[structures: see text] A systematic study was performed to establish general synthesis protocols for forming enantiomerically pure macrocyclic dipeptide lactams. Focusing on macrocycles of 8-, 9-, and 10-membered rings, effective syntheses were achieved by a sequence featuring peptide coupling of allyl- and homoallyl-glycine building blocks followed by ring-closing metathesis. The 8-membered lactam-possessing cis-amide and cis-olefin geometry as well as 9-membered [corrected] lactams having trans-amide and cis-olefin [corrected] configurations were effectively prepared by a general strategy employing the respective protected dipeptide, the first generation Grubbs' catalyst, and temporary protection of the central amide as a benzyl derivative. The 10-membered macrocycle was synthesized possessing cis- or trans-olefin geometry by employing similar metathesis conditions in the presence or absence of temporary benzyl amide protection, respectively [corrected]

Julia olefination between alpha-alkoxy sulfones 2a-c and a wide variety of ketones or aldehydes afforded substituted vinyl ethers in 46-90% yields. Sulfones 2a-c were readily prepared in two steps from commercially available reagents in 68-80% yields. Optimization revealed that the nature of the base, the solvent, and the temperature were crucial to obtaining the desired vinyl ethers. [reaction: see text]

[reaction: see text] Macrocyclic and fused bicyclic dipeptides are complementary motifs for mimicry of different types of beta-turn geometry. Macrocyclic dipeptide mimics have served as precursors for the synthesis of their bicyclic counterparts using electrophilic transannular cyclizations of 9- and 10-membered ring lactams 9-12 to form azabicyclo[4.3.0]- and -[5.3.0]alkanone amino esters 13-16.

Optimization of pyridine-based noncatalytic site integrase inhibitors (NCINIs) based on compound 2 has led to the discovery of molecules capable of inhibiting virus harboring N124 variants of HIV integrase (IN) while maintaining minimal contribution of enterohepatic recirculation to clearance in rat. Structure-activity relationships at the C6 position established chemical space where the extent of enterohepatic recirculation in the rat is minimized. Desymmetrization of the C4 substituent allowed for potency optimization against virus having the N124 variant of integrase. Combination of these lessons led to the discovery of compound 20, having balanced serum-shifted antiviral potency and minimized excretion in to the biliary tract in rat, potentially representing a clinically viable starting point for a new treatment option for individuals infected with HIV.

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