Research Overview ? Research is focused on organic synthesis, with particular interest in developing synthesis strategies and modes of reactivity within organic chemistry that facilitate the construction of complex molecules with potentially valuable medicinal and/or biological properties. We have developed over thirty stereoselective C?C bond-forming reactions based on areas of reactivity that include metallacycle-mediated cross-coupling, [3+2] cycloaddition, vinylcyclopropane rearrangement, and radical cascade chemistry. While some of these have been developed within a program aimed at achieving a foundation of reactivity suitable to realize a wide range of unique ?convergent? C?C bond forming processes, others have emerged within programs in the broad area of natural product synthesis. These combined activities, that aim to advance the fundamental backbone of organic chemistry through innovation within the field of stereoselective synthesis, are routinely embraced as enabling technology to fuel exploration in medicinally relevant science. For example, we have discovered: (1) a non-opioid analgesic from efforts targeting the alkaloid conolidine, (2) unique paralog selective Hsp90 inhibitors stemming from explorations into the synthesis of benzoquinone ansamycins, (3) selectively cytotoxic agents targeting multiple myeloma from activities associated with the synthesis of lehualide B, (4) the first non-peptidic selective ligand to the DBD of p53 with a natural product-inspired oligomerization, and (5) the most potent and selective agonist of the estrogen receptor beta (ER?) from recent investigations targeting terpenoids. Overall Vision of the Program ? This seamless integration of reaction development, natural product synthesis, and efforts to employ our technology as an enabling tool for the discovery of novel compositions of matter with unique biological properties defines the basic fabric of science that has been, and will continue to be, the focus of science in the Micalizio laboratory for decades to come. Goals for the Next Five Years ? Efforts will focus on natural product total synthesis, new reaction development, and establishing a conceptually unified asymmetric entry to tetracyclic and pentacyclic terpenoids. These activities include target-oriented synthesis campaigns around ryanodol, corialactone D, azadiradione (limonoid), samandarin (steroidal alkaloid), oleandrin (cardenolide), euphol (euphane), and lupeol (pentacyclic triterpenoid). These activites have, at their core, the ambition to establish and demonstrate novel synthesis designs and reaction methods in the context of a wide range of complex natural products. An emerging interest is to establish a general ?common? asymmetric and step economical synthetic strategy capable of forging diverse classes of terpenoid skeletons. Contributions in this area will clearly guide our natural product pursuits, but also play a central role in efforts to design/discover natural product-inspired agents targeting a range of medicinally relevant biology.
The manner in which complex molecules are synthesized defines the central role that organic chemistry plays in biology and medicine ? a relationship that derives from the impact that chemical synthesis has on the availability of unique small molecules required to discover agents with medicinally relevant profiles. Chemical advances that enable convergent assembly of sterochemically complex polycyclic targets are highly valuable in organic synthesis, as they can provide workable schemes to establish SAR in medicinal chemistry and to produce therapeutically relevant agents. Our scientific pursuits are aimed at addressing the hypothesis that recently discovered fragment-coupling reactions, and unique post-coupling transformations, will have a profound and beneficial impact on the efficiency with which complex molecules are prepared, and will serve as a platform for the discovery of novel natural product-inspired compositions of matter with unique and clinically relevant biological properties. 1
