As illustrated in Scheme 2, the aldehyde functionality of cycloadduct 4a could be selectively reduced to give alcohol 6 without affecting the unsaturated double bond by using NaBH(OAc)₃ as the reductant. Nevertheless, the activated alkene group of 6 could be smoothly reduced with Hantzsch ester,¹¹ producing product 7 as a single diastereomer.

Scheme 2 Regio- and diastereoselective reduction of 4a.

On the other hand, we found another electron-deficient alkene, nitroolefin 8, could also be applied in the [4 + 2] formal cycloaddition with cyclohexenylidenemalononitrile 2a by the catalysis of a modified cinchona catalyst (DHQD)₂PHAL (hydroquinidine 1,4-phthalazinediyl diether) (Scheme 3).¹² The reaction was conducted in MeCN at ambient temperature, while a nitro-containing bicyclo[2.2.2]octane 9 was obtained in a moderate yield after 2 days and with fair enantioselectivity.

Scheme 3 Asymmetric [4 + 2] formal cycloaddition of vinylogous donor 2a and nitroolefin 8.

Conclusions

We have investigated the application of a new type of multifunctional substrates, cyclohexenylidenemalononitriles, which have been successfully utilized in γ′,δ-regioselective [4 + 2] formal cycloadditions with diversely structured α,β-unsaturated aldehydes by the catalysis of a chiral secondary amine. These reactions proceed in a γ′-regioselecitve vinylogous Michael addition via iminium catalysis, followed by an intramolecular 1,6-addition process via a cascade enamine catalysis.¹³ A spectrum of bicyclo[2.2.2]octane frameworks with dense substitutions were efficiently constructed in excellent yields and stereoselectivity, which might find further application in organic synthesis.

Acknowledgements

We are grateful for the financial support from the NSFC (21122056, 21372160 and 21321061), and 973 Program (2010CB833300).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures, structural proofs, CIF file of enantiopure alcohol of 4g. CCDC 1009387. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4ra07709a

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