Transcript Name of presentation

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;
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.
New Strategies
&
Tactics
Selected Highlights
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
Selected works (total synthesis) by the Grieco Group
OH
OH
O
H
O
O
H
O
O
O
H
O
O
OH
O
Vernomenin
JACS, 1976, 97, 1612
ibid.,1977, 99, 5773
Vernolepin
JACS, 1976, 97, 1612
ibid.,1977, 99, 5773
H
O
O
O
Temisin
JCS, CC,, 1978, 76
Diumycinol
JOC, 1975, 40, 2261
H
OH
H
O
Damsin
JACS, 1977, 99, 7393
ibid.,1982, 104, 4226
O
HO
O
H
HO
O
O
HO
Moenocinol
JACS, 1975, 97, 1597
O
O
OH
O
O
O
Ambrosin
JACS, 1977, 99, 7393
ibid.,1982, 104, 4226
H
OH
O
O
Costunolide
JOC, 1977, 42, 1717
Eriolangin / Eriolanin
JACS, 1978, 100, 1616
ibid.,1980, 102, 5886
H
H
OH
Sirenin
JACS, 1969, 91, 5660
H
N
O
O
O
Tuberiferine
JCS, CC, 1976, 582
O
O
NH 2
S
COOH
O
O
Stramonin B
JOC, 1978, 43, 4552
O
R=H: Mexicanin 1
R=Ac: Linifolin A
TL, 1979, 3265
H H
HO
O
RO
R
O
Helenalin
JACS, 1978, 100, 5946
ibid.,1982, 104, 4233
O
O
Thienamycin
JACS, 1984, 106, 6414
Selected works (total synthesis) by the Grieco Group
O
HO
H
O
O
O
HO
O
O
H
Compactin
JACS, 1986, 108, 5908
OMe
O
H
H
O
H
O
O
OH
O
H
H
H
H
H
O
O
Quassin
JACS, 1980, 102, 7586
ibid., 1984, 106, 3539
H
H
O
O
HO O
OH
HO
O
H
RO
H
HO
Estrone
JOC, 1980, 45, 2247
OH
H
(+)-des-D-Chaparrinone
JOC, 1998, 63, 5929
O
CO2Me
HO O
OH
OH
O
O
H
H
H
Methynolide
JACS, 1979, 101, 4749
OH
O
OH
O
O
O
De-A-quassimarin
JOC, 1987, 52, 3346
H
N
Calcimycin
JACS, 1982, 104, 1436
O
HO
O
H
OH
MeO
H
O
Castelanolide
JOC, 1982, 47, 601
ibid., 1984, 49, 2342
Polyandrane
JACS, 1999, 121, 9891
HO
O
H
H
O
H
N
H
CO2H
N
H
HO
OH
H
H
O
O
OH
O
O
OH
OH
H
O
H
H
O
O
O
Bruceoside C
JACS, 1996, 16, 5316
R
H
OH
O
HO
O
O
OH
(+)-Tylonolide
JACS, 1982, 104, 5781
H
H
H
O
O
R=H ; (-)-Chaparrinone
R=OH ; (-)-Glaucarubolone
JACS, 1993, 115, 6078
Selected works (total synthesis) by the Grieco Group
N
N
H
Ph
H
H
N
H
H
H H
Ibogamine
JOC, 1994, 59, 6898
TL, 1996, 37, 8289
N
H
CO2H
n
H
N
OH
H
H
O
O
H
H
OMe
O
O
O
H
OH O
Lycopodine
JACS, 1998, 120, 5128
(-)-Epothilone B
CC, 1998, 1597
OH
OMe OMe
N
O
O
OH
O
N
OH
Laulimalide
H
O
H
H
CO2Me
Pseudotabersonine
JACS, 1993, 115, 1164
H
N
O
O
Endiandric Acid
SYNLETT, 1997, 493
O
S
HO
H
H
H
H
H
N
O
Br
HN
O
O
O
HN
N
AcO
MeO
OH OH
OH O
Eburnamonine
JOC, 1994, 59, 7197
NH
NH
O
(+)-Jasplakinolide
JACS, 1988, 110, 1630
O
O
O
C(19)-C(27)
Rifamycin S
O
O
OL, 2001, 3, 481
OH
O
OMe
C(19)-C(32)
Scytophycin C
TL, 1998, 39, 1125
OL, 2002, 2, 245
CHO
Organic Synthesis in H2O & Polar Media
Lithium Perchlorate in Diethyl Ether
(LPDE)
Aqueous Intermolecular Diels-Alder Chemistry
Dienes with Dienophiles in H2O
O
1. H2O / r.t. / 1h
+
O
CO2Me
O
2. CH2N2 / 77%
CO2Na
O
H
O
JOC. 1983, 48, 3137
CO2Me
O
1. H2O / r.t. / 7h
+
2. CH2N2 / 77%
O
CO2Na
O
+ Cl
NH 3
O
MeO
N
MeO
Tetrahedron, 1986, 42, 2847
H2O / r.t. / 20 h
95%
O
O
CO2Na
O
Methacrolein
H2O / 550 C
16 h
H
H
CO2H
H
LiAlH4
THF/00 C
OH
HO
J.Chem.Soc., Chem Comm, 1988, 500
Aqueous Intermolecular Diels-Alder Chemistry
Dienes with Dienophiles in H2O
OMe
Benzene
CHO
+
H
reflux / 72h
67%
O
CO2Et
OMe
CHO
H
H
H
CO2Et
O
OMe
OMe
CHO
+
H
O
r.t. / 5 h
75%
CO2Na
HO O
OH
Chaparrinone
CHO
H 2O
H
H
CO2Na
O
OH
JOC. 1983, 48, 3137
JACS. 1990, 112, 9436
JACS, 1993, 115, 6078
O
H
H
H
H
H
O
O
Aqueous Intermolecular Diels-Alder Chemistry
Dienes with Dienophiles in H2O
OBn
BnO
H 2O
+
CHO
CO2Na
1. NaBH4
OHC
NaO2C
O
O
2. H+ / 91%
overall
H
O
OH
O
Vernolepin
OBn
H
O
O
MeO
O
H
H
O
JOC. 1984, 49, 5257
JOC. 1983, 48, 3137
JACS. 1980, 102, 782
Reaction in Highly Polar Media (LPDE)
Nucleophilic Substitutions of Ketene Acetals
OMe
OH
OTBS
O
(2 eq)
OMe
3.0 M LiClO4 in Et2O
rt., 15 min / 86%
OTBS
(2 eq)
OMe
H
OH
OH
OMe
3.0 M LiClO4 in Et2O
rt., 15 min / 92%
O
H
OTBS
OMe
OMe
O
O
OMe
3.0 M LiClO4 in Et2O
75%
4
:
1
TL, 1992, 33, 4735
Reaction in Highly Polar Media (LPDE)
Nucleophilic Substitutions of Indole
1.0 M LiClO4 in Et2O
.01 (eq) HOAc
HO
OH
H
Indole / 1.5 h / 86%
N
H
3.0 M LiClO4 in Et2O
OH
H
H
N
H
OH
H
Indole / 30 min / 97%
N
H
Yuehchukene
J. Chem.Soc.,Chem.Commun, 1993, 510
NH
Reaction in Highly Polar Media (LPDE)
[4+2] Cycloaddition
O
O
NHBOC
O
toluene
O
+
O
O
H
7.7
O
O
O
+
:
O
O
+
N
NHBOC
H
H
5.0 M LiClO4- Et2O
OMe
4h / 80%
OTBS
O
NHBOC
rt ., 4h
O
O
+
41
OTBS
1
O
5.0 M LiClO4- Et2O
O
NHBOC
H
TL., 1993, 34, 7367
NHBOC
O
+
NHBOC
550 C / 7h
86%
O
O
:
1
O
N
H O
TBS
CO2Me
endo : exo
3 : 1
Reaction in Highly Polar Media (LPDE)
Intra/Intermolecular Ionic Diels-Alder Reactions
O
O
5.0 M LiClO4- Et2O
.1 (eq) CSA / 16h
63%
+
+
H
H
H
endo
1
:
endo
4
:
5.0 M LiClO4- Et2O
.01 (eq) CSA / 2h
95%
O
exo
1
O O
O
O
O
O
5.0 M LiClO4- Et2O
O
+
H
O
O
.01 (eq) CSA / 30 min
96%
Synlett., 1995, 1155
Reaction in Highly Polar Media (LPDE)
Intramolecular Diels-Alder reaction of Trienone
H
H
o-dichlorobenzene
reflux / 40 h
53%
H
H
H
+
H
H
H
O
O
O
2
:
1
H
1.0 eq Et2AlCl
DCM / 24h
H
H
H
O
O
1. 2 %
H
1.0 M LiClO4- Et2O
.1 (eq) CSA / 24h
70%
H
H
H
O
O
Acid catalyzed migration of the diene prior to [4+2] cycloaddition
Reaction in Highly Polar Media (LPDE)
Heteroatom-stabilized Allyl Cations Cycloaddition
H
H
OH
3.0 M LiClO4- Et2O
.1 (eq) TFA / 24h
91%
O
H
H
H
+
H
H
H
O
O
4
:
1
+
O
H
OH
3.0 M LiClO4- Et2O
O
.1 (eq) TFA / 24h
87%
H
H
H
O
JACS. 1996, 118, 2095
Reaction in Highly Polar Media (LPDE)
Heteroatom-stabilized Allyl Cations Cycloaddition
OH
H
OH
5.0 M LiClO4- Et2O
OH
H
.1 (eq) TFA / 75%
H
H
TL. 1998, 39, 7047
H
H
H
O
MeO
Ph
H
H
H
OH
5.0 M LiClO4- Et2O
H
.1 (eq) CSA / 88%
OTBS
OH
SPh
H
Ph
H
SPh
Ph
H
5.0 M LiClO4- Et2O
H
TIPSO
H
.1 (eq) TFA / 90%
H
H
H
TIPSO
Ph
H
O
O
H
Endiandric acid A
H
H
H
H
HO2C
H
Ph
Synlett., 1997, 493
Reaction in Highly Polar Media (LPDE)
1,4-Addition of Silyl Ketene Acetal
OTBS
O
+
OTBS
1.0 M LiClO4- Et2O
OMe
rt., 30 min / 87%
O
OMe
TL. 1991, 32, 4665
OTBS
O
+
OTBS
OMe
5.0 M LiClO4- Et2O
rt., 1.5 h / 76%
O
OMe
Reaction in Highly Polar Media (LPDE)
1,4-Addition of Silyl Ketene Acetal
O
OTBS
CO2Me
OTBS
CO2Me
OMe
CO2Me
1.0 M LiClO4- Et2O
H
O
OMe
O
H
O
OMe
O
24 h / 93%
JACS. 1993, 115, 5841
OTBS
O
TBSO
H
OMe
O
O
TBSO
3.0 M LiClO4- Et2O
O
O
H
CO2Me
O
rt., 2h / 65%
OTBS
O
O
O
O
Sesbanimide A
O OHOH
NH
O
J.C.S., Chem.Commun. 1992, 368
PERSPECTIVES IN
TOTAL SYNTHESIS
Diels-Alder Chemistry
Total Synthesis of Pseudotabersonine
(Retro Diels-Alder/intramolecular aza Diels-Alder sequence)
N
H
H
N
H
trans-2-hexenal
O
CO2Me
N
H
Pseudotabersonine
O
tol / Et3N / reflux
18 h / 65%
A
N
H
B
C 3H 7
H
K-diisopropylamide
THF / - 78 0 C / 53%
KO-t-Bu / THF
BnCl / Bu4NI /24 h
65%
N
O
O
N
H
-OTf
+
B
C 3H 7
H
N
N
H
C
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
N
O
N
bn
D
Diels-Alder Chemistry
Total Synthesis of Pseudotabersonine
N
N
bn
N
Aza Diels-Alder
61% / (1.5 : 1 ds)
N
-
O
D
H
BF3OEt2 / tol
1000 C / 2 h
O
N
bn
Retro Diels-Alder
E
H
O
N
bn
Li
CH(OEt)2
H
+
N
N
bn
H
N
O
N
bn
CH(OEt)2
N
H
I
N
H
CHO
•
•
•
H
N
HO
N
OH
bn CH(OEt)2
CH(OEt)2
F
Pseudotabersonine
H
H
H
N
H
O
G
MeCN / Et3N
80 0 C
N
Acetone/H 2O
TsOH
JOC, 1987, 52, 5746
JACS. 1993, 115, 1164
CO2Me
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
Reaction in Highly Polar Media (LPDE)
Application Toward the Synthesis of Ibogamine
N
N
H
COH
H
2
Ibogamine
MeO O
O
CO2Me
O
HO
O
NHCBz
CO2Me
HO
+
N
H
NHCBz
5.0 M LiClO4-Et2O
.05 (eq) CSA / 60%
H
N
H
CO2Me
NHCBz
NHCBz
1. 3 (eq) diborane / THF
H
N
H
2. base / H2O2 / 68%
CO2Me
H
OH
N
H
CO2Me
Electrophilic substitution at C2 of N’-CBz-tryptamine employing
highly polar media (LPDE)
TL. 1996, 37, 8289
Reaction in Highly Polar Media (LPDE)
Synthesis of Ibogamine
NHCBz
HO
I
H
CF 3
NHCBz
O
O
OH
N
H
+
/ DCM / 75%
H
CF 3
O
N
H
CO2Me
CO2Me
NHCBz
H
O
N
H
CO2Me
H
NH
N
H
CO2Me
1. 10% Pd-C / THF-EtOH (1:1)
cyclohexene
H
N
H
2. Na-cyanoborohydride / TFA
75% / ratio (1 : 2.4)
1. Pyrolysis at 2200 C
2. LiAlH4 / THF / 6h
NH
H
NH
N
H
+
CO2Me
CO2Me
N
N
H
Ibogamine
TL. 1996, 37, 8289
N
H
N
H
Epi-Ibogamine
Reaction in Highly Polar Media (LPDE)
Intramolecular Imino Diels-Alder: Total Synthesis of Eburnamonine
H
N
N
H
N
N
N
O
O
O
Eburnamonine
O
O
H
N
O
O
O
N
SiMe3
N
Et
Et
O
SiMe3
ethyl diazoacetate
Cu / 1350C
SiMe3
N
Et
O
O
H
EtO2C
TEOC
N
H
+
EtO2C
64 % (1 : 1)
BF3OEt2 (cat)
DCM / 00C
JOC. 1994, 59, 7197
TEOC
N
H
N
Reaction in Highly Polar Media (LPDE)
Intramolecular Imino Diels-Alder: Total Synthesis of Eburnamonine
H
N
N
N
O
N
H
O
TEOC
N
H
O
H
TEOC
N
EtO2C
O2N
O
H
TEOC
N
O
O
O
O2N
O
N
N
H
H
TEOC
N
O
O
N
O
H
TEOC
N
BTAF / molecular sieves
THF / 8h / 81%
(sensitive imine)
JOC. 1994, 59, 7197
N
Wittig
Olefination
N
O
N
H
TEOC
N
Reaction in Highly Polar Media (LPDE)
Intramolecular Imino Diels-Alder: Total Synthesis of Eburnamonine
N
N
O
96 %
H
N
O
H
N
H
5.0 M LiClO4-Et2O
10 mol % CSA / rt
N
H
O
reflux / EtOH
sulfuric acid
80%
N
H
N
N
O
Eburnamonine
JOC. 1994, 59, 7197
Reaction in Highly Polar Media (LPDE)
Heteroatom-Stabilized Allyl Cation: Total Synthesis of Lycopodine
H
N
H
H
O
H
Lycopodine
H
OH
3.0 M LiClO4- Et2O
H
.1 (eq) TFA / 24h
87%
O
H
H
O
methodology toward the synthesis of lycopodine
O
OH
O
O
OTBDPS
I
OTMS
O
O
1.2 eq LDA / THF
- 780 C
O
O
OTBDPS
JACS. 1998, 120, 5128
OTBDPS
Reaction in Highly Polar Media (LPDE)
Heteroatom-Stabilized Allyl Cation: Total Synthesis of Lycopodine
O
O
Si
i-Pr
O
B
S
Ph
H
Si
OBBN
B
O
O
Ph S
S
i-Pr
Pearson's
OTBDPS allylborane
SiMe3
Ph
O
OTBDPS
OTBDPS
4.0 N NaOH
syn elimination
(E-diene)
OTBS
OH
SPh
Li
O
OTBS
SPh
THF / -780 C
i-Pr
i-Pr
O
O
OTBDPS
OTBDPS
JACS. 1998, 120, 5128
Reaction in Highly Polar Media (LPDE)
Heteroatom-Stabilized Allyl Cation: Total Synthesis of Lycopodine
H
N
Ph
H
OTBS
H
SPh
HO
i-Pr
Lycopodine
H
2.0 M LiClO4-Et2O
10 mol% / TFA / 1h
66%
O
H
S
O
H
iPr-O
OTBDPS
OTBDPS
OTBS
Tricyclic compound possessing the 40 carbon atom and all the necessary carbon
atoms needed for elaboration of lycopodine
Ph
S
Ph
H
H
1. 1.0 N HCl / THF
2. K2CO3 / MeOH / 16h
H
Ph
H
1. Grieco elimination
2. TBAF / THF
H
3. MsCl / Et3N / DCM
4. NaI / acetone / reflux
O
iPr-O
OTBS
S
OTBDPS
HO
OTBDPS
JACS. 1998, 120, 5128
S
H
O
H
H
I
Reaction in Highly Polar Media (LPDE)
Heteroatom-Stabilized Allyl Cation: Total Synthesis of Lycopodine
Ph
S
H
O
Ph
H
n-Bu3SnH / AIBN
benzene / reflux
65%
H
S
H
H
H
H
I
O
.
H
S
Ph
Ph
S
O
O
H
H
1. Li(t-BuO)3AlH / THF / 12h
2. Ac2O / DMAP / DCM
H
H
O
H
3. TMSCl / NaI / H2O
HgCl2 / CH3CN / 2h
O
H
H
1. NH2OH - HCl (2 eq) / EtOH
NaOAc (5 eq)
H
H
AcO
2. SOCl2 / dioxane
(Beckmann rearrangement)
H H
N
H
H
OAc
H
H
JACS. 1998, 120, 5128
Reaction in Highly Polar Media (LPDE)
Heteroatom-Stabilized Allyl Cation: Total Synthesis of Lycopodine
O
Red-Al / benzene / 80%
H
H
Cl
N H
H H
N
H H
N
H
H
NCS / DCM / 30 min
then TPAP / 30 min
O
HO
OAc
H
H
H
Cl
N H
H
H
1.
H
H
AgBF4 / benzene
(Stieglitz rearrangement)
2. NaBH3CN / MeOH
O
H
H
N
H
H
O
H
Lycopodine
JACS. 1998, 120, 5128
Reaction in Highly Polar Media (LPDE)
Direct Ring Opening of Oxabicyclo[3.2.1] Systems
& Its Application to Synthesis
O
OH
1. 5.0 M LiClO4- Et2O
i-Bu2AlH
OTBS
HO
O
O
2.
H2O
OTBS
O
OTBS
OMe
OTBS
5.0 M LiClO4- Et2O
80%
OTBS
MeO2C
Rigid 7-membered ring allowed for selective protonation & reduction
OTBS
OH
1. TBAF / HOAc / THF / 60h
OTBS
OH
2. LiAl(O-t-Bu)3H / THF
MeO2C
MeO2C
OH
CO2Allyl
OH
OTr O
OPMP
TES
OH O
MeO2C
OL. 2001, 3, 481
OL, 2002, 4, 245
O
O
O
Reaction in Highly Polar Media (LPDE)
Direct Ring Opening of Oxabicyclo[3.2.1] Systems
(Synthesis of the C1 - C11 Fragment of Epothilone B)
O
S
11
8
N
O
1
O
3
OH
Epothilone B
5
OH
O
OTBS
OTBS
OMe
O
OTBS
5.0 M LiClO4- Et2O
OTBS
MeO2C
OTMS
OTMS
OMe
O
OTBDPS
5.0 M LiClO4- Et2O
.05 (eq) TMSCl / 60%
O
OTBDPS
MeO
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
O
S
11
8
N
O 1
O
3
OH
Epothilone B
5
OH
O
OH
OTMS
HF / pyridine
THF / 15 h / 94%
OTBDPS
O
O
O
MeO
20
Ph
OMe
OH
Ph
MeO
•
•
•
O
O
O
MeO
:
OMe
1
Ph
O
COOH
DCC / DMAP
DCM / 16 h
85% / 99% de
O
O
MeO
MeO
O
OH
O
O
LiAlH(t-BuO)3
THF / - 780C
6h / 89%
O
OMe
O
OH
MeO
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
O
S
11
8
N
O 1
O
Ph
O
3
OH
OH
5
O
OMe
O
OH
O
Lithium Iodide
py / reflux / 24h
91%
O
OH
1. TBSOTf / DCM
2,6-lutidine
O
2. PtO2 / H2 / EtOH
95%
MeO
O
OTBS
O
O O
OTBS
O
O
LiBH4 / THF
- 500 C / 17 h
97%
HO
HO
OTBS
acetone / 9h
91%
O
HO
*
*
Dealkylation / SN2’ ring cyclization via lithium iodide
Selective oxidation of diols to cyclic hemiketal
OTBS
O
S
11
8
N
O 1
O
3
OH
OH
5
O
HO
HO
O
OTBS
1. m-CPBA / DCM / 4h
2. LiAlH4 / THF / - 200C
81%
OTBS
OH
m-CPBA
LiAlH4
O
Ar
+
O
OTBS
OH
O
O
O
O
O
OTBS
HO
Baeyer-Villiger oxidation of hemiketal
OL. 2000, 2, 1717
OTBS
HO
HO
OTBS
OH
OTBS
p-MeOC6H4CH(OMe)2
TsOH / benzene
O
OH
O
OTBS
1. ArSeCN /n-Bu3P
THF : py (1:1)
O
2. H2O2 / 87%
O
OMe
OMe
OTBS
OTBS
OTBS
1. i-Bu2AlH / DCM
O
O
OTBS
OiPr
2. Dess-Martin
O
OPMB
O
Me2AlCl (2.5 eq)
DCM / -780C
O
OH
OPMB
OMe
*
*
*
Grieco elimination to form the terminal olefin
Regioselective reduction of the acetal via DiBAlH
Chelation controlled aldol
S
O
11
8
N
O 1
O
3
OH
5
O
OH
The Chemistry of Bicyclo[2.2.1]heptenone:
Application to The Total Synthesis of Natural Products
(for further reading)
O
N
H
O
O
H
OH
N
H
CO2H
MeO
Br
H
N
O
NH 2
O
N
O
O
H
O
S
COOH
Thienamycin
Calcimycin
JACS, 1982, 104, 1436
JACS, 1984, 106, 6414
H
H
O
O
O
HO
O
O
Damsin
JACS, 1977, 99, 7393
ibid.,1982, 104, 4226
HO
CO2H
HO
O
Helenalin
JACS, 1978, 100, 5946
ibid.,1982, 104, 4233
OH
12-Methylprostaglandins
JACS, 1976, 4111
Andy Diep