This led us to another route, coupling amine 20 to N-Boc-protected amino acids, followed by acidcatalyzed oxidative cyclization and subsequent simultaneous removal of the Boc and (+)pinanediol protecting groups, obtaining the free amine boronic acid bicycles with no necessary purification. Our group has previously demonstrated that boronic esters are quickly hydrolyzed to their respective boronic acids in the basic buffer used in the in vitro assays. The difference in covalent warhead within this series should therefore have negligible effect on the biological activity of these compounds. The complete synthesis of the boronic esters and acids is detailed in Scheme 3. Linear dipeptide series. As mentioned earlier, we expect that through the loss of flexibility of the dipeptide scaffold afforded by the constrained bicyclic core, this [4.3.0] alkane series would solve the problem of the cyclization of Talabostat in vivo. However, the bicycles are expected to be slightly less active than their linear counterparts, as they cannot adjust their shape to the binding site. Alternatively, reduced entropy penalty may improve their binding affinity over the more flexible Talabostat. To determine the effect of rigidification of the scaffold on biological activity, several linear dipeptide probes were also synthesized, starting from protected L-or D-Ala and L-Val, the latter of which gives inhibitors resembling Talabostat. The complete list of synthesized probes can be found in Table . The synthesis of these linear analogues was rather simple. Non-covalent analogue 23a was synthesized in one step, coupling Cbz-L-Ala to pyrrolidine. The carbonitrile series was previously synthesized by our group, coupling readily available prolinonitrile to Cbz-L-Ala. Several boronic esters were also synthesized to probe for stereochemistry and preference of protecting group (Cbz or Boc). The synthesis of these linear peptide compounds is shown in Scheme 4.