Research

1. Transition-Metal Catalyzed Decarboxylative Formation and Derivatization of alpha-Imino Anions (2-azaallyl anions)

The alpha-imino anion (2-azaallyl anion), not to be confused with the less basic glycine enolate anion, is a versatile synthetic intermediate for the construction of diverse organoamine frameworks. Use of the alpha-imino anion has been limited, however, due to strongly basic conditions required for generation and the relatively poor nucleophilicity of the resulting alkaline salts. As depicted in the above Scheme, we are developing new methods for the synthesis and elaboration of alpha-imino anions via transition metal-catalyzed decarboxylative alkylations. We are exploiting this efficient tactic for the construction of novel analogs of known bioactive small molecule scaffolds, as well as the generation of unprecedented peptidomimetic frameworks. Additionally, we are also employing transition metal-catalyzed decarboxylative alkylations of diphenylglycinate imines for the total synthesis of a variety of alkaloid natural product frameworks; some examples are provided in the figure below.

2. Total Synthesis and Evaluation of Anti-Osteoclastogenic Natural Products

The in vivo maintenance of bone is a complex and dynamic phenomenon regulated primarily by two types of cells: osteoblasts, which deposit bone, and osteoclasts, which degrade bone. An imbalance in the ratio and/or activities of these two cell types favoring osteoclasts can result in serious and sometimes fatal skeletal diseases, e.g. osteoporosis and tumor-induced osteolysis. The most common therapeutic strategy against such diseases is to directly inhibit osteolytic enzymes with small molecules, such as the bisphosphonates. An alternative strategy that is gaining favor due to the mounting side effects of bisphosphonate drugs is the manipulation of the biochemical pathways involved in the differentiaion of osteoclast progenitors induced by the endogenous activator RANKL (receptor activator of NK-kappaB ligand). Recent screens have uncovered a relatively small number of natural products that can inhibit RANKL-induced osteoclastogenesis without exhibiting significant cytotoxicity (see figure below). We are interested in developing efficient and flexible routes toward these natural products that allow for substantial structure-activity relationship (SAR) studies. The overall goal is to gain a better understanding of the signaling pathways invovled in osteoclastogenesis with the hope of developing small molecule-based therapies for osteolytic diseases.

3. Gram-Scale Synthesis of L-Isocitric Acid and Isocitrate-Containing Natural Products

Among all the metabolites within the citric acid cycle (Kreb's or TCA cycle), isocitric acid remains the only member that is not available in multigram quantities as a single enantiomer. To date, only the D enantiomer is commericially available, as the monopostassium salt, for a remarkable $134,212.43 per mole! Even racemic isocitric acid, as the trisodium salt, costs over $3500 per mole. Recently our collaborators Prof. Adam N. Goldfarb and Grant Bullock (UVA Pathology) discovered that either enantiomer of isocitric acid is capable of rescuing EPO-induced erythropoiesis (red blood cell formation) under low iron availablility via similar yet distinct mechanisms. Inspired by this discovery and the lack of commercial sources of L-isocitric acid, we have initiated a campaign toward the synthesis of multigram quantities of both L- and D-isocitrate in enantio- and diastereomerically pure form. This requires the development of a novel synthetic strategy, given that current reported procedues are not ammenable toward scale up. Moreover, we are interested in establishing a synthetic strategy that also allows for the efficient synthesis of the cryptoporic acids, a growing family of fungal metabolites that exhibit a promising array of anti-tumoral activities and contain at least one D-isocitrate fragment. Despite that fact that the first cryptoporic acid was isolated over 20 years ago, there are no reports of a highly efficient asymmetric synthesis of any member of the cryptoporic acid family