Corrin Chemistry: from B12 to the Origin of Life
N. Z. Burns
Vitamin B12 x-ray structure:
Corrin:
3
5
4
2
A
1
19
D
N
HN
N
N
B
9
C
15
C19H22N4
Name "corrin" proposed by those who
established its structure because it is
the core of the vitamin B12 molecules.
The most ancient of the uroporphinoids:
the primitive anaerobes which make B12
can be dated back 3.79 x 109 years.
Some Uroporphinoids:
NH
HN
N
HN
N
HN
N
N
corrole
tetrahydrocorphin:
coenzyme F430
Structure: Crowfoot-Hodgkin 1955
(1964 Chemistry Nobel Prize)
N
NH
HN
N
chlorin:
chlorophyll
N
NH
HN
One of the "finest contributions of British
science to the chemistry of low-molecularweight natural products"
-A. Eschenmoser
N
porphyrin:
heme
1
Nature, 1955, 176, 325.
Corrin Chemistry
N. Z. Burns
H2NOC
Me Me
H
H2NOC
H2NOC
Me
Me
H
N
CONH2
N
N
Me
Me
N
H
NH
HO
O H
O
P
O
O
H
N
CONH2
Co
HO
R=
O
N
Bernhauer
N
vitamin B12
1960
NH2
CONH2
Me
N
H2NOC
Me
Me
H
H2NOC
H
Me
A
H
CN
N
Me
CONH2
H
B
N
CONH2
Co
D
N
CN
N
O
Me
C
Me
H
Me
CONH2
OH
cobyric acid
coenzyme B12
MeO2C
O
Me
N
Me
H
HO
H
Me
O
N
H
R
Me
Me
H2NOC
Eschenmoser's cobyric
acid synthesis:
R = CN vitamin B12
H
Me
O
A
H
MeO2C
NC
OH
Me
O
S
Me
NH
B
Me
H
HN
HO2C
CO2Me
S
Me
H
O
Me
CO2H
O
Me
+
O
O
O
Me
Me
O
O
O
O
H
Me
MeO2C
"Of all that architecture and organic synthesis have in common, one thing is
this: for the works of both, explicit goals are usually set, but after the works
are done, their raison d'être often lies within themselves."
– A. Eschenmoser, Robert Robinson Lecture 1976
H
D
HO2C
N
Br
C
O
H
Me
CN
2
HN
Me
Me
CO2Me
Science, 1977, 196, 1410; Classics in Total Synthesis
Corrin Chemistry
N. Z. Burns
O
O
O
O
HN
Me
H
B
+
Me
C
O
Me
H
CO2Me
S
H
CO2Me
O
B
N
Me
HN
O
Me
Me
benzoyl peroxide,
Me
S
C
O
H
CO2Me
Me
Me
125 °C
(85% overall)
CO2Me
N
(EtO)3P, xylene
HN
HCl, CH2Cl2
Me
H
HN
Me
Me
O
H
CO2Me
CO2Me
MeO2C H
D
N
Br
D
P2S5, 4-methylpyridine,
xylene, 130 °C (84%)
Me
CN
O
I
S
Me
H CO2Me
N
HN
Me
Me
Me
H
CN
CO2Me
S
Me
H
Me
1. MeNH2,
MeOH, 25 ˚C
N
MeO2C H
O
CONMe2
N
2. N-iodosuccinimide
CH2Cl2, 0 ˚C
MeO2C
H
CO2Me
N
HN
Me
Me
Me
H
CN
3
CO2Me
1. t-BuOK, t-BuOH,
THF, 25 °C; D
2. (NC(CH2)2)3P,
TFA, sulfolane,
60 °C
(64% overall)
Me
Me
H
N
CO2Me
HN
Me
Me
S
H
CO2Me
Corrin Chemistry
N. Z. Burns
MeO2C
H
Me
CONMe2
H
1. A, NaHMDS,
PhH, 25 °C
MeO2C
Me
Me
2. Cd(ClO4)2,
MeOH, 25 °C
MeO2C
MeO2C
S
N
N
PhH, 80 °C
Cd(Cl)
NC
N
N
H
Me
2. Cd(ClO4)2, i-Pr2NEt,
PhH, MeOH, 25 °C
then NaCl workup
(46% overall)
3. DBU, sulfolane, 60 °C
Me
Me
H
MeO2C
Me
N
N
Cd(Cl)
N
N
MeO2C
H
Me
Me
CO2Me
CN
H
A
MeO2C
S
1. hν (visible), 60 °C
2. CoCl2, 58 °C
3. KCN, air, H2O,
CH2Cl2, 0 °C
(46% overall)
A
NH
CO2Me
Me
H
MeO2C
Me
CONMe2
H
CO2Me
CN
NC
Me
H
CO2Me 1. Ph3P, TFA,
Me
MeO2C
Me
H
CONMe2
H
N
H
N
H H
N
N
N
hν
N
H
N
MeO2C
N
N
N
H
H
N
N
Me
Me
H
MeO2C
H
N
CN
N
Co
N
CN
N
Me
Me
Me
H
CN
4
CO2Me
CO2Me
Corrin Chemistry
N. Z. Burns
A solution to meso methyl introduction:
Jacobi, JOC, 1999, 64, 1778
MeO2C
1. I2, AcOH
2. ClCH2OCH2Ph
sulpholane, 75 °C
3. PhSH
4. Raney Ni; CH2N2
5. conc. H2SO4
H
Me
Me
CO2Me
H
MeO2C
MeO2C
Me
Me
H
N
CN
H
CO2Me
N
CN
CONH2
Cl
N
Cy
O
cobyric
acid
NH4Cl, 75 °C
(64%)
MeO2C
O
Me
N
CN
CO2Me
O
Me
CN
NH
Me
CO2Me
N
Me
N
Pd0,
O
CuI, Et3N
(69%)
Me
Me
Me
NC
N
Me
Me
Me
H2N
1.
Me
N
Co
Me
Me
Me Me
N
H
N
H
Me
N
NC
H
HN
CCl4, PPh3 (72%)
MeO2C
MeO2C
NH3 (l),
Me
HO(CH2)2OH,
Me
H
Me
2. NH3, (63%)
then H3O+;
Me2NH (57%)
Me
Me Me
Me
N
1. Pd0, R4NCl, Hün.
Cl
NC
Me
CO2Me
Me
NC
O
+
Me
Me
H
Me
HO
Me
Me
Me
Me
AgBF4
Me
Co
N
Me Me
N
Me
2. H+ (83%)
N
Cl
Me
Me
Me
Me
CO2H
H
For a particularly elegant approach to Vitamin B12 by R. V.
Stevens see "Isoxazoles and Isothiazoles in Synthesis"
(Mitsos, 2004)
CO2Me
5
Corrin Chemistry
N. Z. Burns
Synthetic Analysis of Specific Structural Elements
Synthetic Analysis of Specific Structural Elements of
Vitamin B12:
Towards a Chemical Rationalization of Structure
H2NOC
Me Me
H
"Can work done on the chemical synthesis of vitamin B12 be extended to make a
contribution to the problem of vitamin B12 biosynthesis? This question began to
motivate and direct our activity in the field of corrin chemistry soon after the smoke
on the battlefield of total synthesis had disappeared."
H2NOC
H2NOC
"[An] objective that can and should be studied with the tools of natural product
synthesis [is a] systematic delimitation of the boundary separating the reactivity of
biomolecules from structural changes."
Me
Me
H
N
CONH2
Me
Me
N
H
H
Me
O
CONH2
Me
N
NH
HO
Me
H
CN
N
Co
N
Me
"Can experiments aimed at a deeper understanding of the molecular structure
of cofactors tell us something about that early phase of biological evolution?"
CONH2
O H
O P
O
O
H
Me
N
H
O
H
OH
Darwinian paradigm of molecular evolution: structure a result of selection
• specific arrangement of double bonds in corrin chromophore
• contracted dimension compared with corphin ring
structural preformation
biotic
prebiotic
selection
• specific attachment of nucleotide ligand to ring D
emergence of
biosynthetic pathway
• arrangement of substituents on the ligand periphery
mutations
"Chemists engaged in natural product synthesis are probably in the best position to
grasp the vast number as well as the nature of lucky prerequisites that must be fulfilled
for a multistep biosynthesis of a complex natural product to emerge."
reproduction feedback
Eschenmoser, ACIEE, 1988, 27, 5.
6
Corrin Chemistry
N. Z. Burns
Specific arrangement of double bonds in corrin chromophore
Et
What is the position of the tautomeric equilibrium between the tetrapyrrolic
arrangement of double bonds in a porphyrinogen and the arrangement in its
corphinoid counterpart?
Et
Et
Et
NH
NH
NH
HN
NH
HN
?
N
HN
N
N
HN
porphyrinogen
HN
Et
R
R
NH
N
HN
N
R
R
R
N
M
N
Et
Et
(~90%)
MgBr2
moist PhH
Et
Et
Et
Et
N
N
N
XMg
N
N
Et
Me
N
Et
N
Et
Et
Et
Et
H
Et
corrinoid chromophore
Metal ion
N
N
Mg
XMg
Et
R
Et
N
Et
Et
N
Et
R
Et
Et
Et
R
HN
Et
Pyr•HOAc
~ quant.
R
R
R
xylene, 85 ˚C
~ quant.
CH3I/PhH
∆
corphin:
corrin-like chromophore
R
N
Et
Et
R
N
N
Et
Et
Et
MgI
R
R
R
N
• In complexed form, thermodynamic equilibrium of tautomers favors
the corrinoid system
N
M
• Analogous reactivity seen with Zn(II) and Ni(II) complexes
7
ACIEE, 1983, 22, 630 & 632
Corrin Chemistry
N. Z. Burns
Contracted dimension of the corrin ring
Since the coordination hole of corrinoid ligands is better suited to
the spatial demands of the metal(II) ion a corphinoid to corrinoid
rearrangement should be possible:
Unfavorable "ligand ruffling" observed in hydroporphinoid metal
complexes that is not seen in the corresponding corrinoids:
Me
Me
Me
Me
Me
Me
Me
Me
HO
Me
N
Me
N
Ni
N
N
Me
N R
N
260 ˚C, 5 min
Co
Me
Me
Et
Et
Et
Me
N R
Me
N
Co
O
N R N
Me
Me
Me
Me
Me
Me
Me
Me
≤ 40%
N R N
Me
Ni–N = 1.863 Å
Me
Me
Me
R = CN
Me
Me
Proc. Natl. Acad. Sci. 1981, 78, 16.
Et
N
H
N
Specific attachment of nucleoside ligand to ring D
Ni
N
Is the f-ester inherently more reactive?
N
Et
Et
Ni–N = 1.912 Å
Et
O
MeO
Et
b
H
Et
MeO
Et
Et
Et
Co
N
g
N
Et
Et
Et
Et
N
H
d
N
N
O H
Me
R
N
Me
Me
R = CN
O
8
O
OMe
Co
Me H
Co–N = 1.974 Å
R = pyridine
Helv. Chim. Acta. 1985, 68, 1312.
R
OMe
c
Me
a
O Me
Me
H
MeO
N R N
Me
f
OMe
O
e
OMe
O
9 N NH3/MeOH
RT, 5 h
4% e
5% d
9% f
20% b
17% mix
38% SM
Corrin Chemistry
N. Z. Burns
Arrangement of substituents on the ligand periphery
NCH2CO
O
H
Me
N
R
H
N
R'
O
N
OCH2CN
N
Me
O
Me
Me H
O
R,R' = CN, OAc (mix)
OCH2CN
CO2H
HO2C
Co
O H
Me
CO2H
Me
NCH2CO
O Me
Me
H
NCH2CO
HO2C
OCH2CN
Me
O
OCH2CN
HN
NH
HN
H2N
H
N
Me
NH3
+
NH
HO
O H
O P
O
O
H
N
HO2C
Me
N
HO2C
H
CO2H
O
HO2C
H
OH
CO2H
porphobilinogen
PBG
CO2H
uroporphyrinogen III
Uroporphyrinogen substitution patterns:
1. 2,4-pentanediol/THF
20 ˚C, 185 h
2. NH3/NH4Cl, 20 ˚C, 20 h
(50 % conv)
vitamin B12 + cobyramide (~ 1:1)
type I
type II
type III
type IV
• The kinetic product is a type I uro'gen, but under thermodynamic conditions the
type III predominates
• The nucleotide loop to the propionic acid side chain of ring D represents,
of all possible regioisomers, the thermodynamically most stable
• The present day biosynthesis makes no use of this
• The enzymatic biosynthesis of uro'gen III is "chemomimetic," i.e. a non-enzymatic
synthesis takes place with great ease
9
N. Z. Burns
Corrin Chemistry
HO2C
NC
NC
CN
N
CN
CN
N
H
HO2C Me
CN
NC
N
NH
Me
HN
CN
14 wt. eq. K10
CH3CN, 180 ˚C
0.5 h (80%)
H
NH
CO2H
CO2H
Me Me
CN
N
HN
N
N
N
N
vitamin B12
Me
Me
NC
HO2C
CN
Me
HO2C
CO2H
HO2C
CN
NC
Me
precorrin 8x
I:II:III:IV = 1:1:4:2
O
The distribution is the same even at concentrations as low as 1 mg per 5 L!
HO2C
HO2C
N
N
Me
CO2H
HO2C
NH
Me
O
HN
HO
uro'gen III
NH
Me
HN
O
Me
HO
NH
CO2H
CO2H
N
precorrin 3x
NH
HN
H2N
HO2C
CO2H
HO2C
CO2H
CO2H
CO2H
Helv. Chim. Acta 1987, 70, 1115.
HO2C
10
CO2H
JOC, 2003, 68, 2529.
CO2H
CO2H
Me
CO2H
CO2H
precorrin 5
HO2C
CO2H
PBG
N
HO2C
Some glimpses of B12 biosynthesis:
O
NH
Me
The arrangement of side chains around B12 corresponds to the thermodynamically
favored arrangement
CO2H
Me
HO2C Me