Synthesis of 3-substituted 1,5-aldehyde estersvia an organocatalytic highly enantioselective conjugate addition of new carbonylmethyl 2-pyridinylsulfone to enals

Abstract

A highly enantioselective organocatalytic protocol for conjugate addition of new nucleophilic carbonylmethyl 2-pyridinylsulfone to enals has been developed in good yields and with high enantioselectivities. The resulting Michael adducts are versatile building blocks for a variety of organic transformations.

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Despite the fact that chiral 3-substituted 1,5-aldehyde esters are versatile building blocks in organic synthesis, for example, they can be conveniently transformed into synthetically and biologically interesting lactones and lactams,¹ their synthesis remains elusive.²Conjugate additions to enals represent a straightforward approach to the substances and in the past several years impressive organocatalytic approaches have been reported.³ It is noteworthy that in general in these processes, activated methylenes such as malonates,⁴ 1,3-ketoesters,⁵nitroalkanes,⁶ bis-sulfones,⁷ and active thioesters⁸ as nucleophiles are commonly used.⁹ However, the introduction of a more synthetically useful mono-ester (e.g.CH₂CO₂Me) moiety is an unmet synthetic issue.

We envision that introducing a temporary “mask” group such as a sulfone moiety^10–12 instead of a carbonyl can function as a nucleophile, which can be viewed as a CH₂CO₂Me synthon (Scheme 1). The introduction of the sulfone group kills two birds with one stone. It activates the α-carbon of ester allowing for an effective nucleophilic conjugate addition. Moreover, the experience of ours⁹ and several others^10–12 in this area shows that the moiety can be readily removed under mild reaction conditions without affecting enantioselectivity of the end products. Toward this end, a series of carbonylmethyl sulfones 1¹³ including new carbonylmethyl 2-pyridinylsulfone 1a (CMPS) have been developed and explored for the purpose. We have found that the new reagent 1a is the most effective nucleophile in the organocatalytic Michael addition reaction with enals. Notably, high enantioselectivities (89–>99% ee) are achieved. Moreover, the Michel adducts can be conveniently transformed into new functional molecules and the sulfone group can be removed under mild reactions without affecting enantioselectivity of the products. Herein we disclose the results.

Scheme 1 Design of carbonylmethyl sulfones 1 as nucleophiles for organocatalytic Michael reactions of enals.

In our initial efforts, three different methoxycarbonylmethyl heterocyclic sulfones 1a–c, which bear 2-pyridinyl, phenyl and benzothiazoyl sulfone groups, were screened in the reaction with trans-cinnamaldehyde 2a in the presence of diphenylprolinol silyl ether 4a (10 mol%),¹⁴ a commonly used promoter in conjugate addition to enals in THF at rt (Table 1, entries 1–3). We were pleased to find that the novel methoxycarbonylmethyl 2-pyridinylsulfone 1a showed the highest activity among them tested. Even without a base, the reaction proceeded smoothly to provide the desired product 3a in 72% yield and with 95% ee and 8.3 : 1 dr after 48 h (Table 1, entry 1). Screening of solvents revealed that the yield, enantio- and diastereoselectivities of the products varied dramatically (entries 1, 4–6). Among the solvents probed, toluene was of choice for the process (entry 4). In this instance, a high yield (86%), excellent ee (>99%) and good dr (14.3 : 1) were achieved. It was noteworthy that methylene dichloride gave the better dr (20 : 1), but at the expense of the enantioselectivity (91% ee) and yield (53%) (entry 5). When methanol was employed, the yield (90%) was improved but the enantioselectivity (77%) decreased significantly (entry 6). The effect of additives on reactions was also examined (entries 7–9). Among the acids, bases and salts probed, it appeared that they were not beneficial. PhCO₂H and LiCl resulted in decreased dr (entries 7 and 8), while Et₃N reduced the yield (entry 9). Survey of catalysts revealed that the more bulky catalysts 4b–d could promote this reaction by further improving the dr value to an excellent level (dr > 30 : 1) (entries 10–12). Among them, catalyst 4d was the best for the process (Table 1, entry 12). In this case, a high yield (90%), high ee (>99%) and excellent dr (>30 : 1) were obtained. Reducing the loading of 2a from 2.0 equiv. to 1.2 equiv. gave a similar result (entry 14).

Table 1 Optimization of the reaction conditions^a

Entry	1	Cat.	Solvent	Additive	Yield^b (%)	dr^c	ee^d (%)
a Unless stated otherwise, the reaction was carried out with 1 (0.2 mmol), 2a (0.4 mmol), catalyst 4 (0.02 mmol) and additive (0.02 mmol) in 1 mL of solvent at rt for 48 h. b Isolated yield. c The diastereoisomeric ratios were determined by ^1H NMR of products. d Determined by HPLC analysis (Chiralcel AD) by converting to the corresponding methylacetal. e Reaction time: 72 h. f 2a (0.3 mmol) was used. g 2a (0.24 mmol) was used.
1	1a	4a	THF	None	72	8.3 : 1	95
2	1b	4a	THF	None	54	2.3 : 1	91
3^e	1c	4a	THF	None	0	—	—
4	1a	4a	Toluene	None	86	14.3 : 1	100
5	1a	4a	CH2Cl2	None	53	20 : 1	91
6	1a	4a	MeOH	None	90	1.7 : 1	77
7	1a	4a	Toluene	PhCO2H	87	6.7 : 1	>99
8	1a	4a	Toluene	LiCl	91	2.5 : 1	100
9	1a	4a	Toluene	Et3N	80	14.3 : 1	100
10	1a	4b	Toluene	None	40	>30 : 1	100
11	1a	4c	Toluene	None	88	>30 : 1	100
12	1a	4d	Toluene	None	90	>30 : 1	100
13^f	1a	4d	Toluene	None	90	>30 : 1	100
14^g	1a	4d	Toluene	None	90	>30 : 1	100

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Having established optimal reaction conditions, we subsequently explored the scope of the Michael addition of CMPS 1 to structurally diverse α,β-unsaturated aldehydes. As shown in Table 2, a number of trans-cinnamaldehydes bearing electron-donating and electron-withdrawing substituents were successfully applied in the Michael reaction. The corresponding Michael adducts 3a–o were isolated with high to excellent enantioselectivities (89–>99% ee) and in good to excellent yields (54–95%) (entries 1–18). It seems that independent of the electronic characteristics of the substituents attached to the phenyl ring are the enantioselectivities of the processes. Also significant is that heteroaromatic enals could effectively engage in the conjugate addition process with high efficiency (entry 3) when the reaction was performed at 0 °C. Furthermore, the 4d-promoted Michael process was expanded to the less reactive alkyl α,β-unsaturated aldehyde (entries 4–7). Excellent enantioselectivities (90–94% ee) were obtained despite relative low yields (50–65%) with 20 mol% 4d and K₂CO₃ as additive. The low reaction yields are mainly due to an significant side 1,2-addition-dehydration reaction between 1a and 2.¹⁵ In addition to sulfone ester (1a), the ketones arylcarbonylmethyl 2-pyridinylsulfone (1d) and alkylcarbonylmethyl 2-pyridinylsulfone (1e) also efficiently participate in the conjugate process to generate 1,5-ketoaldehydes (entries 19 and 20). Again, high yields (76 and 94%) and excellent diastereo- and enantioselectivity (>30 : 1 dr and >99% ee) were achieved. It should be pointed out that although poor diastereoselectivities were seen in some cases, the removal of the sulfone group would eliminate a stereogenic center. We found that (see below) the high enantioselectivity arises from the β-carbon, which is directly controlled by the 4d-mediated conjugate addition. The absolute configuration of the Michael adducts was determined and confirmed by a single crystal X-ray crystallographic analysis of the derivative 3j (Fig. S1, ESI‡).¹⁶

Table 2 Scope of enantioselective Michael addition of β-methyl ester or β-keto pyridine sulfones (1) with α,β-unsaturated aldehydes (2)^a

Entry	R1	R^2	3	Yield^b (%)	dr^c	ee^d (%)
a Unless stated otherwise, see ESI. b Isolated yield. c Determined by ^1H NMR of products. d Determined by HPLC analysis (Chiralcel AD and AS) by converting to the corresponding methylacetal. e At 0 °C. f 10% K2CO3 and 20% catalyst 4d used. g Reaction time: 72 h.
1	OMe	Ph	3a	90	>30 : 1	100
2	OMe	4-MeOC6H4	3b	83	3 : 1	100
3^e	OMe	2-Furyl	3c	55	1.7 : 1	89
4^f^,^g	OMe	C3H7	3d	54	1.8 : 1	92
5^f	OMe	C4H9	3e	65	1.8 : 1	94
6^f	OMe	C6H13	3f	55	1.6 : 1	94
7^f	OMe	C7H15	3g	51	1.8 : 1	90
8	OMe	2-ClC6H4	3h	80	7.7 : 1	100
9	OMe	4-MeC6H4	3i	88	>30 : 1	100
10	OMe	4-ClC6H4	3j	92	2.1 : 1	100
11	OMe	2-FC6H4	3k	82	2 : 1	100
12	OMe	4-EtC6H4	3l	87	6.3 : 1	100
13	OMe	4-NO2C6H4	3m	95	5.8 : 1	100
14	OMe	3-MeO-4-AcOPh	3n	76	3 : 1	97
15	OMe	4-AcOC6H4	3o	85	14.3 : 1	100
16	OMe	4-MeOCOC6H4	3p	88	1.5 : 1	100
17	OMe	4-Ph-Ph	3q	83	4.8 : 1	100
18	OMe	1-Naphth	3r	85	>30 : 1	100
19	Ph	Ph	3s	76	>30 : 1	100
20	C2H5	Ph	3t	94	>30 : 1	100

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Finally, to demonstrate the synthetic utility of the Michael adducts 3, a series of organic transformations were performed using 3a as an example (Scheme 2). Reduction of the aldehyde or reductive aminations followed by spontaneous cyclization led to synthetically valuable chiral lactone 5 and lactam 6, respectively (eqn (1)). These two classes of compounds have important biological activities¹ and serve as important building blocks in organic synthesis. Moreover, the sulfone can be removed conveniently under mild conditions (eqn (2)). Protection of the aldehyde moiety to corresponding acetal 3′a, and subsequent reductive removal of the 2-pyridinylsulfonyl group under the optimized conditions using activated Mg(0) in the presence of Bu₄N⁺Br⁻ (TBAB) in MeOH^11e (see ESI‡) gave 3-substituted acetal 7, which was transformed into an aldehyde ester 8. It is noteworthy that our initial attempt to form the methoxycarbonylmethylated product under basic conditions (Mg, TBAB, MeOH) without protection of the aldehyde resulted in a significantly low yield of ca. 10%.

Scheme 2 Application transformations of Michael adduct 3a.

In conclusion, we have developed a new nucleophilic reagent CMPS 1a for the direct organocatalytic asymmetric Michael addition to a wide range of α,β-unsaturated aldehydes in moderate to excellent yields and with high enantioselectivities. Moreover, as demonstrated, the Michael adducts serve as versatile building blocks in a variety of transformations. The application of the process in the synthesis of biologically interesting molecules is being pursued in our laboratories.

We gratefully acknowledge the financial support from the National Natural Science Foundation of China (Grants 90813005, 21002028 and 20902022, J. Li), National S&T Major Project, China (Grant 2011ZX09102-005-02, J. Li), the 111 Project (Grant B07023, J. Li and W. Wang), the Fundamental Research Funds for the Central Universities (J. Li) and East China University of Science & Technology (W. Wang).

Notes and references

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16. CCDC 844031 (3j).

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Footnotes

† This article is part of the joint ChemComm–Organic & Biomolecular Chemistry ‘Organocatalysis’ web themed issue.

‡ Electronic supplementary information (ESI) available: Experimental details and spectroscopic data for the compounds 3a–3t, 5–8. CCDC 844031. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c1cc15714k

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