Couladouros, E. A.

Dakanali, M.

Demadis, K. D.

Mitsopoulou, K. P.

Vidali, V. P.

Digital Repository of Hellenic Managing Authority of the Operational Programme &quot;Education and Lifelong Learning&quot; (EDULLL)

Design and Synthesis of Novel Hyperforin Analogues – Fascinating skeletal rearrangements of polycyclic polyprenylated acylphloroglucinols coreK. P. Mitsopoulou, V. P. Vidali,  M. Dakanali, K. D. Demadis, E. A. Couladouros*Chemistry Laboratories, Agricultural University of Athens, Iera Odos 75, Athens, 118 55Laboratory of Natural Products Synthesis and Bioorganic Chemistry, NCSR ‘Demokritos’ 153 10 Ag. Paraskevi,  AthensCrystal Engineering, Growth & Design Laboratory, Department of Chemistry, University of Crete,, Cretee-mail: ecoula@chem.demokritos.grScheme 1. Retrosynthetic Scheme Scheme 3.  Attempts to synthesize  sp2 C-7 analoguesScheme 2. General synthetic scheme of Hyperforin’s analoguesHyperforin, the most known member of this family, has been isolated from Hypericum perforatum (St. Johns’s wort), known for its antidepressant and anticancer properties.  There is a big interest in synthesizing Hyperforin’s analogues in order to improve the molecule’s activity.[1,3] Up-to-date analogues showing highest biological activity possess an enol hydroxyl free [3g-i]. Based on this literature background, our efforts focus on the design and synthesis of new analogues with improved properties.  In our lab, a new short biomimetic approach has been developed leading to the fully functionalized bicyclic core of type A acylphloroglucinols, including Hyperforin.[2] Based on this strategy we targeted in two classes of compounds possessing either an sp2- or an sp3-carbon on C-7, starting from key intermediate 1 (Scheme 1).   A general route leading to 1 is depicted on Scheme 2.  Approaches to sp2 C-7 analogues including either Wittig on Ac-1 (Approach I, Scheme 3) or deprotection after Wittig on Pv-1 led to no desirable results (Approach II).  Thus, approach III was attempted, based on establishing the desirable side chain functionalization before alkylation step.   It is interesting that attempting to saturate C-7 of compound  1,  via Michael addition ,  an unprecedented  skeletal rearrangement  to  a 6,5-bicyclic ring system was observed.  Thus, deacetylation of aldehyde Ac-1, led to analogue 2, which after Michael  afforded sp3 C-7 analogue 3 (Scheme 4), whose structure was confirmed by X-ray analysis .  Derivatives  4 and  5  were  also prepared.  Biological activity results obtained from our first derivatives will lead our design to a new generation of hyperforin analogues.  Moreover, our efforts focus on the improvement of efficiency of our methodology.References1. Mennini, T. et al Lifi Sci. 2004, 75, 1021.2. Elias A. Couladouros, Marianna Dakanali, Konstantinos D. Demadis and Veroniki P. Vidali Org. Lett., 2009, 11, 4430.3. a. Kraus, G. A. et al. Tetrahedron 2005, 61, 2111, b. Nicolaou, K. C. et al Angew. Chem. Int. Ed. Engl. 2005, 44, 3895, c. Young, D. G. et al J. Org. Chem. 2002, 67, 3134, d. Mehta, G. et al Tet. Lett. 2004, 45, 1113, e. Stoltz, B. M. et al Org. Lett. 2002, 4, 1943, f. Grossman, R. B. et al Org. Lett. 2003, 5, 4619, g. Ciochina R. et al. Chem. Rev. 2006, 106, 3963, h. Verotta et al. J. Nat. Prod. 1999, 62, 770, i. Verotta et al. J. Nat. Prod. 2000, 63, 412.OOOOPOR1OOOOPR2R1OOOOPR2R1R3P: H, Ac, PivR1: H, PrenylR2: CH2, CHCOOEtKey intermediate 177R3: PhS-, RO-, H- etc.ClOTBSRHOKOH(3N), AliquatPhClProtectionOHHOOHOOHOOOHOTBSOHROOOOPOTBSRMsCl, THFEt3N(C-cyclization product)OOOPOTBSROHOOOPOTBSOHRHF pyrTHF OOOOPOHR IBXDMSOOOOOPORP: Piv, AcR: H, PrenylR2: CH2, CHCOOEtOKey intermediate - 1(O-cyclization product)ClHOKOH(3N),AliquatPhClacetoneAc2O, pyr.OHHOOHOOHOOOHOHOOOAcMsCl, Et3NTHFOHOOOAcOHOB2OOOAcOOOOOHOOMeONaMeOH70%PPh3CH2PPh3CH2Deprotection and ring opening productTHFTHFAc-12Approach I(direct Wittig on key aldehyde 1)Approach II(Wittig on key aldehyde 1b and deprotection)OOOOPvOOOOOPvOOOOPvDeprotectionOEtODegradation productsX-NaH, Ethanol-NH3/MeOH (1:10), 60 oC-MeONa, MeOH-HCl/MeOH/H2O (1:8:1)-KCN, Et3N-KCN-CH3COOH/H2O (8:2)Pv-1ABConditions: A: PPh3CH2, THF, 78%B: PPH3CHCOOEt, C6H6, 86%DeprotectionDegradation productsXConditions of deprotectionApproach III (Establishment of target unsaturated side chain, before alkylation step)Scheme 4.  An interesting skeleton rearrangement observed, attempting synthesis of sp3 C-7 Hyperforin’s analoguesPPh3CHCOOEtOOOAcOOPhSHPiperidine/THF81%MeONaMeOH OOOHOO90%( for two steps)R = H, prenylAc-1 24O OOHSPhOOH3O OOHSPhOHCOOEtRaney Ni76%O OOHOOH5X-ray crystallographic analysis3OOOHOΥπερφορίνηAcknowledgmentsWe would like to thank the Research Funding Program: Heracleitus II.

Design and Synthesis of Novel Hyperforin Analogues - Fascinating skeletal rearrangements of polycyclic polyprenylated acylphloroglucinols core

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Design and Synthesis of Novel Hyperforin Analogues - Fascinating skeletal rearrangements of polycyclic polyprenylated acylphloroglucinols core

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Digital Repository of Hellenic Managing Authority of the Operational Programme "Education and Lifelong Learning" (EDULLL)

Design and Synthesis of Novel Hyperforin Analogues - Fascinating skeletal rearrangements of polycyclic polyprenylated acylphloroglucinols core

Abstract

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Full text

Available Versions

Digital Repository of Hellenic Managing Authority of the Operational Programme &quot;Education and Lifelong Learning&quot; (EDULLL)

Digital Repository of Hellenic Managing Authority of the Operational Programme "Education and Lifelong Learning" (EDULLL)