A Novel Cyclisation Strategy for the Synthesis of Lactonamycin: A New Route to Highly Functionalised Heterocyclic Rings

Abstract

A novel thermal cascade reaction equivalent to the wellknown [2+2+2] cycloaddition has been developed which is clean and reliable and does not involve the use of metal ions. This highly efficient method has been used to construct a model for the synthesis of the antibiotic lactonamycin. The utility of this new sequence for the formation of furans is also reported.

Approaches to the Synthesis of Highly Substituted Aromatic and Fused Rings: Metal-Catalysed versus Thermal Cyclisation

“…Early investigations, however, led to the unexpected tetracycle 4 in 14% yield when the alkenyl bromide 2 was treated with trin-butyltin hydride and AIBN in refluxing benzene (Scheme 1). 10 Thermal degradation studies were undertaken to determine the stability of alkenyl bromide 2. Thus, in the absence of the tin hydride, substrate 2 provided lactam 4 in improved yields for almost all of the investigated solvents (Table 1).…”

“…Other interesting fused heterocyclic and carbocyclic fused ring systems could also be formed under the cyclisation conditions. 10…”

Model studies for the synthesis of the antibiotic lactonamycin and the discovery of new reactions and mechanisms for the construction of substituted heterocycles

“…tert-Butyl bromide acts as a bulky proton source and is entirely neutral as a quenching agent. 9 Other methods that were used to quench this reaction gave lower yields of the desired alcohol 9 and when ammonium chloride in water was used to work up the reaction mixture the ether 11 was isolated.…”

An Approach to the Core of Lactonamycin

“…The resulting cation is stabilized by a mesomeric effect from the bromine and followed by proton loss. Elimination of the zinc species allows aromatization and affords the naphthalene product (20). Unsurprisingly, the reaction proceeds equally well in the absence of the alkyne.…”