baran group meeting derek h. r. barton will gutekunst€¦ · baran group meeting derek h. r....
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Will GutekunstBaran Group Meeting Derek H. R. Barton
- Born Derek Harold Richard Barton on Sept. 18, 1918- Father died in 1935 and had to take over the family wood business.- In 1937 decided to leave family business and enrolled at London University.- Entered Imperial College in 1938 after passing entrance exams and graduated two years later. Graduate work focused on the synthesis of vinyl chloride- Completed his Ph.D. 1942 and started working with military intelligence developing nonaqueous secret inks.- At the end of the war he started work with Albright and Wilson, Ltd. on the synthesis of organophosphorus compounds.- In 1946 he took the "most junior position" at Imperial College as an assistant lecturer.- From 1949-1950 he was a visiting lecturer at Harvard- In 1950 he was appointed reader at Birkbeck College, then to professor in 1953.- 1955 he moved to University of Glasgow - In 1957 he moved (yet again) to Imperial College- Received the Nobel Prize with Odd Hassel in 1969 for his development of Conformational Analysis- Knighted in 1972 (but only known as "Sir" in Britain)- Moved to France in 1978 to become director of ICSN - Gif Sur-Yvette- Forced to retire, moved to Texas A&M in 1986- Died 1998 at the age of 79
Quick Timeline
Main Areas of Research:
- Conformational Analysis- Stucture Elucidation- Phenol Oxidation- Biosynthesis (lignans, phenolic alkaloids, steroids, triterpenes)- Radical Chemistry- Photochemistry- Fluorine Chemistry - Organometallics- Much, much more
In all of these fields Barton made important contributions, if now start the field altogether. He frequently changed fields stating"
"... I have worked in many fields, but as soon as these fields became popular, I have moved on. I have made the joke of saying that if you cannot remember all the published papers in the field you are working in, then it is time to move on." Gap Jumping, page 111.
Flour + dead beetle pink (and unpalatable) flour surrounding beetle6 days
Compound isolation:500-1000 adult beetles (ca. 5 mL) are placed in a distilling flask. A stream of dry air is passed through the flask for 6 hours. Every 2 hours, cool to 0° C for 20 minutes. The excretion condensed long yellow needles on the cold finger (0.5 mg). Return beetles to flour for 3 days and repeat. Yields reduce with each interation. After 3 or 4 operations the insects were too feeble for further excretion.
O
O
Flour Beetle Study
Biochem. J. 1943, 37, 463-465
ethylquinone!
After a battey of tests, Barton determined that the compound was ethylquinone and when the paper was submitted the journal's editor initially thought it was a joke. This early study was performed during his free time when he was working for military intelligence, stating, "I though then, as now, that chemistry is more interesting that spare time." Gap Jumping, page 9.
Will GutekunstBaran Group MeetingDerek H. R. Barton
Method of Molecular Rotation Differences
RO
Me H
H H
HH
Me
MeMe
cholesterol
RO
Me
H H
H R
HRO
Me
H
H R
HRO
Me H
H
H R
H
RO
Me H
H H
H R
HRO
Me H
H H
H R
RO
Me
H
H R
HRO
Me H
H
H R
H
J. Chem. Soc. 1945, 813-819
Later extended to polyunsaturated compounds, hormones and bile acids
J. Chem. Soc. 1946, 512J. Chem. Soc. 1946, 1116
This method, while empirical, was accurate. Barton used to correct numerous structures in the literature - even one assigned by Nobel laureate Leopold Ruzicka! "It was perhaps unwise for a young man to criticize a distinguished professor at the prestigious ETH... I showed that L. Ruzicka had made an error in the assignment of configuration at the C-3 position in ring A of triterpenoid alcohols. Ruzicka, one of the greatest organic chemists of the day, had received the Nobel Prize just before the war. He was a passionate and fiery man. Our relations for some years were confied to print and somewhat strained"
Vinyl chlorides
Studied the thermal decomposition of various polychlorinated hydrocarbons and found that can occur through three different pathways.
Cl
H Cl
ClH Cl+
Cl
Cl
H Cl
Cl
Cl
H Cl+
Cl
Cl
Cl Cl+
Cl
H Cl
ClH Cl+
"surface"
Notably, 1,1 dichloroethane cannot participate in radical chain processes
Cl MeCl
H
Cl
HCl MeCl
Cl
+
Established "rules" for the decomposition of any chlorinated hydrocarbon.
J. Chem. Soc. 1949, 155.
~300–500° C
Me
Cl
Cl
Cl
Cl
Cl
+ H Cl
At a given temperature and surface area/volume ratio, all three mechanisms operate at the same rate.
!
cis-elimination
radical chain
surface catalyzed
J. Am. Chem. Soc. 1950, 72, 988.
Will GutekunstBaran Group Meeting Derek H. R. Barton
cis-Elimination
H
Me
HAcO
Me
HAcO
Δ
OBz
Originally reported by Plattner (ETH), refuted by MMRD
H
Me
HAcO
Me
HAcO
Δ
OBzH
Inspired by previous work, realizes it is requisite cis-elimination!
J. Chem. Soc. 1949, 2459.J. Chem. Soc. 1949, 2174.
Cl
Me
Me Me
Me
Me Me
Me
Me Me
Further support with menthyl chloride pyrolysis
+Δ
unimolecular
J. Chem. Soc. 1953, 453.
Conformational Analysis
Insprired by Odd Hassl's paper on decalin conformation, Barton became interested in calculating the preferred conformations using force field calculations (logarithmic tables and slide rule!)
Nature 1946, 157, 765.J. Chem. Soc. 1948, 340.
HHor ?
preferred!
This eventually led to the application of these concepts to steroid conformationExperientia 1950, 6, 316.
Using this analysis, he was able to rationalize the relative rates of esterification of equatorial and axial (polar) alcohols, thermodynamic isomerizations, anti-periplanar geometries for elimination, neighboring group participation, etc.
H
H H
H
H H H
H H
H
HH
or ?
"Conformational Analysis for the sutdy of the stability and reactivity of saturate or partly saturated cyclic systems promises to have the same degree of importance as the use of resonance in aromatic systems." – Arthur J. Birch, 1951
"Conformational Transmission"
O
Me
H
H
H
O
Me
H
H
H
O
Me
H
H
Remote conformational effects drastically change the relative rates of aldol reaction.
4 1 645
J. Chem. Soc. 1960, 1297.
Will GutekunstBaran Group MeetingDerek H. R. Barton
H
Me
MeHO2C
H
Me
Me
abietic acid
VO5, HNO3
"good yield"
Structure Elucidation
Me Me
Me
H
Me
Me
H
Me
HMeMe
!-amyrin
Me
Me
Me
HMe
Me
Me
HO
MeH
Me
lanosterol
J. Chem. Soc. 1953, 1027.
J. Chem. Soc. 1953, 576.
Me
Me
Me
HMe
Me
H
HHO
MeMe
cycloartenol
J. Chem. Soc. 1951, 1444.
Me
Me
Me
Me
H
caryophyllene
J. Chem. Soc. 1951, 2988.J. Chem. Soc. 1952, 2210.
OHOH
Me
Me
Me
Me
culmorin
J. Chem. Soc. (C) 1968, 1148.
H MeMe
OAcAcO
O
O
OH
HH
O
O
O
O
OMe
O
MeH
MeMe
H
OH
clerodin limonin
J. Chem. Soc. 1961, 5061. J. Chem. Soc. 1961, 255.
O
O
MeO
OMe
OO
O
O
Me
Me
Me
O
O
O
O
glauconic acid byssochlamic acid
J. Chem. Soc. 1965, 1769.
HO
Me Me
Me
H
OH
MeMe
Me
H
onocerin
J. Chem. Soc. 1955, 2639.
cevine
HO
OH
HO
OH
HO
Me
N
OH
OH
H
Me
Me
OH
H
H
J. Chem. Soc. 1954,3950.
O
O
O
OMe
RO2C
Cl
Me
Cl
OH
R = Me; geodinR = H; erdin
J. Chem. Soc. 1958, 1767.
OHMe
HO
Me
MeO
Me OAcO
O
O
MeMe
HO
AcO
HO
H
`J. Chem. Soc. 1971, 1259; 1265.
fusicoccin
meso compound
Will GutekunstBaran Group MeetingDerek H. R. Barton
H
Me
MeHO2C
H
Me
Me
abietic acid
VO5, HNO3
"good yield"
Me
Me
CO2H
CO2H
HO2C
Structure Elucidation
Me Me
Me
H
Me
Me
H
Me
HMeMe
!-amyrin
Me
Me
Me
HMe
Me
Me
HO
MeH
Me
lanosterol
J. Chem. Soc. 1953, 1027.
J. Chem. Soc. 1953, 576.
Me
Me
Me
HMe
Me
H
HHO
MeMe
cycloartenol
J. Chem. Soc. 1951, 1444.
Me
Me
Me
Me
H
caryophyllene
J. Chem. Soc. 1951, 2988.J. Chem. Soc. 1952, 2210.
OHOH
Me
Me
Me
Me
culmorin
J. Chem. Soc. (C) 1968, 1148.
H MeMe
OAcAcO
O
O
OH
HH
O
O
O
O
OMe
O
MeH
MeMe
H
OH
clerodin limonin
J. Chem. Soc. 1961, 5061. J. Chem. Soc. 1961, 255.
O
O
MeO
OMe
OO
O
O
Me
Me
Me
O
O
O
O
glauconic acid byssochlamic acid
J. Chem. Soc. 1965, 1769.
HO
Me Me
Me
H
OH
MeMe
Me
H
onocerin
J. Chem. Soc. 1955, 2639.
cevine
HO
OH
HO
OH
HO
Me
N
OH
OH
H
Me
Me
OH
H
H
J. Chem. Soc. 1954,3950.
O
O
O
OMe
RO2C
Cl
Me
Cl
OH
R = Me; geodinR = H; erdin
J. Chem. Soc. 1958, 1767.
OHMe
HO
Me
MeO
Me OAcO
O
O
MeMe
HO
AcO
HO
H
`J. Chem. Soc. 1971, 1259; 1265.
fusicoccin
Will GutekunstBaran Group MeetingDerek H. R. Barton
J. Chem. Soc. 1956, 530.
Oxidative Phenol Couping and Biosynthetic Implications
These studies were initiated by a disbelief of the proposed structure of "Pummerer's ketone," despite being commonly held as true for 25 years.
Me
OHK3[Fe(CN)6]
Me
OMe
O
Me
OMe
OH
"Pummer's ketone"
Me
OHK3[Fe(CN)6]
Me
OH
Me
OMe
O
Me
O
H
Barton's Proposal
Me
O
Me
O
H
Me
OH
Me
OH
H+
OH
Ac
HO
Me
OH
HNa2CO3, H2O
K3[Fe(CN)6]
15%
O
Me
Ac
HO
Me
OH
O
AcHO
O
Me
Ac
HO
Me
O
AcHOOH OH
H2SO4
usnic acidmethylphloractophenone
The natural extension of these concepts led to the formalization of modern phenolic alkaloid and lignan biosynthesis, and Barton even proposed compounds as necessary biosynthetic intermediates that were later isolated (e.g. crotonosine, reticuline). Festschrift Arthur Stoll 1957, 117.
Chem. Brit. 1967, 330.
crotonosine
NH
HO
MeO
HO
NH
HO
MeO
HO
NH
O
H
HO
MeO
O
NMe
OH
NMe
HO
MeO
O
K3[Fe(CN)6]high dilution
1.4%
narwedine galanthamine
MeO
OH
NMeO
MeO
LAH
NMe
O
MeO
HO
MeO
NMe
OH
MeO
AcO
MeO
salutaridine
SeO2;hydrolysis
NMe
MeO
O
MeO
thebaine
H
NaBH4, H+
NMe
HO
O
MeO
morphine
H H
J. Chem. Soc. 1962, 806.
Proc. Chem. Soc. 1963, 189.J. Chem. Soc. 1965, 2423.
acetylreticuline
Barton was also actively engaged in elucidating the biosynthesis of many of these phenolic alkaloids though the use of radiolabelling studies.
Will GutekunstBaran Group MeetingDerek H. R. Barton
J. Chem. Soc. 1957, 929.
Photochemistry
AcO
Me
O
Me Me
Initially thought that irradiation would result in racemization of the quaternary center via:
AcO
Me
O
Me Me
AcO
Me
O
Me Me
J. Chem. Soc. 1961, 1215.
But only a single new product was formed whose identity was unknown. To investigate the reaction, a simpler and more readily available model substrate, santonin, was studied.
Me
Me
O
O
Me
O
H
Me
Me
O
O
Me
O
H
O
Me
O
Hh! AcOH
Me OH
Me
O
H
MeMe
O
O
H
Me
O
J. Chem. Soc. 1958, 140.
AcO
Me
O
Me Me
h!
AcO
Me
O
Me Me
As a natural extension, the photochemistry of linear cyclohexadienones were studied and were found to also have interesting behavior.
J. Chem. Soc. 1960, 1.
O
R2
R1R4
R3
h!O
R2
R1
R4
R3
O
R2
R1
R4
R3
NuNu:
This allowed for an expedient synthesis of dimethylcrocetin
Me
O
Me Me
OMe
MeO2C
Me Me
Me Me
CO2Me
Nitrite Ester Photolysis
O
O
OAc
Me
O
H
H H
H
OH
O
O
OAc
Me
OH
H
H H
H
ON
O
O
OAc
Me
O
H
H H
H
H
O
O
OAc
Me
OH
H
H H
H
N
OH
AcOHHNO2
15% overall
O
O
OAc
Me
OH
H
H H
H
H
corticosterone acetate
NOCl
py.
aldosterone acetate
h!
toluene
J. Am. Chem. Soc. 1961, 83, 4083.
ON
Rearrangement to 18-nor-D-homosteroids
ONOMe O
H
H
H
HO
H
H
H
Oh!
toluene
J. Am. Chem. Soc. 1961, 83, 4481.
Br
Br
OH
MeMe
Br
BrBr O
Me
Me
Br
O
Me
Me
Br
h!, MeOH;base
dimethylcrocetin
Chem. Ber. 1977, 110 3582.
Synthesis of aldosterone acetate
Will GutekunstBaran Group MeetingDerek H. R. Barton
J. Chem. Soc. (C) 1969, 332.Converstion of lanosterol into cycloartenol
Me
Me
Me
HMe
Me
Me
HO
MeH
Me
lanosterol
Me
Me
Me
BzO
MeH
Me
HO
H
H
RMe
Me
BzO
MeH
Me
O
H
H
R
h!, I2;
H2CrO4
I
KOt-But-BuOH
Me
Me
BzO
MeH
Me
O
H
R
LiAlH4
dioxane
Me
Me
Me
HMe
Me
HO
MeH
Me
H
cycloartenol
Me
Me
Me
HMe
Me
Me
AcO
MeH
Me
H
H
ONO
h!, O2
44%
Me
Me
HMe
Me
Me
AcO
MeH
Me
H
H
OHONO2
Modification for directed oxygenation
O Me OH
O2
OHO
O
N O
OHO
ONO
Lactone synthesis
Me
Me
O
NH2 O
O
MeMe
h!, I2t-BuOCl;
hydrolysis
J. Chem. Soc., Perkins Trans. 1 1973, 2402.
J. Chem. Soc. 1965, 181.
Me
H
H
H
MsO
O
NH2
H
H
H
MsO
CO2HHO2CPb(OAc)4I2, h!;
basic reductive workup44%
Even higher oxidations states!
J. Chem. Soc. (C) 1968, 2283.
Steroid Biosynthesis
Barton some work on the biosynthesis of steroids in the 1970's (feeding studies, etc) but due to time (and my knowledge of the subject) it will not be discussed.
RMe
Me
HO
H H
ergosterolR = C9H17
a. TsCl, py.b. KHCO3, H2O acetone
c. MnO2 57–64%
RMe
Me
H H
O
TsOH;LiBr, DMF
RMe
Me
AcO
H H
ergosterol acetateR = C9H17
O2, Ar3NSbCl6
dark, -78° CDCM, 5 min
quant.
RMe
Me
AcO
H
HO
O
J. Chem. Soc., Chem. Comm. 1972, 447.
J. Chem. Soc. C. 1970, 1584.
RMe
Me
H H
OH
AgOAc, I2AcOH;Ac2O
cat. HClO4
RMe
Me
H
OAcH
AcO
AcO
CO3H
CO2H
Et2O
RMe
Me
H
OH
AcO
AcO
OH
Ecdysone Synthesis
Light Free Oxygen [4+2]
Me
Me
H
OH
AcO
AcO
OH
H
Me
Me
Me
OH
HO
ecdysone
Will GutekunstBaran Group MeetingDerek H. R. Barton
Tetracycline Studies
J. Chem. Soc., Perkins Trans. 1 1973, 2402.
O O O
O
OMe
OMe
CO2Me
OO O
O
OMe
OMe
CO2Me
H
Hh!, benzene
benzoic acid35%
OH OH
Me
OH
OH
CONH2
OH
6-methylpretetramid
J. Chem. Soc., Perkins Trans. 1 1981, 1840.
O S S
O
OH
OH
CO2Me
OS S
O
OH
OH
CO2Me
H
H
h!, benzene
LHMDS60%, [gram-scale]
benzeneselenicanhydride
64%
O
O
OH
OH
CO2Me
H
HO
Olefin migrations with RhCl3
O Ocat. RhCl3
EtOH/CHCl3
48 hr, 70° Cquant
J. Chem. Soc., Perkins Trans. 1 1977, 359.
"the major effort on tetracycline synthesis convinced me that this sort of work should be left to Industrial friends who have the money and the resources to finish any multi-step synthesis, if it is economically justified. So it is the originality in the reactions and the reagents and any new principles that finally justify academic effort in synthesis. We are far away from the Woodwardian dogma of completely planned synthesis" Reason and Imagination, page 407
Fluorination
At the time, most fluorine chemistry was perfomed electrochemically, with the only known electrophilic fluorine reagent known being the explosive FClO4. Barton developed a number of hypofluorite reagent, especially CF3OF for this purpose
Me
HAcO
AcOMe
H
H
MeOAc
Me
HAcO
OMe
H
H
MeOAc
F
F3COF, CFCl3
-75° C"good yield"
Me
H
O
MeO
H
H
"Acid-sensitive substrates have been protected by the inclusion of CaO, MgO, or NaF. Use of pyridine for this purpose led to the formation of a highly explosive by-product and is therefore discouraged."
Me
H
O
O
H
H
F
OH
MeMe
Me
F
MeF
O Me
O
Me
O O
OCF3
F
F
Me
BrF3CO2C
Me
H
H
O
Br
H
Me
BrF3CO2C
Me
H
F
O
Br
H
same
same
same
same
same
Additionally, he discovered that these reagents add to olefins with exclusively Markovnikov cis-addition.The current process for manufacturing 5-fluorouracil is still the one he developed in 1972.
Chem. Comm. 1968, 804.Chem. Comm. 1968, 806.Nouveau J. Chimie 1980, 4, 239
Will GutekunstBaran Group MeetingDerek H. R. Barton
Vitamin D Syntheses
J. Am. Chem. Soc. 1973, 95, 2748.
Me
Me
Me
H
MeMe
HO
H
H
H
Me
Me
Me
H
MeMe
O
H
H
H
O
1. DDQ2. NaOH H2O2
45%Li/NH3, NH4Cl
THF60%
Me
Me
Me
H
MeMe
HO
H
H
H
HOMe
Me
Me
H
MeMe
AcO
H H
AcO
1. Ac2O, DMAP2. DMDBH
3. P(OMe)3 34%
h!
Me
Me
Me
H
Me
AcO
H
AcO
Me
Me
Me
H
Me
HO
H
OH
Me
1. 75° C2. MeOH, KOH
Me
Me
H
Me
HO
H
Me
cholecalciferol
Me
Me
H
Me
OH
H
Me
1. SO2, PhH/H2O2. EtOH, NaHCO3 heat
90%1. TBSCl2. SeO2, NMO MeOH, DCM 55%
Me
Me
H
Me
OTBS
H
Me
HO
1. h!, acridine2. TBAF
71%
Me
Me
H
Me
HO
H
Me
OH
J. Am. Chem. Soc. 1986, 51, 1637.
cholesterol
1"-Hydroxy vitamin D3
1"-Hydroxy vitamin D3
Will GutekunstBaran Group MeetingDerek H. R. Barton
Barton Olefin Synthesis
Since many of the olefin forming methods of the time were adversely affected by steric hindrance,Barton decided to develop a new olefin synthesis through the use of a two-fold extrusion process. This would allow the C–C formation ot be intramolecular, and therefore less affected by sterics. Tetra t-Butyl ethylene was viewed as the holy grail olefin, but was never successfully prepared.
Concept:
Y
XR1
R2
R3
R4
R1 R3
R4R2
X Y+ +
Systems considered:
SO2
SR1
R2
R3
R4SO2
R1
R2
R3
R4
OS
S
S
R2
R3
R4
R1
S
O
R2
R3
R4
R1
O
S
S
R2
R3
R4
R1
S
N
SO2
N
R2
R3
R4
R1N
SO
N
R2
R3
R4
R1N
S
N
R2
R3
R4
R1N N
R2
R3
R4
R1
O
O
J. Chem. Soc. Perkin Trans. I 1972, 305.
N
S
N
R2
R3
R4
R1
R1 R2
S
R3 R4
N2+
HN
S
NH
R2
R3
R4
R1[o]N N
R2
R3
R4
R1
H2S
MeMe
Me S
N2
Ph
Ph
PPh3, !
90%
MeMe
Me
Ph
Ph
MeMe
Me S
N2
t-Bu
t-Bu
PBu3, !
64%
MeMe
Me
t-Bu
t-Bu
Preparation
Se
Me
Me
Me
N2
t-Bu
t-Bu
Me
Me
Me
Me
Me
MePBu3, !
64%
J. Chem. Soc. Perkin Trans. I 1976, 2079.
Phenylselenic Anhydride
Phenylselenic anhydride proved to be a highly efficient reagent for ketone dehydrogenation and could also be used in catalytic amounts with hypervalent iodine reagents acting as the reoxidant.
HO
Me H
H H
HH
Me
MeMe
HO
Me H
H H
HH
Me
MeMe
3 mol% BSA4 eq
73%
HO
Me H
H H
MeH
Me
HO
Me H
H
MeH
Me
cat. BSAm-iodoxybenzoic acid
64%
OHO
CO2Me CO2Me
Application to the degradation of the Cholic Acid side chain
HO
Me H
H H
MeH
Me
H
CO2H
B(OH)3, xylene
96%
OH
NH2Me
Me
HO
Me H
H H
MeH
Me
H
O
N
Me
Me
HO
Me H
H H
MeH
Me
H
N
O
Me
Me
BSA, py.quant.
O O
OCl3CCOCl
Cl3OCO
Me H
H H
MeH
Me
H
NCOCl3
O
Me
Me
O
J. Chem. Soc. Perkin Trans. I 1982, 1947.
J. Chem. Soc. Perkin Trans. I 1985, 1865.
Will GutekunstBaran Group MeetingDerek H. R. Barton
Cl3OCO
Me H
H H
MeH
Me
H
NCOCl3
O
Me
Me
OO3;
saponificationMe H
H H
MeH
Me
H
O
O
HO
80%
AcO
Me H
H H
MeH
Me
H
N
O
Me
Me
O BSAiodoxybenzene
35-40%
Me H
H H
MeH
Me
H
O
O
AcO
Amines can also be oxidized (primary amines to nitriles, secondary amines to imines, hyroxylamines to nitroso, hydrazines to azo and amides to imides). Nitrogen containing heterocycles can also be oxidized.
NH
NMeHOH2C
H
H
0.5 eq. BSA3 eq. indole
THF, 40° C97% N
H
NMeHOH2C
H
lysergol
NH
SePh
Tetrahedron 1985, 41,4727.J. Chem. Soc. Perkin Trans. I 1990, 707.
Phenol Oxidations
Me
Me
Me
OH
NaH, BSA
55%
OMe OH
MeMe
Me
OHMe
O
J. Chem. Soc. Chem. Comm. 1975, 301.
Me
Me
OH
BSA, HMDS
65%
Me
Me
O
NSePh
J. Chem. Soc. Chem. Comm. 1977, 147.J. Am. Chem. Soc. 1993, 115, 948.
N
SeN Se
N
SeNSe Ph
Ph
PhPh
Radical Revolution
O
S
S
OEt
Due to the strong UV absorption of xanthates, Barton reasoned that they may be photochemically susceptible and lead to bond fissions products. He was pretty much correct.
Acyl xanthates to form acyl radicals.
h!
Et2O97%
S
S
OEt
O
S
S
OEt - CO
J. Chem. Soc. 1961, 1967.
Thiobenzoate Photolysis (Game-of-Bridge Reaction)
O
Me H
H H
HH
Me
MeMe
Me H
H H
HH
Me
MeMe
S
Ph
ambient light5 days
quant.
Ph
S
OPh Me
PhMe
55%
Ph
S OH
Ph
Me
10%
h!
DCM
J. Chem. Soc. Perkin Trans. I 1973, 1580.
In the mid 1970's, there was a need to replace the secondary hydroxyl groups in amino-glycoside antibiotics with a hydrogen. Since traditional methods were ineffective, Barton devised a plan to use radicals to deoxygenate the substrate inspired by the Game-of-Bridge reaction.
O
O O
OO
O
Me
Me
Me
Me
HO
H O
OO
O
Me
Me
Me
Me
H
S
MeS
Bu3SnHToluene reflux
80–90%
J. Chem. Soc. Perkin Trans. I 1975, 1574.
Selenobenzoates were also examined, but were too reactive and gave large amounts of the free alcohol. The tellurium analogs, on the other hand, behaved differently during preparation.
R OH
NMe2
PhCl
NMe2
PhRO
NaHTe
PhRO
Application to lysergol synthesis
Deoxygenation
Will GutekunstBaran Group MeetingDerek H. R. Barton
This method is now a staple of organic synthesis and many modifications have been made. Olefins can be made from 1,2 dixanthates and less toxic alternatives to tin have been demonstrated (hypophosphorous acid being especially cheap and benign).
O
Me H
H H
HH
Me
MeMe
S
Et2NH
Me H
H H
HH
Me
MeMe
H
K, 18-crown-6t-BuNH2/THF
86%
Simple bulky ester reduce in a similar manner, though are less efficient.
Radical Anion Deoxygenation J. Chem. Soc. Perkin Trans. I 1981, 1501.J. Chem. Soc. Perkin Trans. I 1981, 1510.
The deoxygenation method could also be extended to deamination using isonitrile and thioformates as substrates.
O
OAc
AcOAcO
N OAcC
Bu3SnH
> 81%
O
OAc
AcOAcO
OAc
J. Chem. Soc. Perkin Trans. I 1980, 2657.
Radical Decarboxylation
Me Me
H
Me
Me
H
Me
HMe
AcO
OAc
O
ON
St-BuSH
toluene, 3hrs
85%
Me Me
H
H
Me
Me
H
Me
HMe
AcO
OAc
Instead of reduction, the formed alkyl radical can also react with a variety of coupling partners
O ON
S
BrCCl3110° C
98%
Br
In the presence of oxygen hydroperoxides are formed, nitroolefins give nitrosulfides, allyl sulfides to allylated products, sulfur dioxide to thiosulfonates, white phosphorus to phosphonic acids, diazirines, etc. See Reason and Imagination pages 597-696.
These ideas led to the deoxygenation of tertiary alcohols (these substrates were previously inaccessible due to rapid Chugaev elimination)
Me
O
O
O
ON
S
Et3CSHbenzene
70%
Me
In a strange example, these radicals also react with arsenic, antimony and bismuth phenylsulfides. Upon exposure to air, these intermediate species immediately oxidize to the corresponding alcohols.
O
ON
S
Me
S
(PhS)3SbDCM
12 hr, 79%
Sb(SPh)2air, water OH
This method is particularly well suited to sugar synthesis.
CbzHNCO2Bn
OO N
S
h!
62%
CO2NH2
SPh
CbzHNCO2Bn
ONH2
O adenine
O O
Me Me
O
ON
S
h!45%
O adenine
O O
Me Me
CbzHN
CO2Bn
ONH2
HO N
HO OH
H2N
CO2H
NH2
N
N
N
NH2
J. Chem. Soc. Perkin Trans. I 1991,981.sinefungin
Will GutekunstBaran Group MeetingDerek H. R. Barton
Reactions with olefins
CO2Et2.5 eq NaHTe
EtOH
73%
CO2Et
2.5 eq NaHTeEtOH
100%
Me
2.5 eq NaHTeEtOH
Me
Me
Me
no reaction
HO2C
8
3 eq NaHTeEtOH HO2C
8Me
HO2C
8
R1
R2
R1 = H, R2 = Te-alkylR1 = Te-alkyl, R2 = H
Ni2B
quant.
Tetrahedron Lett. 1985, 26, 6197.
Sodium Hydrogen Telluride
Nucleophilic opening of epoxides and reduction of quaternary ammonium salts
Me
15
ONaHTeEtOH
Me
15
OH
TeH
TsCl, py. Me
15
92%
Ni2B
78% Me
15Me
OH
NMe
MeMe
BnOH
NaHTeEtOH
97%N
Me
MeBn
Organobismuth Chemistry
Barton initally investigated bismuth chemistry to explore its potential as an oxidant (which it does well), but also discovered its exceptional ability to arylate a variety of substrates.
Phenol Arylation
Phenols can provide either O-or C- arylated products depending on the bismuth reagent and the pH of the reaction.
OHPh4BiOCOCF3
BTMG
94%
OH
Ph
OPhPh4BiOCOCF3cat. Cl3COOH
91%
Me Me
MeMe
OH Ph5Bibenzene
83%
MeMe
MeMe
OPh
Enolates were also reactive, again under basic conditions C-arylation predominated. Free enols can be O-arylated under acidic or neutral conditions, but normal ketones are unreactive. Nitronates, ester enolates and sulfinates were also viable substrates for arylation under basic conditions.
O OPh
Ph
Ph
Ph
Ph5BiKH, 60° C
93%
N
HO N
MeO N
O N
MeO
Ph
2.5 eq. Ph3BiCO3DCM reflux
92%
Ph
Ph Ph
K Ph3BiCO3
44%
Ph
Ph Ph
Ph
J. Chem. Soc. Perkin Trans. I 1985, 2657.
J. Chem. Soc. Perkin Trans. I 1985, 2667.
Later it was found that copper catalyzed these reactions and now anilines and amines were viable substrates for N-arylation. Similar results were seen with aryl lead (IV) reagents as well.
Tetrahedron Lett. 1986, 27, 3619.Tetrahedron Lett. 1986, 27, 3615.Tetrahedron Lett. 1987, 28, 3111.Tetrahedron Lett. 1996, 53, 4137.
Me
Me Me
NH2
Me
Me Me
NHPh
1.1 eq Ph3Bi(TFA)20.1 eq Cu
DCM
95%
These bismuth reagents also proved to be effective at cleaving alpha glycols, even trans-diols.
OH
OH
OH
OH
O
O
0.1 eq Ph3BiNBS
MeCN/H2O
3.7 hr, 77%
0.1 eq Ph3BiNBS
MeCN/H2O
2.5 hr, 72%
Will GutekunstBaran Group Meeting Derek H. R. Barton
J. Chem. Soc. Perkin Trans. I 1982, 2085.
Miscellaneous ChemistrySterically Hindered Guanidine Bases; Barton's Base
A number of bulky guanidine bases were prepared from the corresponding ureas or thioureas. This resulted in the strongest organic bases known at the time and Barton employed them frequently in his chemistry.
R2N
X
NR2
X = O,S
COCl2R2HN
Cl
NR2
Cl RNH2
R2N
NR
NR2
Me2N
Nt-Bu
NMe2 (i-Pr)2N
Nt-Bu
N(i-Pr)2Barton's Base (BTMG)
pKa = 14
N
NDBN
pKa = 13.5
Synthesis of Vinyl Iodides from Hydrazones Tetrahedron 1988, 44, 147.
NNH2Me
Me
IMe
Me
2.5 eq I23.5 eq BTMG
THF
88%
Also vinyl selenides!
NNH2 SePh10 eq PhSeBr6 eq BTMG
THF88%
Synthesis of a Stable Dithiet
Me
Me R
HMeMe
AcO
Me
Me R
HMeMe
AcO
hν
heptaneS
S
SS
HMeMe
AcOS
S
H
Me R
Me
H
POCl3py.
Me
Me R
MeMeAcO
SS
Me
Me R
MeMeAcO
SS
hν
J. Chem. Soc. Perkin Trans. I 1977, 515.
A Tropone Synthesis
MeO
MeCHCl2
Me
OMe Me
Me
OHMe
Me
Me
CHCl3PTC
aq NaOH
59%
Bu3SnHAIBN, PhH
80° C, quant.
Tetrahedron 1987, 43, 5031.
Ergosterol Isomerization with Chromium
R
H
Me
H
Me
AcO
Cr(CO)6octane
81%
RMe
H
Me
AcOH
RMe
H
Me
AcOH
Cr(CO)6octane
78%
RMe
Me
AcOH
Interestingly, Fe(CO)5 performs the reverse process.
Tetrahedron Lett. 1992, 33, 5041.
Synthesis 1979, 4, 265.
Rhenium Catalyzed Silylation
Me
Me Me
OH1.5 mol% Re2(CO)10
4 eq. PhSiH3
quant.
Me
Me Me
OSiH2Ph
Me MeMe
OO
MeMe
Me
SiPh H
86-88% 12-14%
Will GutekunstBaran Group MeetingDerek H. R. Barton
J. Chem. Soc. Perkin Trans. I 1974,1245.p-Dimethylamino-N-thiosulphinylaniline
Me2N N
O
P4S10DCM
rt
Me2N NS S
crystalline purple compound
N
S
S
Me2N
Trifluoronitrosomethane J. Chem. Soc. Perkin Trans. I 1974, 2344.
ONO
h!
F3CNON N
F3C CF3
OAdAdO
N N
F3C CF3
OAdAdO
HS CO2H
"NH
F3C
AdO
DIPEA NOAd
FF
"wet" MeOHNaOMe
NH2AdO
Enolate Anions as Protecting Groups for Ketones
MeO
Me
HH
Me
O
H
O
2 eq Ph3CLi, rt;LAH, -78° C
50%
MeO
Me
HH
Me
HO
H
O
11-oxo-progesterone
Barton also mentions the potential use of this method in Grignard additions, Wittig reactions, etc.
J. Chem. Soc. Perkin Trans. I 1977, 1075.
Barton-Zard Pyrrole Synthesis
Another Side Chain Degradation
Me
H
O
OH 3 eq. SOCl2py.; CSA;
MeOH
Me
H
O
OMe
SO
Ac2OMe
H
O
OMe
O
cat. Cu(OAc)2-bipyDABCO, O2, DMF
Me
H
O
75-80% from acid
Tetrahedron 1989, 45, 3741.
R O
NC
R1
O2N
R2+
base
NH
R
O
R1R2
another pyrrole synthesis
O
R1
NO2
R2 R3
R4
O
R1
NH
R2 R3
R4
NH
R1
R2R3
R4
PhSSPhBu3P
Tetrahedron 1989, 46, 7587.
Things I did not cover:
- hundreds and hundreds of papers- Penicillin research- Gif chemistry (see alkane hydroxylation group meeting)
"...I found my true role in chemistry as an inventor of chemical reactions. Although, like an artist, I seek elegance and personal satisfaction, I am still pleased when I do something useful. I realize that there is a direct relationship between the utility of chemistry and how much academic research can be funded. It is strange that the same restrictions do not seem to apply for physics or molecular biology." Gap Jumping, page 109