New stereoselective reactions to form amido alkyl C-N and vinyl triflate C-O bonds via carbocation intermediates & ultrafast silicon fluorination methodologies for applications in pet imaging

We report here the development of a Lewis acid catalyzed method for the dehydrative coupling of cyclic alcohols and nitriles to form amides with retention of configuration. By contrast, the formation of amides by nitrile trapping of carbocations (Ritter reaction) usually affords racemic product. The present reaction was accomplished by first converting alcohol starting materials to their corresponding chlorosulfites in situ. Even after an extensive search, only copper (II) salts were able to produce the desired conversion of these chlorosulfites to amides though with low catalytic turnover. Improving the turnover without deteriorating the stereochemical outcome was eventually accomplished by a careful selection of the reagent addition sequence and through the removal of gaseous byproducts. This Ritter-like coupling reaction proceeds in good yields with secondary cyclic alcohols under mild conditions. The stereochemical outcome is likely due to fast nucleophilic capture of a non-planar carbocations (hyperconjomers) stabilized by ring hyperconjugation.;In a second project, we demonstrate that TMSOTf in the presence of several metal catalysts converts alkynes to vinyl triflates under mild conditions. Current methods for the formation of vinyl triflates directly from alkynes generally involve harsh conditions and are exclusively selective for the E-isomer. Further study and optimization revealed that internal alkynes are converted to the Z-vinyl triflate product though with modest selectivity. The reaction efficiently converts aliphatic and aromatic terminal alkynes as well as internal alkynes to their corresponding vinyl triflate products. A mechanism is put forward to explain the unique role of silicon in this system. In this mechanism, we propose a silyl vinyl triflate intermediate that undergoes protodesilylation to afford the vinyl triflate product. Importantly, we believe that silicon may play a similar role in other recently reported reactions.;In a final project pursued in collaboration with NIH researchers, we describe our development of ultrafast silicon fluorination techniques for eventual applications in PET. The demand for physiologically stable organosilicon 18F-fluorides required compounds with a high degree of steric hindrance at the silicon center. This in turn greatly slows the rate of fluorination using current methods which often entail high temperatures and very polar solvents. Our initial solution to this problem centered on the use of metal chelating units attached to silicon substrates to serve as leaving groups. We reasoned that such leaving groups would stabilize negative charge developed on the silicon center in the TS and thus lead to a faster fluorination. Using these leaving groups, we observed fast radiofluorination of bulky silicon substrates at room temperature in 15 minutes without the need for the commonly used phase transfer reagents. Similar rate enhancements were also observed with cyclotron-produced 18F-fluoride (t1/2 = 109.7 min, beta+ = 97%). Based on our proposed mechanism for fluorination rate enhancement with chelating leaving groups, we reasoned that similar results could be achieved even without first attaching a chelating leaving group to a silicon center. As a result, we developed the concept of a Crown Ether Nucleophilic Catalyst (CENC). The use of these new phase transfer agents allows for efficient sequestration and recovery of cyclotron-derived K18F. Using these CENC/K18F complexes, we observed rapid radiofluorination of silicon substrates (5 min) which is significantly faster than currently reported methods.