| Solid-phase synthesis, pioneered by R. B. Merrifield, is the preferred route for synthesis of biologically important peptides and small proteins. This method has also been extended to other biopolymers, as well as to small organic molecules. The solid-phase approach provides a method to synthesize compounds with greatly reduced effort because excess reagents can be used to drive reactions to completion, and they can be removed easily from the insoluble polymeric support, without manipulative losses, by filtration and washing. This thesis addresses both the solid-phase synthesis of organic molecules and that of peptides and proteins.; Two important privileged structures, the furopyridine and furoquinoline rings, were constructed as combinatorial libraries on the solid support by two different chemical pathways. The first library was constructed using a linear, stepwise approach using a Sonogashira coupling. FT-IR and gel-phase 13C NMR were used for monitoring each step of this syntheses. In the second library, a convergent approach was utilized with two fragments of the desired targets coupled in a resin-to-resin transfer reaction. The two fragments of the desired molecules were constructed on separate supports and coupled through a Sonogashira coupling.; Bovine Pancreatic Trypsin Inhibitor (BPTI), a small 58-residue globular protein that contains three disulfides, is often used for protein folding studies due to its diversity of secondary structural elements. A key element is the β-turn connecting the two strands of the antiparallel β-sheet, which is the main initiation site for folding.; In the past, several analogues replacing the disulfides by α-amino- n-butyric acid (Abu) were synthesized, and different degrees of folding were observed. Preserving disulfide Cys14-Cys38 was key to maintain stability. To test the effect of having another type of constraint, rather than a disulfide, circular analogues were constructed. Native BPTI was circularized, the disulfides reduced, and the Cys residues methylated, to obtain c-[R]Smc. Another circular analogue, c-[Cys5(R)Abu], with 5 Abu and 1 Cys, was circularized by solution native chemical ligation. An on-resin circularization by native chemical ligation methodology was also developed for the synthesis of small cyclic peptides. To study the key β-turn of BPTI, analogues containing β-turn mimics were synthesized and characterized. |
