Investigations into the partial reduction of substituted pyridines and its application towards the total synthesis of cylindricine A

ORGN 873

Dale J Johnson, dale.johnson@chem.ox.ac.uk1, Timothy J. Donohoe1, and Mark J Bamford2. (1) Department of Chemistry, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, United Kingdom, (2) Department of Medicinal Chemistry, GlaxoSmithKline Research and Development Ltd, New Frontiers Science Park, Third Avenue, Harlow, CM19 5AW, United Kingdom
The ammonia-free Birch reduction, using lithium and di-tert-butylbiphenyl as a source of electrons, was applied to the pyridinium salt of 4-methoxypicolinic acid methyl ester. The group on nitrogen was found to be important both as an activating group for the reductive process itself and a protecting group for nitrogen after reduction. During reduction the addition of two electrons to the pyridine nucleus generates an enolate stablised by the alpha nitrogen. This can be quenched with a range of electrophiles including acids, alkyl halides and chloroformates with hydrolysis of the enol ether in situ giving a range dihydropyridones. The dihydropyridone was shown to be a versatile intermediate, with functionalisation of every position around the ring achieved with a variety of synthetic techniques. To demonstrate the utility of this methodology and to further probe the properties of this important class of molecule the synthesis of the marine alkaloid cylindricine A was undertaken.

 

Heterocycles and Aromatics
8:00 AM-12:00 PM, Thursday, 14 September 2006 Moscone Center -- Room 135, Oral

Division of Organic Chemistry

The 232nd ACS National Meeting, San Francisco, CA, September 10-14, 2006