DOMINO KNOEVENAGEL/BICYCLIZATION STRATEGY FOR THE SYNTHESIS OF CITRIDONE A ANALOGUES

MISCHNE, M. P.; QUIROGA, G. N.; RIVEIRA, M. J.

Sitges

Simposio; 17TH TETRAHEDRON SYMPOSIUM; 2016

Elsevier

Citridone A (1) is an antifungal and antibacterial cyclopenta[b]furopyridone recently isolated from Penicillium sp. by Nobel Laureate S. Õmuraand coworkers.1 The same research group was shortly after involvedin the total synthesis of natural (-)-1which required more than 20 reaction steps.2Our group recently established thatdicarbonyl substrates (2) anddienals (3) participate in a novel dominoKnoevenagel/bicyclization process toward cyclopenta[b]furan derivatives (4)(Scheme 1).3 Since the use of pyridones and quinolones only led tothe exclusive formation of 2H-pyranisomers (5), a thoroughinvestigation was carried out to make this type of substrates amenable to thebicyclization strategy and thus provide access to citridone A and derivatives.  Apart from well-known Tietze base (ethylenediaminediacetate, EDDA), several catalysts were screened. Lewis and Brønsted acidswere found to be ineffective and produced self-cyclization of dienal substrates3, a transformation for thesynthesis of cyclopentenones that is currently under development in ourlaboratories. On the other hand, standard Knoevenagel conditions, piperidine/aceticacid, did not provide access to products 4but to an unstable isomer that sluggishly rearranges to the former upon acidtreatment. After considerable experimentation, catalyst EDDA in combinationwith microwave irradiation allowed for the success of such organocatalyticcascade (Scheme 2). Derivative 4aa,in particular, is currently being explored as synthetic intermediate towardnatural product 1.In summary, a simple one-pot syntheticmethodology has been developed to access cyclopenta[b]furopyridones/quinolones which may help and promote futurestudies on this promising new class of natural products.  References1- Fukuda, T.; Yamaguchi, Y.; Masuma, R.; Tomoda, H.; Õmura, S. J. Antibiot. 2005, 58, 309. 2- Miyagawa, T.; Nagai, K.;Yamada, A.; Sugihara, Y.; Fukuda, T.; Fukuda, T.; Uchida, R.; Tomoda, H.;Õmura, S.; Nagamitsu, T. Org. Lett. 2011,13, 1158. 3-Riveira, M. J.; Mischne, M. P. Chem.-Eur.J. 2012, 18, 2382.