Pyrocatechols (a.k.a. catechols) comprise an important class of pharmacologically active compounds. Epinephrine and other catecholamines as well as many opiates are derived from catechols, as are the powerful antitumor antibiotics saframycin and ecteinascidin-743. In this proposed pilot project, vinylketeneiron(0) complexes will be synthesized via readily available methodology from vinyllithium compounds and alkylating or acylating agents. The cycloaddition reactions of these vinylketeneiron(0) complexes with 1-haloalkynes will be used to synthesize a variety of halosubstituted catechols, specifically the chloro, bromo, and iodo compounds.
The specific aim of the project is to unambiguously define the optimal reaction conditions for effecting the formal cycloaddition of vinylketenes with haloalkynes. The halocatechols, thus synthesized, will be subjected to palladium catalyzed coupling reactions to provide highly substituted catechol derivatives that would otherwise require lengthy multi-step syntheses. Preliminary studies to assess the applicability of the method toward the synthesis of the common core of the saframycin and ecteinascidin-743 will be carried out via a three-step protocol involving cycloaddition-allylation-asymmetric aminohydroxylation. Relevance: A simple expedient two-step method for the preparation of a large number of catechol derivatives will be made available. Access to novel therapeutic agents will be made available. Synthetic approaches to starting materials for the large scale preparation of the powerful antitumor agent ecteinascidin-743 and its analogues will be provided. Personal Development Plan: The PI will use the SC2 program to generate sufficient preliminary results to justify a more ambitious research program, which will be fundable through the SC1 mechanism, the ultimate goal being independence from SCORE funding and support through other programs (e.g., R15 and R01). The participation of the mentor will facilitate this process greatly by providing guidance in the selection and execution of the preparation of appropriate target molecules.
|Truong, Jimmy; Caze, Vioela; Akhani, Ravish K et al. (2010) Halogenated catechols from cycloaddition reactions of ?-(2-ethoxyvinylketene)iron(0) complexes with 1-haloalkynes. Tetrahedron Lett 51:921-923|
|Akhani, Ravish K; Atiq-Ur-Rehman; Schnatter, Wayne F K (2009) Incorporation of hexafluorobutyne into furans or phenols via reaction with iron(0) carbene or vinylketene complexes. Tetrahedron Lett 50:930-932|