N. Z. Burns

HN

HNNH

N

corrole

N

HNN

N

tetrahydrocorphin:coenzyme F430

N

HNN

NH

chlorin:chlorophyll

N

HNN

NH

porphyrin:heme

Some Uroporphinoids:

Corrin Chemistry: from B12 to the Origin of Life

1

N

HNN

N

1

2

34

5

9

19

15

C

BA

D

Corrin:

Structure: Crowfoot-Hodgkin 1955(1964 Chemistry Nobel Prize)

Nature, 1955, 176, 325.

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 B12can be dated back 3.79 x 109 years.C19H22N4

Vitamin B12 x-ray structure:

One of the "finest contributions of Britishscience to the chemistry of low-molecular-weight natural products"-A. Eschenmoser

N. Z. Burns

N

N

N

N

Me

Me

H2NOC

H2NOC

H2NOC MeMe

CONH2Me

H

HH

H

MeMe

H

CONH2Co

R

Me

NH

O

OP

O

Me

O

O O

OH

HOH

N

NMe

Me

H

HH

R = CN vitamin B12

cobyric acid

Bernhauer

1960

CONH2

N

N

N

N

Me

Me

H2NOC

H2NOC

H2NOCMeMe

CONH2Me

H

H

H

MeMe

H

CN

Me

OHO

CN

CONH2

H

CONH2Co

C

BA

Dvitamin B12

NH

S

MeO2C

H

MeO2CNC

Me

Me

HNS

CO2Me

H

Me

Me

O

O

HN

O

CO2Me

HMe

MeNBr

HMeO2C

CN

Me

A B

CD

O OMe

Me

O O

HO2C

H

O OMe

Me

O O

HO2C

H

Eschenmoser's cobyric acid synthesis:

Science, 1977, 196, 1410; Classics in Total Synthesis2

Corrin Chemistry

"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

OHO

HON

N

N

N

NH2R =

coenzyme B12

Me

OMe

CO2H

+

N. Z. Burns

HNH

O

O

Me

Me

CO2MeS

SN

HN

O

OMe

Me

O Me

Me

H

CO2Me

H

CO2Me

N

HN

Me

Me

H

H

O

O

MeMe

CO2Me

CO2Me

O

benzoyl peroxide,

HCl, CH2Cl2+

(EtO)3P, xylene

125 °C(85% overall)

HN

OH Me

Me

CO2Me

B

B

C

C

N

HNMeMe

H

H

S

O

Me

Me

CO2Me

CO2Me

S

P2S5, 4-methylpyridine,xylene, 130 °C (84%)

1. t-BuOK, t-BuOH, THF, 25 °C; D

2. (NC(CH2)2)3P, TFA, sulfolane, 60 °C (64% overall)

N

HN

Me

Me

H

H

S

O

MeMe

CO2Me

CO2Me

N

Me

CN

MeO2C

H

N

HN

Me

Me

H

H

CO2Me

CO2Me

N

Me

CN

MeO2C H

CONMe2

Me

I

1. MeNH2, MeOH, 25 ˚C

2. N-iodosuccinimide CH2Cl2, 0 ˚C

NBr

HMeO2C

CN

Me

DD

Corrin Chemistry

3

N. Z. Burns

N

S

N

NN

MeO2C

Me

H

NCMe

MeO2C

HMe

CN

CONMe2Me

CO2MeH

Me

Me

CO2MeH

MeO2C

1. A, NaHMDS, PhH, 25 °C

2. Cd(ClO4)2, MeOH, 25 °C

Cd(Cl)

NH

S

MeO2C

H

MeO2CNC

Me

Me

A

1. Ph3P, TFA, PhH, 80 °C 2. Cd(ClO4)2, i-Pr2NEt, PhH, MeOH, 25 °C then NaCl workup (46% overall)3. DBU, sulfolane, 60 °C

N

N

N

N

MeO2C

MeO2C

MeO2CMe

Me

CONMe2Me

H

H

Me

H

CN

Me

CO2Me

H

CO2MeCd(Cl)

N

N

N

N

MeO2C

MeO2C

MeO2CMe

Me

CONMe2Me

H

H

H

MeMe

H

CN

Me

CN

CO2Me

H

CN

CO2Me

Co

(46% overall)

1. hν (visible), 60 °C2. CoCl2, 58 °C3. KCN, air, H2O, CH2Cl2, 0 °C

N N

NN

HH

H

H

N N

NN

HN N

NN

Hhν

A

Corrin Chemistry

4

N. Z. Burns

1. I2, AcOH2. ClCH2OCH2Ph sulpholane, 75 °C

3. PhSH4. Raney Ni; CH2N25. conc. H2SO4

N

N

N

N

MeO2C

MeO2C

MeO2CMe

Me

Me

H

H

MeMe

H

CN

Me

CN

CO2Me

H

CONH2

Me

Me

H

CO2Me

Co CO2Me

N

N

N

N

MeO2C

MeO2C

MeO2CMe

Me

Me

H

H

MeMe

H

CN

Me

CN

CO2Me

H

CO2H

CO2Me

Me

Me

HCO2Me

Co

NH3 (l),HO(CH2)2OH,

NH4Cl, 75 °C(64%)

cobyric acid

ClN

Cy

OAgBF4

then H3O+;Me2NH (57%)

A solution to meso methyl introduction:Jacobi, JOC, 1999, 64, 1778

HO O

MeMe

Me

N

ClMe

Me

MeNC

1. Pd0, R4NCl, Hün.

2. NH3, (63%)+

CCl4, PPh3 (72%)

H2N O

MeMe

NHO

N

N

Me

Me

NC

MeMe

MeMeMe

MeCl

N

N

Me

Me

NC

MeMe

MeMe

O

HN

N

Me

Me

NC

MeMe

MeMe

1. Pd0, CuI, Et3N (69%)

2. H+ (83%)

For a particularly elegant approach to Vitamin B12 by R. V. Stevens see "Isoxazoles and Isothiazoles in Synthesis"(Mitsos, 2004)

Corrin Chemistry

5

N. Z. Burns

N

N

N

N

Me

Me

H2NOC

H2NOC

H2NOC MeMe

CONH2Me

H

HH

H

MeMe

H

CONH2Co

CN

Me

NH

O

OP

O

Me

O

O O

OH

HOH

N

NMe

Me

H

HH

CONH2

Synthetic Analysis of Specific Structural Elements of Vitamin B12:

Towards a Chemical Rationalization of Structure

• specific arrangement of double bonds in corrin chromophore

• contracted dimension compared with corphin ring

• specific attachment of nucleotide ligand to ring D

• arrangement of substituents on the ligand periphery

"Can experiments aimed at a deeper understanding of the molecular structure of cofactors tell us something about that early phase of biological evolution?"

structural preformation

biotic prebiotic

selection emergence ofbiosynthetic pathway

Darwinian paradigm of molecular evolution: structure a result of selection

mutations

reproduction feedback

"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 fulfilledfor a multistep biosynthesis of a complex natural product to emerge."

"[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."

Eschenmoser, ACIEE, 1988, 27, 5.

Corrin Chemistry

Synthetic Analysis of Specific Structural Elements

6

"Can work done on the chemical synthesis of vitamin B12 be extended to make acontribution 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 smokeon the battlefield of total synthesis had disappeared."

N. Z. Burns Corrin Chemistry

N

HNN

N

corphin: corrin-like chromophore

?

HNNHR

R R

RHNN

R

RR

R

NNR

R R

RNN

R

RR

R

MM

Metal ion

Specific arrangement of double bonds in corrin chromophore

N

NN

NHN

HNNH

NHEt

Et Et

Et

Et

EtEt

Et

Et

Et

Et

Et Et

Et

Et

Et

MgN

N NMgI

xylene, 85 ˚C~ quant.

N

NN

NEt

Et Et

Et

Et

EtEt

Et

XMg

HN

HNNH

NH

porphyrinogen

MgBr2moist PhH

corrinoid chromophore

H

N

NN

NEt

Et Et

Et

Et

EtEt

Et

XMg

Me

CH3I/PhH∆ (~90%)

ACIEE, 1983, 22, 630 & 632

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?

Pyr•HOAc~ quant.

7

• In complexed form, thermodynamic equilibrium of tautomers favors the corrinoid system

• Analogous reactivity seen with Zn(II) and Ni(II) complexes

N. Z. Burns

Contracted dimension of the corrin ring

N

NN

NCoR

Et

Et Et

Et

Et

Et

Et

Et

N

NN

NNi

Et

Et Et

Et

Et

Et

Et

Et

H

N

NN

NNi

Me

Me Me

Me

Me

Me

Me

Me

Me

Ni–N = 1.863 Å

Ni–N = 1.912 Å

Co–N = 1.974 ÅR = pyridine

Unfavorable "ligand ruffling" observed in hydroporphinoid metalcomplexes that is not seen in the corresponding corrinoids:

Helv. Chim. Acta. 1985, 68, 1312.

N

NN

N

MeMe

MeMe

HO

Me MeMe

Me

Me Me

CoR

R N

NN

N

MeMe

Me

Me MeMe

Me

Me Me

CoR

RO

Me

260 ˚C, 5 min

≤ 40%

R = CN

Proc. Natl. Acad. Sci. 1981, 78, 16.

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:

Specific attachment of nucleoside ligand to ring D

N

N

N

N

Me

Me

MeO

MeO

MeO

MeMe

OMeMe

H

H

H

MeMe

H

O

O

O

OMe

O

O

R

Me

OMeO

R

H

OMe

O

Co

8

R = CN

9 N NH3/MeOH

RT, 5 h

4% e5% d9% f20% b17% mix38% SM

a

b c

d

ef

g

Is the f-ester inherently more reactive?

Corrin Chemistry

N. Z. Burns

N

N

N

N

Me

Me

NCH2CO

NCH2CO

NCH2CO

MeMe

OCH2CNMe

H

H

H

MeMe

H

O

O

O

OCH2CN

O

O

R

Me

OCH2CNO

R'

H

OCH2CN

O

Co

NH3

OP

O

Me

O

O O

OH

HOH

N

NMe

Me

H

HH

R,R' = CN, OAc (mix)

1. 2,4-pentanediol/THF 20 ˚C, 185 h2. NH3/NH4Cl, 20 ˚C, 20 h (50 % conv)

vitamin B12 + cobyramide (~ 1:1)

+

Arrangement of substituents on the ligand periphery

• 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

HN

HNNH

NH

HO2C

HO2CCO2H

CO2H

CO2H

CO2HHO2C

HO2C

uroporphyrinogen III

9

HN

HO2C

CO2H

H2N

porphobilinogenPBG

type I type III type IVtype II

Uroporphyrinogen substitution patterns:

Corrin Chemistry

• The kinetic product is a type I uro'gen, but under thermodynamic conditions the type III predominates

• The enzymatic biosynthesis of uro'gen III is "chemomimetic," i.e. a non-enzymatic synthesis takes place with great ease

N. Z. Burns

10

NH

HN

HNNH

NH

NC

NCCN

CN

CN

CNNC

NC

CNCN N N

N

CN

NC

CN

14 wt. eq. K10CH3CN, 180 ˚C

0.5 h (80%)

I:II:III:IV = 1:1:4:2

Helv. Chim. Acta 1987, 70, 1115.

Corrin Chemistry

The distribution is the same even at concentrations as low as 1 mg per 5 L!

The arrangement of side chains around B12 corresponds to the thermodynamically favored arrangement

Some glimpses of B12 biosynthesis:

H2N

CO2H

O PBGHN

HNNH

NH

HO2C

HO2CCO2H

CO2H

CO2H

CO2HCO2H

HO2C

HO uro'gen IIIHN

NNH

NH

HO2CCO2H

CO2H

CO2H

CO2HHO2C

HO2C

Me

MeMe

precorrin 3xO

O

HO

N

NNH

N

HO2CCO2H

CO2H

CO2H

CO2HHO2C

HO2C

MeMe

Me

O

HO2C

Me

Me

precorrin 5

JOC, 2003, 68, 2529.

N

NN

N

HO2C

CO2H

Me

CO2HHO2C

HO2C

MeMe

Me

HO2C

Me

Me

Me CO2H

H

Me

precorrin 8x

vitamin B12