DOI: 10.1002/chem.201001616 Isovitamin B 12 : A Vitamin B 12 Derivative That Flips Its Tail Shahzad Murtaza, [a, c] Markus Ruetz, [a] Karl Gruber,* [b] and Bernhard Kräutler* [a] Dedicated to Professor Karl Grubmayr on the occasion of his 60th birthday Vitamin B 12 (cyanocobalamin, 1) features a cobalt corrin and a nucleotide functionality in the stable, “base-on” form, [1–3] a hallmark of Natures “most beautiful” cofactors. [4] The intramolecular coordination of the nucleotide append- age to the corrin-bound cobalt center gives a unique three- dimensional structure [1] and modulates the reactivity of the cobalt center. [5] The complexity of 1 has been considered an impressive challenge for the (current understanding on the) evolution of the catalytic moieties of essential cofactors. Ac- cording to Eschenmoser, the natural corrinoids may repre- sent a further evolved form of the hypothetical B 12 progeni- tor “protocobyrinic acid” and the seemingly specific nucleo- tide loop of 1 may have arisen from adaptation and (non-en- zymatic) self-constitution. [6] This loop is a specific structural selection element for recognition by proteins involved in controlled B 12 uptake [7] or by the protein parts of some B 12 - dependent enzymes. [8] We report on isovitamin B 12 (2, Co b -cyano-5’’,6’’-dimethyl- benzimidazolyl-176-isocobamide, see Figure 1), [9] an isomer of vitamin B 12 , in which n-propanolamine constitutes the linker, rather than (R)-isopropanolamine. Our studies were induced by the discovery of nor-pseudovitamin B 12 , the nat- ural “complete” B 12 cofactor (with an ethanolamine linker) of perchloroethylene reductase from Sulfurospirillum multi- vorans . [10] The corresponding cobalamin analogue, norvita- min B 12 (3, see Scheme 1), was synthesized in more recent studies in this area, [11] and turned out to be a natural corri- noid also, which was detected in Salmonella sp. [12] Isovitamin B 12 (2) was prepared by the method [9, 13] out- lined for the partial synthesis of norvitamin B 12 (3). [11] It was obtained in 65 % yield by condensation of cobyric acid (4) [9, 14] and (3-aminopropyl)-3’-a-ribazolyl-diphosphate (5) (see Scheme 1, Experimental Section and Supporting Infor- mation) and recrystallization from aqueous acetone. The chromatographic behavior of 2 was similar to that of vitamin B 12 (1), and the UV/Vis spectra of 1 and of its isomer 2 were practically indistinguishable. [15] FAB-mass spectra ex- hibited a pseudo-molecular ion at m/z 1355, that is, at the same value as that of 1. UV/Vis and 1 H NMR spectra, as [a] Prof. Dr. S. Murtaza, M. Ruetz, Prof. Dr. B. Kräutler Institute of Organic Chemistry, Innrain 52a and Center of Molecular Bioscience, University of Innsbruck 6020 Innsbruck (Austria) Fax: (+ 43) 512-507-2892 E-mail : bernhard.kraeutler@uibk.ac.at [b] Prof. Dr. K. Gruber Institute of Molecular Biosciences, University of Graz Humboldtstrasse 50/3, 8010 Graz (Austria) Fax: (+ 43) 316-380-9897 E-mail : karl.gruber@uni-graz.at [c] Prof. Dr. S. Murtaza present address: Department of Chemistry, Science Block, Hafiz Hayat Campus University of Gujrat (UOG), 50 700 Gujrat (Pakistan) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201001616. Figure 1. Isovitamin B 12 (2). Left: structural formula. Right: superposition of the structures of two conformers of 2 in the crystal (stick models) ma- genta: inward conformer 2a, yellow: outward conformer 2b.  2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Chem. Eur. J. 2010, 16, 10984 – 10988 10984