Arthur J. Birch
Baran Lab
Hafensteiner
- other Co-A esters are possible, explaining also flavanoid and anthoycanin synthesis
- loss of oxygen can be due to dehydration that gives rise to aromaticity
- aromaticity can be generated by enolization
Biosynthesis of Polyketides
- 1907: J. N. Collie coined the term polyketenes to define fatty acids and terpenes as
"polymers" of ketene subunits, which was later changed to polyketides
- 1951: acetyl Co-A already known to be involved in synthesis of steroids and fatty acids,
Birch was interested in the product possibilities if the oxygen atoms were retained
O
- first polyketide with acetic acid as comfirmed building block
using tracer experiments
OH
Birch, A. J.; Massy Westopp, R. A.; Moye, C. J. Chem. Ind., 1955,
683
- C-methylation occurs as well and addition of other electrophiles
campnospermonol
OH
CO2H
- Birch hypothesis for biosynthesis of polyketides was rejected from some of the best
journals
OH
First hypothesis paper: Birch, A. J.; Donovan, F. W. Aust. J. Chem., 1953, 6, 373
R
Birch, A. J. Science, 1967, 156, 202-206
O
- synthesis of these molecules could take place via aldol or claisen chemistry
O
O
O
O
O
Co-A
O
Co-A
O
O
OH O
CO2H
Co-A
O
OH
Me
Me
HO
O
HO
OH
OH
orsellinic acid
OH
Arthur J. Birch
Baran Lab
Hafensteiner
H+
OH
Biosynthesis
:B
H
*
H
Gibberellic Acid and Rosenolactone
H
H
CO2H H
HO
OH
H
O
OC
Me
HO
O
Me
OH
H
R
H
OH
H
CO2H
H
H
O
:B
- 14C feeding experiments show production from acetic acid and mevalonic lactone
which itself is made from acetic acid
Me
O
- labeled precursors
H
O
O
*
*
*
O
*
*
OH
*
H
*
*
*
O
OC
HO
*
*
*
Me
Me H
OH
*
*
H
H
Me Me
CO2H
(—)-kuarene
*
*
*
*
O
O
H
OH
H
Me Me
O
OC
*
*
HO
Me
H
*
*
OH
*
*
*
Me H
Me
H
H
Gibberellic acid made from 4
molecules of mevalactone or 8
molecules of acetic acid
*
*
HO
H
OH
H
H
X
OH
O
OC
HO
Me
H
CO2H
Phyllocladene
CO2H
- lactone carbonyl does not contain 14C label
- a-methyl group from phyllocladene contains 14C label \ phyllocladene is not precursor
to gibberellic acid
Arthur J. Birch
Baran Lab
Hafensteiner
Aromadendrene and Viridiflorol
H
Me H
OH
HO
Me
O
OC
HO
H
Me Me
Me
Me
H
CO2H
Me
Me
Me
Me
(—)-kuarene
- addition of kuarene gave increase in gibberellic acid
Birch, A. J.; Smith, R. H. Tetrahedron, 1959, 7, 241-251
Birch, A. J.; Winter, J. J. Chem. Soc., 1962, 5547
Me
aromadendrene
Citronellal and Cineol
- isotope labeled acetic acid and mevalactone fed into two varieties of Eucalyptus
viridiflorol
- trans cyclopentane ring junction assumed by analogy to aromadendrene from Eucalyptus
nova-anglica, aromadendrene has trans ring junction, alloaromadendrene has
a cis ring junction
O
O
O3
alkali
Me
O
*
*
*
*
OH
*
H
O
*
Me
Me
Me
from Metrosideros scandens
Me
Me
Me
a-apoaromadendrone
Me
Me
apoaromadendrone
trans ring junction known
X
expected isotope labeling
Me
OH
O
Me
*
*
O
*
* Aromadendrene from E. nova-anglica has cis ring
junction and M. scandens produces trans
Me
Me
from Eucalyptus nova-anglica
O
*
*
expected isotope labeling
HO
Me
O
- degredation shows expected amounts of label incorporated into both products
Birch, A. J.; Boulter, D.; Fryer, R. I.; Thomson, P. J.; Willis, J. L. Tetrahedron Lett., 1959, 3,
1-2
O3
D
Me
Me
Me
Me
viridiflorol
Me
Me
Me
a-aromadendrene
Me
Me
a-apoaromadendrone
Arthur J. Birch
Baran Lab
Hafensteiner
Xanthorrhoein
- from resin of Xanthorrhoea Preisii and Xanthorrhoea reflexa
- possible structures containing 1 C-methyl, 1 O-methyl, no carbonyl or hydroxyl groups
C14H14O2
O
HO
Me
O
RO
Me
Me
Me
viridiflorol
H2SO4
Me Pb(OAc)4
ROH
Me
Me
Me
Me
ledene glycol
H2, Pd/C
No Rxn
C14H14O2
KMnO4
No Rxn
- UV indicates napthalene core containing 2 methoxy groups
Me
C14H14O2
acid; dehydrogenation
CrO3
1. KNH2
O
2. H2, Pd/C
3. CrO3
O
OH
O
OH
OH
Me
alkali
Me
O
O
or
O
O
OH
O
MeO
OMe
OMe
alkali
H2SO4
Me
Me
Me
Me
Me
Me
OMe
O
H2SO4
- concluded that ledol, palustrol, viridiflorol, and globulol are the four stereoisomers at
the alcohol and ring junction positions
Birch, A. J.; Grimshaw, J.; Speake, R. N.; Gascoigne, R. M.; Hellyer, R. O. Tetrahedron
Lett., 1959, 3, 15-18
stable cation
stable cation
Me
OMe
O
C14H14O2
H2SO4
no stable cation \
OMe
Birch, A. J.; Salahud-Din, M.; Smith, D. C. C. Tetrahedron Lett., 1964, 25, 1623-1627
Arthur J. Birch
Baran Lab
Hafensteiner
Eremolactone
D
O
- first proposed structure was incorrect
KMnO4
eremolactone
O
D, NaOD
HO2C
CO2H
HO2C
CO2H
incorporation of 1 D
O
O
O
- same investigation with the proposed and x-ray structures of isoeremolactone
O
proposed eremolactone
proposed isoeremolactone
or
- x-ray structure of isoeremolactone solved (Oh, Y.-L.; Maslen, E. N. Tetrahedron Lett.,
1966, 28, 3291)
O
O
O
O
O
1. KMnO4
2. NaOD, D
O
D
- classical approach taken by Birch to revise structure of eremolactone
D
1. KMnO4
2. NaOD, D
D
D
O
O
D
D
D
D
expected, not observed
D
D
D
expected, observed
or
O
Birch, A. J.; Subba Rao, G. S. R. Tetrahedron Lett., 1966, 39, 4749-4751
O
O
O
1. KMnO4
2. NaOD, D
incorporation of 1 D expected
1. KMnO4
2. NaOD, D
incorporation of 2 D expected
Arthur J. Birch
Baran Lab
Sclerotiorin, Citrinin, Rotiorin, Monascin, Rubropuntatin
Ravenelin
O
- biosynthetic studies using both 1-13C and 1, 2-13C acetate in fungi (Helminthosporium)
Cl
OH
O
Me
OH
O
*
*
O
*
*
*
*
OH
*
*
OH
*
*
*
O
OH
O
O
Me - labeling pattern
shows
incorporation of 7
acetate units
OH
O
O
Me
*
*
*
*
*
O
*
*
*
O
*
Me
*
O
O
rotiorin
label from 14C-formate
intact acetate
O
intact acetates, equal
distribution throughout
ravenelin sample
O
*
*
B
OH HO
Me
OH
Me
O
OH
*
*
*
*
*
*
*
*
O
*
O
*
*
O
monascin
O
*
*
O
rubropunctatin
- tracer work on sclerotiorin and citrinin main skeleton demonstrated their polyketide
origin and by analogy, labeling should be similar for the cores of rotiorin, monascin,
rubropuntatin
O
O
OH
A
Me
*
*
Me
*
*
*
O
Me
O
*
citrinin
O
OH
O
*
OH
OH
Me
*
HO2C
*
- 13C–13C coupling used to define intact acetate units.
O
*
*
O
sclerotiorin
OH
*
fungus
*
*
OH
O
O
O
O
Me
*
Hafensteiner
O
Birch, A. J.; Simpson, T. J.; Westerman, P. W. Tetrahedron Lett., 1975, 47, 4173-4177
Arthur J. Birch
Baran Lab
Me
O
O
ONa
O
multicolor
O
*
Penicillium
H
*
*
*
alkali (aq)
O
*
O
*
*
MeNH2
CO2
*
HO
OH
O
O
*
*
*
*
rma = 177
NH3
- CO2
rma = 18.8, calc = 17.2
Me
*
-OH
*
*
O
rma = 0.4, calc = 0
rma = 7.7, calc = 7.1
Me
*
*
*
*
Me
*
*
*
N
*
*
OH
*
*
O
rma = 67.8, calc = 70.8
*
*
*
*
*
*
O
O
rotioramine
rma = 563
O
rma of CO2 = 0.8
- CO2,
aromatization
N
*
*
*
HO
*
*
*
OH
O
rma = 82
calc = 85
*
*
O
*
O
monascin
rma = 566
*
*
*
*
*
Me
-CO2
*
*
*
*
O
KMnO4
*
rma = relative molar abundance
ONa
14C-acetate
Me
*
*
*
O
*
Me
rma = 161
*
NH
*
Me
O
*
O
*
Me
O
HO
*
*
*
*
O
O
rma = 35.6, rma calc = 37.1
calculated based on
incorporation of 2 14C-atoms
rma = 1
*
Kuhn Roth;
Schmidt
degradation
rma = 554
Kuhn Roth
Oxidation
O
multicolor
ONa
14C-acetate
*
O
Me
Penicillium
*
O
*
Me
O
*
*
*
*
O
14C-formate
rma = 109
rma = 111
Hafensteiner
CO2 rma = 30, calc = 28
O3
Kuhn Roth;
Schmidt
degradation
All activity in MeNH2
O
H
rma = 29
calc = 28
Arthur J. Birch
Baran Lab
O
O
O
H
*
*
O
O
*
O
14C-formate
O
HO
NH3,
-CO2 rma = 2
*
*
*
N
*
*
CO2
MeNH2
rma = 57, calc = 59
rma = 2, calc = 0
Birch, A. J.; Fitton, P.; Pride, E.; Ryan, A. J.; Smith, H.; Whalley, W. B. J. Chem. Soc., 1958,
4576-4581
Birch, A. J.; Cassera, A.; Fitton, P.; Holker, J. S. E.; Smith, H.; Thompson, G. A.; Whalley, W.
B. J. Chem. Soc., 1962, 3583-3586
*
*
Kuhn Roth,
Schmidt degradation
*
rma = 267, calc = 268
*
*
*
O
O
*
O
*
O
rubropunctatin
rma = 892
KMnO4
rubropunctatin
rma = 1735
*
*
Me
*
*
*
*
*
O
O
*
Me
O3
*
*
*
*
*
*
*
O
ONa
H
rma = 26, little
bleeding of formate
subunits into acetate
derived core
Hafensteiner
Methymycin
*
O
OH
Me
rma = 1744, no activity in CO2
HO
Me
Me
Me
O
O
O
O
NMe2
Me
O
O
*
ONa
14C-acetate
O
*
*
*
*
O
*
*
*
*
O
*
Me
*
O
rubropunctatin
rma = 892
OH
- acetyl Co-A as base unit for chains with addition of malonyl Co-A, methyl groups coming
from methionine or choline
- C-methylation occurs at methylene of malonate
- proposed biosynthesis of macrolide antibiotics involves propionic acid subunits instead of
acetate, Woodward, R. B. Angew. Chem. Int. Ed., 1956, 68, 13
O
Me
S
HO2C
*
NH2
Streptomyces
venezuelae
HO
Me
Me
O
O
- N methylation occurs and C methylation does not
Me
O
O
Me
N
OH
Me
Me
Arthur J. Birch
Baran Lab
O
HO
O
O
Me
Me
Me
O
NMe2
Me
N
H
O
OH
O Me
H
N
HO
N
H
N
Me
H
O
brevianamide D
(double bond isomer of brevianamide c)
H
N
N
H
- feeding with labeled acetate
showed no incorporation
Me
N
Me
brevianamide E
brevianamide C
Me
5 propionates, 1 acetate
O
N
O
O
O3;
H2O2, -OH,
O
HO
Me
Me
OO
O
O
O
H
O
Me
Me
Hafensteiner
O
H
H
N
O
brevianamide F
HO2C
Me
- biosynthetic work
Me
-3/5 rma of parent antibiotic from
propionic acid feeding (1-14Cpropionate)
- feeding with 2-14C-propionate
gave same result
CO2H
*
Me
NH2
Birch, A. J.; Djerassi, C.; Dutcher, J. D.; Majer, J.; Perlman, D.; Pride, E.; Rickards, R. W.;
Thomson, P. J. J. Chem. Soc., 1964, 5274-5278
*
CO2H
OH
O
CO2H
*
OH
N
H
*
NH
O
H2N
S
O
Brevianamides A-F
- isolated from Penicillium brevi-compactum in 0.1 to 10 mg / L of culture
- structure elucidation as well as biosynthetic studies carried out
O
N
H
Me
Me H O
H
N
brevianamide A
O
N
H
N
O
N
HN
O
Me
H
Me
O
brevianamide B
incorporated
incorporated
incorporated
incorporated
not incorporated
Birch, A. J.; Wright, J. J. J. Chem. Soc., 1969, 644-645
Birch, A. J.; Wright, J. J. Tetrahedron, 1970, 26, 2329-2344
Birch, A. J.; Russell, R. A. Tetrahedron, 1972, 28, 2999-3008
Baldas, J.; Birch, A. J.; Russell, R. A. J. Chem Soc., Perkin Trans. I, 1973, 50-52
Arthur J. Birch
Baran Lab
Hafensteiner
O
Organoiron Chemistry
NH2
Fe(CO)3
O
(OC)3Fe
Na
Fe(CO)5
NH3
UV, 50 hrs.
NH2
Fe(CO)3
H
N
AcOH
95%
O
(OC)3Fe
Ph3C+•BF4-
(OC)3Fe
BF4-
(OC)3Fe
:Nuc
HONH2•HCl
Nuc
BF4-
NH2
O2N
no reaction under
AcOH conditions
slow reaction
THF, 0 °C;
NH4Cl (aq)
Nuc
OEt
NH2
R
NucM
65%
NH2
(OC)3Fe
R
NucM
H
N
AcOH
Fe(CO)3
- Nuc = RNH2, -OR, phosphites, sulfites, enamines, ketones
- Grignard and alkylithium addition gives reductive coupling or decomposition
- organozinc and organocadmium reagents work well
(OC)3Fe
R
H
N
90%
- Fe(CO)3 used to complex 1, 3 dienes that could be made the cation salt by hydride
abstraction
AcOH, 75 °C
Yeild %
DCM
H
N
70%
H
H
H
Cd
2
Cd
2
Ph2Cd
Fe(CO)3
82
40
Et2NH
83
Zn
2
50
OMe
Zn
2
35
Ph2Cd
AcOH, 75 °C
NEt2
50%
Fe(CO)3
O
Me
H
O
Ph2NH
AcOH, 75 °C
Fe(CO)3
67
Birch, A. J.; Jenkins, I. D. Tetrahedron Lett., 1975, 2, 119-122
No Reaction
Arthur J. Birch
Baran Lab
R3
R2
OTMS
Fe(CO)3
70 - 80%
PF6-
R1
R1
H
H
R2
MeCN
R3
Fe(CO)3
O
H
MeO
Fe(CO)3
PF6-
H
Me
H
Fe(CO)3
PF6-
H
Fe(CO)3
MeO2C
PF6-
Kelly, L. F.; Narula, A. S.; Birch, A. J. Tetrahedron Lett., 1979, 42, 4107-4110
Iron and Chemical Equivalents
O
OMe
OMe
Fe(CO)3 X
OMe
Fe(CO)3
OMe
X-
O
Fe(CO)3
Nuc
75 - 95%
Nuc
Nuc =
Li
[O]
Jones Reagent
or
PCC
OTMS
O
Nuc
TMS
O
OTMS
OTMS
Kelly, L. F.; Dahler, P.; Narula, A. S.; Birch, A. J. Tetrahedron Lett., 1981, 22, 1433-1436
Hafensteiner