Dihydropyrimidones

Kappe CO (2000) Biologically active dihydropyrimidones of the Biginelli-type - a literature survey. Eur J Med Chem 35 1043-1052... 

P rez, R., Beryozkina, T., Zbruyev, O.I., Haas, W. and Kappe, C.O., Traceless solid phase synthesis of bi-cyclic dihydropyrimidones using multidirectional cyclization cleavage, /. Comb. Chem., 2002,4, 501-510 and references cited therein. 

Dondoni and Massi9 executed a Bignelli synthesis to prepare dihydro-pyrimidinones starting from aldehydes, 1,3-dicarbonyl compounds, and urea with ytterbium(III) supported on Amberlyst 15 resin as a Lewis acid (entry 5). After condensation, the reaction mixture is treated with both strongly basic and acid resins to sequester reaction by-products. For more than 30 reported examples, dihydropyrimidones obtained directly from concentration of the filtrates are produced in high yields and in excellent purities. 

As an alternative to the chemical resolution methods described by Atwal et al. (Scheme 4.13), a biocatalytic strategy towards the preparation of enantiopure (R) and (S)-SQ 32,926 was developed (Scheme 4.15). The key step in the synthesis is the enzymatic resolution of an N3-acetoxymethyl-activated dihydropyrimidone precursor by Thermomyces lanuginosus lipase [189]. The readily available racemic DHPM 43 was hydroxymethylated at N3 with formaldehyde, followed by standard acetylation with acetyl chloride. The resulting N3-acetoxymethyl-activated DHPM... 

This acid-catalyzed, three-component reaction between an aldehyde, a i-ketoester and urea constitutes a rapid and facile synthesis of dihydropyrimidones, which are interesting compounds with a potential for pharmaceutical application. 

The ytterbium triflate catalyzed Biginelli reaction of aldehydes, ethyl acetoacetate and urea to give in a one-pot synthesis dihydropyrimidones was performed again in higher yields without any solvent (Scheme 13) [38]. 

In an aqueous buffered medium, over the pH range 1-12, pyrimidone-2 exhibits a single one-electron wave. Preparative electrolysis, at a potential corresponding to the initial limiting current, led to formation of an insoluble product, isolated as a white amorphous powder, and shown by various physico-chemical criteria to correspond to a dimer consisting of two molecules of reduced pyrimidone-2. This was further confirmed by H NMR spectroscopy, which also established the structure of the product as 6,6 (or 4,4 )-bis-(3,6(4)-dihydropyrimidone-2), shown in Scheme 2, below. The structure of the dimer reduction product, and its solid state conformation, were subsequently further established by X-ray diffraction (see Sect. III.3.). 

In aqueous 0.1 M (CH3)4NBr, pyrimidone-2 was found to exhibit two reduction waves of equal height, with E1/2 values of —0.75 V and —1.55 V for waves I and II, respectively 1,2). (Fig. 1) Preparative electrolysis under these conditions at the potential of wave I resulted in formation of the same dimer reduction product as in aqueous buffered medium. By contrast, electrolysis on wave II led to formation of two products, one of which was identical with that formed on wave I. The other, readily soluble in aqueous medium, was identified as 3,6-dihydropyrimidone-2, identical with that synthesized chemically and described earlier by Skaric75). 

The UV absorption spectra, in neutral aqueous medium, of pyrimidone-2 and its dimer reduction product, 6,6 -6u-(3,4-dihydropyrimidone-2), are exhibited in Fig. 2 Particularly interesting was the finding that irradiation of the dimer at 254 nm under these conditions led to the stepwise disappearance of its characteristic absorption spectrum, with the simultaneous appearance o the spectrum of the parent monomer. Additional evidence for the identity of the photoproduct with the parent pyrimidone-2 was furnished by chromatography and polarographic behaviour. The photochemical conversion reaction was shown to be quantitative (under these conditions pyrimidone-2 itself is quite radiation resistant), and to proceed with a quantum yield of 0.1, both in the presence and absence of oxygen 2). This value was unchanged when irradiation was conducted in 2H20 the absence of an isotope effect is clearly of relevance to the mechanism of the photodissociation reaction. 

Chromatography of the electrolysis products formed in acid medium demonstrated that the major one was the photodissociable dimer 6,6 -6w-(3,6-dihydropyrimidone-2) (70%), accompanied by 3,6-dihydropyrimidone-2 (15 %) and about 15 % of a product not fully identified, but the UV absorption spectrum of which was consistent with its being a 1 1 adduct of cytosine and reduced pyrimidone-2 84). 

In acid medium (pH 4.5) electrochemical reduction led to formation of two products. One of these was characterized as the 6,6 -dimer of the riboside of pyrimidone-2. It was photochemically converted to the riboside of pyrimidone-2. The second, on the basis of its chromatographic behaviour, UV spectrum, and reaction with the Fink reagent, was identified as the riboside of 3,6-dihydropyrimidone-2. The mechanism of electrochemical reduction of cytidine in acid medium is consequently analogous to that for 1-methylcytosine. The products of reduction of cytidine at pH 7 were shown chromatographically to contain 5,6-dihydrocytidine 1 84). A comparison of the electrochemical and catalytic reduction products under analogous conditions at pH 7 demonstrated that both led to the same products, one of them 5,6-dihydrocytidine 84). 

The initial 1 e, 1 H+ reduction step leads to a free radical, which rapidly dimerizes to products isolated and identified as 4,4 (6,6 )-h (3,4(6)-dihydropyrimidone-2), or to the corresponding 4,6-dimethyl-, and 1,4,6-trimethyl-derivatives6,7), These dimers are readily photodissociated to quantitatively regenerate the parent monomers in high quantum yields, 0.25 to 0.35, at 254 nm. The initial free radical may also undergo further reduction, observed only for non-methylated 2-thiopyrimidine, via a le process, to 3,4(6)-dihydro-2-thiopyrimidine 7). 

Very recently, Maiti and coworkers150 developed a new methodology for the synthesis of dihydropyrimidones, 246, by a one-pot three-component condensation using a catalytic amount of LiBr, under very mild reaction conditions (Scheme 76). 

A modification of the dihydropyrimidone MCR was performed by applying isothiocyanates 107 as the fourth component, which resulted in the formation of 2-aminothiazines 108 which upon microwave heating could rearrange (Dimroth rearrangement) to dihydropyrimidine-2-thiones 109 [87]. 

Several compounds derived from these libraries were identified as Hsp70 modulators and were further evaluated in cell proliferation assays such as the SK-BR-3 and MCF-7 breast cancer cell lines and the HT29 colon cancer cell line (Fig. 6) [26]. Compounds 22-24 were potent against all three cell lines. The dihydro-pyrimidinone libraries were also tested for replication inhibition of the malarial parasite, Plasmodium falciparum, where Hsp70 chaperones are believed to play an important role in the parasite s homeostasis [24]. Nine compounds that inhibit replication of the parasite were identified. Among them, compounds 25 and 26 were the most potent (Fig. 7) and were prepared by direct couplings of dihydropyrimidone acids 19 with a pyrrolo amine. 

A side effect of a lack of temperature control is that changes can alter the refractive index of the mobile phase, causing basehne disturbances and reducing sensitivity The problem is principally with refractive index detection [39], but it can also influence spectroscopic detectors and their light path can be distorted. Temperature has also been reported to alter the nature of some stationary phases. For example, it caused a change in the chiral selectivity of the resolution of dihydropyrimidone acid and its methyl ester on amylose and cellulose stationary phases [40],... 

F. Wang,T. 0 Brien,T. Dowling, G. Bicker, and J. Wyvratt, Unusual effect of column temperature on chromatographic enantioseparation of dihydropyrimidone acid and methyl ester in amylose chiral stationary phase, J. Chromatogr. A 958 (2002), 69-77. 

Fig. 2. Photochemical transformation, on irradiation at 254 nm in 0.01 M phosphate bufifer (pH 7.2) of 1.7 X 10 M 6,6 -b s-(3,6-dihydropyrimidone-2), with quantitative regeneration of pyrimidone-2, as shown by isosbestic point at 262 nm (see text for further details). The curve marked o is that for the initial reduction product figures beside the other curves represent the time of irradiation in min...

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