Michael R. Pavia

Multiple simultaneous synthesis of phenolic libraries

SummaryA series of analogous arrays of small, non-peptidyl, non-oligomeric compounds were synthesized on polystyrene resin. With the aid of a functionally differentiated phenolic scaffold, the batch preparation of unique benzamide and urea resins was accomplished, which were further derivatized in modified 96-well plates. An efficient cleavage reaction of the phenyl benzoate link enabled the isolation of more than 600 phenolic compounds in milligram quantities that were suitable for direct biological screening. The technology described herein represents a facile, economical approach to non-peptidyl chemical diversity.

The design and synthesis of substituted biphenyl libraries

A novel scaffold system for the generation of diversity libraries has been designed which allows for rapid modification not only of functional groups, but their spatial arrangements as well. The biphenyl scaffold allows for display of three or four diverse functional groups in a wide variety of spatial arrangements depending on the substitution pattern selected. The libraries are generated by a combination of solution and solid-phase chemistries and are cleaved off the solid-support for screening.

Novel Muscarinic Agonists for the Treatment of Alzheimer’s Disease

Alzheimer’s Disease (AD), or senile dementia of the Alzheimer type (SDAT), is an age-related neurodegenerative disorder characterized by a progressive deterioration of cognitive function with impairments in language, visuospatial ability and memory. The total number of individuals suffering from AD is rapidly rising as the percentage of elderly in the population increases with time. At the present, about 4 million Americans are afflicted with AD (for reviews, see Moos et al., 1988).

Use of silica gels and mesoporous molecular sieves as supports for the solid-phase Claisen rearrangement.

A series of silica gels and mesoporous molecular sieves differing in both the range of particle size and mean pore size were derivatized with the p-[(R,S)-α-[1-(9H-fluoren-9-yl)-methoxyformamido]-2,4-dimethoxybenzyl]-p henoxyacetic acid linker and their loading capacities were measured. Loading capacities ranging between 0.4–0.6 mmol Fmoc/g were achieved. Several of these silica based materials were derivatized with the hydroxymethyl benzoic acid linker and used as supports for the solid phase Claisen rearrangement of a support bound phenyl allyl ether. Both the silica gel and mesoporous supports were heated at 225 °C for 3 h to effect the Claisen rearrangement. The results showed that, compared to the same reaction run homogeneously, the silica gel support achieved similar total product yields and ratios for two Claisen products. The mesoporous supports were found to selectively produce one of the Claisen products over the other. Analysis shows that the molecules bound to the mesoporous support are physically further separated from each other as compared to those bound to the silica gel support. A mechanism is presented which accounts for the selectivity of the mesoporous support in forming one Claisen product over the other. The Claisen product was further derivatized to the resulting phenyl ethyl ether through a solid phase Mitsunobu reaction on the mesoporous support.

Combinatorial chemistry: A perspective

Chemically generated libraries are now being widely embraced by researchers in both industry and academia. The field of combinatorial chemistry began only a decade ago. For much of its existence researchers were devoted to preparing large libraries of peptides. Next came the progression to peptide-like oligomeric compounds and, most recently, the preparation of small organic molecules. Today, the vast majority of efforts in the field are devoted toward the preparation of these small, non-oligomeric molecules.