10.1021/ol4012019 r XXXX American Chemical Society ORGANIC LETTERS XXXX Vol. XX, No. XX 000–000 Synthesis of a Functionalizable Water-Soluble Cryptophane-111 Emmanuelle Dubost, † Naoko Kotera, † S  ebastien Garcia-Argote, † Yves Boulard, ‡,§ Estelle L  eonce, § C  eline Boutin, § Patrick Berthault, § Christophe Dugave, † and Bernard Rousseau* ,† CEA, iBiTec-S/SCBM, LabEx LERMIT, F-91191 Gif-sur-Yvette, France, CEA, iBiTec-S/SBiGeM, CEA Saclay, 91191 Gif-sur-Yvette, France, and CEA, IRAMIS/ SIS2M, Laboratoire Structure et Dynamique par R esonance Magn etique, F-91191, Gif-sur-Yvette, France bernard.rousseau@cea.fr Received April 29, 2013 ABSTRACT The development of optimized xenon host systems is of crucial importance for the success of molecular imaging using hyperpolarized 129 Xe MRI. Cryptophane-111 is a promising candidate because of its encapsulation properties. The synthesis of cryptophane-111-based biosensors requires both water-solubilizing and chemically activatable groups. An expeditious synthesis of a water-soluble and functionalizable cryptophane-111 is described. Magnetic resonance imaging (MRI) is a powerful meth- od for scanning deep tissues or opaque biological samples, but its low sensitivity precludes its use for imaging mole- cular targets. In this context, laser-polarized 129 Xe NMR spectroscopy is a highly attractive tool for in vitro and in vivo MRI. Xenon is a nontoxic gas, soluble in biological fluids, and readily delivered by inhalation. Moreover, thanks to an NMR signal enhanced by 4 or 5 orders of magnitude through optical pumping, 1 small amounts of gas dissolved in biological tissues can be easily detected with an excellent signal-to-noise ratio. Development of xenon biosensors, which capture xenon atoms in molecular cages suitably functionalized to bind the desired target, have been the subject of particular attention over the past decade. 2 Cryptophanes are molecular cages made by the connection of two cyclotriveratrylene units through covalent bridging (Figure 1). They exhibit outstanding properties for xenon encapsulation. The cavity size, which directly depends on the length of the molecular bridge, dramati- cally affects both the affinity for xenon and the rate of in and out exchange of xenon. Today, biosensors are only constructed from cryptophane A. 3 Although cryptophane- 111 displays the highest affinity for xenon in both organic solvents 4 and water, 5 it has never been used for the synthe- sis of biosensors. Indeed, no congener that is simulta- neously water-soluble and functionalizable has been de- scribed. In addition, the challenge of current chemical developments is rendering the cryptophane moiety more hydrophilic in order to avoid the biosensor’s uptake by biological membranes 3f or formation of self-assemblies. 3d Only two water-soluble cryptophanes-111 were de- scribed independently by Travis Holman and our group. The former, functionalized with six cationic electron-with- drawing [(η 5 -C 5 Me 5 )Ru II ] þ ([Cp*Ru]) moieties, is soluble at neutral pH (>30 Â 10 À3 mol 3 dm À3 , 293 K) and exhibits a high xenon binding constant in water (2.9 Â 10 4 mol À1 3 dm 3 ) (Figure 2). 6 However, the possible instability of the organometallic moieties in biological fluids might be a drawback to the use of such derivatives. Moreover, the † CEA, iBiTec-S/SCBM. ‡ CEA, iBiTec-S/SBiGeM. § CEA, IRAMIS/SIS2M, Laboratoire Structure et Dynamique par R esonance Magn etique. (1) Desvaux, H.; Gautier, T.; Le Goff, G.; P etro, M.; Berthault, P. Eur. Phys. J. D 2000, 12, 289–296. (2) Spence, M. M.; Rubin, S. M.; Dimitrov, I. E.; Ruiz, E. J.; Wemmer, D. E.; Pines, A.; Yao, S. Q.; Tian, F.; Schultz, P. G. Proc. Natl Acad. Sci. U.S.A. 2001, 98, 10654–10657.