Helena C. Malinakova

Synthetic Organic Chemistry: development of methodology for total synthesis of natural products, transition metal mediated C-C bond formation, asymmetric synthesis, cascade reactions, metal-induced C-H bond activation.

In recent years, transition metal complexes became recognized as powerful synthetic tools capable of creating new carbon-carbon bonds under impressively mild conditions and in a highly selective manner. The principal aim of our research is to develop new synthetic methods using transition metal-based reagents and catalysts. Our studies are expected to contribute powerful new synthetic tools for the drug discovery effort and synthesis of biologically active natural products.

Directed Asymmetric Palladation. The goal of this project is to investigate carbon-carbon bond-forming reactions utilizing novel organometallic complexes with a sp3-hybridized stereogenic carbon directly attached to the transition metal. We aim to develop methods for the synthesis of nonracemic palladacycles 1, and to use the palladacycles as stoichiometric templates and/or catalytic intermediates in reactions with organic electrophiles yielding high-enantiopurity organic compounds 2-4. The conversion of palladacycles 1 into the products 2-4 will be based on transient palladium(IV) intermediates, and ourwork will further expand the current knowledge of the chemistry of palladium(IV) complexes. To date, we have utilized regio- and diastereocontrolled insertions of alkynes and allenes into palladacycles 1 to prepare a series of highly functionalized enantiomerically enriched 2H-1-benzopyrans and 1,2-dihydroquinolines. These studies demonstrated a high configurational stability of the palladium-bonded stereocenter, highlighting the synthetic potential of palladacycles 1. In the next stage of this project, we will apply the new reactions to syntheses of biologically significant natural products. Thus, in addition to expertise in transition metal-mediated reactions, researchers in our group will gain experience with a broad range of “classical” synthetic transformations.

Palladium-Catalyzed Multi-Component Coupling and Cascade Processes. In the second focus area of our research, we are designing new palladium-catalyzed reactions that would allow for the formation of multiple carbon-carbon bonds and new stereogenic carbon centers from simple achiral substrates in one operation. Recently, a new protocol for a palladium-catalyzed three-component coupling of boronic acids, allenes and aldehydes providing highly substituted homoallylic alcohols 5 or lactones 6, has been developed.

Recently, a new protocol for a palladium-catalyzed three-component coupling of boronic acids allenes and aldehydes or imines providing highly substituted homoallylic alchohols 5 or lactones 6, amines 7 and unnatural amino acids 8 was discovered.

Furthermore, as part of this project, we have been exploring new strategies for the umpolung of the traditional reactivity of allylpalladium(II) complexes with nucleophiles, and identified conditions, under which a commercially available Pdii catalyst (Pd(OAc)2) could mediate the reaction of the allylpalladium(II) intermediate with an electrophile (e.g. imine).

In the future, the new processes will be used to execute total syntheses of small biologically active natural products, for example acromelic acid or lariciresinol.

New Methods for Combinatorial Synthesis of Medicinally Relevant Heterocycles:

In the third area of our research, we are designing new transition metal-catalyzed reaction sequences, which would allow for highly modular syntheses of structurally complex heterocycles with drug-like properties. In a recent project, we have synthesized a series of substituted isoindolones 10 structually related to cytotoxic cytochalasins.

We have utilized α -N-substituted amides 9as reactive intermediates, and shown that the amides can serve as templates in diversity oriented synthesis, exploiting an intramolecular Diels-Alder reaction, followed by Pd(0)-catalyzed cross-coupling. Synthesis of combinatorial libraries of isoindolones based on this methodology is in progress.