Synthesis of 10-epi-ABCDE ring fragment of pectenotoxin 2

Thumbnail Image
Journal Title
Journal ISSN
Volume Title
Doctoral thesis (monograph)
Checking the digitized thesis and permission for publishing
Instructions for the author
Degree programme
Verkkokirja (1632 KB, 167 s.)
TKK dissertations, 180
The pectenotoxins (PTXs) are a family of marine macrolactones produced by Dinophysis dinoflagellates and found in coastal areas worldwide. The PTXs have drawn considerable attention not only because of their complex structure and toxicity but also because of their potential medical applications. Pectenotoxins have shown selective cytotoxicity against a variety cancer cell lines and they are known to interact with the actin cytoskeleton by unique mechanism. These properties could be of great clinical importance for the development of new cancer chemotherapy agents. The scarcity of the PTXs has hampered further studies into their biological activity, and as such access to synthetic PTXs would be immensely helpful. The exquisitely complex structure of the PTXs presents a considerable challenge for a synthetic chemist. One of the most challenging structural elements is the AB spiroketal ring fragment that is in the more unstable and less easily accessible nonanomeric configuration. Importantly, the PTX congeners that contain this nonanomeric spiroketal ring system, has been reported to be the most biologically active. In the literature part, a short discussion of the anomeric effect is presented. The previously published syntheses of the AB spiroketal ring fragment of PTXs are discussed. And finally, a brief insight into other natural products containing nonanomeric spiroketals and their recent syntheses are presented. In this work the objective was to synthesize the ABCDE ring fragment of PTX2 using a highly convergent strategy. Three advanced ring fragments corresponding to the A, C and DE ring systems were synthesized. The A ring lactone was also used for the synthesis of the AB spiroketal ring fragment of PTX2. During these studies we developed kinetic spiroketalization conditions that delivered for the first time the desired nonanomeric spiroketal isomer of the PTXs as the major product. For the C ring fragment an efficient synthesis was developed that delivered the key center peace with the right stereochemistry in excellent 46% total yield over nine steps. The connection of the C ring aldehyde with the DE ring fragment using Mukaiyama aldol reaction gave access to the CDE ring system in highly stereoselective manner. The CDE ring allylic alcohol was connected with the A ring fragment via cross-metathesis. As the final step, the kinetic spiroketalization delivered a 3:1 mixture of the nonanomeric and the anomeric spiroketal. Unfortunately, it was discovered that the final ABCDE ring product had the wrong stereochemistry at C10. Studies targeting the inversion of this stereocenter are under way, which would finally give access to the natural ABCDE ring fragment of PTX2.
pectenotoxin, total synthesis, spiroketal, nonanomeric, anomeric
Other note