Synthetic studies on the preparation of shape selective mimics of cytochrome P450

Michael M Pollard
Synthetic efforts towards preparing a shape selective mimic of cytochrome P450 using a derivatized porphyrin are described. The target biomimetic catalysts can be described as a metalloporphyrin, modified on one or both faces, with a torus shaped molecular scaffolding restricting access to the porphyrin chelated metal which performs the C-H bond activation. Several general synthetic strategies are presented. The first strategy focused on capping a tetraphenylporphyrin (TPP) derivative with a
more » ... lic octapeptide on both faces of the porphyrin. To facilitate capping, TPP derivatives with electrophilic functionality in the meta positions of TPP were prepared, including tetrakis(3,5-bis(bromomethyl)phenyl)porphyrin (31). Synthetic efforts to prepare the peptide cap focused on octapeptides with L-Lys or L-Om as residues 1, 3, 5, and 7. Linear octapeptides with alternating D-Phe and ©-protected L-Orn residues failed to cyclize under standard coupling conditions, whereas cyclization of linear octapeptides with alternating Gly and ©-protected L-Lys or L-Orn residues proceeded smoothly. Attempts to link the deprotected cyclic octapeptide to the porphyrin did not afford the desired capped porphyrin. In the second approach, the porphyrin was used as a template to preorganize four segments of the crown cap to address one face of the porphyrin. An intramolecular ring opening metathesis (ROMP) was attempted by tethering 4 strained olefins to the meso positions of a porphyrin. This approach may have been unsuccessful because of excessive rigidity in the system. Capping was also attempted using a porphyrin tethered to 4 semi-rigid dienes. When treated with Grubbs' second generation catalyst, this Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. I gratefully ackowledge my supervisor, Professor John C. Vederas, for his support, for providing an excellent example to mentor under, and for providing an environment in which creativity and the spirit of scientific curiosity can flourish. I would like to thank those members of our research group, past and present, who have contributed to a positive, encouraging, and communal work environment, and who have shared a drive to understand the chemical world we navigate. I am especially grateful to Drs. Chris Diaper and Rajendra Jain for their diligent and careful proofreading of this manuscript. I would like to thank several of my generous supporters including Prof. Neil Branda, Andrew Myles, and Elisa Murguly for their unfaltering belief in my ability. I would like to thank my partner, Anu Sandhu, for her support, encouragement, and understanding of my work schedule, and for making me happy through difficult times. I would like to thank Mark Nitz, who has continued to inspire me with his dedication, his breadth of knowledge, and balanced views on the world. Finally, and perhaps most importantly, I owe thanks to Jan, Max, and Otty, my mother, father, and grandmother, who have always given me the unconditional support which has helped me persevere throughout all of life's challenges. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. chemical shift in parts per million downfield from TMS ^-abs absorbance maxima Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
doi:10.7939/r3-dag8-k553 fatcat:vrxkhvie25gctdzb3joshnm67q