61st Annual Report on Research 2016

During the second year of funding we have made significant advances in the are of both metal carbenoid chemistry and in new cycloaddition reactions. First, we have published our work on esterification that was described in the first annual report. Second, we have completed a manuscript comprising a full account of the work that was published as a communication during the first year. This paper focuses on benzodihydrofurans and includes new catalyst results, computational studies, and new mechanistic details that have emerged. Third, we have made significant progress toward publications on the enantioselective synthesis of both indanes and indolines. Each paper will be published in the next 6 months if everything continues to go smoothly. Finally, we have observed interesting dipolarcycloaddition chemistry that we are thoroughly exploring. and anticipate publishing in the middle of next year. All of the results described above formed the basis of a grant submission (NIH/NIGMS, R01) that was completed for the October 5, 2016 deadline.

The synthesis of benzodihydrofurans took many twists and turns after our first publication. Although we knew that sometimes separation of the oxidant (MnO2) from the catalysts improved yield, we never knew why. After careful experimentation, we have now determined that when the oxidation is slow, the hydrazone that has not yet reacted can react with the metal carbenoid to effectively disproportionate to two equivalents of the corresponding imine. As such, the separation is irrelevant and it is just the added time of filtering that formed the difference in performance. This revelation has enabled a complete re-evaluation of some of our failed substrates and catalysts. In addition, we never observe cyclopropanation with the allylic substrates. That said, we have now confirmed that we get diastereoselective [1,3] dipolar cycloaddition, which also occurs with alkynes. Finally, we have also partnered with the laboratory of Joe Fox (University of Delaware) to work on computational analysis of our reaction, and those studies have revealed the underlying interactions responsible for both diastereo- and enantioselectivity. These results have been assembled in a manuscript that is now in the final editing stages for submission later this year.

Our initial work included single examples of the synthesis of indanes and indolines. We have now expanded both studies significantly. A Masters Student (Blanka Hodur) worked out substrate syntheses and got results for eight new asymmetric reactions, six of which will be part of a new publication. She finished her MS degree and has taken a job in the Process Group at Gilead Sciences. That project is now being completed by an intermediate graduate student (Leslie Nickerson) and an undergraduate (Ashly Lewis). Indolines have recently been advanced by a senior graduate student (Rich Squitieri) working with a new undergraduate (Corinne Penrod). The results are pretty dramatic in that many substrates work in very high yield and stereoselectivity, even in to form products with basic nitrogen atoms and free NH groups! Rich plans to finish up this project and apply for postdoctoral positions with the goal of becoming a professor and Corinne is on track to apply to graduate school next year.

During the last year we made several interesting advances with regard to reactions that do not involve catalysis. Although allylic ethers are good substrates for C–H insertion, if the catalyst is omitted, they do undergo [1,3]-dipolar cycloaddition (DPC). In the case of cinnamyl ethers, DPC is the major product. A similar story has unfolded for alkynes, which perform poorly with regard to enantioselectivity for CH insertion. In the absence of catalyst they undergo DPC and, more interestingly, the pyrazole products undergo subsequent van Alphen-Hüttel rearrangements, i.e. the pyrazole substituents shift to form new products! This chemistry is currently being investigated and will likely result in a completely new direction in the coming year.

All of the results described above, i.e. all of the research during the funding period for the ND grant, has formed the basis for what we hope is a very competitive grant application to the NIH/NIGMS. Overall, the proposed research of this ND grant has been extremely successful in discovering new reactions and in training students and postdocs, many of whom have worked on this project part or full time. More importantly, the ND funding has opened up an entire research project in my group that will attract durable funding from a federal agency.