Paul Grieco Chemistry

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Paul Grieco Chemistry

  1. 1. The Chemistry of Prof. Paul A. Grieco Montana State University Prepared by Andy Diep Senior Medicinal Research Scientist Forest Laboratories, Inc
  2. 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. 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. 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.
  3. 3. Total Synthesis Natural product New Strategies & Tactics Designed & Discovered methods Selected Highlights <ul><li>Organic Synthesis in Water </li></ul><ul><li>By Paul A. Grieco </li></ul><ul><li>Published by Springer, 1998 </li></ul><ul><li>ISBN 0751404101, 9780751404104 </li></ul><ul><li>Development of Cationic Diels-Alder Reaction in Highly Polar Media, </li></ul><ul><li>Lithium Perchlorate in Diethyl Ether (LPDE) </li></ul><ul><li>* [1,3]-Sigmatropic Rearrangement of Allyl Vinyl Ethers </li></ul><ul><li>* Catalytic Acid in LPDE to Promote: </li></ul><ul><li># Intra / Intermolecular Imino Diels-Alder </li></ul><ul><li># Intramolecular Cycloaddition of Heteroatom-Stabilized </li></ul><ul><li>Allyl Cations </li></ul><ul><li>* Nucleophilic Substitution and Ring Opening </li></ul><ul><li>via Silyl Ketene Acetal </li></ul><ul><li>Stereospecific Synthesis of Natural Products via Bicyclo[2.2.2]heptenone & </li></ul><ul><li>Oxabicyclo[3.2.1]octenes as templates </li></ul><ul><li>Total Synthesis of Natural Products </li></ul>
  4. 4. Diumycinol JOC , 1975 , 40, 2261 Moenocinol JACS , 1975 , 97, 1597 Costunolide JOC, 1977 , 42, 1717 Sirenin JACS , 1969 , 91, 5660 Temisin JCS, CC, , 1978 , 76 Tuberiferine JCS, CC , 1976 , 582 Eriolangin / Eriolanin JACS , 1978 , 100, 1616 ibid., 1980 , 102, 5886 Vernolepin JACS , 1976 , 97, 1612 ibid., 1977 , 99, 5773 Vernomenin JACS , 1976 , 97, 1612 ibid., 1977 , 99, 5773 Damsin JACS , 1977 , 99, 7393 ibid., 1982 , 104, 4226 Ambrosin JACS , 1977 , 99, 7393 ibid., 1982 , 104, 4226 Stramonin B JOC , 1978 , 43, 4552 Helenalin JACS , 1978 , 100, 5946 ibid., 1982 , 104, 4233 R=H: Mexicanin 1 R=Ac: Linifolin A TL , 1979 , 3265 Thienamycin JACS , 1984 , 106, 6414 Selected works (total synthesis) by the Grieco Group
  5. 5. Compactin JACS , 1986 , 108, 5908 Quassin JACS , 1980 , 102, 7586 ibid ., 1984 , 106, 3539 Castelanolide JOC , 1982 , 47, 601 ibid ., 1984 , 49, 2342 De-A-quassimarin JOC , 1987 , 52, 3346 Estrone JOC , 1980 , 45, 2247 Calcimycin JACS , 1982 , 104, 1436 Methynolide JACS , 1979 , 101, 4749 (+)-Tylonolide JACS , 1982 , 104, 5781 Polyandrane JACS , 1999 , 121, 9891 Bruceoside C JACS , 1996 , 16, 5316 R=H ; (-)-Chaparrinone R=OH ; (-)-Glaucarubolone JACS , 1993 , 115, 6078 (+)-des-D-Chaparrinone JOC , 1998 , 63, 5929 Selected works (total synthesis) by the Grieco Group
  6. 6. Endiandric Acid SYNLETT , 1997 , 493 Lycopodine JACS , 1998 , 120, 5128 (-)-Epothilone B CC , 1998 , 1597 Eburnamonine JOC , 1994 , 59, 7197 Ibogamine JOC, 1994 , 59, 6898 TL , 1996 , 37, 8289 (+)-Jasplakinolide JACS , 1988 , 110, 1630 Pseudotabersonine JACS , 1993 , 115, 1164 C(19)-C(32) Scytophycin C TL , 1998 , 39, 1125 OL , 2002 , 2, 245 C(19)-C(27) Rifamycin S OL , 2001 , 3, 481 Laulimalide Selected works (total synthesis) by the Grieco Group
  7. 7. Organic Synthesis in H 2 O & Polar Media Lithium Perchlorate in Diethyl Ether (LPDE)
  8. 8. Highlights Aqueous Intermolecular Diels-Alder Chemistry Dienes with Dienophiles in H 2 O JOC . 1983 , 48, 3137 1. H 2 O / r.t. / 1h 2. CH 2 N 2 / 77% 1. H 2 O / r.t. / 7h 2. CH 2 N 2 / 77% H 2 O / r.t. / 20 h 95% Tetrahedron, 1986 , 42, 2847 Methacrolein H 2 O / 55 0 C 16 h LiAlH 4 THF/0 0 C J.Chem.Soc., Chem Comm, 1988 , 500
  9. 9. Aqueous Intermolecular Diels-Alder Chemistry Dienes with Dienophiles in H 2 O Benzene reflux / 72h 67% H 2 O r.t. / 5 h 75% JOC . 1983 , 48, 3137 JACS . 1990 , 112, 9436 JACS , 1993 , 115, 6078 Chaparrinone Highlights
  10. 10. Vernolepin JOC . 1984 , 49, 5257 JOC . 1983 , 48, 3137 JACS . 1980 , 102, 782 Aqueous Intermolecular Diels-Alder Chemistry Dienes with Dienophiles in H 2 O H 2 O 1. NaBH 4 2. H + / 91% overall Highlights
  11. 11. Reaction in Highly Polar Media (LPDE) Nucleophilic Substitutions of Ketene Acetals Highlights TL, 1992 , 33, 4735
  12. 12. Highlights Reaction in Highly Polar Media (LPDE) Nucleophilic Substitutions of Indole J. Chem.Soc.,Chem.Commun, 1993 , 510
  13. 13. Highlights Reaction in Highly Polar Media (LPDE) [4+2] Cycloaddition TL., 1993 , 34, 7367
  14. 14. Highlights Reaction in Highly Polar Media (LPDE) Intra/Intermolecular Ionic Diels-Alder Reactions Synlett., 1995 , 1155
  15. 15. Highlights Reaction in Highly Polar Media (LPDE) Intramolecular Diels-Alder reaction of Trienone Acid catalyzed migration of the diene prior to [4+2] cycloaddition
  16. 16. Highlights Reaction in Highly Polar Media (LPDE) Heteroatom-stabilized Allyl Cations Cycloaddition JACS . 1996 , 118, 2095
  17. 17. Highlights Reaction in Highly Polar Media (LPDE) Heteroatom-stabilized Allyl Cations Cycloaddition TL . 1998 , 39, 7047 Endiandric acid A Synlett., 1997 , 493
  18. 18. Highlights Reaction in Highly Polar Media (LPDE) 1,4-Addition of Silyl Ketene Acetal TL . 1991 , 32, 4665
  19. 19. Highlights Reaction in Highly Polar Media (LPDE) 1,4-Addition of Silyl Ketene Acetal JACS . 1993 , 115, 5841 Sesbanimide A J.C.S., Chem.Commun . 1992 , 368
  20. 20. PERSPECTIVES IN TOTAL SYNTHESIS
  21. 21. Total Synthesis Diels-Alder Chemistry Total Synthesis of Pseudotabersonine (Retro Diels-Alder/intramolecular aza Diels-Alder sequence) Pseudotabersonine A B C B D JOC, 1987 , 52, 5746 JACS . 1993 , 115, 1164 Compound D is anticipated to undergo a tandem retro Diels-Alder / intramolecular aza Diels-Alder reaction under aprotic conditions.
  22. 22. Total Synthesis Diels-Alder Chemistry Total Synthesis of Pseudotabersonine JOC, 1987 , 52, 5746 JACS . 1993 , 115, 1164 D E Pseudotabersonine F G H I <ul><li>The use of cyclopentadiene as a protective group </li></ul><ul><li>Mixture of [E] is of no consequence, since both will be transformed </li></ul><ul><li>into intermediate [H] </li></ul><ul><li>Pericyclic reaction Cascades: tandem retro Diels-Alder/intramolecular </li></ul><ul><li>aza Diels-Alder sequence </li></ul>
  23. 23. Ibogamine Reaction in Highly Polar Media (LPDE) Application Toward the Synthesis of Ibogamine Total Synthesis Electrophilic substitution at C2 of N’-CBz-tryptamine employing highly polar media (LPDE) TL . 1996 , 37, 8289
  24. 24. Ibogamine Reaction in Highly Polar Media (LPDE) Synthesis of Ibogamine Epi-Ibogamine Total Synthesis TL . 1996 , 37, 8289
  25. 25. Eburnamonine Total Synthesis Reaction in Highly Polar Media (LPDE) Intramolecular Imino Diels-Alder: Total Synthesis of Eburnamonine JOC . 1994 , 59, 7197
  26. 26. Total Synthesis Reaction in Highly Polar Media (LPDE) Intramolecular Imino Diels-Alder: Total Synthesis of Eburnamonine JOC . 1994 , 59, 7197
  27. 27. Total Synthesis Reaction in Highly Polar Media (LPDE) Intramolecular Imino Diels-Alder: Total Synthesis of Eburnamonine JOC . 1994 , 59, 7197 Eburnamonine
  28. 28. Lycopodine Total Synthesis Reaction in Highly Polar Media (LPDE) Heteroatom-Stabilized Allyl Cation: Total Synthesis of Lycopodine JACS . 1998 , 120, 5128
  29. 29. Total Synthesis Reaction in Highly Polar Media (LPDE) Heteroatom-Stabilized Allyl Cation: Total Synthesis of Lycopodine JACS . 1998 , 120, 5128
  30. 30. Total Synthesis Reaction in Highly Polar Media (LPDE) Heteroatom-Stabilized Allyl Cation: Total Synthesis of Lycopodine JACS . 1998 , 120, 5128 Tricyclic compound possessing the 4 0 carbon atom and all the necessary carbon atoms needed for elaboration of lycopodine Lycopodine
  31. 31. Total Synthesis Reaction in Highly Polar Media (LPDE) Heteroatom-Stabilized Allyl Cation: Total Synthesis of Lycopodine JACS . 1998 , 120, 5128
  32. 32. Total Synthesis Reaction in Highly Polar Media (LPDE) Heteroatom-Stabilized Allyl Cation: Total Synthesis of Lycopodine JACS . 1998 , 120, 5128 Lycopodine
  33. 33. Highlights Reaction in Highly Polar Media (LPDE) Direct Ring Opening of Oxabicyclo[3.2.1] Systems & Its Application to Synthesis Synthesis OL . 2001 , 3, 481 OL , 2002 , 4, 245 Rigid 7-membered ring allowed for selective protonation & reduction
  34. 34. Highlights Reaction in Highly Polar Media (LPDE) Direct Ring Opening of Oxabicyclo[3.2.1] Systems (Synthesis of the C 1 - C 11 Fragment of Epothilone B) Synthesis Epothilone B 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. 35. Highlights Synthesis Epothilone B <ul><li>Selective protonation </li></ul><ul><li>(S)-O-methylmandelic ester served as a resolving agent, protecting group, </li></ul><ul><li>and a leaving group for the latter stage </li></ul><ul><li>Reduction from the  - face avoiding the diaxial hydrogens </li></ul>
  36. 36. Highlights Synthesis * Dealkylation / S N2’ ring cyclization via lithium iodide * Selective oxidation of diols to cyclic hemiketal
  37. 37. Highlights Synthesis Baeyer-Villiger oxidation of hemiketal OL . 2000 , 2, 1717
  38. 38. Highlights Synthesis * Grieco elimination to form the terminal olefin * Regioselective reduction of the acetal via DiBAlH * Chelation controlled aldol
  39. 39. Helenalin JACS , 1978 , 100, 5946 ibid., 1982 , 104, 4233 Damsin JACS , 1977 , 99, 7393 ibid., 1982 , 104, 4226 12-Methylprostaglandins JACS , 1976 , 4111 Calcimycin JACS , 1982 , 104, 1436 Thienamycin JACS , 1984 , 106, 6414 Andy Diep The Chemistry of Bicyclo[2.2.1]heptenone: Application to The Total Synthesis of Natural Products (for further reading)

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