Professor Koji Nakanishi
David Lin
Magic
Notorious for his magic tricks at conferences
My personal favorite is the magic bag trick, where a
person climbs into a bag which is tied up. After the
magician performs his charm, the person appears from
behind a nearby curtain. Nakanishi has performed this
trick on Raymond Lemieux, Gilbert Stork, Jack
Baldwin, Ron Breslow, and others.
Bioorganic Chemistry
•Studies into the bioactivity of the ginkgolides
•Synthesis and study of the activity of retinal
chromophores
•Determining the cause of macular degeneration, the
primary form of blindness in the elderly
Spectroscopic Methods in Structure Determination
•First discovered phenomenon of NOE in natural
products
•Development of exciton chirality method for
determining absolute stereochemistry
Natural Products Isolation and Characterization:
•Elucidated the structures of over 180 natural products
•Highlights include: the ginkgolides, brevetoxin A & B,
the illudins, periplanone B, the taxcins, the
ecdysteroids
“A Wandering Natural Products Chemist”
Natural Products Chemistry: Koji Nakanishi
•Born 1925 in Hong Kong
•B.S., Nagoya University, 1947
•Ph.D., Nagoya University, 1954 (Fujio Egami)
•Studied at Harvard (Louis Fieser), 1950-1952
•Asst. Professor, Nagoya University, 1955-1958
•Professor, Tsukuba University (Tokyo), 1958-1963
•Professor, Tohoku University (Sendai), 1963-1969
•Professor, Columbia University, 1969-present
•Married to Yasuko
•Two children, Keiko and Jun
Baran Group Meeting
8/11/04
O
HO
O
HO
CO 2Me
OH
OH
COOH
taxicin
OAc
OAc
OAc
abscisic acid
OH
illudin
O
AcO
antheridiogen
H
H
HO
Baran Group Meeting
8/11/04
O
HO
HO
HO
O
O
Me
O
HO
O
H
O
O
H
CMe3
O
O
O
ponasterone A
HO
OH
CO2Me
periplanone B
O
pristimerin
O
O
ginkgolide B
O
O HO
HO
O
O
N
O
N
H
OH
OH
H
N
O
H
H
O
HO
H
Me
O
HO
H
H
HO
neosaxitoxin
H2N
HO N
H2N
O
H
O
O
OH
OH
NH2
CHO
H
Me
O
H
Me
tauranin
OH
O
Me
H
HO
H
OH
OH
Me
HO
H
O H
OH
OH
O
H
OH
O
H
O
O
O
H
David Lin
tunichrome B
O
NH
OH
cabenegrin
O
H O
OH
HO
O
H
N
H2N
HO
brevetoxin B
H
Me
O
OH
grayanotoxin I
OAc OH
HO
HO
warburganal
OHC
Natural Products Chemistry: Koji Nakanishi
Natural Products Chemistry: Koji Nakanishi
The Exciton Chirality Method
Baran Group Meeting
8/11/04
David Lin
Serendipity: Typhoon hits Sendai, Japan and uproots
many ginkgo trees. Nakanishi group members rush
to Sendai to obtain material.
Problem: Ginkgolide extracted from the root bark of
the ginkgo tree, removal of which kills the tree.
David Lin
Serendipity: Undergraduate contaminates sample of
LAH-reduced ginkgolide with acid and leaves it in
drying oven while he goes off to play baseball.
Sample goes to tar in oven. However,
chromatography of the tar produces ginkgolide
triether derivative which provides more useful NMR
data and…
Problem: NMR spectra of ginkgolide not very helpful
in structure elucidation.
Characterization of the Ginkgolides: Serendipity Rocks!
Natural Products Chemistry: Koji Nakanishi
Characterization of the Ginkgolides: Serendipity Rocks!
Baran Group Meeting
8/11/04
NOTE: For a comprehensive review of the biology and
chemistry of the ginkgolides and the related bilobalides,
see Nakanishi’s recent review: Angew. Chem. Intl. Ed.
2004, 43, 1640.
David Lin
EtO2C
>350 nm
100%
hv
O
1.2:1 dr
OH
2. i-Bu2AlH
95% overall
1. t-Bu2CuCNLi2
CMe3
OHC
2
Et3SiO
O
CO2Et
CMe3
O
CuBr . SMe2
HMPA, Et2O, THF
82%
MECHANISM?
Zn
CO2Et
O
O
Et3SiO
CMe3
CO2Et
2. n-BuLi, ClCO2Et
THF, -78 oC
95% overall
O
THF, -78 oC
97%
BrMg
1. Et3SiCl, Et3N
CH2Cl2
CMe3
O
RATIONALIZE THE OBSERVED
DIASTEREOSELECTIVITY.
CMe3
O
1. DEAD, Ph3P,
p-NO2C6H4CO2H, PhCH3
2. NaOH, THF, H2O
99%
CMe3
Et3SiO
OH
EtO2C
O
Crimmins synthesis of ginkgolide B: J. Am. Chem. Soc. 1999, 121, 10249;
J. Am. Chem. Soc. 2000, 122, 8453.
Natural Products Chemistry: Koji Nakanishi
…The Discovery of NOE
Baran Group Meeting
8/11/04
Zn
Et3SiO
CO2Et
2
CMe3
O
O
Et3SiO
CMe3
CO2Et
EtO2C
O
Et3SiO
CMe3
CO2Et
O
Et3SiO
O
O
CO2Et
CMe3
O
H
H
CMe3
EtO2C
Et3SiO
O
-
Et3SiO
EtO
rationalizing diastereoselectivity of the [2+2]:
EtO2C
O
O
CMe3
O
CO2Et
CMe3
O
3. EtOH, H2O, reflux
4. PPTS, PhH, reflux
63% over four steps
1. HF/CH3CN
2. MsCl, Et3N
O
O
O
CMe3
O
David Lin
HC(OMe)3
p-TsOH
95%overall
MeOH
PhSeCl, HCl,
then NaIO4
O
O
O
O
O
O
1:5.5 de
H2O, acetone
94%
MECHANISM?
O
O
O
O
O
6 N HCl, acetone
OMe
OH
CMe3
O
H OMe
CMe3
O
DMDO, then
p-TsOH
O
OH
OH
CMe3
H OH
OMe
OH
CMe3
O
H OMe
O
Notice that a stereocenter has been inverted. This route was
taken to improve the diastereoselectivity of the [2+2]
cycloaddition, which was poorer with the trans stereochemistry.
Et3SiO
O
Natural Products Chemistry: Koji Nakanishi
mechanism of Crimmins' homoenolate cyclopentenone formation:
Baran Group Meeting
8/11/04
O
O
O
O
O
H2O
CMe3
O
O
Ph
O
NSO2Ph
O
O
O
O H
O
66%
O
O
O
CMe3
O
O OMe
Et
OMe
OH
OH
CMe3
O
OH
OH
CMe3
H OH
O
O
HNEt2, t-BuLi, THF O
1.
CMe3
O
OMe 2. (EtCO)2O, Et3N
OH
OH
CMe3
O
OH2
H OMe
H
O
O
O
This somewhat curious deoxygenation temporarily removes a hydroxyl which
proved troublesome in the upcoming ring-closing step.
2. Bu3SnH, AIBN,
60 oC
78%
O
DMDO
CMe3
O
1. CS2, MeI, DBU O
O
O
+
O
O
O
O
LDA
o
OMe
100%
CSA
88%
MeOH
THF, -78 C HO
OMe
CMe3
O
OMe
CMe3
O
O OMe
Et
O
O
HO
O
O
VO(acac)2,
t-BuOOH
CH2Cl2, p-TsOH
81%
HO
CO2Me
O
O
HO
O
HO
O
O
MeO
H
O
O
CMe3
O
O
HO
O HO
O
O
H
O
O
ginkgolide B
O
HO
CMe3
H
CMe3
O
David Lin
OMe
O
CMe3
O
H
MeOH
50%
MeONa
2. AcOH, Me
NaOAc, Br2
HO
52%
O
O
O
O
OMe
CO 2Me
CMe3 1. DMDO
C6H5Cl
85%
PPTS, pyr
O
CMe3
O
OMe
MeO2C
O
O
Here they racemize a troublesome stereocenter to
achieve the poor 50% yield, but the undesired
diastereomer was easily recovered and recycled.
HO
O
O
O
O
Natural Products Chemistry: Koji Nakanishi
mechanism for cyclobutane ring rupture:
Baran Group Meeting
8/11/04
O
OH
OH
R
R2
R1
HO
α-OH: illudol
β-OH: epi-illudol
OH
OH
OH
illudene
OH
OH OH
COOH
Illudin B
O
Illudinic Acid
O
HO
•Highly toxic sesquiterpene first isolated from the bioluminescent mushroom tsuki-yo-take
•Possesses potent antitumor activity, probably by crosslinking DNA base pairs
•Subject of intense medicinal chemistry/SAR studies
OH
OH
Illudin A
O
R1, R2 = H:
Illudin C
R1 = OH, R2 = H: Illudin C2
R1 = H, R2 = OH: Illudin C3
O
Illudin M (R=H)
Illudin S (R=OH)
HO
David Lin
Ac2O
O
OMe
O
OMe
O O
2. acetylation
1. tBuOK
AcO
O
O
S
S
O
O
OAc
O
S
O
O
OAc
AcO
HO
O
HO
O
O S
H
O S
O
OAc
O
OAc
stereoselective; other
diastereomer not observed
O
O
S
selective for ketone shown,
and stereoselective as well!
MeMgBr
heat
EtOH
NaOEt
O
O
O
MeOH
MECHANISM?
I2
NaH
AcO
benzene, reflux
O O
CHO
O
O
OAc OAc
O O
O S
H
O
O
O
AcO
Na+
2. acetylation
3. dilute HCl
1. NaBH4
OEt
NAME
REACTION?
MECHANISM?
AcO
O
O
S
O
The First Synthesis, Illudin M: Matsumoto et al (J. Am. Chem. Soc. 1968,
90, 3280)
Natural Products Chemistry: Koji Nakanishi
The Illudins, Illudanes, and Protoilludanes
Baran Group Meeting
8/11/04
-HI O
O O
S
O
S
O
OMe
I
H+
O
S
AcO
O
HO
O S
H
Ac2O
S
O
OAc
base
AcO
H
MeO
O O
AcO
2. HgCl2
acetone
-
S
O
OH
S
S
O
I
OMe
O
OMe
illudin M (racemic)
HO
OMe
S
OAc
O O
O
OH
O
OH O
I
MeOH
S
O
I-
H
1. NaBH4
the Pummerer rearrangement:
O
O O
I
O
O
Bu
N2
O
Rh2(OAc)4
MECHANISM?
Bu
ArSO2
t
O
H
SO2Ar
O
O
exo
73%
MECHANISM?
NaO2SAr
98%
2:1 exo:endo O
Bu
t
X=halide
Et3SnX
Et3Sn
O
O
80%
KOH/MeOH
90%
MeMgI
HO
HO
H
H
OH
O
O
SO2Ar
O
75%
5:3 de
Swern
87%
Na(Hg)
HO
HO
O
O
H
H
H
O
O
endo
O
SO2Ar
O
PhI+CN-OTf
David Lin
Note that stereoconfiguration at bridgehead carbons
ultimately do not matter, so both isomers carried forward.
O
t
O
TfO- PhI
ArSO2
Na
Padwa et al, J. Org. Chem. 1997, 62, 1317.
Natural Products Chemistry: Koji Nakanishi
mechanism of oxidative cyclization:
Baran Group Meeting
8/11/04
PhI
O
Bu
ArSO2
O
t
-
H
O
S
Ar
ArSO2
PhI
ArSO2
O
O
ArSO2
O
O
O
N2
O
O
H
exo
O
SO2Ar
O
O
Rh
O
O
O
O
H
SO2Ar
O
endo
tBu
H
Here Padwa intercepts a known
intermediate from another total
synthesis.
O
DDQ
HO
14%
(desired)
O
O
O
56%
(undesired)
HO
O
David Lin
HO
HO
OH
illudin-M
30%
O
O
O
OH
O
HO
undesired isomer
23%
HO
74%
LiAlH4
OH
LiAlH4
OH
pyridine
NBS
Completion of the Padwa synthesis: Kinder and Bair, J. Org. Chem. 1994,
59, 6965.
HO
O
Natural Products Chemistry: Koji Nakanishi
Padwa's Rh(II)-catalyzed 1,3-dipolar cycloaddition:
TfO-
O
mechanism of cyclization:
Baran Group Meeting
8/11/04
Br
N
O
EtOH, 40oC
H
O
Et2O
-78 oC --> rt
58%
SO2NHCl
A
N
B
OH
EtOH, H2O
82%
O
N
A
H
Br
2. MsCl, Et3N
CH2Cl2, -78 oC;
DBU, rt
73%
1. Ra-Ni, H2, B(OH)3,
MeOH/H2O
72%
THF, -78 oC
68%
t-BuLi, 3 eq
2. DBU, 80 C
58%
o
1. PPh3, I2, imid.
benzene, rt
82%
Br
O
OH
H
HO
DMF, 3 eq
CH2Cl2, rt, 72 h
64%
NH2OH.HCl,
NaOAc
LiAl(O-tBu)3H
(chloramine-T)
H
HO
O
Et3SiO
POBr3 , 2.5 eq
O
HO
illudin-C
OH
OH
O
N
B
O
O
O
O
EtO OEt
MeO2C
AcO
O
MeO2C
O
hv
OEt
OEt
O
O
O
steps
EtO OEt
AcO
PhCHO, KOH
NaBH4
Ac2O/pyr HO
O3
KOH
EtOH, 40oC
1.
2.
3.
4.
5.
2. 20% HClO4
1. Br
O
OH
MgBr
2. Ac2O/pyr
1. Bi2O3
2. H2/Pd-C
1. NaH
David Lin
OH
illudol
2. O3
3. Ag2O, then CH2N2
4. MsCl/pyr
1.
OH
Illudol: Matsumoto et al (TL 1969, 3913; TL 1971, 3521):
Natural Products Chemistry: Koji Nakanishi
Funk's synthesis of illudin-C (Org. Lett. 2001, 3, 2611):
Baran Group Meeting
8/11/04
OBn
O
EtO
[4+2]
OEt
3. LDA, PhSeCl
4. H2O2
1. LDA, CO2
2. CH2N2
O
3. BnBr, NaH
O
H
H
Matsumoto
intermediate
EtO OEt
EtO OEt
MeO2C
MECHANISM?
3. CrO3, pyridine
OEt
OEt
1. 3A mol sieves
2. LiBEt3H
OTMS
EtO2C
CO2Et
OEt
EtO
OTMS
99%
LDA,TMSCl
63%
[2+2]
1. LiAlH4
2. Li, NH2Et, ClPO(NR2)2
70-75%
>20:1 de
CO2Et
OEt
EtO
OEt
OEt
CO2Et
OTMS
CO2Et
steps
1. CpCo(CO)2
toluene, hv, 110 oC
OH
OH
OH
2. CuCl2.2H2O
1,2-dimethoxyethane
MECHANISM?
OSiMetBu
H
illudol
Illudol: Vollhardt (J. Am. Chem. Soc. 1991, 113, 381):
Natural Products Chemistry: Koji Nakanishi
Illudol: Semmelhack (J. Am. Chem. Soc. 1982, 104, 747):
Baran Group Meeting
8/11/04
OSiMetBu
David Lin
OH
steps
NAME
REACTION?
mCPBA
THF, 70 oC
KH, 18-crown-6
OEE
O
OTMS
OEE
O-
O
periplanone B
O
O
Me3SiCl, -78 oC
O
63%
MgBr
HO
H
H
KH, 18-crown-6
72%
hv, Et2O
O
O
2:1 de
60 oC
75%
anionic oxy-Cope rearrangement
H
H
H
Periplanone B: S.L. Schreiber (J. Am. Chem. Soc. 1984, 106, 4038):
OEE
O
OEE
OTMS
OEE
OH
O
O
steps
O
periplanone B
O
O
[2+2] electrocyclic ring opening
H
hv, benzene
82%
175 oC, toluene
77%
Natural Products Chemistry: Koji Nakanishi
Periplanone B: W.C. Still (J. Am. Chem. Soc. 1979, 101, 2493.
Baran Group Meeting
8/11/04
David Lin
Natural Products Chemistry: Koji Nakanishi
Additional References
•Circular Dichroism: Principles and Applications. 2nd Ed.
Berova, N., K. Nakanishi, R.W. Woody, eds. New York:
Wiley-VCH, 2000.
•Nakanishi, K. A Wandering Natural Products Chemist.
J.I. Seeman, ed. Washington, D.C.: American Chemical
Society, 1991.
•Nicoloau, K.C., E.J. Sorensen. Classics in Total
Synthesis. New York: VCH Publishers, 1996.
•A complete list of Nakanishi’s publications may be found
at his group’s website:
http://www.columbia.edu/cu/chemistry/groups/nakanishi/
Baran Group Meeting
8/11/04
David Lin