The first asymmetric synthesis of potential cyclic urea HIV protease inhibitors of Type 2 is reported. The synthesis is short and highly versatile in the choice of the substitution pattern and absolute configuration of the products starting from readily available materials. Nonchiral central building block 5 was synthesized and subsequently asymmetrically alkylated under (R)-/(S)-1-amino-2-(methoxymethyl)pyrrolidine (RAMP/ SAMP)-auxiliary control to provide 8a ± e. The alkylated ketones then were reduced to the target compounds 9a ± e, with good-to-excellent overall yields, as well as diastereoisomeric and enantiomeric purities. Introduction. ± An infection with the HI virus (Human-Immunodeficiency Virus) is the causal reason for the AIDS disease [1]. The pol-gene of the HI-1 virus encodes an aspartate protease (HIV protease), which proteolytically cleaves gag-and gag-polpolyproteins into structural and functional proteins, which in turn play an important role in the function of the mature virus (for a review, see [2]). Inhibition of HIV-1 protease results in the production of non-infectious virions [3]. Therefore, the HIV protease is an interesting target for AIDS therapy [2] [4]. Although already several HIV-1-protease inhibitors such as Saquinavir, Ritonavir, Indinavir, and Nefinavir have been developed, because of rapid development of viral resistance [5], there is always a great need for structurally new inhibitors. One important class of compounds are cyclic ureas, which replace a structural H 2 O molecule bound at the active site of the HIV protease (for a review, see [6]). In recent years, many cyclicurea-based inhibitors have been synthesized, examples of which are depicted below.
Structure-activity relationships (SAR) of the inhibitors based on seven-membered rings of type I have been intensively studied [6] [7]. In the design of these drug molecules, the C 2 symmetry of the homodimeric HIV-1 protease was incorporated into the structure of the inhibitors. As may be seen from the X-ray crystal-structure analysis of enzyme-inhibitor complexes [8], the two substituents R 2 in the type-I inhibitor are in a trans-diaxial orientation, which seems to be important for their biological activity.