‘Bioinspired’ Total Synthesis of Agelastatin A and Derivatives for Cellular Target Identification; Syntheses of ^(15)N-labeled Oroidin and Keramadine Analog for ‘Metabiosynthetic’ Studies

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 4pi 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^( 15)N-oroidin labeled oroidin was developed and pulse labeling and analysis by 1D ^(1)H-^(15)N HSQC NMR and FTMS experiments was validated as a direct method for measurement of ^(15)N incorporation into P2-AIs. Studies toward the synthesis of a ^(15)N-keramadine analog, which will be used to investigate the biosynthetic origin of agelastatin A, are also described.