Asymmetric total synthesis of (–)-phaeocaulisin A Áron Péter, Giacomo E. M. Crisenza and David J. Procter 1 * The University of Manchester, UK
The therapeutic properties of plant genus Curcuma (ginger and turmeric’s family) have long been known in traditional Indian and Chinese medicine. 1 A recent report by the European Medicines Agency also highlights their potential societal worth. 2 However, only recently have guaiane-type sesquiterpenes extracted from Curcuma phaeocaulis – featuring the characteristic 5,7-fused carbocyclic skeleton – been submitted to biological testing, and their enhanced bioactivity highlighted. 3 Amongst these compounds, phaeocaulisin A has shown remarkable non-cytotoxic anti-inflammatory and anti-melanoma activity, which appears to be tied to the unique bridged acetal moiety embedded in its tetracyclic framework. 3 Prompted by the promising biological profile of phaeocaulisin A, and by the absence of a synthetic route for its provision, we have implemented the first enantioselective total synthesis of phaeocaulisin A in 17 steps with 2% overall yield. 4 Our route design builds on the identification of the 1,4- and 1,6-dioxygenated patterns within the natural product’s structure, which has led to the design of an enantioenriched lactone intermediate, tailored with both a ketone moiety and a conjugated diene system. Its synthesis was achieved by E -selective alkyne carboalumination followed by a Negishi cross-coupling, a Sharpless asymmetric dihydroxylation – to set the guiding stereocentre – and a gold-catalysed Markovnikov hydration of a terminal alkyne. At this point in our synthesis, exploiting the archetypal single electron reductant samarium diiodide (SmI 2 ) in two sequential umpolung carbonyl-olefin cyclizations, the key lactone intermediate was stereoselectively converted into the polycyclic core of phaeocaulisin A. Our asymmetric route has allowed us to elucidate the naturally occurring isomer of phaeocaulisin A and, more importantly, it provides a synthetic platform to access other guaiane-type sesquiterpenes from Curcuma phaeocaulis – as well as their synthetic derivatives – for medicinal chemistry and drug design.
References 1. Prasad, S.; Aggarwal, B. B. Herbal Medicine: Biomolecular andClinical Aspects; 2nd editio.; Benzie, I. F. F.; Wachtel-Galor, S., Eds.; CRC Press/Taylor & Francis: 2011 . 2. Committee on Herbal Medicinal European Medicines AgencyCurcumae longae rhizoma; https://www.ema.europa.eu/en/ medicines/herbal/curcumae-longae-rhizoma (accessed Sept 22, 2022). 3. Qiu, F. et al . J. Nat. Prod. 2013 , 76 , 1150–1156. 4. Péter, Á.; Crisenza, G. E. M; Procter, D. J. J. Am. Chem. Soc . 2022 144 , 7457-7464
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