Progress toward a stereoselective synthesis of tetrodotoxin (TTX) is presented. Oxidative dearomatization of a tetrasubstituted guaiacol arene yielded a masked ortho-benzoquinone that intercepted an acyl nitroso species generated in situ by the copper-catalyzed aerobic oxidation of an acyl hydroxylamine. The subsequent alkene dihydroxylation and reduction of a bisneopentylic ketone proceeded with perfect diastereoselectivity to reveal advanced intermediates toward the synthesis of TTX.
A stereoselective intermolecular Diels–Alder cycloaddition of an intermediate pyrazinone with both achiral and chiral acrylate-derived dienophiles provides rapid access to the bicyclo[2.2.2]diazaoctane core shared among several prenylated indole alkaloids. The product derived from cycloaddition with 2-nitroacrylate required an additional five to six synthetic operations to intercept established precursors to premalbrancheamide and brevianamide B. The chemistry detailed in this manuscript constitutes a formal total synthesis (12 steps each) of these [2.2.2]diazabicyclic natural products from proline methyl ester.
The synthesis of the stereotriad core in the eastern portion of the Veratrum alkaloids jervine (1), cyclopamine (2), and veratramine (3) is reported. Starting from a known βmethyltyrosine derivative (8), the route utilizes a diastereoselective substrate-controlled 1,2-reduction to establish the stereochemistry of the vicinal amino alcohol motif embedded within the targets. Oxidative dearomatization is demonstrated to be a viable approach for the synthesis of the spirocyclic DE ring junction found in jervine and cyclopamine.
This Account describes new reactions that have been developed in the Johnson laboratories at UNC Chapel Hill enabled by considerations of N–O bond cleavage. Three main case studies are highlighted: the metal-catalyzed electrophilic amination of O-acyl hydroxyl amines, multihetero-Cope rearrangements driven by O–N bond breakage, and merged dearomatization/N=O cycloadditions for the synthesis of complex 4-aminocyclohexanols such as those found in the natural product tetrodotoxin.1 Introduction2 Electrophilic Amination3 Multihetero-Cope Rearrangements4 Progress toward a Total Synthesis of (–)-Tetrodotoxin5 Conclusion
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