Journal of Organic Chemistry: 1974
A Brief Synopsis
-Mike DeMartino
-Group Meeting: 10-29-2003
Overview
• Some general observations
• The “prime-time-players”…what were they
doing in JOC? (Thanks Dick Vitale, baby!)
• Some selected total syntheses
General Observations from
Title Perusing
• Heterocyclic chemistry prevalent
• Surprisingly little Tin/Palladium chemistry
• Lots of Rearrangements:
– Thermal
– Photolytic
– Acid Catalyzed
• 13C spectroscopy a new thing in organic chemistry?!?
• Not many total syntheses, mostly steroids
• Sulfur chemistry very prevalent
• A lot of degradation chemistry
E.J. Corey (Harvard)
-Preparation of an optically active intermediate for the prostaglandins (p. 356)
-A racemic route had previously been developed from (+/–) 1 to (+/–)-11-deoxyprostaglandins
O
O
1
O
O
LiOH
OH
O
(–)-1-(1naphthyl)ethylamine
OH
1
OH
O
3 recrystalizations
1. Removal of salt
• (–)-1-(1naphthyl)ethylamine
OH
2. 10 N HCl
-g-Condensation of an allylic Phosphonium Ylide (p. 821)
-Generally, allylic phosphorous ylides condense on the a carbon
-Many geometric isomers usually obtained
1
E. J. Corey (p. 256)
O
C5H11
O
H
Ph
P
Ph
•HBr
CO2Me
Me
Hunig's Base
9-10%
+
Hexanal
CO2Me
Me
C5H11
90-92 %
Generally, E/Z > 1
Samuel Danishefsky (Univ. of Pitt)
-A route to funtionalized heterocycles by homoconjugate addition (p. 1979)
-The use of a highly substituted cyclopropane as an electrophile (generated by reacting the olefin with dimethyl
diazomalonate ine the presence of copper bronze)
O
N
CO2Me
CO2Me
CO2Me
Hydrazine
CO2Me
NH2
MeOH
H
CO2Me
N
O
O
1. 10 % HCl
2.HCl, MeOH
H
H
N
O
Desired pyrrolizidine
N
H
H
O
Desired indolizidine
-Showed in earlier work that mechanism goes through "Spiro-mode"
NH
•HCl
CO2Me
Samuel Danishefsky (Univ. of Pitt)
-Furanoid systems by intramolecular homoconjugate addition (p. 2658)
CO2Me
O
O
CO2Me
NaH
MeO2C
PhH
O
O
(CO2Me)2
CO2Me
O
CO2Me
O
O
NaH
PhH
OR
DMSO
O
O
O
(CO2Me)2
Geometry highly dependent on solvent and
therefore solvation of reaction pathway
-O-Alkylation was dominant pathway in all systems they tried in this paper
Gilbert Stork (Columbia)
-Regiospecific Aldol condensations of the kinetic lithium enolates of methyl ketones (p. 3459)
-It had previously been difficult to trap the kinetic enolate with alkyl halides
-So, used a more reactive electrophile to trap the enolate
O
LDA,
O
Li
Butyraldehyde
O
OH
THF, –78°
65% (90% Kinetic enolate)
O
LDA,
O
Li
Benzaldehyde
O
OH
THF, –78°
Ph
75-80%
O
LDA,
O
Li
Crotonaldehyde
O
THF, –78°
70%
OH
Barry M. Trost (Wisconson, Madison)
-Chemospecificity of allylic alkylations (p. 737)
-Use of cis and trans geranylacetone
Conditions: PdCl2, NaCl, CuCl, NaOAc
in AcOH
-p-allyl complexes are remarkably stable
Ethylene Gylcol
2
TsOH, PhH, Reflux
PdCl/2
80%
O
O
Barry M. Trost (Wisconson, Madison)
Alkylations
NaH
1, 2, or 3
CH3SO2CH2CO2CH3
1. HOCH2CH2OH,
TsOH, PhH, Reflux
2. Li, C2H5NH2, 0°C
3.H2O, HCl
H3CO2S
CO2CH3
LiI, NaCN, DMF
130°C
H3CO2S
Barry M. Trost (Wisconson, Madison)
-Alkylation of Lactam Derivatives (p. 2475)
N
Me
O
–78°C
N
Me
O
OMe
1
Li
N
Me
–78°C
N
Li
O
E
E+
LDA, THF
N
E
E+
LDA, THF
2
OMe
N
OMe
-Both of the above examples proceeded with C-alkylation exclusively with alkyl halides,
chlorosilanes.
-For 1 (Stronger enolate), reaction with methyl vinyl ketone proceeds with 1,2 addition;
for 2, (weaker reagent), reaction to MVK proceeded with conjugate addition
This selectivity is due to the less reactive reagent having its charge more delocalized in the
transition state. To test this hypothesis, a controll exmeriment:
O
MVK
N
Me
OMe
22hr,
RT
N
Me
O
Exclusively 1,4 addition, 29%
Barry M. Trost (Wisconson, Madison)
-A convienent approach to Methyl 3-oxo-4-pentenoate (p. 2648)
-Not easily synthesized
-The two main previous methods either ended with a final step of 7-12% (acid catalyzed elimination),
or was based on a retro-Diels-Alder step (great yield, but requires special high-temp pyrolysis apparatus).
-Utility seen as an "annelating agent" in the synthesis of terpenes and alkaloids
O
PhSH
1. SOCl2
O
Ph
O
S
OH
2.
O
Ph
Li
O
TMSO
OTMS
S
O
O
MeO
62-76 %
O
H+
OMe
O
Ph
O
PhSCH2I
NaH
PhLi
O
O
1
Sodium
Metaperiodate
O
Ph
S
O
D
63-80%
O
O
OMe
MeO
1 MeO
O
OMe
OMe
S
O
Summary: 3-step route, 60-76% overall; 5-step route, 60-72% overall
O
R. F. Heck (Univ. of Delaware :-) )
-Palladium caralyzed Amidation of aryl, heterocyclic, and vinylic halides (p. 3327)
O
NH2
Br
R
+
CO
+
+
R'3N
Pd(Br)2(PPh3)2
100°C
Possible Mechanism:
R
N
H
R. F. Heck (Univ. of Delaware :-) )
-Palladium caralyzed carboalkoxylation of aryl, benzyl, and vinylic halides (p. 3318)
O
Br
R
+
CO
+
R1OH
+
R23N
Pd(Br)2(PPh3)2
100°C
Possible Mechanism:
R
O
R2
• The following people did wonderful chemistry in JOC, ‘74,
but time constraints cause their omission:
– David Evans (UCLA)
• Useful Prostaglandin Intermediate (p. 3176)
• Applications of trimethylsilyl cyanide (p. 914)
– Herbert C. Brown
• New organoborane structures via alpha-bromination of borapolycyclanes
(p. 861)
• Synthesis of olefins: alpha-elimination of alpha-chloroboronic esters
(p. 2817)
• Synthesis of terminal acetylenes via treatment of lithium
ethynyltrialkylborates with Iodine (p. 731)
– Herbert House
• Chemistry of Carbanions (p. 3102)
• Electron transfer reactions: reduction of enones with Cr(II) compounds
(p. 1173), and of nonconjugated acetylenes (p. 747)
– Robert E. Ireland
• Claisen rearrangement of N-Allylketene O,N-Acetals (p. 421)
– And of course, many others…
(S)-Carlosic Acid
Blommer and Kappler, p. 113
Temple University
O
O
O
O
OH
OMe
MeO
O
HO
Br
O
MeO2C
O
O
MeO2C
Et3N (cat), PhH
80%
HO
t-BuOK
O
CO2Me
O
t-BuOH
39%
O
O
O
O
HO
HO
Cl
AcOH
O
O
TiCl4
PhNO2
MeO2C
MeO2C
HO
O
AcOH
MeO2C
O
H2, Pd/C
Br2
O
HO2C
(S)-Carlosic Acid
Note: all yields in the synthesis were 70-80%, except the "key step," the cyclization
HCl
NaOH
Cassamedine
Cava and Libsch, p. 577
UPenn
-An alkaloid isolated from Cassytha americana
OMe
H
N
O
OMe
NH2
O
OH
O
+
O
O
Br
POCl3
Br
PhH, 2hr
O
O
O
CH3CN
20 hr, 90%
76%
O
Known Compounds
O
OMe
OMe
O
O
N
•HCl
O
Br
O
Ethyl
Chloroformate
N
O
t-BuOK
hn, 7hr
OEt
O
Br
PhH, t-BuOH
32%
Et3N, 0°C
90%
O
O
O
OMe
OMe
OMe
O
N
O
OEt
O
O
O
LiAlH4, AlCl3
Et2O, reflux
O
O
O
N
O
1.5 hr, 87%
Me
O
O
AcOH
23%
N
O
H
O
O
O
O
Cassamedine
Me
The Sex Pheromone of the Pink Bollworm
Phillip E. Sonnet, p. 3793
U.S. Dept. of Agriculture, Maryland
-Isolated from the Pectinophora gossypiella, the pink bollworm moth
-Isolated as 1:1 mixture of geometric isomers
H
Cl
OTHP
Li
84%
OTHP
Cl
OTHP
1. n-BuLi, THF
2. Cl(CH2)3Br,
HEMPA, THF
53%
H
OTHP
PPh3
84%
Ph3P
•HCl
1. n-BuLi, THF/HMPA
AcCl
2. Me(CH2)3CHO
AcOH
58%
OTHP
The Sex Pheromone of the Pink Bollworm
Phillip E. Sonnet, p. 3793
U.S. Dept. of Agriculture, Maryland
-Isolated from the Pectinophora gossypiella, the pink bollworm moth
-Isolated as 1:1 mixture of geometric isomers
H2, Pd/BaSO4
OAc
OAc
Pentane, 84%
NaNO2 (aq)
HNO3 (aq)
74%
The Sex Pheramone of the
Pink Bollworm
H2, Pd/BaSO4
Pentane, 80%
OAc
OAc
A Trail Pheromone of the Pharaoh Ant
Sonnet, Oliver, p. 2663
U.S. Dept. of Agriculture, Maryland
-Isolated from the Monomorium pharaonis, the Pharaoh Ant
-It was known that the pheromone had the general structure of 3-butyl-5methoctahydroindolizine, but absolute stereochemistry of active pheromone was not
elucidated
-Synthesized all four stereoisomers because they were interested in the
pheromone's utility as a pest control agent
H
N
N
C4H9
H
C4H9
A
H
N
N
C4H9
H
C4H9
C
B
A Trail Pheromone of the Pink Bollworm
D
1. BuLi
2.
N
N
O
OH
C4H9
1. PhP3•Br2
2. Et3N
H2
PtO2
Na
EtOH
H
N
H
N
H
OH
1. PhP3•Br2
2. Et3N
Br–
OH
C4H9
H2
PtO2
1. PhP3•Br2
2. Et3N
A
C+D
A+B
H
N
C4H9
A
N
H
C4H9
N
N
C4H9
C
B
A Trail Pheromone of the Pink Bollworm
H
N
H
C4H9
D
OH
H3CO
Fagaronine Chloride
OCH3
N
H3CO
Cl–
Fagaronine Chloride
Stermitz, p. 3239
Colorado St. Univ., Fort Collins
-Extremely active antileukemic alkaloid
-Isolated from Faraga zanthoxyloides
-Note: synthesis also proved structure
K2CO3
i-PrBr
DMF, 92%
OCH3
HNO3:HOAc
1:1
OCH3
HOAc
NO2
NO2
OCH3
H2NNH2,
EtOH
Oi-Pr
10% Pd/C
100°C, 99%
NO2
OCH3
hn, 1hr
OCH3
CH3CN:0.8N NaOH
90%
OCH3
OH
H3CO
NH2
OCH3
Br
H
H3CO
O
Oi-Pr
PhH, 91%
Fagaronine Chloride
Stermitz, p. 3239
Colorado St. Univ., Fort Collins
-Extremely active antileukemic alkaloid
-Isolated from Faraga zanthoxyloides
-Note: synthesis also proved structure
Oi-Pr
H3CO
Br
OCH3
N
H3CO
1
Oi-Pr
1. Na, NH3(liq)
H3CO
2. 1
3. NH4Cl, 24%
H3CO
OCH3
N
PhNO2/Xylene
180°C
OH
OH
H3CO
H3CO
OCH3
N
CH3OSO3–
H3CO
8% NaCl(aq)
88%
H3CO
OCH3
N
Cl–
Fagaronine Chloride
Dimethyl Sulfate,
(+/–) 11-deoxyprostaglandin E2
Jonh Petterson, John Fried, p. 2506
Syntex, California
I
LiCu
C5H11
O
OMe
1.
C5H11
O
Previous
Preocedures
2. Br
C5H11
2. TMSCl, THF
O
O
CO2Me
C5H11
CO2Me
OTMS
Et2O, -78°C
OMe
2
1. Li, NH3(liq)
Ferric Nitrate (trace)
O
OH
(+/–) 11-deoxyprostaglandin E2
OMe
3-Arylcephalosporins
H
N
S
O
N
Merck Sharp and Dohme Research, New Jersey
-Semisynthetic B-Lactam Antibiotics
-High potency, acid stable, high degree of tolerance by man
-Many modifications prior to this work
H
O
OMe
NH
+
Cl
O
Et2O3P
Acetone
O
Reported in 1973 by
same the group
N3
S
N3CH2COCl
Ar
CO2CH2C6H4OMe
O2N
N
N
O
Et3N
N
CHO
H
N
O
O2N
H
H
H2
Ar
CO2CH2C6H4OMe
Ar
CO2CH2C6H4OMe
Glyme
H2N
S
S
NaH
Ar
PO3Et3
CO2CH2C6H4OMe
Ar = C6H5
p-C6H4-CO2Me
4-thiazolyl
O
N
S
K2CO3
Ar
N
O
Pt
N
H+
S
Ar
CO2CH2C6H4OMe
H
N
O
H2O
O2N
S
Ar
CO2H
3-Arylcephalosporins
O
Firestone, Maciejewicz, Christensen, p. 3384
S
H
S
Ar
CO2CH2C6H4OMe
3-Arylcephalosporins
Firestone, Maciejewicz, Christensen, p. 3384
Merck Sharp and Dohme Research, New Jersey
-Semisynthetic B-Lactam Antibiotics
-High potency, acid stable, high degree of tolerance by man
-Many modifications prior to this work
2,4-DNPH
H2N
H
N
O
S
H
N
Et3N
Ar
CO2CH2C6H4OMe
Anisole
S
O
H
N
S
Ar
CO2H
3-Arylcephalosporins
O
O
N
O
Cl
S
H
N
TFA
S
O
H
S
Ar
CO2CH2C6H4OMe