Stereodivergent Synthesis of (+)- and (−)-Isolineatin

A stereodivergent approach to (+)- and (−)-isolineatin using (<i>S</i>)-4-methyl-5-pivaloyloxymethyl-2­(5<i>H</i>)-furanone as the single source of asymmetry by exploiting the inherent chirality at the C-5 stereocenter is described

Intramolecular Photoreactions of (5<i>S</i>)‑5-Oxymethyl-2(5<i>H</i>)‑furanones as a Tool for the Stereoselective Generation of Diverse Polycyclic Scaffolds

The photoactivated evolution of a series of enantiomerically pure 5-oxymethyl-2­(5<i>H</i>)-furanones has been investigated. The observed intramolecular photoreactions have proven to be a straightforward entry to diverse and stereochemically rich fragment-molecules, most of which contain the privileged tetrahydropyran (THP) scaffold. The formation of the THP involves a 1,5-hydrogen atom transfer process, leading to a diradical intermediate that recombines to form a new σ C–C bond. These reactions take place under both sensitized and nonsensitized conditions, and they are highly stereoselective. When the substrate contains an allyl residue, the intramolecular [2 + 2] cycloaddition leading to cyclobutanes competes advantageously. When the substrate contains a THP residue, the cyclization involves the concomitant formation of [6,6]-spiroketals with nonanomeric relationships

A comparison of two complete feed blocks based on sorghum stover of two different cultivars on weight gain in sheep and economy of feeding

The effect of different sorghum stover fodder quality in densified total mixed ration (DTMR) feed blocks was investigated. An experimental feed block with a low cost stover was compared with a commercial feed block produced by Miracle Feeds and Fodder Pvt. Ltd. that consisted of a premium sorghum stover (about 50%) and concentrate in equal proportions. Concentrate component consisted of bran and husks/hulls (18%), oilcakes (18%), molasses (8%) with the rest contributed by maize grain, urea, minerals and vitamins. In the experimental DTMR feed block the premium stover was replaced by low cost stover and rest of the composition was same. The two blocks were fed ad libitum to growing sheep measuring intake, digestibility and weight gain. No difference was observed in digestibility between the groups fed the commercial and the experimental block. Intake in the group fed the commercial block was 37 g/kg LW compared to 32.8 g/kg LW in the experimental block group (P=0.07). Daily live weight gain in the former group was twice that of the latter (90 vs. 45g; P=0.04). However, both feeding regimes were uneconomical, with the experimental feeding regime even resulting in monetary loss

Intramolecular Photocycloaddition of 2(5<i>H</i>)‑Furanones to Temporarily Tethered Terminal Alkenes as a Stereoselective Source of Enantiomerically Pure Polyfunctionalyzed Cyclobutanes

Allyloxymethyloxymethyl and 4-pentenoyloxymethyl substituents have been used as tethering groups to study the intramolecular [2 + 2] photocycloaddition of chiral 5-substituted 2­(5<i>H</i>)-furanones. The photoreactions proceed in good yield and provide the expected regio- and diastereoselective tricyclic compounds with complementary regioselectivity, which depends on whether the vinyl chain is attached to the furanone by an acetal or an ester linkage. Computational simulations agree with experimental observations and indicate that the origin of the different observed regioselectivity in the intramolecular photochemical reaction of lactones <b>5</b> and <b>6</b> arises from the relative stability of the initial conformers. The synthetic potential of the enantiomerically pure photoadducts is illustrated by preparing an all-<i>cis</i> 1,2,3-trisubstituted cyclobutane bearing fully orthogonally protected hydroxyl groups

Flexible Approach to <i>Stemona</i> Alkaloids: Total Syntheses of (−)-Stemospironine and Three New Diastereoisomeric Analogs

Total syntheses of (−)-stemospironine and three new diastereoisomeric analogs have been completed through a flexible strategy devised for <i>Stemona</i> alkaloids. The azabicycle <b>7</b> is the pivotal intermediate, from which the sequence splits according to each particular target. The most remarkable differential feature for stemospironine is the installation of the spiranic γ-lactone through an intramolecular Horner–Wadsworth–Emmons olefination. The configuration of the stereogenic center at C-11 was controlled by fine-tuning of the synthetic sequence

Intramolecular Photocycloaddition of 2(5<i>H</i>)‑Furanones to Temporarily Tethered Terminal Alkenes as a Stereoselective Source of Enantiomerically Pure Polyfunctionalyzed Cyclobutanes

Allyloxymethyloxymethyl and 4-pentenoyloxymethyl substituents have been used as tethering groups to study the intramolecular [2 + 2] photocycloaddition of chiral 5-substituted 2­(5<i>H</i>)-furanones. The photoreactions proceed in good yield and provide the expected regio- and diastereoselective tricyclic compounds with complementary regioselectivity, which depends on whether the vinyl chain is attached to the furanone by an acetal or an ester linkage. Computational simulations agree with experimental observations and indicate that the origin of the different observed regioselectivity in the intramolecular photochemical reaction of lactones <b>5</b> and <b>6</b> arises from the relative stability of the initial conformers. The synthetic potential of the enantiomerically pure photoadducts is illustrated by preparing an all-<i>cis</i> 1,2,3-trisubstituted cyclobutane bearing fully orthogonally protected hydroxyl groups

Computational Prediction of HIV‑1 Resistance to Protease Inhibitors

The development of mutations in HIV-1 protease (PR) hinders the activity of antiretroviral drugs, forcing changes in drug prescription. Most resistance assessments used to date rely on expert-based rules on predefined sets of stereotypical mutations; such an information-driven approach cannot capture new polymorphisms or be applied for new drugs. Computational modeling could provide a more general assessment of drug resistance and could be made available to clinicians through the Internet. We have created a protocol involving sequence comparison and all-atom protein–ligand induced fit simulations to predict resistance at the molecular level. We first compared our predictions with the experimentally determined IC₅₀ values of darunavir, amprenavir, ritonavir, and indinavir from reference PR mutants displaying different resistance levels. We then performed analyses on a large set of variants harboring more than 10 mutations. Finally, several sequences from real patients were analyzed for amprenavir and darunavir. Our computational approach detected all of the genotype changes triggering high-level resistance, even those involving a large number of mutations