Steric Interactions at the Active Site

The net attractive interaction between efavirenz and the surrounding amino acid residues amounts to 22 kcal/mol, the most important contribution, 11.3 kcal/mol, being provided by two hydrogen bonds between the backbone LyslOl and the carbamate group of the benzoxazin-2-one ring, as schematically presented in Fig. 13.2. 

These hydrogen bond interactions have not been observed in other HIV-1-RT/ antiviral agent complexes and are considered to be a distinguishing property of efavirenz. Most importantly, these interactions provide the basis for the capacity of efavirenz to dimerize two critical subunits of HIV-1 RT and inhibit DNA polymerization. These two subunits are p66 and p51, which form a heterodimer with 

Efavirenz 1 and its congeners 2-4 are prepared in a higher than 98% enantiomeric excess on a scale of up to 5,000 kg. All of them either reached a late stage of clinical testing or have been introduced into the regular therapy of AIDS [14, 15]. The remarkable synthetic achievements that resulted in the availability of this valuable drug on the world market are outlined in the following sections. 

3 Asymmetric Addition of Alkyne Anion to C=0 Bond with Formation of Chiral Li Aggregates 

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