f GRL007 and GRL008, two structurally related nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs) containing 3(R),3a(S),6a(R)-bis-tetrahydrofuranylurethane (bis-THF) as the P2 moiety and a sulfonamide isostere consisting of benzene carboxylic acid and benzene carboxamide as the P2= moiety, respectively, were evaluated for their antiviral activity and interactions with wild-type protease (PR WT ). Both GRL007 (K i of 12.7 pM with PR WT ) and GRL008 (K i of 8.9 pM) inhibited PR WT with high potency in vitro. X-ray crystallographic analysis of PR WT in complex with GRL007 or GRL008 showed that the bis-THF moiety of both compounds has three direct polar contacts with the backbone amide nitrogen atoms of Asp29 and Asp30 of PR WT . The P2= moiety of both compounds showed one direct contact with the backbone of Asp30= and a bridging polar contact with Gly48= through a water molecule. Cell-based antiviral assays showed that GRL007 was inactive (50% effective concentration [EC 50 ] of >1 M) while GRL008 was highly active (EC 50 of 0.04 M) against wild-type HIV-1. High-performance liquid chromatography (HPLC)/mass spectrometry-based cellular uptake assays showed 8.1-and 84-fold higher intracellular concentrations of GRL008 than GRL007 in human MT-2 and MT-4 cell extracts, respectively. Thus, GRL007, in spite of its favorable enzyme-inhibitory activity and protease binding profile, exhibited a lack of antiviral activity in cell-based assays, most likely due to its compromised cellular uptake associated with its P2= benzene carboxylic acid moiety. The anti-HIV-1 potency, favorable toxicity, and binding profile of GRL008 suggest that further optimization of the P2= moiety may improve its antiretroviral features.

Analysis of a series of unsaturated [13]-macro-dilactones showed that the configuration of a single carbon dictates the planar chirality of a macrocycle backbone and in turn remotely switches the facial display of an embedded alkene unit.

DMDO epoxidation of carbohydrate fused [13]-macro-dilactones was found to be highly diastereoselective. Facial selectivity of the epoxidation depended on the identity of the fused carbohydrate. Gluco-configured macro-dilactones gave the R, R epoxide, whereas the galacto- configuration gave the S, S epoxide. The epoxide stereochemisty was confirmed by independent syntheses of dimethyl 4 R,5R-epoxyoctanedioate via Shi epoxidation of dimethyl E-oct-4-enedioate and by transesterification of the epoxide derived from the gluco-[13]-macro-dilactone. We demonstrate diastereoselectivity in alkene reactivity driven by remote rather than adjacent stereocenters.

[reaction: see text] An S-phenyl alpha-D-idoseptanoside donor was used in the selective preparation of a series of alpha-D-idoseptanosyl glycosides. Glycosylation of a methyl beta-D-glycero-D-guloseptanoside acceptor with the new donor constituted the first synthesis of a septanose disaccharide.