Progress toward the Total Synthesis of Pleurotin

Transcription

1 Progress toward the Total Synthesis of Pleurotin SINYA IIMURA Wipf Research Group Meeting July 9th, 2005 Shinya Wipf Group 1 7/10/2005

2 Presentation utline! Isolation and Structure! Biological Activity! art's Total Synthesis (Racemic)! Kraus' Studies toward Total Synthesis! Previous Studies in the Wipf Group! Current Total Synthesis Efforts in the Wipf Group! Future Plans Shinya Wipf Group 2 7/10/2005

3 Isolation and Properties of Pleurotin C 3 Pleurotin!"First isolated from the fungus Pleurotus griseus in 1947 by Robbins et al., and later obtained from ohenbuehelia geogenius.! Pleurotin began to melt with decomposition at temperatures between 200 C and 215 C depending upon the rate of heating.! Pleurotin was optically active with [#] 23 D = -20 (c 0.59, CCl 3 ).! The solubility of pleurotin at 25 C: mg/ml (water), 6.8 mg/ml (95% ethanol), 0.37 mg/ml (5% ethanol), 3.5 mg/ml (ether), more than 200 mg/ml (chloroform).! Pleurotin was not thermostable. Solutions of pleurotin in 0.1 M. phosphate buffer when boiled for 10 min lost 50% of their biological activity at p 3, 75% at p 6.5, and all of their activity at p 8.5.! Pleurotin was 75% destroyed in 1 h at p 8.5 and 25 C.! Pleurotin in solution was rendered inactive by exposure to light for a few hours. Robbins, W. J. et al. Proc. Natl. Acad. Sci. USA, 1947, 33, 171. Shinya Wipf Group 3 7/10/2005

4 Poster Presented at the 2004 International Congress on Natural Products Research, A joint meeting of the ASP, AFERP, GA and the PSE July 31 August 4, 2004 Phoenix, AZ; Podium Presentation at the July 2004 Society of Microbiology meeting, Anaheim, CA Shinya Wipf Group 4 7/10/2005

5 Structure and the Synthetic Challenges C 3 Pleurotin! Structure originally assigned on the basis of degrative studies in 1968 and later confirmed by X-ray crystallography in ddoux, L. et al. Arzneim. Forsch. 1981, 31, 293. Cohen-Addad, P. C. et al. Acta Crystallogr. 1981, B37, 1309.! The Challenge to Synthetic Chemists: The unique compact hexacyclic framework The six contiguous stereogenetic centers No enantioselective total synthesis Shinya Wipf Group 5 7/10/2005

6 Biological Activity C 3 Pleurotin! Antibiotic activity against Gram-positive bacteria. Robbins, W. J. et al. Proc. Natl. Acad. Sci. USA, 1947, 33, 171.! Antitumor activity against two rapidly grafted tumors: Ehrlich ascites carcinoma and L-1210 lymphoid leukemia, as well as a slow growing spontaneous mammary tumor. ddoux, L. et al. Arzneim. Forsch. 1981, 31, 293.! A potent inhibitor of the thioredoxin thioredoxin reductase system (IC nm). Powis, G. et al. Anti-Cancer Drug Des., 1997, 12, 659. Powis, G. et al. Mol. Cancer Ther., 2003, 2, 235. Wipf, P. et al. rg. Biomol. Chem., 2004, 2, Shinya Wipf Group 6 7/10/2005

7 Bioreductive Alkylation! The concept of bioactivation as a mechanism of drug action is one that is especially appealing to the medicinal and synthetic organic chemist. The challenge of designing compounds in a biologically inactive form which become activated only subsequent to an in vivo transformation allows the synthesis chemist to take advantage of his arsenal of methodology and mechanistic probes and to directly apply them to potentially important problems of drug action.! Moore,. W. Science (Washington, D.C.) 1977, 197, 527. The concept of bioreductive alkylation which is compounds which become potent alkylating agents after they undergo a reduction in vivo, is a particularly fascinating area within the field of bioactivation. Lin. A. J. et al., J. Med. Chem. 1972, 15, Moore,. W. Science (Washington, D.C.) 1977, 197, 527. Shinya Wipf Group 7 7/10/2005

8 Bioreductive Alkylation 2 N N CN 2 Me N 2 N N Me CN 2 N Me 2 N N CN 2 N Mitomycin C 2 N N CN 2 N 2 DNA First alkylation step 2 N N CN 2 DNA N 2 CN 2 2 N N DNA N 2 Second alkylation step (cross-linking) 2 2 N N DNA N 2 Tomasz, M., Chem. Biol. 1995, 2, 575. Shinya Wipf Group 8 7/10/2005

9 Suggested Bioactivation of Pleuotin Nu 1 Nu 2 pleurotin Nu dihydropleurotin acid Moore,. W. Science (Washington, D.C.) 1977, 197, 527. art, D. J. et al. J. Am. Chem. Soc. 1989, 111, Shinya Wipf Group 9 7/10/2005

10 art: First Total Synthesis of Pleurotin (Racemic) C 3 C 2 Et pleurotin dihydropleurotin acid C 2 Et C 3 Key feature Biomimetic conversion of dihydropleurotin acid to pleurotin* Stereoselective free-radical cyclization *Arigoni group has demonstrated that dihydropleurotin acid is converted to pleurotin by cultures of Pleurotus griseus. Vogt, P.M. Ph. D. Thesis, Eidgenossischen Technischen ochschule, Zurich, Switzerland, art, D. J. et al. J. Am. Chem. Soc. 1988, 110, art, D. J. et al. J. Am. Chem. Soc. 1989, 111, Shinya Wipf Group 10 7/10/2005

11 art: First Total Synthesis of Pleurotin (Racemic) 1. Li, N 3 ; Br(C 2 ) 2 C(C 2 C 2 ) 1. I 2, TF/ 2 2. C 2, 2 I C 2 Et C 2 2. DPPA, Et 3 N, pyrrolidine, TF N 3. Ph 3 P=C(C 3 )C 2 Et 66% (2 steps) 78% (3 steps) n Bu 3 Sn, AIBN benzene,! 80% C 2 TBS 1. Li, EtN 2 2. C 2 N 2 C 2 Et 1. LiEt, Me, 2 ; Cl, 2 2. (CCl) 2 ; NaB 4 3. TBSCl, imidazole, DMF 85% (3 steps) C 2 TBS 3. (CCl) 2, DMS, Et 3 N TF 59% (3 steps) C 2 Me 91% C 2 TBS 2,5-(Me)C 6 3 C 2 MgCl CeCl 3 1. mcpba 2. LiNEt 2, Et 2 66% (2 steps) Me C 2 Me C 2 TBS Me art, D. J. et al. J. Am. Chem. Soc. 1988, 110, art, D. J. et al. J. Am. Chem. Soc. 1989, 111, Shinya Wipf Group 11 7/10/2005

12 art: Stereoselectivity in the Free-Radical Cyclization I R 1 R 2 n Bu 3 Sn, AIBN benzene,! Me C 2 Et Me C 2 Et 1: R 1 = Me, R 2 = C 2 Et 80% 4% 4% 4% 2: R 1 = C 2 Et, R 2 = Me 37% 2% 15% 12% + C 2Et Me + + Me C 2 Et R 2 R 1 R 1 R 2 + R 1 R 2 Me C 2 Et Me. (Et) Et (. ) Sn n Bu 3 Me C 2 Et Shinya Wipf Group 12 7/10/2005

13 art: First Total Synthesis of Pleurotin (Racemic) Me C 2 Me C 2 TBS 1. SCl 2, pyridine* 2. LiAl 4 Me 3. (CCl) 2, DMS, Et 3 N C 37% (3 steps) C 2 TBS Dowex-50 ( + ), Me 99% Me Me Me *Inseparable 1:1 mixture Me Me BF 3 Et 2 toluene 52% Me Me 1. B 3 TF; Na, (CCl) 2, DMS, Et 3 N 3. TosMIC, K t Bu, DME 4. DIBAL-, toluene 5. Ag 2, Na 36% (5 steps) 2 C Me Me Me Me art, D. J. et al. J. Am. Chem. Soc. 1988, 110, art, D. J. et al. J. Am. Chem. Soc. 1989, 111, Shinya Wipf Group 13 7/10/2005

14 art: First Total Synthesis of Pleurotin (Racemic) Me Me CAN C3CN/2 89% Mn2 C2Cl2 32% 26 steps from benzoic acid 0.3% overall yield an average of 80% yield per step art, D. J. et al. J. Am. Chem. Soc. 1988, 110, art, D. J. et al. J. Am. Chem. Soc. 1989, 111, Shinya Wipf Group 14 7/10/2005

15 Kraus: Retrosynthetic Analysis of Pleurotin Tandem Photoenolization/Diels Alder Reaction C 3 Me G Me C Me Me G Kraus, G. A. et al. Synlett 1991, 89. Kraus, G. A. et al. Synth. Commun. 1993, 23, Shinya Wipf Group 15 7/10/2005

16 Kraus: Synthetic Studies toward Pleurotin Me Me n BuLi, TF DMF 66% Me Me 1. S(C 2 ) 2 S, BF 3 Et 2 2. RC 2, DCC, DMAP 3. MeI, aq. MeCN 31% (3 steps) Me C Me Me C 1. h!, Benzene Me Ag, N 3 Me C, 40 h 50% Me TF 28% Comparable activity with pleurotin against SR leukemia cell line {log 10 GI 50 = (pleurotin: -5.51)} and most colon cancer cell lines {log 10 GI 50 ranging from to (pleurotin: -5.17)}. Kraus, G. A. et al. Synlett 1991, 89. Kraus, G. A. et al. Synth. Commun. 1993, 23, Shinya Wipf Group 16 7/10/2005

17 Acknowledgments Prof. Dr. Peter Wipf Dr. Sonia Rodríguez Dr. Steven Geib (X-ray) Wipf research group members University of Pittsburgh $ National Institutes of ealth (GM66509) $ Shinya Wipf Group 17 7/10/2005