Streocontrolled Construction of Six Vicinal Stereogenic Centers on Spiropyrazolones via Organocascade Michael/Michael/1,2-Addition Reactions

Abstract

A highly stereoselective one-pot procedure for the synthesis of spiropyrazolone derivatives bearing six contiguous stereogenic centers including two tetrasubstituted carbons has been developed. Under sequential catalysis by two organocatalysts, a cinchona-derived aminosquaramide and DBU, a series of diversely functionalized spiropyrazolones are obtained in good yields (47–62%) and excellent stereoselectivities (up to >25:1 dr and 98–99% ee). The opposite enantiomers of the spiropyrazolones are also accessible by employing a pseudoenantiomeric aminosquaramide catalyst.

Graphical Abstract

The synthesis of pyrazolone derivatives has attracted considerable attention in recent years due to their wide spectrum of applications in dye, analytical, and pharmaceutical chemistry.^1,2 Edaravone (A), a neuroprotective agent, and metamizole (B), an effective analgesic and antipyretic agent, are two important pharmaceutically valuable pyrazolones (Figure 1).^1c–f In addition to these, the pyrazolone derivatives such as C exhibit HIV inhibition activity.^1g Recently, the pyrazolones were found to be inhibitors of the CD80 protein and also possess potent activity in inhibiting protease-resistant prion protein accumulation, cytokines, and p38 kinases.^1h–k Pyrazol-3-one derivatives have also been studied as multidrug resistance modulators.^1l

Figure 1.

Biologically active pyrazolone derivatives.

On the other hand, spirocyclic frameworks frequently found in many synthetic bioactive compounds and natural products fascinated many researchers to develop synthetic strategies for their construction. Because of their complex three-dimensional structure, the stereoselective synthesis of spirocyclic molecules from simple precursors in an atom-economic fashion is considered as a tough challenge.³ Recently, the organocatalytic cascade/domino reactions emerged as an efficient strategy to provide such complex structures in an operationally simple one-pot procedure,⁴ and we have witnessed tremendous growth in the asymmetric synthesis of spirocyclic oxindole derivatives especially employing organocascade sequences.⁵ Despite the many important applications of the pyrazolone moiety, the catalytic asymmetric synthesis of spiropyrazolones is less explored.

The Rios group reported the asymmetric synthesis of spiropyrazolones bearing three contagious stereogenic centers via a secondary amine catalyzed domino reaction (Scheme 1).⁶ Rios and co-workers were also able to construct four stereocenters on a spiropyrazolones in a three-component domino reaction.⁷ The cinchona-derived primary amines were found to catalyze the domino Michael/Michael reaction of the enones with the pyrazolones⁸ and the unsaturated pyrazolones⁹ to afford the spirocyclohexanonepyrazolones with three consecutive stereogenic centers. Recently, spiropyrazolones bearing an N-heterocyclic ring with three adjacent stereogenic centers were synthesized by aminothioureas¹⁰ and quinine¹¹ catalyzed domino Michael/cyclization reactions.

Scheme 1. Catalytic Enantioselective Strategies for the Synthesis of Spiropyrazolone Derivatives.

To the best of our knowledge, the asymmetric synthesis of spirocyclohexanepyrazolones bearing more than four stereocenters are not known. We took up this challenge and developed a one-pot protocol for the asymmetric synthesis of the spiropyrazolones bearing as many as six stereogenic centers including two adjacent tetrasubstituted ones. It was envisaged that an organocascade sequence involving a stereoselective Michael/Michael/1–2-addition reaction between β-dicarbonyl compounds 1, nitroalkenes 2, and unsaturated pyrazolones 3 mediated by sequential organocatalysis¹² using a chiral bifunctional organocatalyst¹³ and an achiral base could afford such highly functionalized spiropyrazolones (Scheme 1).

To attain our objective at the onset, we performed a one-pot reaction that involved a quinine-derived squaramide (1 mol %) catalyzed Michael addition of ethyl acetoacetate (1a) to (E)-β-nitrostyrene (2a) in dichloromethane. After 24 h, the unsaturated pyrazolone 3a and a guanidine base TBD (20 mol %) in dichloromethane were added sequentially. To our delight, the desired spiropyrazolone bearing four tertiary and two tetrasubstituted stereogenic centers was obtained in a good yield of 41% and excellent enantio- (99% ee) and diastereoselectivity (>25:1 dr) (Table 1, entry 1). The screening of other achiral bases (entries 2–6) showed that the DBU provides the best yield as well as excellent stereoselectivity (entry 2). The screening of solvents such as chloroform, toluene, and THF did not result in any improvement in the product yield (entries 7–9). Further efforts for optimizing the yield of 4a by increasing the catalyst loading of DBU revealed that with 50 mol % DBU a better yield was observed; however, a further increase in the amount of DBU did not show any improvement in the product yield. Using 2 equiv of 3 the spiropyrazolone 4 was isolated in maximum yield of 60% with excellent stereoselectivity (entries 13 and 14).

Table 1. Optimization of the Reaction Conditions for the Asymmetric Synthesis of the Spiropyrazolone 4a^a.

entry	base (x mol %)	solvent	yieldb (%)	eec (%)
1	TBD (20)	CH2Cl2	41	99
2	DBU (20)	CH2Cl2	44	99
3	DBN (20)	CH2Cl2	43	99
4	DABCO (20)	CH2Cl2	12	99
5d	piperidine (20)	CH2Cl2	14	98
6d	pyrrolidine (20)	CH2Cl2	12	98
7	DBU (20)	CHCl3	35	99
8	DBU (20)	toluene	34	99
9	DBU (20)	THF	35	99
10	DBU (30)	CH2Cl2	46	99
11	DBU (50)	CH2Cl2	52	99
12e	DBU (100)	CH2Cl2	36	99
13f	DBU (30)	CH2Cl2	57	99
14f	DBU (50)	CH2Cl2	60	99

^aReaction conditions: 0.2 mmol of 1a, 0.2 mmol of 2a, 1 mol % of I, 0.24 mmol of 3a, and x mol % of base (0.1 M in solvent).

^bYield of isolated 4a after flash column chromatography.

^cEnantiomeric excess of the major diastereomer (>25:1 dr) determined by HPLC analysis on a chiral stationary phase.

^dThe reaction was run for 96 h in the second step.

^eThe reaction was run for 0.5 h in the second step.

^f0.40 mmol of 3a was used.

Armed with optimized conditions, we further evaluated the substrate scope on a 0.5 mmol scale (Table 2). Various pyrazolone-derived olefins bearing electron-withdrawing and electron-releasing substituents at the different aromatic position reacted efficiently under the standard reaction conditions to afford the desired spiropyrazolones 4b–i in good yields and excellent enantio- and diastereoselectivities (entries 2–9). The heteroaromatic pyrazolone derivative was also tolerated under this one-pot organocascade procedure, thus resulting in the desired spiropyrazolone 4j in 55% yield with excellent ee (entry 10). The unsaturated pyrazolone bearing an o-chlorophenyl group gives 47% yield of product 4k with 99% ee (entry 11).

Table 2. Substrate Scope of the Asymmetric Synthesis of Spiropyrazolones 4 with Catalyst I^a.

entry	R1	R2	R3	R4	4	yieldb (%)	eec (%)
1	OEt	Ph	Ph	Ph	4a	62	99
2	OEt	Ph	4-ClC6H4	Ph	4b	58	99
3	OEt	Ph	4-BrC6H4	Ph	4c	62	99
4	OEt	Ph	4-CF3C6H4	Ph	4d	61	99
5	OEt	Ph	3-ClC6H4	Ph	4e	60	99
6	OEt	Ph	4-MeC6H4	Ph	4f	52	99
7	OEt	Ph	4-MeOC6H4	Ph	4g	57	99
8	OEt	Ph	2-MeC6H4	Ph	4h	55	99
9	OEt	Ph	3-MeOC6H4	Ph	4i	57	99
10	OEt	Ph	2-thienyl	Ph	4j	55	99
11	OEt	Ph	Ph	2-ClC6H4	4k	47	99
12	OEt	4-FC6H4	Ph	Ph	4l	57	99
13	OEt	4-ClC6H4	Ph	Ph	4m	58	99
14	OEt	4-MeC6H4	Ph	Ph	4n	56	98
15	OEt	4-MeOC6H4	Ph	Ph	4o	56	99
16d	OEt	2-furanyl	Ph	Ph	4p	55	99
17	OEt	2-thienyl	Ph	Ph	4q	59	99
18	OMe	Ph	Ph	Ph	4r	57	99
19	Me	Ph	Ph	Ph	4s	53	99

^aReaction conditions: 0.5 mmol of 1, 0.5 mmol of 2, 1 mol % of I, 1.0 mmol of 3, and 50 mol % of DBU (0.1 M in CH₂Cl₂).

^bYield of the isolated product after flash column chromatography.

^cEnantiomeric excess of the major diastereomer (>25:1 dr).

^d12:1 dr.

Different aromatic nitroalkenes bearing electron-withdrawing as well as electron-donating substituents also allowed an efficient access to the spiropyrazolones 4l–o in good yield and excellent ee of 98–99% (entries 12–15). The nitroalkenes bearing heteroaromatic groups also provide the desired adducts 4p and 4q in good yields and excellent stereoselectivities (entries 16 and 17). We also tried other dicarbonyl compounds such as methyl acetoacetate and acetylacetone, which efficiently reacted under this one-pot protocol to afford the adducts 4r and 4s in 57% and 53% yield and 99% ee (entries 18 and 19).

After generating two tetrasubstituted adjacent carbon atoms on the spiropyrazolone, we tried to create three consecutive tetrasubstituted carbons by employing a trisubstituted β-ketoester. A one-pot organocatalytic sequence promoted by I and DBU between the β-ketoester 5, (E)-β-nitrostyrene (2a), and pyrazolone 3a provided the spiropyrazolone 6 bearing three contiguous tertiary and three tetrasubstituted stereogenic centers in excellent stereoselectivity (>25:1 dr and 95% ee), albeit in a low yield of 16% (Scheme 2).

Scheme 2. Asymmetric Synthesis of Spiropyrazolone with Three Contiguous Tetrasubstituted Stereocenters.

The absolute configuration of the spiropyrazolones 4a–s could be assigned as (1R), (2S), (3S), (4S), (5S), and (6R) based on the X-ray structure of 4c.¹⁴

We have also tested the catalytic potential of aminosquaramide catalyst II derived from quinidine in place of catalyst I to generate the opposite enantiomer of the corresponding product. With catalyst II, various spiropyrazolone derivatives were accessible in good yields and excellent enantio- and diastereoselectivities (Table 3).

Table 3. Substrate Scope of the Asymmetric Synthesis of Spiropyrazolones ent-4 with Catalyst II^a.

entry	R1	R2	R3	ent-4	yieldb (%)	eec (%)
1	OEt	Ph	Ph	ent-4a	61	99
2	OEt	Ph	4-ClC6H4	ent-4b	57	97
3	OEt	Ph	3-ClC6H4	ent-4e	60	98
4	OEt	Ph	4-MeC6H4	ent-4f	50	98
5	OEt	Ph	3-MeOC6H4	ent-4i	57	98
6	OEt	4-FC6H4	Ph	ent-4l	60	97
7	OEt	4-ClC6H4	Ph	ent-4m	57	98
8	OEt	4-MeC6H4	Ph	ent-4n	56	97
9d	OEt	2-thienyl	Ph	ent-4q	61	98
10	OMe	Ph	Ph	ent-4r	59	98

^aReaction conditions: 0.5 mmol of 1, 0.5 mmol of 2, 1 mol % of II, 1.0 mmol of 3, and 50 mol % of DBU (0.1 M in CH₂Cl₂).

^bYield of the isolated product after flash column chromatography.

^cEnantiomeric excess of the major diastereomer (>25:1 dr).

^d10:1 dr.

In order to demonstrate the practical utility of this one-pot protocol, we have performed a gram-scale cascade Michael/Michael/1,2-addition reaction between 1a, 2a, and 3a using a lower loading (0.5 mol %) of catalyst I (Scheme 3). The desired spiropyrazolone 4a was obtained in 59% yield without deteriorating the stereochemical outcome of the reaction.

Scheme 3. Gram-Scale One-Pot Stereoselective Synthesis of Spiropyrazolone 4a.

In conclusion, we have disclosed a one-pot procedure for the synthesis of a new series of potentially biologically important spiropyrazolone derivatives. A variety of spirocyclohexanepyrazolone derivatives bearing six stereocenters including two vicinal tetrasubstituted carbons were obtained in good yields and excellent stereoselectivities via sequential organocatalytic Michael/Michael/1,2-addition reactions facilitated by a low loading of a cinchona-derived amino squaramide and a readily available achiral base. This one-pot cascade sequence can be scaled up without losing the reaction efficiency in terms of product yield and stereoselectivity. The opposite enantiomer of the spiropyrazolones can be also synthesized in good yield and excellent stereoselectivity by employing a pseudoenantiomeric catalyst.