Search tips
Search criteria 


Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Org Lett. Author manuscript; available in PMC 2010 May 21.
Published in final edited form as:
PMCID: PMC2694574

Catalytic, Asymmetric Michael Reactions of Cyclic Diketones with β,γ-Unsaturated-α-ketoesters


An external file that holds a picture, illustration, etc.
Object name is nihms-111038-f0001.jpg

Newly synthesized cinchona alkaloid-derived pyrimidines function as effective asymmetric catalysts for the Michael reaction between cyclic diketones and β,γ-unsaturated-α-ketoesters. The reactions of electrophiles with either aryl or alkyl γ-substituents give 64−99% yields and 94−99% ee.

The Michael reaction stands as one of the fundamental methods for creating carbon-carbon bonds. As this reaction also often results in the creation of stereocenters, much effort has focused on the discovery of catalytic, asymmetric versions of the Michael reaction.1 Several excellent methods using metal complexes2 or organic molecules as catalysts have emerged;3 however, these methods all apply only to certain substrate classes. We were particularly interested in the addition of cyclic diones to enones, as the product of such a Michael reaction could potentially provide an advanced intermediate in the synthesis of the hexahydroquinoline class of calcium channel blockers (Scheme 1).4 Although Itoh et al. have reported high enantioselectivities for the related addition of diones to unsaturated pyrazole amides,2d the highest enantioselectivity reported for the addition of diones to enones is 45%.3d Therefore, we set out to maximize the asymmetric induction of this type of reaction.

Scheme 1
Target Michael Reaction

Our results with the catalytic, asymmetric, interrupted Feist-Bénary (IFB) reaction strongly influenced our exploration of the Michael reaction.5 The IFB reaction employs a dione nucleophile, and an α-ketoester electrophile. In order to maximize the similarity between the IFB and Michael reactions, we chose β,γ-unsaturated-α-ketoesters as the electrophiles for the Michael reaction. As we had found that pyrimidine-bis-cinchona alkaloid derivatives provide the highest enantioselectivity in the IFB reaction, we first tested these compounds as catalysts for the Michael reaction.

We used the reaction between dimedone (1a) and β,γ-unsaturated-α-ketoester 2a to screen for the optimal catalyst (Table 1). The product of this reaction cyclizes to form lactol 3a as an equilibrating mixture of anomers. These anomers equilibrate slowly enough that they show up as separate compounds by 1H and 13C NMR, but quickly enough that they do not resolve by chromatography. The trace of racemic 3a on a Chiralpak AD HPLC column shows only two peaks for the two enantiomers. By screening catalysts previously synthesized in our group,5 we immediately found a promising catalyst, 4d, which gives 84% ee. We also observed that increasing the bulk of the pyrimidine C5-substituent led to more dramatic increases in enantioselectivity than increasing the size of the C2-substituent (5 to 4c vs. 5 to 4b). We therefore postulated that converting the C5-tBu substituent into a triethylmethyl group would further improve the enantioselectivity.

Table 1
Catalyzed Michael Reaction of 1a and 2a

Accordingly, we prepared four catalysts built on the C2-tBu-C5-CEt3-pyrmidine core. These new catalysts, 6a, 6b,7a and 7b, were synthesized by the reaction of dichloropyrimidine 10 with quinidine (QDH), dihydroquinidine (DHQDH), quinine (QNH) and dihydroquinine (DHQNH), respectively (Scheme 2). We prepared 10 from known diester 86 by pyrimidine formation and chlorination.7 To our surprise, all the substitution reactions of 10 with cinchona alkaloids afforded only the mono-substituted compounds.8 The very bulky triethylmethyl group most likely blocks the 4-position of the pyrimidine from further attack by the alkaloid.

Scheme 2
Synthesis of New Catalysts

Gratifyingly, catalyst 6a afforded over 90% ee in the test reaction (Table 2, entry 1). The corresponding quinine-based catalysts gave lower enantioselectivity for the opposite enantiomer, but the dihydroquinine-based catalyst 7b slightly outperformed quinine-based 7a (entry 4 vs. entry 3). We then studied the effects of temperature and solvent on the enantioselectivity with optimal catalysts 6a and 7b. Running the reaction at 0 °C does not lower the asymmetric induction, but did improve the reaction rate and yields. The enantioselectivity did begin to suffer at room temperature, however, so we carried out the solvent screening at 0 °C. We found this reaction functions in several commonly used solvents besides methylene chloride, such as benzene, toluene, ether and tetrahydrofuran. However, toluene clearly provided the best enantioselectivities, and therefore allowed dihydroquinine-based catalyst 7b to provide synthetically useful levels of selectivity for the (S)-enantiomer.

Table 2
Optimization of Reaction Conditions for the Michael Reaction of 1a with 2a using catalysts 6a, 6b, 7a and 7b.

With the optimized reaction conditions in hand, we then tested the substrate scope of the reaction by varying the γ-substituent of the electrophile (Table 3). Changing the electronic nature of the aryl substituent in this position had no effect on the rate, yield or enantioselectivity of the reaction (entries 1−3). We assigned the absolute stereochemistry of 3d, and, by analogy, the remaining Michael products, as R by anomalous dispersion analysis of single crystal X-ray data. Alkyl-substituted enones also produced excellent results. We also found that catalyst recovered from the reaction mixture using silica gel flash chromatography gives the same results as the original one (entry 6, Table 3 vs. entry 7, Table 2). Finally, we found that cyclohexane dione (1b) itself functions as a satisfactory nucleophile for the reaction.

Table 3
Substrate Scope of the Michael Reaction.

The assays for the optical activity of compounds 3b-3d and 3g paralleled that for 3a, but we needed to develop a new assay for compounds 3e and 3f, as these compounds did not possess a chromophore adequate for accurate HPLC analysis. We subjected these compounds to dehydrating conditions to afford dihydropyrans 11a and 11b (Scheme 3). The dihydropyrans gave excellent enantiomeric separations on the HPLC.

Scheme 3
Dehydration of 3e and 3f

Finally, we have shown that the Michael adducts can be transformed into hexahydroquinolines with negligible loss of optical activity. Reaction of 3b (96% ee) with ammonium acetate yields hexahydroquinoline 12 (94% ee) (Scheme 4).9

Scheme 4
Conversion of 3b into hexahydroquinoline 12

In summary, cinchona alkaloid-derived pyrimidine organocatalysts were synthesized and afford excellent enantioselectivity in the asymmetric Michael reaction of β,γ-unsaturated-α-ketoesters with cyclic diketones. The reaction runs under mild conditions in a variety of solvents under the influence of a readily available and recoverable catalyst, while tolerating functional group variation on the γ-carbon of the electrophile. We are currently exploring an expansion of the nucleophile and electrophile scope of this Michael reaction.

Figure 1
Cinchona alkaloid-derived pyrimidine organocatalysts

Supplementary Material




We thank the NIH for financial support of this work. We acknowledge Dr. Ryan Phillips (IRIX Pharmaceuticals) for preliminary experiments. We also acknowledge Dr. Christopher Incarvito at the Yale University X-ray Crystallographic Facility for completing the X-ray structure of 3d.


Supporting Information Available. Complete experimental details and characterization data for all new compounds, along with the details of the X-ray structure of 3d. This material is available free of charge via the Internet at


1. Yamaguchi M. In: Comprehensive Asymmetric Catalysis. Jacobsen EN, Pfalz A, Yamamoto H, editors. Springer; Berlin: 1999. Chapter 31.2.
2. a. Jautze S, Peters R. Angew. Chem. Int. Ed. Engl. 2008;47:9284–9288. [PubMed] b. Agostinho M, Kobayashi S. J. Am. Chem. Soc. 2008;130:2430–4231. [PubMed] c. Desimoni G, Faita G, Jørgensen KA. Chem. Rev. 2006;106:3561–3651. [PubMed] d. Itoh K, Hasegawa M, Tanaka J, Kanemasa S. Org. Lett. 2005;7:979–981. [PubMed]
3. a. Chen Y-C. Synlett. 2008:1919–1930. b. Mukherjee S, Yang JW, Hoffman S, List B. Chem. Rev. 2007;107:5471–5569. [PubMed] c. Pellissier H. Tetrahedron. 2007;63:9267–9331. d. Halland N, Velgaard T, Jørgensen KA. J. Org. Chem. 2003;68:5067–5074. [PubMed]
4. Rodrigo GC, Standen NB. Curr. Pharm. Design. 2005;11:1915–1940. [PubMed]
5. Calter MA, Phillips RM, Flaschenriem C. J. Am. Chem. Soc. 2005;127:14566–14567. [PubMed]
6. Holmberg C. Liebigs Ann. Chem. 1981:748–60.
7. Crispino GA, Jeong KS, Kolb HC, Wang ZM, Xe D, Sharpless KB. J. Org. Chem. 1993;58:3785–3786.
8. We adapted the conditions for this step from reference 7. For another example of mono-substitution of a dichloropyrimidine with a cinchona alkaloid, and use of the resulting compound as a catalyst for a different type of Michael reaction, see Wu F, Hong R, Khan J, Liu X, Deng L. Angew. Chem. Int. Ed. Engl. 2006;45:4301–4305. [PubMed].
9. Nenajdenko VG, Druzhinin SV, Balenkova ES. J. Fluorine Chem. 2006;127:865–873.