Name of presentation

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
Natural product
New Strategies Tactics

• 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 Bicyclo2.2.2heptenone
• Oxabicyclo3.2.1octenes as templates

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
Eriolangin / Eriolanin JACS, 1978, 100, 1616
ibid.,1980, 102, 5886
Ambrosin JACS, 1977, 99, 7393 ibid.,1982, 104,
4226
RH Mexicanin 1 RAc 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
RH (-)-Chaparrinone ROH (-)-Glaucarubolone J
ACS, 1993, 115, 6078
()-Tylonolide JACS, 1982, 104, 5781
Bruceoside C JACS, 1996, 16, 5316
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) 42
Cycloaddition
TL., 1993, 34, 7367
Highlights
14
Reaction in Highly Polar Media (LPDE) Intra/Interm
olecular Ionic Diels-Alder Reactions
Highlights
Synlett., 1995, 1155
15
Reaction in Highly Polar Media (LPDE) Intramolecul
ar Diels-Alder reaction of Trienone
Highlights
Acid catalyzed migration of the diene prior to
42 cycloaddition
16
Reaction in Highly Polar Media (LPDE) Heteroatom-s
tabilized Allyl Cations Cycloaddition
Highlights
JACS. 1996, 118, 2095
17
Reaction in Highly Polar Media (LPDE) Heteroatom-s
tabilized 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/intramolecula
r 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) Intramolecul
ar Imino Diels-Alder Total Synthesis of
Eburnamonine
Eburnamonine
Total Synthesis
JOC. 1994, 59, 7197
26
Reaction in Highly Polar Media (LPDE) Intramolecul
ar Imino Diels-Alder Total Synthesis of
Eburnamonine
Total Synthesis
JOC. 1994, 59, 7197
27
Reaction in Highly Polar Media (LPDE) Intramolecul
ar Imino Diels-Alder Total Synthesis of
Eburnamonine
Total Synthesis
Eburnamonine
JOC. 1994, 59, 7197
28
Reaction in Highly Polar Media (LPDE) Heteroatom-S
tabilized Allyl Cation Total Synthesis of
Lycopodine
Lycopodine
Total Synthesis
JACS. 1998, 120, 5128
29
Reaction in Highly Polar Media (LPDE) Heteroatom-S
tabilized Allyl Cation Total Synthesis of
Lycopodine
Total Synthesis
JACS. 1998, 120, 5128
30
Reaction in Highly Polar Media (LPDE) Heteroatom-S
tabilized 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-S
tabilized Allyl Cation Total Synthesis of
Lycopodine
Total Synthesis
JACS. 1998, 120, 5128
32
Reaction in Highly Polar Media (LPDE) Heteroatom-S
tabilized Allyl Cation Total Synthesis of
Lycopodine
Total Synthesis
Lycopodine
JACS. 1998, 120, 5128
33
Reaction in Highly Polar Media (LPDE) Direct Ring
Opening of Oxabicyclo3.2.1 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 Oxabicyclo3.2.1 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
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