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Hydroxylated derivatives were designed and synthesized based on the information of oxidative metabolites. Compounds derived from β-substituted (2 R ,3 R )-2-amino-3-hydroxypropionic acid showed improved inhibitory activities against the binding of MIP-1α to human CCR5, compared with the non-hydroxylated derivatives and the other isomers.

The acetylene biscobalthexacarbonyl complex can catalyze hydrosilylation of acetylenes to produce vinylsilanes. The regioselectivity is extremely high with phenylthioacetylenes, while it is hardly selective depending upon the substituents other than the sulfide group. High selectivity with dihydropyranyl-phenylthioacetylene prompted us to establish a practical convenient route to obtain the electrophilic precurosr of vinylsulfones in heteroconjugate addition. A new empirical rule for the assignment of synlanti stereochemistry of the products can be formulated, the 13C NMR chemical shifts of the anti-isomer being higher than those of the syn-isomer.

C-Glycosidation is of great significance in the organic synthesis of optically active materials, since it allows the introduction of carbon chains to sugar chirons and the use of sugar nuclei as a chiral pool as well as a carbon source. Silylacetylenes are sufficiently reactive to form ‘sugar acetylenes’ for the selective introduction of various acetylenic groups in an alpha-axial manner at the anomeric position of D-hexopyranose rings. 1,4-Anti induction, on the other hand, gives a different stereochemical outcome in the case of C-glycosidation of pentopyranose glycals. The mechanism of these reactions includes oxonium cation intermediates in which stereoelectronic and/or steric factors drive the direction of the incoming silylacetylene. Bis-C-glycosidation allows the introduction of sugars at both ends of some bis(trimethylsilyl)acetylenes. A 2,3-dideoxyglucose derivative provides the corresponding C-1 α-acetylenic compounds, which would increase the scope of C-glycosidation with silylacetylenes. In sugar acetylenes, the alkynyl group at the anomeric position of a pyranose ring is epimerized via a hexacarbonyldicobalt complex by treatment with trifluoromethanesulfonic acid. The three steps—cobalt complexation, acidic transformation and decomplexation—afford overall epimerization and thus one can obtain either the α- or β-alkynyl C-glycoside as desired. Ring opening of a dihydropyran derivative using Nicholas-type cation intermediates is also part of this study. Several sets of decomplexation conditions for endo-type acetylene–cobalt complexes provide various olefins possessing potential utility for synthesis. These methodologies have been utilized for the synthesis of polyoxygenated natural products and derivatives.

Isomeric spirodiketopiperazines are separately synthesized as potential orally-available anti-HIV drug candidates.

A novel series of pyridyl carboxamide-based CCR5 inhibitors was designed, synthesized, and demonstrated to be highly potent against HIV-1 infection in both HOS and PBL assays. Attempts to evaluate this series of compounds in a rat PK model revealed its instability in rat plasma. A hypothesis for this liability was proposed, and strategies to overcome this issue were pursued, leading to discovery of highly potent 40 and 41, which featured dramatically improved rat PK profiles.

Based on the original spirodiketopiperazine design framework, further optimization of an orally available CCR5 antagonist was undertaken. Structural hybridization of the hydroxylated analog 4 derived from one of the oxidative metabolites and the new orally available non-hydroxylated benzoic acid analog 5 resulted in another potent orally available CCR5 antagonist 6a as a clinical candidate. Full details of a structure-activity relationship (SAR) study and ADME properties are presented.

Following the discovery that hydroxylated derivative 3 (Fig. 1) was one of the oxidative metabolites of the original lead 1, it was found that hydroxylated compound 4 possesses higher in vitro anti-HIV potency than the corresponding non-hydroxylated compound 2. Structural hybridation of 4 with the orally available analog 5 resulted in another orally-available spirodiketopiperazine CCR5 antagonist 6a that possesses more favorable pharmaceutical profile for use as a drug candidate.

C-Glycosidation is of great significance in the organic synthesis of optically active materials, since it allows the introduction of carbon chains to sugar chirons and the use of sugar nuclei as a chiral pool as well as a carbon source. Silylacetylenes are sufficiently reactive to form ‘sugar acetylenes’ for the selective introduction of various acetylenic groups in an alpha-axial manner at the anomeric position of D-hexopyranose rings. 1,4-Anti induction, on the other hand, gives a different stereochemical outcome in the case of C-glycosidation of pentopyranose glycals. The mechanism of these reactions includes oxonium cation intermediates in which stereoelectronic and/or steric factors drive the direction of the incoming silylacetylene. Bis-C-glycosidation allows the introduction of sugars at both ends of some bis(trimethylsilyl)acetylenes. A 2,3-dideoxyglucose derivative provides the corresponding C-1 α-acetylenic compounds, which would increase the scope of C-glycosidation with silylacetylenes. In sugar acetylenes, the alkynyl group at the anomeric position of a pyranose ring is epimerized via a hexacarbonyldicobalt complex by treatment with trifluoromethanesulfonic acid. The three steps—cobalt complexation, acidic transformation and decomplexation—afford overall epimerization and thus one can obtain either the α- or β-alkynyl C-glycoside as desired. Ring opening of a dihydropyran derivative using Nicholas-type cation intermediates is also part of this study. Several sets of decomplexation conditions for endo-type acetylene–cobalt complexes provide various olefins possessing potential utility for synthesis. These methodologies have been utilized for the synthesis of polyoxygenated natural products and derivatives.

The acetylene biscobalthexacarbonyl complex can catalyze hydrosilylation of acetylenes to produce vinylsilanes. The regioselectivity is extremely high with phenylthioacetylenes, while it is hardly selective depending upon the substituents other than the sulfide group. High selectivity with dihydropyranyl-phenylthioacetylene prompted us to establish a practical convenient route to obtain the electrophilic precurosr of vinylsulfones in heteroconjugate addition. A new empirical rule for the assignment of synlanti stereochemistry of the products can be formulated, the 13C NMR chemical shifts of the anti-isomer being higher than those of the syn-isomer.

Using the previously reported novel spirodiketopiperazine scaffold, the design and synthesis of orally available CCR5 antagonists was undertaken. Compounds possessing a carboxylic acid function in the appropriate position showed improved oral exposure (AUC) relative to the initial chemical leads without reduction in the antagonist activity. The optimized compound 40 was found to show potent anti-HIV activity. Full details of structure-activity relationship (SAR) study are presented.

Spirodiketopiperazine-based CCR5 antagonists, showing improved pharmacokinetic profiles without reduction in antagonist activity, were designed and synthesized. We also demonstrate the anti-HIV activity of a representative compound 12, as measured in a p24 assay.