Communication Cite This: J. Am. Chem. Soc. 2017, 139, 15308-15311
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Catalytic Asymmetric Synthesis of Quaternary Barbituric Acids Sandra del Pozo, Silvia Vera, Mikel Oiarbide,* and Claudio Palomo* Departamento de Química Orgánica I, Universidad del País Vasco, Manuel de Lardizabal 3, 2018 San Sebastián, Spain
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ABSTRACT: The catalytic asymmetric α-functionalization of prochiral barbituric acids, a subtype of pseudosymmetric 1,3-diamides, to yield the corresponding 5,5disubstituted (quaternary) derivatives remains essentially unsolved. In this study 2-alkylthio-4,6-dioxopirimidines are designed as key 1,3-diamide surrogates that perform exceedingly in amine-squaramide catalyzed C−C bond forming reactions with vinyl ketones or Morita−Baylis− Hillmann-type allyl bromides as electrophiles. Mild acid hydrolysis of adducts affords barbituric acid derivatives with an in-ring quaternary carbon in unprecedented enantioselectivity, offering valuable materials for biological evaluations.
B
arbituric acids and derivatives are very interesting 1,3diamide scaffolds for the development of therapeutic agents and functional materials.1 Several approaches for the asymmetric synthesis of chiral barbiturates in which chirality resides outside of the ring (I, R1 = R2) are reported.2 In contrast, the enantioselective synthesis of chiral barbiturates with in-ring chirality remains unsolved (Figure 1a). The groups of Brunner3 and Trost,4 independently, described palladiumcatalyzed asymmetric allylic alkylation reactions of I (R1 = H, R2 = Me, R3 = alkyl) with allyl acetates or carbonates to proceed with enantioselectivities from poor to modest. Lam’s group has described the Rh(III)-catalyzed oxidative annulations of cyclic 1,3-dicarbonyl compounds with alkynes,5 including a single example involving nonsymmetric barbiturates I (R1 = H, R2 = Me, R3 = Ph) that yields the corresponding spiroindene adduct in 11% ee. It is thus not surprising that, among the thousands of 5,5-disubstituted barbiturates synthesized and selected for clinical trials, the great majority are racemic,6 even though pharmacological profile may be configuration-dependent.7 Here we describe a catalytic highly enantioselective route to barbiturates with an in-ring all-carbon quaternary stereocenter for the first time. For this realization 2-alkylthio-4,6dioxopyrimidines III are designed as key barbituric acid equivalents that perform exceedingly under bifunctional Brønsted base/H-bond activation (Figure 1c). Chiral organobase catalysis is recognized as one of the operationally simplest approach for the enantioselective functionalization of acidic CH pro-nucleophiles.8 Recently, while our work was in progress, Rawal and co-workers reported the enantioselective conjugate addition of symmetrically N,N′disubstituted barbituric acids to prochiral nitroalkenes triggered by a bifunctional amine-thiosquaramide organocatalyst.2d Whereas N,N′-disubstituted barbituric acids thus seems to be suitable for a mild Brønsted base deprotonation,9 the © 2017 American Chemical Society
Figure 1. Asymmetric α-functionalization of 1,3-diamides toward barbituric acid derivatives with an in-ring stereogenic carbon.
asymmetric organocatalytic C(5)-functionalization of prochiral barbiturates of general structure II (R1 ≠ R2, Figure 1b) has not yet been realized. A major problem concerns the pseudosymmetrical structure of the 1,3-diamide moiety (Figure 1b) which makes enantioface discrimination complicated,10 a situation that would be critical during generation of a quaternary stereocenter.11 For example (Scheme 1), at the outset of our investigation barbiturates 1 and 2, as well as their thioScheme 1. Initial Experiments with (Thio)Barbiturates 1−4
Received: August 29, 2017 Published: October 12, 2017 15308
DOI: 10.1021/jacs.7b09124 J. Am. Chem. Soc. 2017, 139, 15308−15311
Communication
Journal of the American Chemical Society analogues 3/4Aa, were treated with vinyl ketone 6a in the presence of 10 mol % catalyst C1 (Figure 2) to give,
Table 1. Catalyst Screening for the Reaction of 5Aa with 6a To Give 11a entry
catalyst
yield (%)
ee (%)
1 2 3 4 5 6 7 8 9 10
C1 C2 C3 C4 C5 C6 C7 C8 C8c C9
67 71 60b 69 67 59 66 72 60 62
66 36 n.d. 32 73 54 75 80 96 78
a Reactions carried out at r.t. using 0.2 mmol of 5Aa, 0.6 mmol of enone 6a and 10 mol % catalyst in 0.5 mL of CH2Cl2; yields of isolated product after chromatography; ee determined by chiral HPLC. b Conversion. cReaction run at 0 °C.
Table 2. Scope of the Reaction of 2-Benzylthio-4,6dioxopyrimidines 5 with Aryl Vinyl Ketones 6a
Figure 2. Barbituric substrates and catalysts used in this study.
respectively, adducts 7−10 as essentially racemic material (
