Classics in Tetrahedron Letters
Jeremy Richter
Baran Group Meeting: 9/24/03
The Plan
•
•
•
•
Methodology
Protecting Groups
Natural Products
Syntheses
Methodology
Oxidation of Vicinal Diols
HO
OH
R
1. Cl2, DMSO,
CH2Cl2, -78oC
H
R'
R''
HO
O
R
2. Et3N, RT
R'
R''
Can selectively oxidize the secondary alcohol in the presence
of the tertiary alcohol without cleavage.
Corey. 1974, 287
cis-Hydroxylation of alkenes
O
CN
Br
HO
TsCl
Py/CH2Cl2
HO
Br
1. 5:1 THF:1N HCl
NaH
O
HO
OH
O
O
2. K2CO3, MeOH
CN
Allows selectivity during bromohydrin formation
Corey. 1982, 4217
O
CN
Indole Synthesis
Li
Br
E
E
1. MeLi
H
N
R
Li
2. tBuLi
N
R
N
R
Biselectrophiles used: a-chloroketones, a,b-epoxyketone (Li enolate),
and enediones
Also used 5-substituted anilines
R is a general protecting group: best results with BOC
Yields: 50-90%
Wender. 1981, 1475
An Interesting Reaction:
H
H
1. ClNHODNP
B
NH
H
2. H2O2/NaOH
H
H
OH
acid or
heat
H
Mueller. 1976, 2925
Mueller. 1979, 1991
CrO3/H2SO4/H2O
H
H
N
N
H
H
Alcohol Oxidations
Collins Reagent1
PCC2
Collins. 1968, 3363
Corey. 1975, 2647
Corey. 1979, 399
PDC3
Protecting Groups
N,N-Diallyl
Br
R
N
RNH2
Hunig's Base
(Ph3P)3RhCl
"Wilkinson's
Catalyst"
Acid/Base Stable and Nucleophile Inert
Ganem. 1981, 1483
RNH2
MEM1 and MTM2
MEMCl
Hunig's Base
O
O
R
O
ZnBr2 or
TiCl4
ROH
ROH
1. NaH
2. MTMI
1Corey.
2Corey.
1976, 809
1975, 3269
O
R
S
HgCl2
or AgNO3
Protection for Alkynes
Fe3+
Co2(CO)8
(OC)3Co
Co(CO)3
Alkyne now protected from reagents which can affect alkenes or alkynes.
Nicholas. 1971, 3475
Not New, But Improved:
Thioacetals
R'
S
O
R
PIFA
S
R
R'
Improved method of removal which is selective for thioacetals.
Stork. 1989, 287
O
O
RO
BOB1
Protection:
1. Fisher Esterification
2. Mitsunobo Esterification
3. Jacobsen Asymmetric Epoxide Opening with
Carboxylic acids, catalyzed with Co(salen)2
Deprotection:
1. Hydrogenolysis/lactonization:
H2, Pd/C then KOtBu
Protecting Capability:
1. Assumed similar to other esters
2. Can remove in presence of other esters
1Ganem.
2000, 9523
1997, 773
2Jacobsen.
Natural Products
Reported in
Tetrahedron Letters
Natural Products
Br
CO2Me
O
O
O
CH3
O
Cl
H3C
O
H
OH
Br
Johnstonol
3, 1972, 195
O
OH
OH
Pseudopterane Metabolite,
36, 1991, 4661
OMe
HO
H3C
O
H
OH
OH
O
CH3
CH3
Blazeispirol A
40, 1999, 329
H
H
H
H
HO
H
O
H
O
CH3
H
O
H
H
CH3
OH
OH
Blepharocalyxin A
40, 1996, 7283
H3CO
OH
CH3
Natural Products
OH
OH
O
Br
H
O
O
HO
OH
O
OH
O
O
O
O
Br
HO
O
Floreside 4
44, 2003, 1243
Arabidopside A
44, 2003, 5553
O
O
HO
O
OH
O
O
O
H
Brazilide A
43, 2002, 1731
O
O
O
O
OH
O
Coleophomone A
41, 2000, 8705
Syntheses
(±)-Decaline
O
H
H
O
H
N
O
OMe
OMe
Arata. 1973, 2355
(±)-Decaline
H
O
O
H
N
O
HO
NaOH
+
H2O
HN
MeO
Br
Br
OR
OMe
H
H
(MeO)2SO2, NaOH
RO
R=H
R=Me, 76% (2 steps)
H
N
IrCl4, HCl,Me3P,
iPrOH, 84%
Br
"Henbest catalyst"
OMe
OMe
Ac2O, Py
Arata. 1973, 2355
R=H
R=Ac
9:1
axial:equitorial
Proc. Chem. Soc. 1964, 361
Org. Synth. 1970, 13
(±)-Decaline
H
H
AcO
OMe
H
CO2R
O
N
H
H
R'O
OH
H
CuO, Py
34%
Br
N
"Ullman Condensation"
O
OMe
OMe
OMe
O
OMe
H
H
NaOH, H2O
O
R=Me, R'=Ac
R=R'=H
H
N
pTSA, PhH
O
D, 55% (2 steps)
OMe
(±)-Decaline
Arata. 1973, 2355
OMe
(±)-Bakkenolide A
O
O
H
Evans. 1973, 4691
(±)-Bakkenolide A
1. OsO4, NaIO4,
t-BuOH/H2O, 93%
O
2. KOtBu, tBuOH/Et2O, 65%
3. H2, Pd/C, EtOH
O
H
Li
1.
70%
2. PBr3
3. TosHNN
SNa
SMe
75%
S
NaH, THF, heat
MeS
60%
H
S
TosHNN
Evans. 1973, 4691
SMe
H
(±)-Bakkenolide A
Sigmatropic RAR
Tos
H
N
S
N
Tos
N
S
N
SMe
SMe
S
MeS
S
Evans. 1973, 4691
SMe
(±)-Bakkenolide A
O
S
1. HgO, HgCl2, 75%
MeS
O
2. SeO2
H
H
(±)Bakkenolide A
Evans. 1973, 4691
Echinulin
O
H
NH
H
HN
CH3
N
H
Kishi. 1971, 4665
O
Echinulin
NH2
N
NH2
ZnCl2
Kishi. 1971, 4661
Echinulin
NH2
O
O
O
OEt
Br
EtO
N
H
1. LAH
2. Ac2O-DMSO
3. Ph3P=CH2
N
NHEt2, HCOH
N
H
Kishi. 1971, 4665
"Mannich"
N
H
Echinulin
O
MeO2C
N
O
MeO2C
NH
H
NH
HN
HN
O
H
CH3
N
H
O
1. 0.1N NaOH/Dioxane
2. Heat
3. Resolution
O
H
NH
H
HN
CH3
N
H
Kishi. 1971, 4665
CH3
O
dl-Cepharamine
OCH3
HO
O
H3CO
N
Kitano. 1969, 1611
dl-Cepharamine
OCH3
OCH3
H3CO
H3CO
I
CN
NC
O
O
MVK,
NaOH
OCH3
OCH3
H3CO
H3CO
NC
NaOEt
O
O
HN
Kitano. 1969, 1611
O
OH
dl-Cepharamine
OCH3
OCH3
H3CO
H3CO
1. Ethylene glycol
2. NaH, MeI
O
O
HN
O
O
N
O
H2NNH2-H2O
KOH
OCH3
OCH3
RO
AcO
R
R
1. Hydrolysis
2. Br2, AcOH
O
N
Kitano. 1969, 1611
O
Freshly Fused
NaOAc in HOAc
O
R=Br
R=O
O
N
R=H
R=Ac
O
dl-Cepharamine
OCH3
OCH3
AcO
AcO
O
methanol
O
BF3
O
N
H3CO
O
N
OCH3
LAH
HO
O
dl-Cepharamine
H3CO
N
Kitano. 1969, 1611
O
(-)-Bilobalide
O
OH
OH
tBu
O
O
O
O
O
Corey. 1988, 3423. Racemic synthesis originally presented in J. Am. Chem. Soc. 1987, 7534
(-)-Bilobalide
CO2M
CO2M
DIBALCl1
88%, 99% de
MO2C
CO2M
1. LDA
M=
2. t-Bu
O
CO2Ph
91%
Co2M
tBu
CO2M
H
tBu
KHMDS
80%
CO2M
CO2M
O
Corey. 1988, 3423. 1Developed by Yamamoto. 1986, 4507
O
(-)-Bilobalide
Co2M
tBu
BH3-THF
H
N
CO2M
Co2M
O
tBu
Ph
Ph
O
B
CO2M
H
45%
10:1 desired isomer
OH
1. O3, NaHCO3
DCM/MeOH
2. DMSO
3. pTsOH, MeOH
75%
MeO
tBu
MeO
1. LAH, THF, 55oC, 84%
2. i) Oxalyl Chloride, DMSO
MeO
ii) Et3N, -78oC to -40oC
O
O
O
O
3. 1N HCl/THF, 0oC
4. PCC, 4A mol siv, DCM
62%
tBu
MO2C
MO2C
O
OMe
Corey. 1988, 3423.
OMe
(-)-Bilobalide
RO
tBu
tBu
O
O
Hunig's Base
O
O
75% (3 steps)
OMe
OMe
KOH
MeSO2Cl
O
O
O
O
R=OMe
R=OH
R=Cl
O2N
COOOH
10eq
NO2
NaHCO3, DCM,
95%
AcO
OAc
O
tBu
tBu
O
O
1. 0.5 N HCl/H2O/THF,
O
2. Ac2O, DMAP, DCM, RT
89%
O
O
Corey. 1988, 3423.
O
60oC
OMe
O
O
O
O
OMe
AcO
(-)-Bilobalide
O
OAc
OAc
tBu
tBu
O
O
O
1. 0.5N HCl/AcOH/THF, 80oC
O
O
2. PCC, DCM, 96%
O
O
O
O
O
R
R'
O
R=H, R'=OMe
R=R'=O
mCPBA, BF3-Et2O
92%
O
trimethylsilane
Tol, 300 oC, 90%
O
OR
OAc
tBu
OH
tBu
O
R'
OsO4, Py, Et2O
O
O
O
O
MeO2COCCl, Hunig's, 100%
Bu3SnH, AIBN, 55%
3N HCl, reflux, 36 hrs, 70%
O
O
O
O
Corey. 1988, 3423.
O
R=Ac, R'=OH
R=Ac, R'=OCOCO2CH3
R=Ac, R'=H
R=R'=H
(-)-Bilobalide
Conclusions