Bret E. Huff

A new method for the preparation of tetrazoles from nitriles using trimethylsilylazide/trimethylaluminum

Abstract Tetrazoles are prepared in good yields from alkyl and aryl nitriles by treatment with equimolar trimethylaluminum and trimethylsilylazide. Yields, substrate compatibility, and reaction temperature are comparable with the use of other metal azides such as Al(N3)3 and n-Bu3SnN3. The reactions are run in toluene or with added THF at 80 °C.

Glycopeptide antibiotic derivatives

The present invention provides glycopeptide antibiotic derivative compounds. These derivative compounds possess antibacterial activity aginst a wide variety of bacteria, including activity against vancomycin-resistant isolates. Methods of making and using these glycopeptide antibiotic derivative compounds are also provided.

Protection, metalation, and electrophilic substitution of 5-methyl tetrazole

Abstract 5-Methyl tetrazole was N-protected with the trityl group and deprotonated using n-BuLi. The resulting 5-methyl anion was trapped with a variety of electrophiles to provide 5-substituted tetrazoles in good yields. The trityl protecting group was readily removed using HCl in methylene chloride.

Synthesis of 2′,3′-dideoxy-3′-hydroxymethylcytidine; a unique antiviral nucleoside

Abstract The synthesis of 2′,3′-dideoxy-3′-hydroxymethylcytidine 1 was accomplished using two different approaches. First, uridine and cytidine were used to prepare the key intermediate epoxides 15 and 31 which were opened with cyanide, deoxygenated by elimination to vinyl nitriles 17 and 36, and reduced by 1,4 hydride addition to the saturated nitriles 18 and 37. Secondly, a novel Rh-catalyzed hydroformylation reaction of 2′,3′-didehydro-2′,3′-dideoxycytidine 46 was used to prepare 1 in four steps. The attempted use of 2′-deoxyuridine and 2′-deoxycytidine to prepare 1 is also discussed.

Machine learning and genetic algorithms in pharmaceutical development and manufacturing processes

We develop an adaptive Automated Intelligent Manufacturing System (AIMS) for Case 1:to a well-understood-pharmaceutical-process to demonstrate our methodology, Case 2:with clustering, to a not-well-controlled or understood-process for seemingly identical experiments yielding disparate results, Case 3:to scale-up a process from development to manufacturing, and Case 4:to deploy AIMS adaptively, to modify the process model and reoptimize the system contemporaneously, when predictive errors are significant. The results showed AIMS had both explanatory and predictive power. We have developed the following methodological extensions: a random probe method for feature selection, a simulation approach to establish tolerances for target inputs, and an adaptive capability integrated with statistical-process-control to modify the model.

Diastereoselectivity in the heterogeneous hydrogenation reactions of phosphorous substituted olefins

Phosphorous substituted methylenecyclohexane olefins show enhanced diasteroselectivity in heterogeneous hydrogenation reactions using Pd/C. A model system, derived from 4-t-butylcyclohexanone was used to explore the effects of solvent polarity and catalyst on the reduction reaction. It was found that olefins hydrogenated with catalytic Pd/C in polar solvents afford the highest diastereoselectivities (>15:1).