The olefin cross-metathesis reaction provides a rapid and efficient method for the synthesis of α,β-unsaturated 1,5-dicarbonyl derivatives which then serve as effective precursors to mono-tetrasubstituted pyridines. Manipulation of the key 1,5-dicarbonyl intermediate allows access to pyridines with a wide range of substitution patterns. An extension of this methodology facilitates the preparation of pyridines embedded within macrocycles, as exemplified by an efficient synthesis of (R)-(+)-muscopyridine. High levels of regiocontrol, short reaction sequences, and facile substituent variation are all notable aspects of this methodology.
The natural products cochliomycin A (1) and cochliomycin B (2), two resorcylic acid lactones obtained from marine sources, have been prepared in a concise and stereocontrolled manner from the readily accessible building blocks 4-6. Olefin cross-metathesis, trans-esterification and Nozaki-Hiyama-Kishi (NHK) macrocyclization reactions were employed in the key steps. Hydrolysis of the immediate precursor to cochliomycin B affords the resorcylic acid lactone zeaenol (24).
RCM can be used to make aromatic heterocycles, namely pyridines and, for the first time, pyridazines; the key step after RCM involves elimination of sulfinate to provide the aromatic system.
Heck reactions were performed on α,β-unsaturated-δ-sulfonamido intermediates, derived from cross metathesis, to allow the instalment of substituents at the β position. Subsequent one-pot cyclisation/elimination provides an operationally simple, catalytic and convergent synthesis of 2,4,6-trisubstituted pyridines.
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