New developments in solid phase synthesis supports.

Developments in solid phase synthesis supports for the end of 1996 and much of 1997 are reviewed. Issues regarding support induced impurities and enhancing solid phase reaction rates are also discussed.

The use of power ultrasound coupled with magnetic separation for the solid phase synthesis of compound libraries.

Enhanced reaction rates are observed when power ultrasound is utilized as a substitute for mixing during solid phase organic chemical reactions on a paramagnetic support. Power ultrasound is also used to facilitate the washing of the paramagnetic support as it is magnetically separated from the reaction mixture. Selective examples from a library targeting the kappa-opioid receptor are presented.

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-alpha-[1-(9H-fluoren-9-yl)-methoxyformamido]-2,4-di methoxybenzyl]- phenoxyacetic 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 degrees 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 either through a solid phase Mitsunobu reaction on the mesoporous support.

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.