and Michael reactions, we chose ꢀ,γ-unsaturated R-ke-
toesters 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 ꢀ,γ-
unsaturated R-ketoester 2a to screen for the optimal catalyst
(Table 1). The product of this reaction cyclizes to form lactol
Table 1. Catalyzed Michael Reaction of 1a and 2a
Figure 1
.
Cinchona alkaloid-derived pyrimidine organocatalysts.
entry
catalyst
yield (%)
ee (%)a
Scheme 2. Synthesis of New Catalysts
1
2
3
4
5
6
quinuclidine
85
58
69
55
95
47
0
59
65
74
84
63
4a
4b
4c
4d
5
a Determined by HPLC analysis of the purified product.
3a as an equilibrating mixture of anomers. These anomers
equilibrate slowly enough that they show up as separate
1
compounds by H 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 (Figure 1)
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 enantioselec-
tivity 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.
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 substitution
reactions of 10 with cinchona alkaloids afforded only the
monosubstituted compounds.8 The very bulky triethylmethyl
group most likely blocks the 4-position of the pyrimidine from
further attack by the alkaloid.
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 did not lower the asymmetric induction
but did improve the reaction rate and yields. The enantiose-
lectivity began 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
(5) Calter, M. A.; Phillips, R. M.; Flaschenriem, C. J. Am. Chem. Soc.
2005, 127, 14566–14567.
(8) We adapted the conditions for this step from ref 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. 2006, 45, 4301–4305.
(6) Holmberg, C. Liebigs Ann. Chem. 1981, 748–60.
(7) Crispino, G. A.; Jeong, K. S.; Kolb, H. C.; Wang, Z. M.; Xe, D.;
Sharpless, K. B. J. Org. Chem. 1993, 58, 3785–3786.
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Org. Lett., Vol. 11, No. 10, 2009