Preparation and Structure of Novel Chiral 4,6-Disubstituted Tetrahydropyrimidinones

The synthesis of a number of novel 4,6-disubstituted tetrahydropyrimidinones is described. The synthetic route described is applied to the synthesis of two stereoisomers. The structure of one tetrahydropyrimidinone was determined by XRD and showed an interesting hydrogen-bonded ribbon in the direction of crystal growth. These pyrimidinones are members of a class of compounds with diverse bioactivity. An initial study of their activity versus HIV protease is included. 1. Introduction Cyclic ureas including tetrahydropyrimidinones are common heterocyclic motifs in biologically active molecules (Figure 1). Molecules of this type have been reported as having antineoplastic 1 [1], anti-viral 2 [2, 3], 3 [4, 5] and anti-arrhythmic 4 [6] activity amongst many others. The antineoplastic activity is linked to inhibition of dihydroorotase, a key enzyme which is present in problematic organisms such as clostridium bacteria and as such may be treatment target [7]. In the case of anti-viral drugs such as DMP-450 2 the interaction of the heterocycle with HIV-protease is understood via the reported X-ray structures of their complexes and extensive modelling leading to structure activity relationships [8–10]. Figure 1: Cyclic ureas with biological activity. Synthetic methods for the synthesis of these heterocycles (5–7 membered) have previously been reported. Syntheses usually involve the reaction of an appropriate diamine with phosgene or a synthetically equivalent safer reagent [11–13]. We have recently developed the synthesis of diamines 5–8 for the preparation of novel asymmetric catalysts (Figure 2) [14–16]. We compared these to the structures of existing bioactive cyclic ureas 3. These ureas had shown good antiviral activity but their oral bioavailability was poor. We thought our new functionalised diamines, which we synthesised with control of the relative and absolute stereochemistry from sugar based precursors, could be transformed to novel tetrahydropyrimidinones. The synthetic route we chose would allow access to a large number of novel functionalised tetrahydropyrimidinones. What we present in this paper is the synthesis of the first few such tetrahydropyrimidinones. Figure 2 2. Results and Discussion We initially synthesised the tetrahyropyrimidinone ring from the TBS protected diaminodialcohols 7 and 8 by reaction with bis(trichloromethyl)carbonate (BTC) in the presence of pyridine (Scheme 1). The heterocycles 9 and 10 were isolated in moderate yields. Compound 9 when crystallised from DCM/hexane gave a very small number of very fine needles with aspect