1. Project Summary/Abstract:
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 (ERß) 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.