N. Z. Burns Chemistry: from B12 to the Origin of Life

Corrin: x-ray structure:

3 5 4 2 Name "corrin" proposed by those who A B established its structure because it is 1 N HN 9 the core of the vitamin B12 molecules.

19 N N D C The most ancient of the uroporphinoids: 15 the primitive anaerobes which make B12 9 C19H22N4 can be dated back 3.79 x 10 years.

Some Uroporphinoids:

NH HN N HN

N HN N N

tetrahydrocorphin: coenzyme F430

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

One of the "finest contributions of British NH N NH N science to the chemistry of low-molecular- weight natural products" -A. Eschenmoser

: :

1 Nature, 1955, 176, 325. N. Z. Burns Corrin Chemistry

H2NOC Eschenmoser's cobyric Me acid synthesis: H Me CONH2 H2NOC H Me Me H CONH2 H2NOC A CN B Me N N N N Me H Co CONH2 H NOC R H 2 Me N N Bernhauer N N N Me N H2NOC CN Me Co CONH2 vitamin B12 D C H HO H NH 1960 Me N N Me 2 Me H2NOC R = O H H Me Me HO H CONH2 Me Me CONH2 O OH O Me coenzyme B12 cobyric acid N MeO C NH 2 O Me HO N R = CN vitamin B H Me CO2Me H 12 Me O Me O H S O P O A Me B O NH HN H O H H MeO C 2 HO2C S OH NC Me Me H O O Me CO2H O O Me O + Me Me O O O O H Me HO C H N 2 HN MeO2C C Me D Br "Of all that architecture and have in common, one thing is O Me this: for the works of both, explicit goals are usually set, but after the works H are done, their raison d'être often lies within themselves." Me – A. Eschenmoser, Robert Robinson Lecture 1976 CN CO2Me

2 Science, 1977, 196, 1410; Classics in Total Synthesis N. Z. Burns Corrin Chemistry

O O Me H CO2Me O O Me O B H CO2Me Me N Me HN S N O Me C Me benzoyl peroxide, (EtO)3P, xylene H + O Me B Me HN HN H HCl, CH Cl 125 °C HN Me 2 2 O C Me CO Me 2 (85% overall) Me H O S CO2Me Me H

CO2Me CO2Me

MeO C H N 2 D Br D P2S5, 4-methylpyridine, xylene, 130 °C (84%) Me

CN O O I CONMe2 Me S Me S Me H CO2Me H H 1. MeNH , Me 1. t-BuOK, t-BuOH, Me N 2 N N MeOH, 25 ˚C THF, 25 °C; D CO2Me CO2Me MeO2C H H N HN Me N HN Me HN Me 2. N-iodosuccinimide 2. (NC(CH2)2)3P, Me CH2Cl2, 0 ˚C Me TFA, sulfolane, Me MeO2C S Me H Me H 60 °C H (64% overall) CN CO2Me CN CO2Me CO2Me

3 N. Z. Burns Corrin Chemistry

MeO2C Me CONMe2 MeO2C H S H Me CONMe 1. A, NaHMDS, H 1. Ph P, TFA, 2 MeO C CO2Me 3 PhH, 25 °C 2 N N PhH, 80 °C H Me MeO C Me Cd(Cl) 2 N N NC Me 2. Cd(ClO4)2, 2. Cd(ClO4)2, i-Pr2NEt, Cd(Cl) CO Me N N Me 2 MeOH, 25 °C MeO C PhH, MeOH, 25 °C 2 N N Me H Me then NaCl workup MeO2C H Me Me (46% overall) H 3. DBU, sulfolane, 60 °C Me H CN CO2Me MeO2C CN CO2Me

H Me S 1. hν (visible), 60 °C A NH A 2. CoCl2, 58 °C MeO2C 3. KCN, air, H2O, NC Me CH2Cl2, 0 °C (46% overall)

MeO2C Me H CONMe2

H CO2Me MeO C CN N N N 2 N N N N N Me H hν Me H Co H H N H N N N N N N N Me H MeO2C CN H H Me Me H

CN CO2Me

4 N. Z. Burns Corrin Chemistry

MeO2C A solution to meso methyl introduction: Me Jacobi, JOC, 1999, 64, 1778 H Me CO2Me 1. I2, AcOH H Me 2. ClCH2OCH2Ph Me MeO2C CN Me Me sulpholane, 75 °C Me N N Me Me Co CO Me H 2 O NC 3. PhSH HO 0 N N N Me Me 1. Pd , R4NCl, Hün. 4. Raney Ni; CH N MeO2C CN 2 2 H + Me 5. conc. H2SO4 Me Me Me Cl 2. NH3, (63%) HN H Me Me Me N O Me CONH CO Me NC 2 2 Me

Cl Cy + CCl4, PPh3 (72%) N then H3O ; Me2NH (57%) Me AgBF4 O Me Me Me Me NC O Me MeO2C Me N 1. H2N Me Me Me Pd0, CuI, Et N NC H CO2Me O Me 3 (69%) N H NH N NH (l), MeO2C CN Me Me 3 Me N N + HO(CH ) OH, Me 2. H (83%) N 2 2 Me Co CO Me Me Me cobyric H 2 Me acid N N Me Cl Me NH4Cl, 75 °C MeO2C CN (64%) H Me Me H Me For a particularly elegant approach to Vitamin B12 by R. V. CO Me CO2H 2 Stevens see "Isoxazoles and Isothiazoles in Synthesis" (Mitsos, 2004)

5 N. Z. Burns Corrin Chemistry

Synthetic Analysis of Specific Structural Elements of Synthetic Analysis of Specific Structural Elements Vitamin B12:

Towards a Chemical Rationalization of Structure H2NOC Me H Me CONH2

"Can work done on the chemical synthesis of vitamin B12 be extended to make a H contribution to the problem of vitamin B12 ? This question began to H2NOC CN motivate and direct our activity in the field of corrin chemistry soon after the smoke Me N N on the battlefield of total synthesis had disappeared." Me Co CONH2 H N N Me H2NOC H Me "[An] objective that can and should be studied with the tools of natural product H synthesis [is a] systematic delimitation of the boundary separating the reactivity of Me Me CONH2 biomolecules from structural changes." O Me N NH Me HO N "Can experiments aimed at a deeper understanding of the molecular structure H of cofactors tell us something about that early phase of biological evolution?" Me O H O P O O O H H OH

Darwinian paradigm of molecular evolution: structure a result of selection • specific arrangement of double bonds in corrin

• contracted dimension compared with corphin ring

• specific attachment of nucleotide to ring D structural preformation selection emergence of biosynthetic pathway • arrangement of substituents on the ligand periphery

mutations biotic prebiotic "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 reproduction feedback for a multistep biosynthesis of a complex natural product to emerge."

Eschenmoser, ACIEE, 1988, 27, 5. 6 N. Z. Burns Corrin Chemistry

Specific arrangement of double bonds in corrin chromophore

Et Et Et Et What is the position of the tautomeric equilibrium between the tetrapyrrolic MgI arrangement of double bonds in a and the arrangement in its N N corphinoid counterpart? Et Et Et Et NH HN N N N Mg NH HN xylene, 85 ˚C N N Et Et ~ quant. Et Et NH HN ? N HN Et Et Et Et NH HN N N CH3I/PhH ∆ (~90%) MgBr2 moist PhH porphyrinogen corphin: Pyr•HOAc corrin-like chromophore ~ quant. Et Et Et Et

Et Et Et Et R R R R N N N N R R R R XMg XMg NH HN N HN N N N N Et Et Et Et Et Et Me Et H Et chromophore Metal ion R R R R

R R R R N N N N • In complexed form, thermodynamic equilibrium of tautomers favors M M the corrinoid system • Analogous reactivity seen with Zn(II) and Ni(II) complexes

7 ACIEE, 1983, 22, 630 & 632 N. Z. Burns Corrin Chemistry

Contracted dimension of the corrin ring Since the coordination hole of corrinoid is better suited to Unfavorable "ligand ruffling" observed in hydroporphinoid metal complexes that is not seen in the corresponding : the spatial demands of the metal(II) ion a corphinoid to corrinoid rearrangement should be possible:

Me Me Me Me Me Me Me Me Me Me Me Me N N N R N N R N Me Me 260 ˚C, 5 min Me Ni Me Co O Co N N HO N R N ≤ 40% N R N Me Me Me Me Me Ni–N = 1.863 Å Me Me Me Me Me Me Me Me R = CN

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

Et Et N N H Specific attachment of nucleoside ligand to ring D Ni N N Is the f-ester inherently more reactive? Et Et O Ni–N = 1.912 Å MeO Et Et OMe b Me c H Me Et Et MeO a O H R Et Et N N d O Me OMe N R N Me Co H MeO O 4% e Co N N Me 9 N NH /MeOH 5% d g R 3 H 9% f N N O Me 20% b Et Et Me RT, 5 h 17% mix 38% SM Co–N = 1.974 Å Me H O Et Et R = pyridine R = CN e O f OMe OMe

Helv. Chim. Acta. 1985, 68, 1312. 8 N. Z. Burns Corrin Chemistry

Arrangement of substituents on the ligand periphery

O HO2C NCH2CO OCH2CN Me CO2H H Me HO2C CO2H NCH2CO O H R H2N H Me N N NH HN N O OCH2CN Me Co Me H NCH CO O N 2 N N Me NH NH HN R' 3 HO2C H Me O Me HO N Me + H HO2C CO2H Me O CO2H Me H H O O P O porphobilinogen O CO2H PBG O HO2C OCH2CN O H H OCH2CN R,R' = CN, OAc (mix) OH 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 • The nucleotide loop to the propionic acid side chain of ring D represents, type III predominates 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 Me Me CO2H CN CO H HO C Me 2 N NC CN 2 CN N N N N CN NH HN Me vitamin B12 CN CN H N N Me NH HN 14 wt. eq. K10 Me N HO C H CH3CN, 180 ˚C 2 Me NC CN Me 0.5 h (80%) HO2C CO2H HO2C CO2H NC CN Me Me CO2H precorrin 8x HO2C I:II:III:IV = 1:1:4:2 O NH N

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

The arrangement of side chains around B12 corresponds to the thermodynamically favored arrangement HO C 2 Me CO2H

CO2H HO2C Some glimpses of B12 biosynthesis: precorrin 5

HO2C HO2C CO H CO H 2 Me 2 HO2C CO2H Me CO2H CO2H NH HN O NH N O precorrin 3x O PBG HO uro'gen III Me NH HN HO NH HN

H2N HO C HO2C CO2H 2 CO2H

CO2H CO2H CO2H HO2C

Helv. Chim. Acta 1987, 70, 1115. 10 JOC, 2003, 68, 2529.