Modular total syntheses of the marine-derived resorcylic Acid lactones cochliomycins a and B using a late-stage nozaki-hiyama-kishi macrocyclization reaction.

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).

Synthesis of substituted pyridines and pyridazines via ring closing metathesis.

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.

Heteroaromatic synthesis via olefin cross-metathesis: entry to polysubstituted pyridines.

The olefin cross-metathesis reaction provides a rapid and efficient method for the synthesis of α,ß-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.

Synthesis of 2,4,6-trisubstituted pyridines via an olefin cross-metathesis/Heck-cyclisation-elimination sequence.

Heck reactions were performed on α,ß-unsaturated-δ-sulfonamido intermediates, derived from cross metathesis, to allow the instalment of substituents at the ß position. Subsequent one-pot cyclisation/elimination provides an operationally simple, catalytic and convergent synthesis of 2,4,6-trisubstituted pyridines.

Olefin cross-metathesis-based approaches to furans: procedures for the preparation of di- and trisubstituted variants.

Olefin cross-metathesis (CM)-based protocols enable short, flexible and regiocontrolled access to substituted furan derivatives. Specifically, CM of allylic alcohol and enone components provides γ-hydroxyenone intermediates that are cycloaromatized to the final furan derivatives on exposure to either acid or a discrete Heck arylation step. This latter process concomitantly introduces an extra substituent onto the furan target with complete control of regiochemistry. The methodology described here serves as the basis for developing other CM-based entries to diverse heteroaromatic compounds. This protocol describes in detail the following stages of the furan procedures: (i) the tandem formation and acid-catalyzed cyclization of the γ-hydroxyenone to afford a 2,5-disubstituted furan directly; (ii) CM of an allylic alcohol with an enone to provide an isolated γ-hydroxyenone; and (iii) Heck arylation of this γ-hydroxyenone to afford a 2,3,5-trisubstituted furan. The reaction procedure given for the formation of the 2,5-disubstituted furan (option A) takes ∼26.5 h to complete. The procedure described for the formation of the 2,3,5-trisubstituted furan (option B) takes ∼52.5 h.