. Z. Burns rrin Chemistry: from B 12 to the rigin of Life rrin: Vitamin B 12 x-ray structure: 2 1 3 4 A 5 B 9 ame "corrin" proposed by those who established its structure because it is the core of the vitamin B 12 molecules. 19 D C 15 C 19 22 4 The most ancient of the uroporphinoids: the primitive anaerobes which make B 12 can be dated back 3.79 x 10 9 years. ome Uroporphinoids: corrole tetrahydrocorphin: coenzyme F430 tructure: Crowfoot-odgkin 1955 (1964 Chemistry obel Prize) ne of the "finest contributions of British science to the chemistry of low-molecularweight natural products" -A. Eschenmoser chlorin: chlorophyll porphyrin: heme 1 ature, 1955, 176, 325.
. Z. Burns rrin Chemistry 2 C 2 C 2 C P C 2 C 2 C 2 = = C vitamin B 12 "f 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, obert obinson Lecture 1976 2 coenzyme B 12 Eschenmoser's cobyric acid synthesis: vitamin B 12 2 C 2 C 2 C C C 2 + Bernhauer A 1960 D C Br 2 C 2 C 2 C 2 C 2 C A C B D C C B C C 2 C 2 C 2 cobyric acid C 2 C 2 2 cience, 1977, 196, 1410; Classics in Total ynthesis
. Z. Burns rrin Chemistry B + C 2 C C 2 benzoyl peroxide, Cl, C 2 Cl 2 B C C 2 () 3 P, xylene 125 C (85% overall) C 2 C 2 C 2 2 C D Br D P 2 5, 4-methylpyridine, xylene, 130 C (84%) I C 2 C 2 C C C 2 1. 2,, 25 C C 2 2. -iodosuccinimide C 2 Cl 2, 0 C 2 C C C 2 C 2 1. t-buk, t-bu, TF, 25 C; D 2. (C(C 2 ) 2 ) 3 P, TFA, sulfolane, 60 C (64% overall) C 2 C 2 3
. Z. Burns rrin Chemistry 1. A, amd, Ph, 25 C 2. Cd(Cl 4 ) 2,, 25 C 2 C 2 C 2 C C 2 C C Cd(Cl) C 2 C 2 C 2 1. Ph 3 P, TFA, Ph, 80 C 2. Cd(Cl 4 ) 2, i-pr 2, Ph,, 25 C then acl workup (46% overall) 3. DBU, sulfolane, 60 C 2 C 2 C 2 C Cd(Cl) C C 2 C 2 C 2 2 C C A A 1. hν (visible), 60 C 2. Cl 2, 58 C 3. KC, air, 2, C 2 Cl 2, 0 C (46% overall) 2 C C 2 hν 2 C 2 C C C C 2 C C 2 4
. Z. Burns rrin Chemistry 1. I 2, Ac 2. ClC 2 C 2 Ph sulpholane, 75 C 3. Ph 4. aney i; C 2 2 5. conc. 2 4 2 C 2 C 2 C C C C 2 C 2 C 2 C 2 A solution to meso methyl introduction: Jacobi, JC, 1999, 64, 1778 C + Cl 1. Pd 0, 4 Cl, ün. 2. 3, (63%) C cobyric acid 3 (l), (C 2 ) 2, 4 Cl, 75 C (64%) Cl Cy then 3 + ; AgBF 4 2 (57%) 2 C C 2 2 C 2 C C C 2 C C 2 C 2 CCl 4, PPh 3 (72%) C 1. 2 Pd, CuI, 3 C (69%) 2. + (83%) Cl For a particularly elegant approach to Vitamin B 12 by. V. tevens see "Isoxazoles and Isothiazoles in ynthesis" (Mitsos, 2004) 5
. Z. Burns rrin Chemistry ynthetic Analysis of pecific tructural Elements of Vitamin B 12 : Towards a Chemical ationalization of tructure "Can work done on the chemical synthesis of vitamin B 12 be extended to make a contribution to the problem of vitamin B 12 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." "[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." "Can experiments aimed at a deeper understanding of the molecular structure of cofactors tell us something about that early phase of biological evolution?" Darwinian paradigm of molecular evolution: structure a result of selection ynthetic Analysis of pecific tructural Elements 2 C 2 C 2 C P C C 2 C 2 C 2 specific arrangement of double bonds in corrin chromophore contracted dimension compared with corphin ring structural preformation selection emergence of biosynthetic pathway specific attachment of nucleotide ligand to ring D arrangement of substituents on the ligand periphery biotic prebiotic 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 fulfilled for a multistep biosynthesis of a complex natural product to emerge." Eschenmoser, ACIEE, 1988, 27, 5. 6
. Z. Burns rrin Chemistry pecific arrangement of double bonds in corrin chromophore 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? porphyrinogen? corphin: corrin-like chromophore MgI xylene, 85 C ~ quant. C 3 I/Ph (~90%) Pyr Ac ~ quant. Mg MgBr 2 moist Ph XMg XMg tal ion corrinoid chromophore M M In complexed form, thermodynamic equilibrium of tautomers favors the corrinoid system Analogous reactivity seen with Zn(II) and i(ii) complexes 7 ACIEE, 1983, 22, 630 & 632
. Z. Burns rrin Chemistry ntracted dimension of the corrin ring Unfavorable "ligand ruffling" observed in hydroporphinoid metal complexes that is not seen in the corresponding corrinoids: ince 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: i i = 1.863 Å = C 260 C, 5 min 40% Proc. atl. Acad. ci. 1981, 78, 16. i pecific attachment of nucleoside ligand to ring D i = 1.912 Å = 1.974 Å = pyridine Is the f-ester inherently more reactive? b a g = C f c d 9 3 / T, 5 h e 4% e 5% d 9% f 20% b 17% mix 38% M elv. Chim. Acta. 1985, 68, 1312. 8
. Z. Burns rrin Chemistry Arrangement of substituents on the ligand periphery C 2 C C 2 C C 2 C,' = C, Ac (mix) ' C 2 C C 2 C C 2 C 3 C 2 C + P 2 C C 2 2 C C 2 2 C C 2 2 C C 2 uroporphyrinogen III 2 2 C C 2 porphobilinogen PBG 1. 2,4-pentanediol/TF 20 C, 185 h 2. 3 / 4 Cl, 20 C, 20 h (50 % conv) Uroporphyrinogen substitution patterns: vitamin B 12 + cobyramide (~ 1:1) type I type II type III type IV The nucleotide loop to the propionic acid side chain of ring D represents, of all possible regioisomers, the thermodynamically most stable The kinetic product is a type I uro'gen, but under thermodynamic conditions the type III predominates 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
. Z. Burns rrin Chemistry C C C C C 14 wt. eq. K10 C 3 C, 180 C 0.5 h (80%) C C C C C C C C I:II:III:IV = 1:1:4:2 2 C 2 C 2 C 2 C precorrin 8x C 2 C 2 C 2 2 C 2 C vitamin B 12 C 2 C 2 The distribution is the same even at concentrations as low as 1 mg per 5 L! The arrangement of side chains around B 12 corresponds to the thermodynamically favored arrangement 2 C C 2 ome glimpses of B 12 biosynthesis: C 2 2 C precorrin 5 C 2 2 C 2 C C 2 C 2 2 C C 2 C 2 2 PBG 2 C C 2 uro'gen III 2 C precorrin 3x C 2 C 2 C 2 2 C C 2 elv. Chim. Acta 1987, 70, 1115. 10 JC, 2003, 68, 2529.