Vitamin B12: chemical modifications

Chem Soc Rev View Article Online Published on 29 May 2013. Downloaded by Insytut Chemii Organicznej Pan Bibilioteka on 05/06/2015 20:43:55. TUTORIAL REVIEW View Journal | View Issue Vitamin B12: chemical modifications† Cite this: Chem. Soc. Rev., 2013, 42, 6605 Keith ó Proinsias, Maciej Giedyk and Dorota Gryko* Received 13th February 2013 Vitamin B12 plays a key role in many metabolic processes occurring in all mammals. Over the years its biological role has been extensively studied generating a lot of interest in the chemistry of this vital DOI: 10.1039/c3cs60062a molecule. This established a variety of new methodologies for the synthesis and analysis of new cobalamin derivatives as well as creative purification techniques. This tutorial review summarizes all the advancements made in this area, providing a deeper insight into vitamin B12 chemistry. www.rsc.org/csr Key learning points – – – – The nomenclature of corrinoids. The chemistry of vitamin B12. Selective modifications of cobalamin. Purification and analysis of cobalamin and its derivatives. 1 Introduction Lord Alexander B. Todd wrote: ‘‘Vitamin B12 turned out to be a substance of frightening complexity’’.1a As a consequence it took more than ten years to accomplish its total synthesis. Hence, to date vitamin B12 derivatives have been exclusively obtained via modifications of the natural compound. This review focuses on the chemistry of vitamin B12 and its derivatives giving the researcher an introduction to the field of this fascinating molecule. Vitamin B12 (1) combines many aspects from biology and chemistry. For many applications it is not used in its original state, instead it is specifically tailored to please its handler and allow for the binding of appropriate groups or exposing particular active sites. The coupling of therapeutic agents to vitamin B12 (1) has been a major goal for many researchers due to vitamin B12 possessing a specific uptake pathway.2 Furthermore, the chemical synthesis of co-enzymes (adenosylcobamide and methylcobamide) from vitamin B12 is important as they work in unison with enzymes to catalyze rearrangement and methyl transfer reactions respectively.3 Cobalamin derivative, cobinamide is used for cyanide detection in solution and in blood, and has also been utilized in the separation of different cobalamin-binding Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland. E-mail: [email protected] † Electronic supplementary information (ESI) available. See DOI: 10.1039/ c3cs60062a This journal is c The Royal Society of Chemistry 2013 proteins, such as transcobalamin (TC), intrinsic factor (IF) and haptocorrin (HC), within various excreted substances from mammals and fish.4,5 It can also be employed in soluble guanylyl cyclase (sGC) regulation, activating the enzyme through the catalytic domain whereas other activating agents target the regulatory domain.6 Vitamin B12 derivatives have also been studied as catalysts in dehalogenation reactions.7 From an environmental point of view this method shows promising results for converting pollutants, such as 1,1-bis(4-chlorophenyl)-2,2,2trichloroethane (DDT), into less harmful 1,1-bis(4-chlorophenyl)2,2-dichloroethane (DDD). A similar type of reaction has also been utilized in the detoxification of inorganic arsenic.8 2 Nomenclature Vitamin B12 (1) is a highly functionalized tetrapyrrolic compound with three acetamides and four propionamides attached to the periphery of the macrocycle. The five-membered pyrrolic rings, highlighted in various colors, are labeled from A to D and the numbering of the corrin ring begins at the A ring and goes clockwise around the macrocycle. In Fig. 1, each amide group is labeled in red from position a to g. The central cobalt ion is coordinated by four pyrrolic nitrogen atoms and two ligands situated on both sides of the corrin ring (a-bottom and b-upper face). The fifth ligand at the b-face is usually the cyanide ion, whereas the sixth ligand at the a-face is the nitrogen atom Chem. Soc. Rev., 2013, 42, 6605--6619 6605 View Article Online Published on 29 May 2013. Downloaded by Insytut Chemii Organicznej Pan Bibilioteka on 05/06/2015 20:43:55. Tutorial Review Chem Soc Rev present in 5 0 ,6 0 -dimethylbenzimidazole. The other nitrogen is linked to a five-carbon sugar (ribose, highlighted in gray color) and bears the R5 0 -OH group. Ribose in turn connects to the phosphate group, and hence back onto the corrin ring via the propionamide group at the f-position. By adhering to a few simple rules the naming of old or new vitamin B12 derivatives is straightforward. Vitamin B12 (1) itself, also known as cobalamin, is abbreviated as (CN)Cbl. This type of abbreviation is common in the literature and will be used throughout the review so the reader should refer to this section as a guide. The term Cbl indicates that the structure is that of cobalamin (1). In the abbreviation of vitamin B12 the (CN) at the beginning states that there is a cyanide ligand present on the b-face side of the central cobalt ion. By changing the ligand the first section of the abbreviated name changes (compounds 2–9) e.g. hydroxocobalamin (OH)Cbl 2 which now bears the hydroxyl ligand instead of the cyano. The oxidation state of cobalt can be demonstrated in the compound name after the ‘‘cob’’ prefix e.g. cob(III)alamin, cob(I)alamin or in the subscript, in which case vitamin B12 (1) indicates the +3 oxidation state, vitamin B12r the Keith ó Proinsias Maciej Giedyk 6606 Keith ó Proinsias was born in Dublin, Ireland, in 1982. He completed his PhD at the Institute of Tallaght Dublin in 2009, under the supervision of Dr Fintan Kelleher. After a brief stint as a chemistry research technician in 2009 he started a post-doctoral stay at the Institute of Organic Chemistry of the Polish Academy of Science where he is currently working. His current research interests are vitamin B12 chemistry and the activation of sGC enzyme. Maciej Giedyk was born in Legionowo, Poland, in 1988. He joined the research group of Prof. Dorota Gryko in 2010 and in 2012 he graduated from Warsaw University of Technology with Masters in Engineering. He is currently undertaking a PhD at the Institute of Organic Chemistry of the Polish Academy of Science. His research interests include chemical modifications of vitamin B12 and enzymatic catalysis in organic synthesis. Chem. Soc. Rev., 2013, 42, 6605--6619 Fig. 1 Numbering of vitamin B12.1a,9,10 +2 oxidation state and vitamin B12s the +1 oxidation state. The word ‘‘nor’’ before vitamin B12 means the lack of certain groups, for example the methyl group at the C5 (compound 10), C15 (compound 11) or Pr3 (compound 12).9,11 When a number is included in the name it specifies the position where a change has occurred e.g. C5-nor-(CN)Cbl which relates to cobalamin that lacks the methyl group at the C5 position. Employing the word ‘‘epi’’ along with the number of a position indicates a change in the stereochemistry at this particular position. A special case of such stereoisomers are 13-epi-derivatives, which are also called neo-derivatives (Fig. 2). Cleavage of the ribose moiety, together with the phosphate and dimethylbenzimidazole groups, gives cobinamide (Cbi) 16 (Fig. 3). The same rules apply to Cbi derivatives as in (CN)Cbl except that the central cobalt now bears two cyanide ligands and therefore is written as (CN)2Cbi (see compounds 17–19). Removal of the 2-hydroxypropyl group at the f-position leaves the carboxylic acid group giving cobyric acid (20). A terminal Dorota Gryko obtained her PhD from the Institute of Organic Chemistry of the Polish Academy of Sciences in 1997, under the supervision of Prof. J. Jurczak. After a post-doctoral stay with Prof. J. Lindsey in North Carolina State University (1998– 2000), she started her independent career in Poland. In 2009 she received the prestigious TEAM grant from the Foundation for Polish Science. Her current Dorota Gryko research interests are focused on vitamin B12 chemistry, the activation of sGC enzyme and organocatalysis. This journal is c The Royal Society of Chemistry 2013 View Article Online Published on 29 May 2013. Downloaded by Insytut Chemii Organicznej Pan Bibilioteka on 05/06/2015 20:43:55. Chem Soc Rev Fig. 2 Tutorial Review Nomenclature of vitamin B12.10 number of OMe groups has dropped by one and the position of the lactone is in italics. This rule is also true for the 10-position (also called meso) e.g. (CN)2Cby(OMe)7(10-Cl) 27. Examples: (CN)2Cby(OiPr)7 is an ester of cobyrinic acid with isopropanol groups, (CN)2Cby(NH2)7 is a primary amide, (CN)2Cby(OMe)6(c-CO2H) possesses six methyl esters and the acid function in the c-position, etc. 3 Vitamin B12 3.1 Fig. 3 Nomenclature of cobinamide and its derivatives.1,10 amide (CONH2) instead of an acid at this position gives cobyramide/cobyrinamide (21). Partial cleavage of the ribose moiety leaving the phosphate gives (CN)2Cbi-P 22. Complete hydrolysis of vitamin B12 (1) gives cobyrinic acid (CN)2Cby 24 (Fig. 4). The names for cobyrinic acid derivatives indicate the position and type of conversion at the periphery of the macrocycle. For example dicyano cobyrinic acid heptamethylester (25) is abbreviated as (CN)2Cby(OMe)7. Once again two cyanide ligands (CN)2 are indicated, Cby tells that the structure is that of cobyrinic acid. The final section details the type of terminal groups present. In this case there are seven methylester groups (OMe)7. Changes to the structure can be easily noted by including the additional description at the end of the formula e.g. the formation of c-lactone at the c-position is written as (CN)2Cby(OMe)6(c-lactone) 23. Notice that the This journal is c The Royal Society of Chemistry 2013 Reactions on the central cobalt ion The central cobalt ion in (CN)Cbl (1) is coordinated to the cyanide ligand and to the nitrogen atom of dimethylbenzimidazole. There is an equilibrium between the free (base-off) and coordinated (base-on) form which is shifted by adjusting pH (Scheme 1).3 The exchange of ionic ligands is straightforward as it involves aquacobalamin formation and its subsequent treatment with an appropriate salt solution e.g. KCN, KN3, NaSCN, etc. (Scheme 2). Reactions occurring at the cobalt ion on vitamin B12 (1) have been at the centre of research for many years due to its biological importance. Cobalt-alkyl vitamin B12 analogues are produced by enzymatic systems as intermediates in the synthesis of coenzymatic forms of corrinoids e.g. methylcobalamin or adenosylcobalamin, which are cofactors for such vitamin B12-dependent enzymes as methyltransferase, methylmalonylCoA mutase, dioldehydratase, glyceroldehydratase, deaminases, etc. The formation of a covalent Co–C bond appears to be a more demanding process. In order to react, the cobalt ion must be first reduced. The process can be monitored visually as a colour change is observed. Cbl (red) reduces to Co(II) (brown) and then to Co(I) (blue/green) (Scheme 3).1,10 Chem. Soc. Rev., 2013, 42, 6605--6619 6607 View Article Online Published on 29 May 2013. Downloaded by Insytut Chemii Organicznej Pan Bibilioteka on 05/06/2015 20:43:55. Tutorial Review Fig. 4 Chem Soc Rev Nomenclature of cobyrinic acid and its derivatives.1,10 Scheme 1 Vitamin B12 base on/base off modes. Scheme 4 Scheme 2 Synthesis of various Cbl analogues. Scheme 3 Reduction of cobalt. There is an array of methods to achieve this goal.13 Commonly used examples of reducing agents are: NaBH4, Zn, sodium formate and chromium(II) acetate. Cbl 1 can also be reduced catalytically using the Adams catalyst giving Co(II)-derivative 1r. However, the synthesis of Co(I) compound 1s cannot be achieved using this method. The most controlled manner for reduction is utilizing electrochemical methods giving either Co(II) or (I) compound selectively. The synthesis of a Co(I) species 1s is usually achieved using chemical means. Unfortunately, an excess of reducing agent can reduce the formed (alkyl)Cbl, hence Co2+ ions 6608 Chem. Soc. Rev., 2013, 42, 6605--6619 Reactions on Co(I) species 1s. are added to the cobalamin-borohydride solution. This method is suitable for vitamin B12 coenzyme synthesis. All the reduced forms of Co are extremely reactive and spontaneously oxidize to Co(III) species under aerobic conditions. High reactivity of blue/green cobalamin Co(I) 1s is often utilized for the synthesis of coenzyme possessing Co-alkyl bonds, e.g. Ado-Cbl or Me-Cbl. Co(I) derivative 1s reacts with various electrophiles such as alkyl and acyl halides, aryl diazonium salts, epoxides, Michael acceptors as well as unsaturated hydrocarbons (Scheme 4).10–13 Handling of the product is extremely important as the presence of air or light causes decomposition. Therefore, adhering to strict anaerobic conditions and having an arsenal of aluminium foil is a must for any vitamin B12 chemist. One exception to the rule is EtPhCbl 34, also known as antivitamin B12, which is one of the most stable Cbl derivatives of this type.12 Although cobalt ions can be bound to a number of moieties (Scheme 4), the method possesses limitations, mostly involving steric hindrance of an electrophile, stability of the products as some of them are rapidly oxidized (e.g. benzylcobalamin) or hydrolyzed (e.g. methyl acrylate derivative) and therefore are impossible to isolate.13 In the case of alkene or alkyne analogues the substrate must be activated by conjugation with an electron withdrawing group e.g. acetylene is used for vinylCbl 33 synthesis, however employing ethylene gives no reaction.13 Furthermore, due to low solubility of vitamin B12 This journal is c The Royal Society of Chemistry 2013 View Article Online Chem Soc Rev Tutorial Review derivatives and required stability of the solvent in reducing environment the choice of solvent is restricted to H2O, methanol, ethanol and aq. acetic acid. Published on 29 May 2013. Downloaded by Insytut Chemii Organicznej Pan Bibilioteka on 05/06/2015 20:43:55. 3.2 Modifications to the side chains Mono-acids. Currently, partial hydrolysis of (CN)Cbl 1 is the only method of exposing reactive sites at the b-, d- and e-positions via the formation of mono-carboxylic acid. This method is low yielding and requires a painful and difficult purification process. In 1972 Yamada and Hogenkamp showed that incubation of (CN)Cbl 1 in 0.5 N HClaq solution at 37 1C for 3 h gives a mixture of partially hydrolyzed mono-carboxylic acids.14 In 1980 Matwiyoff et al. further extended this study by confirming the structure of each isomer using 13C NMR resonance studies.14 For the synthesis of mono-acids he used 1 N HCl. After purification the final isolated yields were b-acid 35 15% and d-acid 36 7% and e-acid 37 9% (Scheme 5). Cobinamide. The synthesis of cobinamide 16 dates back to 1956. Friedrich and Bernhauer (see within ref. 17) reacted (CN)Cbl 1 with cerium(III) hydroxide in the presence of excess cyanide achieving phosphodiester cleavage in good yield (60–80%, Scheme 6).17 The isolation of (CN)2Cbi 16 from the crude reaction mixture is difficult, involving several phenol extractions and column chromatography. The synthesis of Cbi 16 can also be achieved under acidic conditions. Brown found that reacting (CN)Cbl 1 with CF3SO3H under strict anhydrous conditions gives b-CF2HCbi in 78% yield (Scheme 6).17 The presence of water in the reaction leads to a decrease in the yield due to epimerization at the 13-position. In 1971 Bonnett et al. made a simple, but very important discovery.15 Treatment of (CN)Cbl (1) with trifluoroacetic acid at 25 1C for 2 h gives three major products, neo-Cbl 15, neo-Cbi 17 and cobinamide (16), which surprisingly are completely separable using paper chromatography.9 Scheme 5 Partial hydrolysis of (CN)Cbl 1. This journal is c The Royal Society of Chemistry 2013 Scheme 6 Cobinamide synthesis. Scheme 7 Phosphate coupling to cobinamide. (i) (CN, Cl)Cbi, methyl dichlorophosphate, NaOH, pyridine, freshly distilled DMF, DCC. Treatment of (CN)Cbl 1 with ZnCl2 and NaBH4 as a reducing agent furnished Cbi 16 in 56% yield, a decrease from the original yield, but with much less demanding purifications required.16 Reactions with other metal salts, including Cu(II) in MeOH, affords a mixture of two isomers (a-aqua-b-cyanoand a-cyano-b-aqua-) of Cbi 16 in a combined yield of 63%.17 There has been a small number of reports involving the coupling of phosphates to Cbi 16. In 1993 Toraya successfully coupled methyldichlorophosphate to Cbi (Scheme 7).18 The procedure required strict anaerobic conditions (no yield given). Finke and White also attempted this type of coupling, claiming superior methodology.18 However, four consecutive column chromatography purifications were required giving desired compound 39 in 26% yield. Cobyric acid. Modification of the ribose moiety includes the complete cleavage of the tail end of (CN)Cbl 1 giving cobyric acid (20) (Fig. 3). In 1971 Renz reported the first synthesis of this compound, a procedure that is still used today as a standard method.19 This methodology, though effective, uses extremely harsh reaction conditions (anhydrous ZnCl2, dry MeOH, 170 1C oil bath, 1 h followed by treatment with piperidine), which contributes to a low yielding product 20 (11% yield). Although the reaction is quick and straightforward, the mishmash of by-products in the crude reaction mixture makes the purification process very long, requiring an assortment of chromatographic techniques. Bonnett et al. continued this work using a 35% HCl solution to create cobyric acid (20) Chem. Soc. Rev., 2013, 42, 6605--6619 6609 View Article Online Published on 29 May 2013. Downloaded by Insytut Chemii Organicznej Pan Bibilioteka on 05/06/2015 20:43:55. Tutorial Review Chem Soc Rev Fig. 6 Fig. 5 from (CN)Cbl 1 with 10% yield.20 Unlike Renz, he identified the three components in his reaction mixture i.e. b-, d- and e-monoacids a typical mixture for this type of unselective hydrolysis. The use of cobyric acid (20) in further reactions has been mainly studied by Kraütler and Zelder. By using an indirect approach, Kräutler first synthesized nor-vitamin B12 (12), a derivative of (CN)Cbl lacking the methyl Pr3 group in the f-amide chain (Fig. 5).21 Cobyric acid (20) was coupled to (2-aminoethyl)-3 0 -(a-ribazolyl)diphosphate in the presence of ethylchloroformate giving the desired nor-vitamin B12 (12) in a decent 73% yield. Using the developed methodology nor-11 18 and iso-Cbi’s22 19 and iso-Cbl23 13 were synthesized. Zelder and Zhou completely removed the phosphate moiety and attached to (CN)Cbl 1 a peptide backbone by directly coupling the appropriate peptide linker to dicyano cobyric acid (Scheme 8).24 These types of compounds favour base off mode as a result of f-side chain flexibility. Thus, when such a monomer was exposed to a pH 8.1 solution, inter base-on dimer 41 was formed in 38% yield (Fig. 6). Using a different approach Wilbur and co-workers also synthesised two stable (CN)Cbl dimers.3 By reacting either stannylbenzoylaminophthalate di-TFP ester or benzene tricarboxylate tri-TFP ester with an e-functionalized Cbl derivative the desired dimers were obtained in approximately 45% yield. Lactone and lactam. Compared to the remaining three rings B is the most reactive site on (CN)Cbl 1. It is the only part on the corrinoid that can be selectively modified in high yields giving access to cobalamin derivatives. Scheme 8 Synthesis of a (CN)Cbl 1 derivative with a peptide backbone. (i) Dimethylamino pyridine-N 0 -(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride, EDC
HCl, DMAP, dry DMF, 0 1C–rt, 4 h. 6610 Inter base-on dimer. Nor- and iso-vitamin B12 and cobinamide derivatives. Chem. Soc. Rev., 2013, 42, 6605--6619 Scheme 9 Ligand effect on chlorination. (i) (CN)Cbl 1, chloroamine-T hydrate, glacial AcOH, H2O; (ii) MeCbl 42, chloroamine-T hydrate, 1.0 M HCl. Treatment of (CN)Cbl 1 with chloramine-T allowed chlorination at both the meso- and 8-position followed by spontaneous lactone formation giving (CN)Cbl(c-lactone)(10-Cl) 43 in an incredible 90% yield (Scheme 9).10 By replacing the cyano ligand with a methyl one the nature of the compound altered allowing for selective chlorination at the 10-position in a fantastic 82% yield. Expanding on this type of synthesis; it is also possible to selectively synthesize either (CN)Cbl(c-lactone) 45 or (CN)Cbl(c-lactam) 46 directly from (CN)Cbl 1 (Scheme 10).10 The synthesis of (CN)Cbl(c-lactone) 45 is also fairly straight-forward, usually being obtained in quantitative yields. Both Todd and Wilbur reported an excellent methodology for (CN)Cbl(c-lactone) 45 synthesis using the chloroamine-T or NCS/NaI approaches. We found that using Keese’s modified procedure, e.g. employing Scheme 10 Synthesis of (CN)Cbl(c-lactone) 45 and (CN)Cbl(c-lactam) 46 from (CN)Cbl 1. (i) NaOH, H2O, 100 1C, 10 min; (ii) NBS, 2 M AcOH, rt, 24 h. This journal is c The Royal Society of Chemistry 2013 View Article Online Published on 29 May 2013. Downloaded by Insytut Chemii Organicznej Pan Bibilioteka on 05/06/2015 20:43:55. Chem Soc Rev Tutorial Review Scheme 11 Reduction and ring opening of (CN)Cbl(c-lactone) 45. (i) 10% (w/v) aq. NH4Cl, zinc wool, 3 h; (ii) 1,4-diaminobutane, 50 1C, 2.5 h or diaminododecane, 80 1C, 24 h. NBS with a prolonged reaction time, gives (CN)Cbl(c-lactone) 45 in high yield.25 Todd and co-workers show that applying 0.1 N aq. sodium hydroxide at 100 1C for 10 min gives c-lactam 46 in a respectable 53% yield. (CN)Cbl(c-lactone) 45 has been found to be most useful in the functionalization of (CN)Cbl 1. Brown demonstrated that (CN)Cbl(c-lactone) 45 can be reduced to (CN)Cbl(c-CO2H) 47 in 80% yield or it can be reacted under melt conditions with primary diamines to give (CN)Cbl with terminal amine functionality (Scheme 11).26 When (CN)Cbl(c-lactone) 45 was treated with granulated NaBH4 in water at 60 1C the reaction gives a mixture of products. It emerged that the stereogenic center at the 8-position partially epimerizes giving the mixture of two epimeric forms of c-acids that can be readily separated via HPLC, with (CN)-8-epi-Cbl-c-CO2H and (CN)Cbl(c-CO2H) 47 being isolated in a modest yield of 23% and 46% respectively. The epimerized compound was subsequently coupled with NH4Cl giving (CN)-8-epi-Cbl 14 in 80% yield.27 3.3 Reactions at R5 0 -OH Toraya et al. was the first to report the selective modification at the 5 0 -OH position by reacting (CN)Cbl 1 with succinic anhydride in the presence of pyridine giving a mixture of two compounds (Scheme 12).28 The major product was the desired 50 -monosuccinyl(CN)Cbl 50 (90% yield) while the minor one was the 20 ,50 -disuccinyl(CN)Cbl derivative. Activation of the 5 0 -OH position via the reaction of (CN)Cbl 1 with CDT or CDI followed by the addition of a nucleophile is the most versatile method of Cbl functionalization (Scheme 13).3 The synthesis of such carbamates is a one pot procedure; (CN)Cbl 1 is Scheme 12 Coupling of succinic anhydride to (CN)Cbl. (i) Succinic anhydride, pyridine, DMSO, 1 h, 85%. This journal is c The Royal Society of Chemistry 2013 Scheme 13 Coupling at the 5 0 -OH position using CDT. (i) (a) CDT, NMM, DMSO, GlyOMe, rt-40 1C, 1 h, 58%; (b) 0.1 M NaOH, 30 min, 100%. first activated with CDI in DMSO at 30 1C for 25 min, followed by the addition of a primary amine giving the desired product in a decent yield. For example, Grissom et al. synthesized two simple derivatives using GlyOMe 51 and 4,7,10-trioxa-tridecanediamine (Scheme 13).29 NMR studies showed that modifications to the 5 0 -OH position only affect the chemical shifts of the ribose moiety leaving the remaining corrinoid unaffected. This publication is an excellent reference tool for those deciphering (CN)Cbl derivatives, in particular those conjugated at the 50 OH position. Recently, Doyle et al. reported the synthesis of (CN)Cbl(50 -CO2H) 52, the first direct modification at this position (Fig. 8).30 Oxidation of the 5 0 -hydroxy group with 2-iodoxybenzoic acid (IBX) and 2-hydroxypyridine (HYP) as the O-nucleophile gives the desired acid in 30% yield. Subsequently, a reliable synthetic route to ‘‘clickable’’ vitamin B12 53 was established by Gryko and Chromiński.31 The formation of the azido group at the 50 -OH position was accomplished via 50 -OMs Fig. 7 Synthesis of (CN)Cbl(5 0 -CO2H). Chem. Soc. Rev., 2013, 42, 6605--6619 6611 View Article Online Published on 29 May 2013. Downloaded by Insytut Chemii Organicznej Pan Bibilioteka on 05/06/2015 20:43:55. Tutorial Review Chem Soc Rev Scheme 14 Elimination of the c-position. (i) (a) Diphenylphosphoryl azide, Et3N, MeOH, rt, 48 h and (b) 1.0 N KOH; (ii) pH 10 CAPS buffer, 50 1C, overnight. Scheme 15 Fracturing the B-ring. (i) (CN)Cbl, 0.2 M NaHCO3 buffer (pH 9.0), incubated at 50 1C, 3 weeks, 6%; (ii) NaBH4, oxygen free H2O, 15 min, 84%. intermediate (Fig. 7). Reactions were conducted on a large scale with little purification required – a joy for any chemist. 3.4 Modifications to the macrocycle Modifications to the core of (CN)Cbl 1 have been laid by the waste side for many years. It was not until recently that some of these unique compounds came to light. Brown first showed that treatment of (CN)Cbl(c-NH2) 54, synthesized from (CN)Cbl(c-NHCO2CH3), with a basic solution under strict anaerobic conditions leads to complete elimination of the c-position forming the green corrinoid 55 in 95% yield (Scheme 14).32 On the other hand incubation of (CN)Cbl 1 with a milder base e.g. 0.2 M NaHCO3 for 3 weeks at 50 1C slightly cracks the B-ring giving blue corrinoid 56 in a low yield of 6% (Scheme 15).33 By reducing corrinoid 56 with NaBH4 tetrapyrrolic ring reforms furnishing (CN)Cbl(c-acid)(8-OH) 57 in 84% yield. Electrochemicalreduction gives a similar compound but with a –CH2OH group at the C5-position in 18% yield.34 Photo-oxidation of (CN)Cbl 1 in the presence of methylene blue selectively breaks the corrinoid in half into AD 59 and BC Scheme 16 Fragmentation of (CN)Cbl. (i) (a) hn, O2, methylene blue, KCN, ethylene glycol–CD3CN (1 : 1), 20 1C, 120 h; (b) 80 1C, 3 h. 6612 Chem. Soc. Rev., 2013, 42, 6605--6619 60 fragments held together by coordination to the cobalt (Scheme 16).35 However, by using high temperature the cobalt ion can be removed. Furthermore, it is also possible to synthesize nor-Cbl derivatives, devoided of the C5 and/or C15 methyl groups.10 Under oxidative conditions, using KMnO4 in dry pyridine, C5/C15 methyl groups oxidize to a carboxyl group, which is followed by decarboxylation in the presence of Ce(OH)2 giving C5-nor 10 or C15-nor-Cbl 11. As usual some unwanted hydrolysis occurred, but the most interesting was that it only occurred at the peripheral amide groups surrounding either the C5/C15 position. 4 Cobyrinic acid derivatives 4.1 Hydrophobic cobyrinic heptaesters Transformation of (CN)Cbl 1 to cobyrinates 25, 61–63 cannot be easier. By simply dissolving (CN)Cbl 1 in the appropriate alcohol with concentrated sulfuric acid the desired product can be isolated within a few days (Scheme 17).3 A few tips: ensure Scheme 17 Synthesis of (CN)2Cby(OR)7. (i) Alcohol, H2SO4, 60 1C, 72 h. This journal is c The Royal Society of Chemistry 2013 View Article Online Published on 29 May 2013. Downloaded by Insytut Chemii Organicznej Pan Bibilioteka on 05/06/2015 20:43:55. Chem Soc Rev that the alcohol solution is degassed prior to the addition of acid. In our experience the best degassing method is bubbling argon through the solution with sonication at approximately 40 1C for 30 min. The synthesis of other cobyrinic acid derivatives is scarce. In 1994 Munk used (CN)2Cby(OMe)7 25 to form heptanitrophenylesters which were reacted with long alkyl chains bearing N-terminal and C-terminal protected groups to give hepta-acid compounds.36 By subjecting (CN)2Cby(OMe)7 25 or (CN)2Cby(OMe)6(c-lactone) 23 to excess of a primary amine in the presence of cyanide or azide aminolysis of the peripheral methylesters occurs affording cobinamide derivatives (Scheme 18).6 The synthesis of hydrophobic amides cannot be achieved from (CN)2Cby(OMe)7 25 due to undesired hydroxylation at the 8-position. The complete modification to the peripheral methyl esters via reduction to alcohol with LiAlH4 in THF was reported by Gossauer (Scheme 19).3 Subsequent treatment of (CN)2Cby(CH2OH)7 68 with methanesulfonyl chloride gives (CN)2Cby(CH2OMs)7 69 in a decent yield (61%), which upon further reduction with Li(Et3BH) in THF affords (CN)2Cby(alkyl)7 70 soluble in hexane and other non-polar solvents. Scheme 18 Synthesis of (CN)2Cby(amide)7. (i) (CN)2Cby(OMe)6(c-lactone) 23, ethanolamine, Bu4N+Cl , CCl4, 50 1C, 24 h; (ii) (CN)2Cby(OMe)6(c-lactone) 23, n-butylamine, NaN3, CCl4, 50 1C, 72 h; (iii) (CN)2Cby(OMe)7 25, ethanolamine, Bu4N+Cl , toluene, 50 1C, 24 h. Tutorial Review Scheme 20 Synthesis of (CN)2Cby(CN)7 71. (i) DMF, (COCl)2, pyridine, 0 1C, 1 h. 76%. Scheme 21 Hydrolysis of (CN)2Cby(OMe)7 25. (i) TFA, toluene, 14 days, rt. Kreppelt reported that the terminal amide groups of cobyramide (21) could be transformed into cyano groups by treatment with phosgene and pyridine in DMF (Scheme 20).3,37 Cby dimers were prepared from (CN)2Cby(OMe)7 25 derivatives. Partial hydrolysis of (CN)2Cby(OMe)7 25 and (CN)2Cby(OMe)7(c-lactone) 23 gives a mixture of mono-acids, which can be isolated in low yields of approx. 10% (Scheme 21).38 Subsequently (CN)2Cby(OMe)6(b-acid) 72 was transformed into (CN)2Cby(OMe)6(b-NH2) through a multistep process involving acyl azide synthesis and Curtius rearrangement. When (CN)2Cby(OMe)6(b-NH2) reacts with (CN)2Cby(OMe)6(f-nitrobenzyl) the desired dimer is formed. This methodology was then transferred into the synthesis of a,c/c,a-dimers via the usage of (CN)2Cby(OMe)5(a-acid)(c-lactone). (Links to all theses mentioned above can be found in the ESI.†) 4.2 Scheme 19 Synthesis of (CN)2Cby(CH3)7 70. (i) (CN)(H2O)Cby(OMe)7, LiAlH4, THF, 2 h, 0 1C; (ii) MsCl, DMF, Et3N, 5 1C–rt, 25 h; (iii) 0.1 M Li(Et3BH) in THF, THF, 0 1C–rt, 60 h. This journal is c The Royal Society of Chemistry 2013 Lactone synthesis and reactions The most useful cobyrinic acid derivative for further functionalization is (CN)2Cby(OMe)6(c-lactone) 23. The original method for c-lactone synthesis used chloroamine-T, however this approach is littered with unwanted by-products and requires control over the cobalt ligands.39 On the other hand, Keese’s methodology for c-lactone synthesis is the definitive way to isolate this handy compound.25 Utilizing N-bromosuccinimide in 2 M AcOH the c-lactone is first formed on (CN)Cbl (ensure NBS is added portionwise), followed by methanolysis of the six remaining Chem. Soc. Rev., 2013, 42, 6605--6619 6613 View Article Online Published on 29 May 2013. Downloaded by Insytut Chemii Organicznej Pan Bibilioteka on 05/06/2015 20:43:55. Tutorial Review Scheme 22 Synthesis of (CN)2Cby(OMe)6(c-lactone) 23 from (CN)Cbl 1. (i) (a) NBS, 2 M AcOH aq. rt, 5 h; (b) MeOH, H2SO4, 60 1C, 5 days. amide groups (Scheme 22). One point that has not been mentioned by Keese is that when you separate the desired c-lactone it is worthy to collect unreacted and partially hydrolyzed material for further hydrolysis. This will greatly increase your yield. Further functionalization of (CN)2Cby(OMe)6(c-lactone) 23 can be achieved via reduction to either c-acid or c-alcohol, or via lactone ring opening (Scheme 23). Treatment of (CN)2Cby(OMe)6(c-lactone) 23 with Zn/AcOH in toluene gives (CN)2Cby(OMe)6(c-acid) 75 within minutes (Scheme 23).25 Be sure to activate zinc before use and degas the AcOH/toluene solution. The reaction takes approx. 20 min, usually when it turns dark green it is completed. However, monitoring by TLC is advised as appearances can be deceiving. (CN)2Cby(OMe)6(c-acid) 76 can be further coupled using various protocols forming esters or amides.3 Amide and ester formation is straightforward utilizing EDC/DMAP or DEPC methodology. In our experience (CN)2Cby(OMe)6(c-acid) 76 can be temperamental when it comes to choosing Chem Soc Rev coupling reagent, so if one fails just try another one. Average yields do not exceed 60–70%. Another but less productive method is the activation of the (CN)2Cby(OMe)6(c-acid) 75 with ClCO2C(Me)2CCl3 and then coupling to give amides or esters in approx. 30% yield. On the other hand (CN)2Cby(OMe)6(c-lactone) 23 is reduced with NaBH4 to alcohol 77.40 The ring opening of (CN)2Cby(OMe)6(c-lactone) 23 opens a gateway to the diverse selective functionalization at c- and d-positions (Scheme 24).41 Addition of a primary amine depending on the reaction condition gives either mono- or di-amides in excellent yields. Mono-amides upon treatment with cyanide convert to spirolactone 82 which can be opened with another primary amine or reduced to d-acid 86. (CN)2Cby(OMe)5(c-acid)(d-amide) 87 can also be obtained from di-amide. By mixing di-amide with an acid e.g. TFA, c-lactone 85 reforms and can be reduced to c-acid 87. Both c- and d-acids can then be easily coupled to compounds, such as amino acids, using DEPC as a coupling reagent. Moreover, in the presence of ascorbic acid and oxygen yellow compound 88 bearing a lactone located between the C6 and C7-positions with the hydroxyl group at the C5-position is formed in a low yield of 10% (Scheme 25).42 Subsequently, it serves as a starting material for the synthesis of spirolactone 89. Furthermore utilizing c-amide 90, synthesized by coupling of NH3 to (CN)2Cby(OMe)6(c-lactone) 23, a yellow corrinoid derivative 91 can be obtained. Scheme 23 Synthesis of (CN)2Cby(OMe)6(c-CO2H) 76 and (CN)2Cby(OMe)6(c-OH) 77 and coupling with various amines. (i) (CN)2Cby(OMe)6(c-CO2H) 76 synthesis: Zn, AcOH, toluene, rt, 20 min; (ii) (CN)2Cby(OMe)6(c-OH) 77 synthesis: NaBH4. Example of coupling: (iii) (CN)2Cby(OMe)6(c-CO2H) 76, 1-(6-hydroxy-hexyl)-cytosine, EDC
HCl, DMAP, DCM, DMF, 0 1C–rt, 2 h; (iv) (CN)2Cby(OMe)6(c-CO2H) 76, n-butylamine, DEPC, Et3N, DMF, rt, 18 h.41 Scheme 24 (CN)2Cby(OMe)6(c-lactone) 23 ring opening. (i) Amine, dioxane, rt, 24 h; (ii) KCN, dioxane, rt, 48 h; (iii) Zn, AcOH, toluene, rt, 20 min; (iv) amine DCM, rt, 24 h; (v) 50% TFA in DCM, rt, 1 h. 6614 Chem. Soc. Rev., 2013, 42, 6605--6619 This journal is c The Royal Society of Chemistry 2013 View Article Online Published on 29 May 2013. Downloaded by Insytut Chemii Organicznej Pan Bibilioteka on 05/06/2015 20:43:55. Chem Soc Rev Tutorial Review Scheme 25 Synthesis of the yellow corrinoids. (i) Ascorbic acid, NaHCO3, phosphate buffer (pH 7.2), 0.01 M EDTA, MeOH, O2, 65 1C, 3 h; (ii) ascorbic acid, KHCO3, phosphate buffer (pH 7.2), 0.01 M EDTA, MeOH, O2, 65 1C, 3 h; (iii) ascorbic acid, KHCO3, phosphate buffer (pH 7.2), 0.01 M EDTA, MeOH, O2, 70 1C, 3 h. Scheme 26 meso-Modifications. (i) NO2BF4, acetic acid, 4 d, rt. 76%; (ii) NaBH4, methanol, 53%; (iii) N-iodosuccinimide, acetic acid, 48 h, rt. 54%; (iv) N-bromosuccinimide, glacial acetic acid, 15 min, rt. 91%. 4.3 Modifications at the meso-position Upon exposure to either N-bromosuccinimide or N-iodosuccinimide, (CN)2Cby(OMe)7 25 is easily halogenated at the meso-position (Scheme 26).39 Similarly, nitration with nitrosulfuric acid gives (CN)2Cby(OMe)6(10-NO2) 94.43 The most commonly used derivative of this class is (CN)2Cby(OMe)7(10-NH2) 28, which is synthesized from the (CN)2Cby(OMe)6(10-NO2) 94 intermediate. It reacts with anhydrides, acids and aldehydes.3,43 In the case of coupling with acids only DCC can be utilized, in our experience this is the only method that works efficiently. The use of different coupling reagents only hinders the reaction, when EDC
HCl is used a lactam by-product Scheme 28 Synthesis and further transformations of pyrocobester (100). (i) Decalin, reflux, 45 min; (ii) Pd/C, formic acid, benzene, THF, glass ampule, no light, 85 1C, 6 h or zinc, AcOH, N2, rt, 12 min; (iii) CCl4, O2, 200 W W-lamp, 5 min. between the d-position and C10 forms (Scheme 27).43 This is due to the presence of acid, hence reacting meso-amine 28 in DCM with TFA furnishes (CN)2Cby(OMe)6(10-d-lactam) 95 in 79% yield. After Boc-protection it can be opened with a primary amine, allowing access to selectively functionalized derivatives at the d- and meso-position of type 99. 4.4 Core modifications By refluxing (CN)2Cby(OMe)7 25 in decalin the acetyl group at the c-position magically disappears to give green pyrocobester 100 in 34% yield, which after reduction furnishes 7-decarboxymethyl-cobyrinate 101 in 62% yield Scheme 28.44 Pyrocobester 100 is very sensitive to oxygen and light, making its purification difficult. After oxidation the compound turns from green to violet furnishing secocorrinoid 102 in 96% yield. This type of oxidation can also occur with (CN)2Cby(OMe)6(c-O-octadecyl) 103 or even (CN)Cbl 1 using methylene blue (Scheme 29).45 5 Purification Scheme 27 Selective functionalization of the d- and meso-position. (i) 50% TFA in DCM, rt, 5 h. 79%; (ii) (Boc)2O, DMAP, DCM, rt, 23 h. 73%; (iii) ethanolamine, NaCN, Et3N, DMF, rt, 24 h. 85%; (iv) TFA, triethylamine, DCM, rt, 30 min. 61%; (v) Boc-b-Ala-OH, EDC, DCM, 0 1C–rt, 6 h. 74%. This journal is c The Royal Society of Chemistry 2013 A quantitative yielding Cbl reaction that requires no purification is like looking for a needle in a haystack. Due to many Cbl analogues possessing similar physical and chemical properties Chem. Soc. Rev., 2013, 42, 6605--6619 6615 View Article Online Published on 29 May 2013. Downloaded by Insytut Chemii Organicznej Pan Bibilioteka on 05/06/2015 20:43:55. Tutorial Review Scheme 29 Oxidation of (CN)2Cby(OMe)6(c-O-octadecyl) 103. (i) Methylene blue, CD3OD, O2, light, 30 min. purification can be tricky. The following gives a brief overview of diverse purification techniques used in Cbl chemistry. 5.1 Cobalamin derivatives Purification of Cbl derivatives is a skill in itself usually involving multistep processes. However some good strategies are known. Phenol extraction used for salts and organic soluble compounds removal. The first step in Cbl purification is usually phenol extraction, a very important technique to master.10 However, there are only a handful of reports detailing the full extraction process, usually the crude reaction is diluted with water and washed with phenol–DCM (w/v, 1 : 1). The phenol solution is then diluted with DCM approx. four times its volume. A product is then back extracted using fresh water. If the product remains in the phenol phase; just add more DCM. This process can be repeated two or three times to ensure complete removal of all salts and compounds soluble in organic solvents. An alternative to phenol extraction is Sep-Pak chromatography. Chromatography. Column chromatography of Cbl involves a number of techniques. In the early days ion exchange column chromatography was used with a Dowex stationary phase.37 Nowadays, reverse phase (RP) C-8 or C-18 silica is more common, although some examples of using the normal phase are known.6 HPLC on an analytical and preparative scale is often used throughout the literature for difficult separation. Precipitation. Most of the hydrophilic derivatives are soluble in water and/or simple alcohols and can be precipitated using such systems as H2O–acetone, MeOH–Et2O, EtOH–DCM, etc. many of these systems have produced crystals suitable for X-ray analysis. 5.2 Cobyrinic acid derivatives Extraction. Most Cby derivatives are hydrophobic therefore work-up is quite easy. The first step involves extraction, in which the crude mixture is diluted with an organic solvent (DCM, etc.) and washed consecutively with aqueous media. The last wash usually involves an aq. KCN wash. Warning: it is important to remember that CN is a strong base and under acidic conditions protonates giving poisonous 6616 Chem. Soc. Rev., 2013, 42, 6605--6619 Chem Soc Rev HCN. The choice of solvent is also important for extraction. For example, in the synthesis of (CN)2Cby(OMe)7 25 Murakami et al. described the use of CCl4, which selectively separated the desired product from not fully esterified by-products (see within ref. 3). Chromatography. Column chromatography is the best method for purification of Cby derivatives. Although Cby derivatives can be complex and difficult compounds to work with they do have intense colours making purification a little bit easier. Back in the day paper or TLC chromatography was used for the separation of small amounts of organic material.44 More modern approaches involve using flash chromatography, dry column vacuum chromatography (DCVC) or HPLC.44 The eluent of choice for these techniques is a mixture of a nonpolar (DCM, chloroform, AcOEt, toluene) and polar (EtOH, MeOH, i-PrOH) solvents. More complex systems include the use of hexane–i-PrOH–MeOH–HCN.25 Other less often utilised stationary phases, used most often for desalting reaction mixtures, include such materials as Sephadex or Amberlite.18 In our opinion, dry column vacuum chromatography (DCVC) is a superior method for separating Cby derivatives.46 The basic concept is using a very small meshed silica which is packed into a sintered column. Vacuum is required to draw the eluent through hence separating your compound. It is recommended to include cyanide on the column if a dicyano product is required. Due to the acidity of the silica (CN)Cby (red) can form making purification more difficult. In our experience the addition of solid NaCN on the top of the column is the safest and most practical method. We also advise the use of EtOH over MeOH when possible. However, when separating Cby bearing carboxylic moieties MeOH is required as the fraction becomes more sharp on the column making it possible to separate compounds of similar polarity. For more difficult separations the use of toluene–MeOH is helpful. Precipitation. The precipitation of the pure product is advisable. In our experience the product is stable for longer. Typical solvent systems used are AcOEt–hexane, DCM–pentane and chloroform–heptane, but depending on the product others are also possible. 6 Analysis of (CN)Cbl 1 and its derivatives 6.1 NMR spectra At first look the NMR spectra below would scare a ghost (Fig. 8). However please do not despair, with a little help and practice the general elucidation of these spectra is easy. When a full assignment is required e.g. COSY, HSQC, HMBC, etc. techniques are employed, it can get a bit more tricky. When using 2D NMR always start from the most clearly resolved signal, which is usually C10 at approx. 6 ppm. In the case of (CN)Cbl 1 the spectra are easier to solve, due to the signals being well separated and defined (Fig. 8). Also there is a lot of literature now based primarily on NMR analysis of (CN)Cbl 1 further helping in tackling these spectra. A rough guide to the 1H NMR can be seen in Fig. 8. For more precise direction see ref. 1. This journal is c The Royal Society of Chemistry 2013 View Article Online Published on 29 May 2013. Downloaded by Insytut Chemii Organicznej Pan Bibilioteka on 05/06/2015 20:43:55. Chem Soc Rev Fig. 8 Tutorial Review 1 NMR of (CN)Cbl 1 in DMSO. Fig. 10 UV-Vis spectra of CNCbl 1 in H2O (0.35 mM) and (CN)2Cby(OMe)7 25 in DCM (0.35 mM). Fig. 9 1 NMR of (CN)2Cby(OMe)7 25 in CD3Cl. The choice of solvent is very important in both the analysis of (CN)Cbl 1 and Cby derivatives. In order to visualise the amide peaks of (CN)Cbl 1 the sample must be run in DMSO. In the case of Cby derivatives the choice of solvent is critical due to the loss of the CN ligand occurring causing splitting of peaks. In our experience [D8]toluene is the best solvent, however if solubility is an issue CD2Cl2 is very useful. If there is an hydroxyl group on the macrocycle then [D6]DMSO is recommended. As with (CN)Cbl, Fig. 9 shows a rough guide to (CN)2Cby(OMe)7 25 elucidation. Unfortunately, in our experience even a small alteration to the Cby derivative can cause a multitude of shifts. 6.2 UV-Vis spectroscopy Cbl analogues possess very intensive and deep colours. Their light absorption is due to p–p transitions in the corrin ring, where we can find six conjugated double bonds.9 In the absorption spectra of (CN)2Cby(OMe)7 25 characteristic bands are observed: ab series at E600–450 nm, ED series at E400 nm, g at E370–350 nm and d at E330–300 nm (Fig. 10).9 Intensity of these bands and their bathochromic or hypsochromic shift vary for each derivative and are influenced by such factors as axial ligands, central metal ion and substituents in the corrin ring (Fig. 11).47 The effect of ligands is highlighted in Fig. 11. The value of the extinction for a, b and g bands in dicyanocobalamin is by far the biggest, but at the same time ED and d bands display This journal is c The Royal Society of Chemistry 2013 Fig. 11 The influence of the axial ligand on absorption spectra of (CN)Cbl (—), ethynylCbl(



), vinylCbl (-
-) and methylCbl (---).47 (Reproduced with permission from Prof. Williams. Copyright 1965, Royal Society Publishing.) the smaller extinction. Solvent can also have such an effect, however the difference is only slight but noticeable.1,10 6.3 Circular dichroism spectroscopy CD not only gives the same information as UV-Vis but contributes in confirming conformational and epimeric changes in the corrin ring (Fig. 12).1 A good example is a set of two epimers: (CN)Cbl 1 (A) and neo-Cbl 15 (B), which differ only in the configuration at the C13 carbon atom (Fig. 12). In the wavelength around 300 nm compound A exhibits a positive peak whereas compound B – negative. Also, Fig. 12 CD of (CN)Cbl 1 (A) and neo-Cbl 15 (B) in 0.1 M KCN (reproduced from ref. 45 with permission from The Royal Society of Chemistry).48 Chem. Soc. Rev., 2013, 42, 6605--6619 6617 View Article Online Tutorial Review extinction coefficients for the signals at 400 nm differ significantly in value, making these two compounds easy to distinguish using this technique. Published on 29 May 2013. Downloaded by Insytut Chemii Organicznej Pan Bibilioteka on 05/06/2015 20:43:55. 7 Summary Vitamin B12 is a highly functionalized molecule with a variety of methodologies available for exposing its reactive sites. Modifications to (CN)Cbl 1 can be selectively conducted on the central cobalt giving a wide range of Cbl analogues. Other selective reactions can occur at the 5 0 -OH position by reacting with anhydrides or CDI/CDT, or at the c-position utilizing a easily prepared lactone. 5 0 -OH can be further transformed into either a carboxylic acid (5 0 -CO2H) or azide (5 0 -N3). Other less selective reactions include the popular partial hydrolysis, which is the only known method that gives mono-acids at the b, d or e positions. Complete removal of the ribose moiety gives cobyric acid, which can be coupled with a variety of simple and complex groups to synthesize a number of cobalamin and cobinamide derivatives. Partial cleavage of the tail end gives cobinamide which can also be used for the same purpose. Modifications to the macrocyclic core are rare although examples such as breaking of the B-ring or fragmentation of the vitamin are known. The most commonly used derivatives are those created from cobyrinic acid (20). Its derivatives consist of hepta-esters giving hydrophobic analogues. As with cobalamin it is possible to form (CN)2Cby(OMe)6(c-lactone) 23, which can be reduced to (CN)2Cby(OMe)6(c-CO2H) 79 or opened using primary amines under mild conditions giving c- or c/d-amides. In this case the spirolactone intermediate can be isolated and reduced to d-acid. Further selective modifications can occur at the mesoposition e.g. (CN)2Cby(OMe)7(10-NH2) 28 which allows for the coupling of various anhydrides or acids, it is even possible to create (CN)2Cby(OMe)6(d,10-lactam). This gives access to functionalization of both the d- and 10-position. Aminolysis of (CN)2Cby(OMe)6(c-lactone) 23 and (CN)2Cby(OMe)7 25 gives hydrophobic and hydrophilic cobinamides. The chemistry of vitamin B12 has been studied for many years providing an array of useful derivatives that has been utilized in a variety of applications. However this work is still ongoing with a vast amount of possibilities still available for our young scientists. Chem Soc Rev 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Acknowledgements This work was supported by the European Regional Development Fund with the TEAM program, grant no. TEAM/2009-3/4. References 1 (a) R. Banerjee, Chemistry and Biochemistry of B12, ed. R. Banerjee, John Wiley & Sons, Inc, 1999; (b) B. Kräutler, D. 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