Total Synthesis Highlights - Organic Chemistry Portal
graphically illustrates the value of a shift in emphasis from structure to function and how a hypothesis on the pharmacophore requirements coupled with synthesis informed design can be used to access simpler targets with comparable or better function in a timely step economical fashion. Our first experimental exploration of this approach was reported in the 1980s in connection with phorbol esters (228). While the phorbol ester synthesis, then in progress, required several years to complete, it is noteworthy that the synthesis of the designed functional arene analog 229 (R = lipids) required only 2 weeks. Both compounds activate protein kinase C (PKC). This study thus produced the first designed PKC modulators. The power and unique benefit of this FOS approach to leads lies principally between random screening and lead optimization. In the former, one screens for activity, while in the latter one seeks to optimize activity. FOS tests hypotheses and seeks to design for activity inspired by, but not constrained to, the structure of the natural lead.
Bryostatin 16 Total Synthesis - SlideShare
Obviously, one solution that continues to merit attention is to grow the base of synthetic methodology so that it would be able to deliver even more complex targets in a practical and timely fashion, i.e., with step and time economy. That takes development time and, for many current problems, time is in short supply. For some systems, another approach is to recognize that a major factor driving interest in natural products is not only the synthetic challenge associated with their structure but also that associated with their function, including biological activity. Thus, if instead of focusing only on target structure one would focus also on target function, one could, with careful and creative analysis of a natural product lead, identify key features that might be necessary for activity and design new, more accessible and even more active targets. Translating nature’s library in this way provides a blueprint for the design of targets that would exhibit superior function and be accessed in a more step and time economical fashion. As this author has noted in other venues, when we humans learned that the concavity of a bird’s wings was a key to flight, we did not seek to synthesize birds but instead used that fundamental knowledge to create planes and jets whose functions vastly exceeds natural systems. This “function oriented synthesis” (FOS) approach thus addresses many of the problematic issues associated with natural products as synthesis- and function-informed design allows one to create molecules with potentially superior activity that can be produced in a practical fashion. Creative design can win the day, producing more readily accessed targets with superior activity.
While unrelated to the above methodological studies, our successful efforts with the synthesis of phorbol provided the expertise needed more recently to address another tigliane problem of synthetic and therapeutic significance. Prostratin (227, ) is currently a pre-clinical lead being advanced for the eradication of HIV/AIDS. Current anti-retroviral therapy (ART) stops disease progression by reducing or eliminating active virus. However, it does not eradicate disease. Genomically encoded provirus harbored in reservoir cells in infected individuals resupplies active virus over time. To eradicate the disease, this latent viral source must be eliminated. Prostratin activates latent cells, potentially allowing for their clearance by viral cytopathic effects, immune effector mechanisms, or other processes. If used in combination with ART, eradication of both the active and latent sources could be realized. Until recently, prostratin was available only in limited and variable amounts from plant sources. In 2008, we reported a five-step semi-synthesis of prostratin from phorbol, exploiting our prior synthetic studies with the latter system (). Our approach recognized that deoxygenation next to a cyclopropane would proceed with strain-driven cleavage of the latter. This was indeed observed. While seemingly undesired, the process did serve to remove the C12 oxygen of phorbol and thus what remained was to rebuild the cyclopropane ring. Using a variant of chemistry explored by Kishner and Freeman, we were able to rejoin carbons 13 and 15 to produce prostratin (227) and, more importantly, designed analogs. The power of synthesis and design is apparent here as this synthesis not only provides a reliable and scalable laboratory source of the natural product and clinical lead but also a source of more active analogs. Our designed analogs are up to 100-fold more potent that prostratin in binding to PKC, the target implicated in the HIV activation pathway. Significantly, these are also effective in inducing activation of reservoirs cells ex vivo in blood samples taken from patients on suppressive therapy.