Sarang Kulkarni Current Literature Presentation April 9, 2011 Enantioselective Total Synthesis of (-) Jiadifenolide Xu, J; Trzoss, L; Chang, W. K; Theodorakis, E. A Angew. Chem. Int. Ed. 2011 , 50 , 3672-3676 Sarang Kulkarni @ Wipf Group Page 1 of 9 4/16/2011
Jiadifenolide and Related Natural Products O OH O - Isolated from the pericarps of Illicium jiadif engpi by Fukuyam a and c o-work er s in 2009 - Highly oxygenated pentacy clic cage s tr uc tur e OH -Pr om oter of neurite growth O -Potential therapeutic v alue for neurodegener ative diseas es O O (- )-Jiadifenolide CO 2 M e HO O - Isolated fr om the per icarps of Illic ium jiadif engpi by Fukuyama and co-wor kers in 2002 - First total s ynthesis by Danishefs ky and c o-work er s O OH - B iologic al studies s howed J iadifenin upregulates the action of NGF (Nerv e growth factor) O O jiadifenin H H O O O O HO HO O O O O O OH O OH OH OH O O O HO HO HO HO HO O O O O O J iadifenoxolane A Jiadif enoxolane B Noemajucin A nisatin Kubo, M.; Okada, C.; Huang, J-M.; Harada, K.; Hioki, H.; Fukuyama, Y. Org. Lett. 2009 , 11 , 5190 Yokoyama, R.; Huang, J-M.; Yang, C.S.; Fukuyama, Y. J. Nat. Prod. 2002 , 65 , 527 Cho, Y. S.; Carcache, D. A.; Tian, Y.; Li, Y. L.; Danishefsky, S. J. J. Am. Chem. Soc. 2004 , 126 , 14358 Carcache, D. A.; Cho, Y. S.; Hua Z.; Tian, Y.; Li, Y. L.; Danishefsky, S. J. J. Am. Chem. Soc. 2006 , 128 , 1016 Sarang Kulkarni @ Wipf Group Page 2 of 9 4/16/2011
Oxidative Conversion of Neomajucin to Jiadifenolide H + H O OH O OH HO O O O O Dess- Martin O O -H 2 O O OH P er iodinane O OH O O O O HO O HO HO O O O O H + Neom ajucin H + O O O OH H 2 O O O O OH H + O OH O OH O O O O O O O O J aidifenolide Kubo, M.; Okada, C.; Huang, J-M.; Harada, K.; Hioki, H.; Fukuyama, Y. Org. Lett. 2009 , 11 , 5190 Sarang Kulkarni @ Wipf Group Page 3 of 9 4/16/2011
Retrosynthesis O O O OH O O OTES OTES OH OH OH O O O O O O O O O Jaidifenolide ( 1) 2 3 O TBSO TBSO O O OH O O O O O 6 5 4 Xu, J; Trzoss, L; Chang, W. K; Theodorakis, E. A Angew. Chem. Int. Ed. 2011 , 50 , 3672 Sarang Kulkarni @ Wipf Group Page 4 of 9 4/16/2011
Synthesis of tricyclic lactone 5 1. Pd[(C 3 H 5 )Cl 2 ] 2 O dppe, ally l acetate O O D-prolinamide (30 mol%) 1. NaB H 4 E tO H B SA , NaOAc PP TS (30 mol%) 2. TBS Cl. NH 4 NO 3 2. MV K, Ac OH, H 2 O MeCN, 14 days O DMF, 92% 2 S teps 63%, 2 Steps O O 74%, >90% ee O 7 8 6 O 1. H 3 CO OM gOCH 3 1. LiA lH 4 TBS O T BSO 1. K HM DS, PhNTf 2 then, E t 3 O + BF 4- 2. TB SCl, Im T BSO 2. CO (1 atm ) 2. TM SOT f, 2,6-Lutidine 3. IB X [Pd(P Ph 3 ) 4 ] ( 1 m ol%) O then TBA F, M eI O 85%, 3 S teps NEt 3 O 43%, 2 S teps then, TFA, CH 2 Cl 2 O OEt OTB S 69%, 2 Steps 9 10 11 TBS O O O 5 Ruprah, P. K.; Cros, J-P.; Pease, J. E.; Whittingham, W. G.; Williams, J. M. J. Eur. J. Org Chem. 2002 , 3145-3152 Zhang, X-M.; Wang, M.; Tu, Y-Q.; Fan, C-A.; Jaing, Y-J.; Zhang, S-Y, Zhang, F-M. Synlett, 2008 , 18 , 2831-2835 Sarang Kulkarni @ Wipf Group Page 5 of 9 4/16/2011
O O O Base, RX , s olvent R O O OR A B Yield % ( A ) R X Conditions M e I NaOH/H 2 O/diox ane reflux 35 I T lOE t/M eI, 41 C 5 CH 2 CH=CHC 2 H 5 Cl K OH/H 2 O 41 CH 2 C CC 2 H 5 Br Na 2 CO 3 /H 2 O/PTC 65 Sc hick, H.; E ic hhorn, I. Sy nthes is , 1989 , 477-492 NaH, CO 2 O O COOH 25-45% O H + H 3 CO OM gOCH 3 O O O COOH Mg O O 41-64% M ec heli, R. A .; Hajos, Z. G.; Cohen, N.; Parr ish, D. R.; Portland, L. A .; S ciam anna, W .; Sc ott, M. A.; Wehrli, P. A. J . Or g. Chem. 1975, 40 , 675-681 Sarang Kulkarni @ Wipf Group Page 6 of 9 4/16/2011
Synthesis of Lactone 14 O TB SO TB SO 1. OsO 4 (1 mol%) TBSO O H 2 O 2 , 3 M NaOH NaIO 4 O O H 2. Jones r eagent 99% O O O 70% (2 Steps ) O O O 5 12 4 X - ray, 4.5 g O O HO O O 1. m CP BA T BAF OH O H OH O 2. Des s-M ar tin Periodinane 95% O O 38%, 2 Steps O O 13 14 m CP BA O O O HO O DM P O H OH O H H + O O O O H O O Sarang Kulkarni @ Wipf Group Page 7 of 9 4/16/2011
Completion of the Synthesis O O O O O 1. KHM DS 1. H 2 , 10% Pd/C OH O TES O TES Comins r eagent O H OH O O H O O 2. T ESO Tf 2. AlMe 3 , [P d(PP h 3 ) 4 ] O O O 2,6-Lutidine 57%, 2 S teps O O 90%, 2 Steps O 14 15 16 O O O H OH O 1. H 2 , P tO 2 O TES Jones r eagent OH O H O O 2. NaHM DS O O Dav is oxaziridine O O 17 Jaidifenolide ( 1) Cl O Ph Tf N N N PhO 2 S H Tf Comins Reagent Davis Oxaz iridine Hirota, K.; Isobe, Y.; Maki, Y. J. Chem. Soc. Perkin Trans 1 , 1989 , 2513 Davis, F. A.; Chattopadhyay, S.; Towson, J. C.; Lal, S.; Reddy, T. J. Org. Chem. 1988 , 53 , 2087 Sarang Kulkarni @ Wipf Group Page 8 of 9 4/16/2011
Conclusions • First total synthesis of (-)-jiadifenolide, in 1.5% overall yield and 25 total steps • Acid-induced cascade reaction to setup desired lactone • Gram scale synthesis of tetracyclic lactone 4 , can be used in synthesis of related natural products and analogs Sarang Kulkarni @ Wipf Group Page 9 of 9 4/16/2011
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