1 / 39

The Chemistry of Prof. Paul A. Grieco Montana State University Prepared by Andy Diep

The Chemistry of Prof. Paul A. Grieco Montana State University Prepared by Andy Diep Senior Medicinal Research Scientist Forest Laboratories, Inc. Paul A. Grieco Regents Professor of Chemistry and Biochemistry Montana State University. B.A., Boston University, 1966;

menora
Download Presentation

The Chemistry of Prof. Paul A. Grieco Montana State University Prepared by Andy Diep

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. The Chemistry of Prof. Paul A. Grieco Montana State University Prepared by Andy Diep Senior Medicinal Research Scientist Forest Laboratories, Inc

  2. Paul A. Grieco Regents Professor of Chemistry and Biochemistry Montana State University B.A., Boston University, 1966; M.A., Columbia University, 1967; Ph.D., Columbia University, 1970; NSF Postdoctoral Fellow, Harvard University, 1970-71. Since 1997 Paul Grieco has been at Montana State University, where he is now Regents Professor of Chemistry and Biochemistry. Before that, he was the Earl Blough Professor and chairman of the chemistry department at Indiana University. He has published more than 250 articles in scientific journals and received many major awards. He has mentored 98 Ph.D. students and 75 postdoctoral fellows in his career. His research interests are center on the invention of new reactions, methods development of medium effects in organic reactions, and strategies in organic synthesis of natural products. Awards Charles & Nora L. Wiley Award for Meritorious Research, 1999; ACS Award for Creative Work in Synthetic Organic Chemistry, 1991; ACS Arthur C. Cope Scholar Award, 1990; National Cancer Institute Merit Award, 1988; ACS Ernest Guenther Award in the Chemistry of Essential Oils and Related Products, 1982; Award of the Akron Section of the ACS, 1982; Member, Medicinal Chemistry Study Section, NIH, 1998-01; Chairman Medicinal Chemistry Study Section, NIH, 1999-01; Japan Society for the Promotion of Science Fellow, 1978-79; Alfred P. Sloan Fellow, 1974-76; Eli Lilly Fellow, 1973-75.

  3. Selected Highlights New Strategies & Tactics Natural product • Organic Synthesis in Water • By Paul A. Grieco • Published by Springer, 1998 • ISBN 0751404101, 9780751404104 • Development of Cationic Diels-Alder Reaction in Highly Polar Media, • Lithium Perchlorate in Diethyl Ether (LPDE) • * [1,3]-Sigmatropic Rearrangement of Allyl Vinyl Ethers • * Catalytic Acid in LPDE to Promote: • # Intra / Intermolecular Imino Diels-Alder • # Intramolecular Cycloaddition of Heteroatom-Stabilized • Allyl Cations • * Nucleophilic Substitution and Ring Opening • via Silyl Ketene Acetal • Stereospecific Synthesis of Natural Products via Bicyclo[2.2.2]heptenone & • Oxabicyclo[3.2.1]octenes as templates • Total Synthesis of Natural Products Total Synthesis Designed & Discovered methods

  4. Selected works (total synthesis) by the Grieco Group Vernomenin JACS, 1976, 97, 1612 ibid.,1977, 99, 5773 Temisin JCS, CC,, 1978, 76 Vernolepin JACS, 1976, 97, 1612 ibid.,1977, 99, 5773 Diumycinol JOC, 1975, 40, 2261 Damsin JACS, 1977, 99, 7393 ibid.,1982, 104, 4226 Moenocinol JACS, 1975, 97, 1597 Helenalin JACS, 1978, 100, 5946 ibid.,1982, 104, 4233 Ambrosin JACS, 1977, 99, 7393 ibid.,1982, 104, 4226 Eriolangin / Eriolanin JACS, 1978, 100, 1616 ibid.,1980, 102, 5886 R=H: Mexicanin 1 R=Ac: Linifolin A TL, 1979, 3265 Costunolide JOC,1977, 42, 1717 Sirenin JACS, 1969, 91, 5660 Tuberiferine JCS, CC, 1976, 582 Thienamycin JACS, 1984, 106, 6414 Stramonin B JOC, 1978, 43, 4552

  5. Selected works (total synthesis) by the Grieco Group Castelanolide JOC, 1982, 47, 601 ibid., 1984, 49, 2342 Polyandrane JACS, 1999, 121, 9891 Compactin JACS, 1986, 108, 5908 Calcimycin JACS, 1982, 104, 1436 De-A-quassimarin JOC, 1987, 52, 3346 Methynolide JACS, 1979, 101, 4749 (+)-des-D-Chaparrinone JOC, 1998, 63, 5929 Quassin JACS, 1980, 102, 7586 ibid., 1984, 106, 3539 R=H ; (-)-Chaparrinone R=OH ; (-)-Glaucarubolone JACS, 1993, 115, 6078 Bruceoside C JACS, 1996, 16, 5316 (+)-Tylonolide JACS, 1982, 104, 5781 Estrone JOC, 1980, 45, 2247

  6. Selected works (total synthesis) by the Grieco Group Ibogamine JOC, 1994, 59, 6898 TL, 1996, 37, 8289 Endiandric Acid SYNLETT, 1997, 493 Pseudotabersonine JACS, 1993, 115, 1164 Laulimalide Lycopodine JACS, 1998, 120, 5128 (-)-Epothilone B CC, 1998, 1597 C(19)-C(32) Scytophycin C TL, 1998, 39, 1125 OL, 2002, 2, 245 Eburnamonine JOC, 1994, 59, 7197 C(19)-C(27) Rifamycin S OL, 2001, 3, 481 (+)-Jasplakinolide JACS, 1988, 110, 1630

  7. Organic Synthesis in H2O & Polar Media Lithium Perchlorate in Diethyl Ether (LPDE)

  8. Aqueous Intermolecular Diels-Alder Chemistry Dienes with Dienophiles in H2O 1. H2O / r.t. / 1h 2. CH2N2 / 77% JOC. 1983, 48, 3137 Highlights 1. H2O / r.t. / 7h 2. CH2N2 / 77% Tetrahedron, 1986, 42, 2847 H2O / r.t. / 20 h 95% Methacrolein H2O / 550 C 16 h LiAlH4 THF/00 C J.Chem.Soc., Chem Comm, 1988, 500

  9. Aqueous Intermolecular Diels-Alder Chemistry Dienes with Dienophiles in H2O Benzene reflux / 72h 67% Highlights H2O r.t. / 5 h 75% JOC. 1983, 48, 3137 JACS. 1990, 112, 9436 JACS, 1993, 115, 6078 Chaparrinone

  10. Aqueous Intermolecular Diels-Alder Chemistry Dienes with Dienophiles in H2O H2O 1. NaBH4 2. H+ / 91% overall Highlights Vernolepin JOC. 1984, 49, 5257 JOC. 1983, 48, 3137 JACS. 1980, 102, 782

  11. Reaction in Highly Polar Media (LPDE) Nucleophilic Substitutions of Ketene Acetals Highlights TL, 1992, 33, 4735

  12. Reaction in Highly Polar Media (LPDE) Nucleophilic Substitutions of Indole Highlights J. Chem.Soc.,Chem.Commun, 1993, 510

  13. Reaction in Highly Polar Media (LPDE) [4+2] Cycloaddition TL., 1993, 34, 7367 Highlights

  14. Reaction in Highly Polar Media (LPDE) Intra/Intermolecular Ionic Diels-Alder Reactions Highlights Synlett., 1995, 1155

  15. Reaction in Highly Polar Media (LPDE) Intramolecular Diels-Alder reaction of Trienone Highlights Acid catalyzed migration of the diene prior to [4+2] cycloaddition

  16. Reaction in Highly Polar Media (LPDE) Heteroatom-stabilized Allyl Cations Cycloaddition Highlights JACS. 1996, 118, 2095

  17. Reaction in Highly Polar Media (LPDE) Heteroatom-stabilized Allyl Cations Cycloaddition TL. 1998, 39, 7047 Highlights Endiandric acid A Synlett., 1997, 493

  18. Reaction in Highly Polar Media (LPDE) 1,4-Addition of Silyl Ketene Acetal Highlights TL. 1991, 32, 4665

  19. Reaction in Highly Polar Media (LPDE) 1,4-Addition of Silyl Ketene Acetal Highlights JACS. 1993, 115, 5841 Sesbanimide A J.C.S., Chem.Commun. 1992, 368

  20. PERSPECTIVES IN TOTAL SYNTHESIS

  21. Diels-Alder Chemistry Total Synthesis of Pseudotabersonine (Retro Diels-Alder/intramolecular aza Diels-Alder sequence) Pseudotabersonine A B Total Synthesis C D B Compound D is anticipated to undergo a tandem retro Diels-Alder / intramolecular aza Diels-Alder reaction under aprotic conditions. JOC, 1987, 52, 5746 JACS. 1993, 115, 1164

  22. Diels-Alder Chemistry Total Synthesis of Pseudotabersonine E D Total Synthesis H G F Pseudotabersonine JOC, 1987, 52, 5746 JACS. 1993, 115, 1164 I • The use of cyclopentadiene as a protective group • Mixture of [E] is of no consequence, since both will be transformed • into intermediate [H] • Pericyclic reaction Cascades: tandem retro Diels-Alder/intramolecular • aza Diels-Alder sequence

  23. Reaction in Highly Polar Media (LPDE) Application Toward the Synthesis of Ibogamine Ibogamine Total Synthesis Electrophilic substitution at C2 of N’-CBz-tryptamine employing highly polar media (LPDE) TL. 1996, 37, 8289

  24. Reaction in Highly Polar Media (LPDE) Synthesis of Ibogamine Total Synthesis Ibogamine TL. 1996, 37, 8289 Epi-Ibogamine

  25. Reaction in Highly Polar Media (LPDE) Intramolecular Imino Diels-Alder: Total Synthesis of Eburnamonine Eburnamonine Total Synthesis JOC. 1994, 59, 7197

  26. Reaction in Highly Polar Media (LPDE) Intramolecular Imino Diels-Alder: Total Synthesis of Eburnamonine Total Synthesis JOC. 1994, 59, 7197

  27. Reaction in Highly Polar Media (LPDE) Intramolecular Imino Diels-Alder: Total Synthesis of Eburnamonine Total Synthesis Eburnamonine JOC. 1994, 59, 7197

  28. Reaction in Highly Polar Media (LPDE) Heteroatom-Stabilized Allyl Cation: Total Synthesis of Lycopodine Lycopodine Total Synthesis JACS. 1998, 120, 5128

  29. Reaction in Highly Polar Media (LPDE) Heteroatom-Stabilized Allyl Cation: Total Synthesis of Lycopodine Total Synthesis JACS. 1998, 120, 5128

  30. Reaction in Highly Polar Media (LPDE) Heteroatom-Stabilized Allyl Cation: Total Synthesis of Lycopodine Lycopodine Total Synthesis Tricyclic compound possessing the 40 carbon atom and all the necessary carbon atoms needed for elaboration of lycopodine JACS. 1998, 120, 5128

  31. Reaction in Highly Polar Media (LPDE) Heteroatom-Stabilized Allyl Cation: Total Synthesis of Lycopodine Total Synthesis JACS. 1998, 120, 5128

  32. Reaction in Highly Polar Media (LPDE) Heteroatom-Stabilized Allyl Cation: Total Synthesis of Lycopodine Total Synthesis Lycopodine JACS. 1998, 120, 5128

  33. Reaction in Highly Polar Media (LPDE) Direct Ring Opening of Oxabicyclo[3.2.1] Systems & Its Application to Synthesis Highlights Rigid 7-membered ring allowed for selective protonation & reduction Synthesis OL. 2001, 3, 481 OL, 2002, 4, 245

  34. Reaction in Highly Polar Media (LPDE) Direct Ring Opening of Oxabicyclo[3.2.1] Systems (Synthesis of the C1 - C11 Fragment of Epothilone B) Epothilone B Highlights Synthesis The C4 quaternary carbon atom was established through ring opening reaction Functionalized cycloheptadiene provided all the necessary carbon atoms needed for further elaboration into the C3 - C11 fragment of epothilone

  35. Epothilone B Highlights Synthesis • Selective protonation • (S)-O-methylmandelic ester served as a resolving agent, protecting group, • and a leaving group for the latter stage • Reduction from the -face avoiding the diaxial hydrogens

  36. Highlights Synthesis *Dealkylation / SN2’ ring cyclization via lithium iodide * Selective oxidation of diols to cyclic hemiketal

  37. Highlights Synthesis Baeyer-Villiger oxidation of hemiketal OL. 2000, 2, 1717

  38. Highlights Synthesis * Grieco elimination to form the terminal olefin * Regioselective reduction of the acetal via DiBAlH * Chelation controlled aldol

  39. The Chemistry of Bicyclo[2.2.1]heptenone: Application to The Total Synthesis of Natural Products (for further reading) Thienamycin JACS, 1984, 106, 6414 Calcimycin JACS, 1982, 104, 1436 Helenalin JACS, 1978, 100, 5946 ibid.,1982, 104, 4233 Damsin JACS, 1977, 99, 7393 ibid.,1982, 104, 4226 12-Methylprostaglandins JACS, 1976, 4111 Andy Diep

More Related