| Abstract: | Numerous marine-derived pyrrole 2-aminoimidazole alkaloids (P-2-AIs), including the highly potent antitumor natural product agelastatin A, are presumed to be derived from the simple precursor oroidin and related stuctures. The molecular complexity of P-2AIs, significant biological activities, as well as the interesting biosynthetic routes proposed for their origin has made this family of alkaloids the subject of numerous synthetic investigations. Herein, a bioinspired total synthesis of agelastatin A is described premised on the isolation of two other P-2AIs, keramadine and nagelamide J. Two biosynthetically relevant cyclizations rapidly convert a linear precursor, resembling an oxidized keramadine, to agelastatin A. A facile and highly diastereoselective C-ring formation via a 5-exo-trig cyclization or a Nazarov 4π-electrocyclization, proceeding through a deep-red colored N-acyliminium intermediate, constructs the three contiguous stereocenters of the cyclopentane core found in the agelastatins and nagelamide J. A possible templating effect was discovered in a silica gel-assisted reaction that enables the final B-ring closure. The described synthesis provided access to various agelastatin A derivatives leading to a bioactive biotin probe that is proving to be useful for cellular target identification. In an effort toward understanding the biosynthesis of P-2-AIs, a synthesis of ¹⁵N-oroidin labeled oroidin was developed and pulse labeling and analysis by 1D ¹H-¹⁵N HSQC NMR and FTMS experiments was validated as a direct method for measurement of ¹⁵N incorporation into P2-AIs. Studies toward the synthesis of a ¹⁵N-keramadine analog, which will be used to investigate the biosynthetic origin of agelastatin A, are also described. The electronic version of this dissertation is accessible from http://hdl.handle.net/1969.1/151657 |
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