Solid-phase synthesis design

K. Gordon and S. Balasubramanian, Solid phase synthesis - designer linkers for combinatorial chemistry A review J Chem Technol Biotechnol 74 835-851 7999. 

Nakamura K, Hanai N, Kanno M, Kobayashi A, Ohnishi Y, Ito Y, Nakahara Y. Design and synthesis of silyl ether-based linker for solid-phase synthesis of glycopeptides. Tetrahedron Lett 1999 40 515-518. 

Charybdis Technologies. In the Calypso Reaction Block , multi-well reaetion arrays are designed for both solution and solid-phase synthesis applications. Well volumes range from 2 to 10 mL, pressures up to 207 kPa (30 psi), and temperatures from —80 to +180°C. 

More recently, the Pam amino acid chimera has also been incorporated into a small j0j0a-motif peptide scaffold [28]. The family of BBA peptides was developed in our laboratory as structured platforms for the design of functional motifs. These motifs are attractive because they are small enough (23 residues) to be easily synthesized by standard solid phase synthesis methods. Additionally, the motifs appear to possess sufficient structural complexity to influence coenzyme properties while still being amenable to structural characterization by standard spectroscopic techniques [3, 29, 30]. The BBA peptides include a -hairpin domain with a type IT turn connected by a loop region to an a-heli-cal domain (Fig. 10). Packing of the sheet and helix against one another is accomplished by hydrophobic contacts created by a hydrophobic core of residues. 

A linker originally designed for solid-phase synthesis of peptides is the backbone amide linker (11) (BAL), this anchoring approach has now been extended to the combinatorial synthesis of diverse amide [31], hydroxamate [32], oligosaccharide [33] and heterocyclic small molecule libraries [34-36]. 

Given the extensive biology associated with peptides, it is not surprising that considerable effort has been devoted to the synthesis of peptidomimetics to overcome the unfavorable properties and therapeutic deficiencies of peptides. In particular, since the advent of solid-phase synthesis and, more recently, combinatorial chemistry, interest in peptido-mimetic design and preparation has exploded. In theory, the peptide chemist is only limited by their imagination in the novel modifications that can be tailored for synthetic peptide analogues. 

Reduction of the carbonyl in the r >[CO-CH2-NH] link 7 (R1 = H) results in the (hy-droxy)ethyleneamino or r >[CH(OH)-CH2-NH] link 8 (R1 = H), which has proved to be a very potent analogue of the tetrahedral hydrated intermediate of the scissile amide bond. It has been widely used for the design of various inhibitors of HIV protease 141,142 14 154 and ACE, 155-157 and to synthesize angiotensin II, III, and IV analogues. 158,159 Indeed, the chirality of the hydroxylated carbon is critical for HIV protease inhibition, but separation of the epimers may be difficult. Therefore, the stereoselective synthesis from epoxides has been actively investigated. An example of a C-methylated tp[CMe(OH)-CH2-NH] link, obtained from an epoxide with chromatographic separation of the epimers, has also been described. 157 Most of the [(hydroxy)ethyleneamino] peptides have been prepared by solution procedures, but two examples of solid-phase synthesis have been reported. A theoretical study of the (hydroxy)ethyleneamino replacement for the amide bond has been carried out on a HIV protease inhibitor. 160 ... 

The combination of microwave-assisted chemistry and solid-phase synthesis applications is a logical consequence of the increased speed and effectiveness offered by microwave dielectric heating. While this technology is heavily used in the pharmaceutical and agrochemical research laboratories already, a further increase in the use of microwave-assisted solid-phase synthesis both in industry and in academic laboratories can be expected. This will depend also on the availability of modern microwave instrumentation specifically designed for solid-phase chemistry, involving for example dedicated vessels for bottom filtration techniques. 

Mimotopes has been involved in the development, use, and commercialization of radiation-grafted polymer surfaces for multiple parallel synthesis since the late 1980s.10-12 Although other workers have reported the use of radiation-graft polymers in solid-phase synthesis,13,14 as far as we are aware, the graft polymer devices manufactured and sold by Mimotopes (SynPhase Crowns, SynPhase Lanterns) are the only current commercial products of this type. These products are presented in Fig. 1. The SynPhase Lanterns are the current design for small molecule synthesis. The initial... 

Benzodiazepines were the first class of heterocyclic compounds to be synthesized on the SynPhase surface. In 1994, Ellman and co-workers24 reported a 192 member library of structurally diverse 1,4-benzodiazepines. These compounds were prepared on Mimotopes pins that were grafted with polyacrylic acid, the surface originally used for antibody epitope elucidation.10 Ellman and co-workers25 subsequently synthesized a 1680-member 1,4-benzodiazepine library on SynPhase Crowns that were grafted with a methacrylic acid/dimethylacrylamide copolymer, one of the first SynPhase surfaces designed for solid-phase synthesis. The synthesis was performed on a preformed linker-template system in order to avoid low aminobenzophenone incorporation in this case the HMP acid-labile linker... 

Combinatorial chemistry has moved from specially centralized laboratories, often equipped with multimillion-dollar robots, onto the bench of individual medicinal chemists. This change in direction requires the availability of personal chemistry tools that are simple to operate, easy to arrange in the laboratory, and reasonably priced. Such instruments are now available for the effective synthesis of combinatorial libraries. The Encore synthesizer represents a simple and efficient personal chemistry tool that allows the execution of directed split-and-pool combinatorial synthesis. The current version of the Encore synthesizer is designed for solid-phase synthesis on SynPhase Lanterns however, it can be modified for synthesis on alternative solid supports such as resin plugs from Polymer Laboratories (e.g., StratoSpheres Plugs). 

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