JOC YEAR IN REVIEW
1972
ALEXANDROS ZOGRAFOS
THE BARAN GROUP MEETING
08/20/2003
The difficult decision
Some statistics
!Number of articles 1225!
!Full articles 480
!More than 25 total synthesis
!Isolation and characterization of 52
molecules
!Several novel methods
Total synthesis
COOH
O
H
OH
HO
H
O
HO
OH
HOOC
HO
O
OH
OH
O
Mirestrol
(-)-Seychellene
HOOC
Prostagladins
O
Cubane derivatives
OH
O
O
O
Guaiol
OH
O
N
HO
O
O
O
HO
H
Cinobufacin
Dehydrojoubertiamine
O
(-)-Patchouli alcohol
Jasmone
O
Total Synthesis of cis-Jasmone
O
! Isolated from flower oils of Jasminum
! Indispensable in the reproduction of jasmine
fragrance
! Several preparations have been reported
First synthesis at 1952 by Harper
! Two total synthesis in 1972.
Crombie, L.; Harper, S.; J. Chem Soc.; 1952, 869; Harper, S; Smith, J.; J. Chem. Soc.;
1955, 1512; Buchi, G.; Egger, B.; J. Org. Chem.; 1971, 36, 2021; Mc Murry, J.; Melton, J.;
J. Am. Chem. Soc.; 1971, 93, 5309.
Two Efficient Methods for the
Construction of cis-Jasmone
Berkowitz, W.; J. Org. Chem., 1972, 37, 341; Grieco, P.; J. Org. Chem., 1972, 37, 2363.
Cl
Cl
C
Cl
O
O
O
Et3N, 00C
hexanes
Cl
+
Corey, E.; Tetr. Lett.,
1970, 307.
O
H2O2
Acetic acid
Zn,
Acetic acid
Cl
Cl
O
O
DIBAL
Toluene
-780C
O
OH
Cl
Ph3P=CHCH2CH3
DMSO
O
O
1.MeLi
2.CrO3
NaOH/H2O
700C
Jasmone
5150C
glass wool
-EtOH, CO
Berkowitz, W.;J. Org. Chem.
1971, 36, 3787
Cl
O
O
O
NaH
Benzene
O
O
O
cyclopropyloxopropanoate
O
Jones
Reagent
OH
Highlights
Baeyer-Villiger Ring Expansion
O
O
O
O
H
H2O2
acetic acid
H
O
O
O
O O
O
A Thermal Two Carbon Ring-Expansion
O
O
+ CO
O
C
O
O
O
-EtOH
O
O
Glass
catalysed
O
H
O
O
O
O
O
H
Si
C
O
O
H
HO
Si
O
+
EtOH
O
Total Synthesis of Patchouli Alcohol
HO
!A tricyclic sesquiterpene isolated from
patchouli oil
!An important raw material for the
composition of perfumes
!First total synthesis by Buchi at 1956
Buchi, G.; Erickson, R.; J. Am. Chem. Soc., 1956, 78, 1262; Buchi, G.; Erickson,
R.; J. Am. Chem. Soc., 1961, 927; Buchi, G.; McLeod, W.; J. Am. Chem. Soc.,
1962, 84, 3205; Buchi, G.; McLeod, W.; Padilla, O.; J. Am. Chem. Soc., 1964, 86,
4438.
A Synthetic Route to Racemic Patchouli
Alcohol
Mirrington, R.; Schmalzl, K.; J. Org. Chem., 1972, 37, 2871
O
Diels
Alder
O
+
O
BrZn
O
OH
O
O
POCl
pyridine
TrCl
Et3N
OTr
1.B2H6, THF
2.CrO3 pyridine
O
OH
H
AcCl
DMA
Li,NH3
H
EtOH
+
O
+
O
O
O
O
OTr
OH
Both E and Z
regioisomers
H
Ratio 4:1
NaH, MeI
EtONa
O
O
3 steps
O
O
O
OTr
H
O
I
Na
sealed tube
1000C
H
HO
(-)-Patchouli alcohol
Mirrington, R.;Tetr.Lett., 1969, 5017.
Danishefsky, D.; Chem.Commun., 1968, 1287.
Highlights
OH
O
O
H+
maybe by carbocation
O
O
O
O
AcCl
O
O
O
O
H
O
Base
elimination
O
O
:B
Li, NH3
EtOH
Assisted cleavage
O
OH
Both E and Z
regioisomers
OH
H
4
Selective dehydration
H
1
O
H
O
O
H
Proton attacks from the less hindered side
Stereochemistry of the reduction
O
Synthesis Of Cubane Derivatives
HOOC
! Interesting molecular structure
! Original work by Eaton et al. at 1964 reporting
several derivatives of cubane skeleton
! First synthesis of homocubane from 2cyclopentanone in less than 10% yield
A Facile Synthesis of Homocubane
Paquette, L.; Ward, J.; J. Org. Chem., 1972, 37, 3569
Jones
Reagent
SeO2
OH
1.Br2
2.Et3N
Br
H
O
O
First synthesis of cubane derivatives
hv
O
O
COOH
1.KOH
HOOC
Br
O
2.H3O
Br
1.KOH
hv
2.H3O
Br
Br
O
HOOC
Br
O
1.NBS, CCl4
2.Br2, pent-DCM
O
Spontaneous
dimerization
Br
Et2NH, -200C
Br
O
O
Br
Eaton, P.; Cole, T.; J. Am. Chem. Soc., 1964, 86, 962
Br
Favorskii type rearrangement
Highlights
Spontaneous cyclization of bromo-cyclopentanones
An intermolecular Diels-Alder Reaction
O
Br
Br
O
Br
Br
O
O
Favorable intermediate
O
O
Br
Br
Br
Br
O
O
Favorskii type rearrangement
-Br
OH
Br
Br
O
OH
O
HOOC
Total Synthesis of Prostaglandins F1a and
E1
O
O
O
OH
OH
OH
HO
HO
HO
Prostaglandin F1a
HO
Prostaglandin E1
! Prostaglandins are discovered by von Euler in
1932
! Carbocyclic oxygenated C-20 molecules are
hormones that elicit an unusually diverse array
of physiological response
! Several preparations have been reported
A New Method for the Preparation of
Prostaglandins
Schaaf, T.; Corey, E.; J. Org. Chem., 1972, 37, 2921
O
O
O
HO
O
OH
O
1.THP, TsOH
2.DIBAL -780C
Ph3P
OH
DMSO, NaH
THPO
OCH2Ph
OH
OH
THPO
OCH2Ph
OCH2Ph
O
P(OMe)2
O
O
1.CH2N2, ether
2.Ac2O, pyridine 500C
3.H2, Pd/C 1atm 5%Acetic acid Ethanol
Corey, E.; J. Am. Chem. Soc., 1969, 91, 5675
O
O
O
O
Collins
Reagent, DCM 00C
O
O
O
THPO
O
O
O
O
NaH, DME
THPO
THPO
OH
O
O
Corey, E.; J. Am. Chem. Soc., 1968, 90, 3247
NaBH4
DME, 250C
O
O
O
O
THPO
1.Acetic acid/H2O, 400C
2.separation of epimers
3.KOH, MeOH, THF, 250C
O
OH
OH
HO
HO
HO
O
O
OH
HO
Prostaglandin F1a
HO
Prostaglandin E1
Highlights
Synthesis of Corey’s lactone
PhH2CO
PhH2CO
NaH, THF
Cl
KOH, H2O
DMSO
CN
Cu(BF4)2, 00C
BnOCH2Cl
-550C
PhH2CO
Cl
O
CN
mCPBA
NaHCO3
DCM
O
O
1.Ac2O, pyr.
2.n-Bu3SnH
AIBN, PhH
O
O
KI3, NaHCO3
H2O, 00C
O
I
HO
NaOH, H2O
CO2
AcO
OCH2Ph
HO
OCH2Ph
HO
OCH2Ph
PhH2CO
O
O
Novel Methods
! Thallium chemistry in organic synthesis
! Novel etherification of alcohols
! Palladium-Catalyzed Vinylic Hydrogen
Substitution (Heck reaction)
Novel Etherification of Alcohols
Kashman Y.; J. Org. Chem., 1972, 37, 912
Dialkyl phosphites react with alcohols to give the corresponding
ether in the presence of catalytic amount of acid
R
HOP(OCH3)2
O
HO
O P O
R: C8H17
HOP(OCH3)2
H+
H
OH
RO:
O P O
H
H
protonated
dimethyl phospite
OH
RO
H
-H+
ROCH3
O
+
O P O
H
Paladium-catalyzed Vinylic Hydrogen
Substitution
Background before the discovery of Heck Reaction
H
R
H
M'
RMX +
R
+
M'X
HM'X
M: Hg, Sn, etc
HgOAc
+
example:
Pd(OAc)2
+
Hg(OAc)2
Transmetaletion
PdOAc
Easy to isolate
H
H
+
PdOAc
H
PdOAc
H
+
PdOAc
H
HPdOAc
+
+
H
HPdOAc
+
β-elimination
Disadvantages
! There is often a problem obtaining the
organomercury, lead or tin compounds
! Thick slurries of salts difficult to manipulate if the
reaction is carried out catalytically in palladium
A New Method for the Arylation and
Benzylation of Vinylic Hydrogen
Heck R.; Nolley, J.; J. Org. Chem., 1972, 37, 2320
Mechanism of Heck Reaction
RX
+
Pd
RPdX
H
RPdX
+
H
R
PdX
HPdX
•Use of a base is essential in order to
neutralize the hydrogen halide from the reaction
R
•Tolerate a number of functional groups
•Iodides react rapidly. Benzyl halides are less reactive
•Loss of stereochemistry. Both cis and trans products
Thalium Chemistry in Organic Synthesis
Background
! Thalium acetate was first described at 1903 by
Meyer and Goldschmidt
! Among its applications are oxidative cleavage of
cyclopropanes, the conversion of chalcones into
isoflavones and the hydration of acetylenes
Year 1972
! Direct synthesis of allenic esters from βketoesters
! Oxidation of cyclohexanones to adipoins
A New Synthesis of Allenic Esters
Taylor, E.; Robey, R.; McKillop, A.; J. Org. Chem., 1972, 37, 2797
O
R1
O
R1
O
R2
R
H2N-NH2
R3
R2
N
R3
N
H
R1
R3
C C C
R2
O
O
TTN
O
MeOH
R1, R2, R3=alkyl
Mechanism
R1
R1
R3
R2
N
N
H
R3
R2
HN
O
TTN
R2
HN
O
N
H
R1
H
R3
Tl(NO3)2
O
N
H
-H2
R1
R1
R3
C C C
R2
O
O
R1
R3
Tl(NO3)2
R2
N
N
O
MeOH
TTN
R3
Tl(NO3)2
R2
HN
N
H
O
Oxidation of Cyclohexane to Adipoins
McKillop, A.; Hund, J.; J. Org. Chem., 1972, 37, 3381
McKillop, A. et al. J. Am. Chem. Soc., 1971, 93, 4919
O
OH
HO
OH
Tl
Y
HO
O
OH-
HO
OH
OH
Y
H+
COOH
H O
-H2O
O
OH
+
OH