Vitamin B 12. structure & modifications. Mikołaj Chromiński Group XV Institute of Organic Chemistry PAS

Transcription

1 Vitamin B 12 structure & modifications Mikołaj Chromiński Group XV Institute of rganic Chemistry PAS

2 Introduction Structure omenclature (not only) according to IUPAC Possible modifications Modifications of carboxyl groups Modifications on C-10 Modificatons on Ribose- 5 Functionalisation of atom

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4 General information water soluable Key role in the normal functioning of the brain and nervous system anf formation of blood Affects DA synthesis and regulations 2µg/day for adult concentration in blood : ng/l Sources in nutrition: meat (liver), fish, eggs, milk

5 Why it is interesting for chemists? Drug design, drug delivery Electrochemistry Catalysis Enzymology

6 Some History Discovery : 1948 by Folkers at Merk Structure: very looooong process First total synthesis accomplished 1973 Woodward Eshenmoser

7 H 2 C CH 2 H 2 C H 2 C C H H H H CH 2 Structure CH 2 H H P - H Molecular Weight [g/mol] MolecularFormula C 63 H P

8 IUPAC ame: cobalt(3+);[(2r,3s,4r)-5-(5,6-dimethylbenzimidazol-1-yl)- 4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2R)-1-[3-[(1R,2R,3R,5Z,7S,10Z,12S,13S,15Z,17S,18S,19R)- 2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)- 3,5,8,8,13,15,18,19-octamethyl-2,7,12,17-tetrahydro-1H-corrin-24-id-3-yl] propanoylamino]propan-2-yl] phosphate; cyanide omenclature H 2 C cyanocobalamin C-Cbl Cyanocob(III)alamin Vitamin- B12 V2876_SIAL α (5,6Dimethylbenzimidazolyl)cyanocobamine H 2 C H 2 C C CH 2 CH 2 CH 2 H H P - H

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10 A D H 22 B 23 C

11 b c a H 2 C CH 2 g H 2 C H 2 C C CH 2 d CH 2 e f H H - P H ribose 5'

12 β L 1 L 2 α

13 H 2 C CH 2 (ligand in β) cobalamine H 2 C H 2 C L CH 2 ifl = C: cyanocobalamine(vit. B 12 ) or C-Cbl CH 2 ifl = H 2 : H H aquacobalamine (vit. B 12 a) or(aq)cbl - P H

14 H 2 C CH 2 H 2 C H 2 C L CH 2 byrinic acid (Cby) for example HC L CH 2 (C)MeCby Me(aq)Cby

15 H 2 C CH 2 H 2 C H 2 C L CH 2 binic acid (Cbi) for example (C)MeCbi (C)(2-AcBu)Cbi CH 2 R H L for more complex ligands, we use specific abbreviations ( for example aminoacids abbreviations)

16 Some simplifications H 2 C CH 2 H 2 C H 2 C L CH 2 L = or L CH 2 H H H - P H

17 hydrolysis/conjugation H 2 C CH 2 H 2 C C CH H 2 C Modifications 2 hydrolysis/conjugation CH 2 hydrolysis/conjugation H H P - H

18 H 2 C CH 2 lactonisation/reduction/conjugation H 2 C H 2 C C CH 2 CH 2 H H - P H

19 H 2 C CH 2 H 2 C H 2 C C CH 2 nitration/reducrion/conjugation CH 2 H H P - H

20 H 2 C CH 2 H 2 C H 2 C C CH 2 CH 2 H H P - H direct conjugation

21 conjugation on cobalt H 2 C CH 2 H 2 C H 2 C C CH 2 CH 2 H H P - H

22 H 2 C CH 2 H 2 C H 2 C C CH 2 CH 2 hydrolysis/conjugation H H P - H

23 Modification of carboxylic groups H 2 C CH 2 H 2 C H 2 C C CH 2 CH 2 RC CR RC RH/H 2 S 4 C KC RC C CR H H RC CR - P H Murakami, Hisaeda et al. Bull.Chem. Soc. Jpn. 1983, 56, 3642 Murakami, Hisaeda et al. Bull.Chem. Soc. Jpn. 1984, 57, 2091 Murakami, Hisaeda et al. Bull.Chem. Soc. Jpn. 1984, 57, 405 (C) 2 b(iii)c 1 ester (C) 2 b(iii)c 2 ester (C) 2 b(iii)c 3 ester (C) 2 b(iii)c 4 ester Yields up to 85%

24 RC CR RC CR + RC RC C C CR HCl 4 aq RC C RC H 2 CR Cl 4 - RC CR RC CR RC CR + RC abh 4 RC CR Cl 4 - RC CR [b(ii)ester] Cl 4

25 H 2 C CH 2 H 2 C H 2 C C CH 2 0,4M HCl CH 2 H H P - H Russel-Jones et al. Bioconjugate Chem. 1995, vol 6, 34 Anton et al. J. Am. Chem. Soc., 1980, 120, 2215 Russel-Jones et al. Bioconjugate Chem. 1996, vol 7, 217

26 HC CH 2 H 2 C CH 2 H 2 C CH 2 H 2 C H 2 C C H 2 C C CH 2 H 2 C CH H 2 C H 2 C C CH 2 H H P - H CH 2 H H P - H CH 2 H H P - H CH 17% 16% 6%

27 H 2 C CH 2 H 2 C CH 2 H 2 C H 2 C C H H P - H CH 2 CH H 2 + H 2 EDAC ph 6.d buffer H 2 C H 2 C C H H P - H CH 2 CH H 2 65% Russel-Jones et al. Bioconjugate Chem. 1995, vol 6, 34

28 H 2 C CH 2 H 2 C H 2 C H 2 C C CH 2 BS, AcH aq H 2 C H 2 C C CH 2 CH 2 CH 2 H H P - H H H P - H 100% Keese et al. Helvetica Chimica Acta, 1998, vol.81, 1105 Russel-Jones et al. Bioconjugate Chem. 1996, vol 7, 217

29 B CH 2 + H 2 H 2 reflux B H H CH 2 70% H 2 Russel-Jones et al. Bioconjugate Chem. 1996, vol 7, 217

30 H 2 C H 2 C H 2 C C CH 2 CH 2 MeC MeC MeH/H 2 S 4 C MeC C CMe H H P - H MeC CMe 70% Keese et al. Helvetica Chimica Acta, 1998, vol.81, 1105

31 MeC H MeC MeC MeC C C CMe abh 4 MeC MeC MeC C C CMe CMe MeC CMe Zn/AcH MeC MeC MeC H C CMe C 80% CMe MeC Murakami, Hisaeda et al. Chemistry Letters, 1992, 909 Keese et al. Helvetica Chimica Acta, 1998, vol.81, 1105

32 H B + H 2 HBoc CMe 1. Cl Et 3, DCM 2. CF 3 CH CCl 3 B H CMe H 2 33% CH HC CH CH CH 56% H H B CMe Scheffold et al. Helvetica Chimica Acta, 1997, vol 80, 1183

33 B H CMe + EDC, DMAP B CMe H 65% C Keese et al. Helvetica Chimica Acta, 1998, vol.81, 1105

34 Si(Me) 3 MeC CH + MeC H MeC MeC C H 2 CMe Cl 4 - H 2 Si(Me) 3 MeC DEPC MeC C C CMe MeC CMe MeC CMe P C

35 MeC MeC MeC C C H CMe abh 4 CCl Me MeC MeC MeC Me C CMe 68% MeC CMe MeC CMe Murakami, Hisaeda et al. Chemistry Letters, 1992, 909

36 itration at C -10 MeC CMe MeC CMe MeC MeC C C CMe 1. 2 BF 3 2. abh 4 MeC MeC C C H 2 CMe CMe CMe MeC MeC 13% Murakami et al., J. Chem. Soc. Perkin Trans 2, 1995, 1175

37 MeC MeC MeC C C CMe H 2 CMe HC CMe B C CMe MeC CMe CMe 56% Hisaeda et al. Tetrahedron Letters, 2003, 44, 6421

38 mbibation of lactone and C-10 approach MeC MeC MeC C C H CMe CMe MeC Murakami et al., J. Chem. Soc. Perkin Trans 2, 1995, 1175

39 5 Ribose modifications H 2 C CH 2 H 2 C CH 2 H 2 C H 2 C C CH 2 CDT H 2 C H 2 C C CH 2 CH 2 CH 2 H H H H P - H McEwan et al. Bioconjugate Chemistry, 1999, vol. 10, P

40 C H 2 C H 2 C H 2 C C CH 2 CH 2 GlyMe H H 95% CH 2 C H H P - diamine H 65-98% H 2 n

41 Thanks for attention!

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