Scalable Synthesis of Cryptophane-1.1.1 and its Functionalization

Traoré, Ténin; Delacour, Léa; Garcia‐Argote, Sébastien; Berthault, Patrick; Cintrat, Jean‐Christophe; Rousseau, Bernard

doi:10.1021/ol902952h

Cited by 39 publications

(29 citation statements)

References 25 publications

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“…Due to our interest in dissymmetric [29–36] and concave molecular building blocks [37] and their implementation in supramolecular architectures like (allosteric) receptors [38–44] or metallosupramolecular helicates and cages [45–57] we were intrigued by the class of chiral CTVs. This is especially true for derivative 1 (Scheme 2) due to its interesting trifold substitution pattern with an almost orthogonal orientation of the functional groups which make it an ideal precursor for the synthesis of other elaborated derivatives [58–59] and the ease of a recently established large-scale synthesis reported by Rousseau and co-workers [60].…”

Section: Introductionmentioning

confidence: 99%

Efficient resolution of racemic crown-shaped cyclotriveratrylene derivatives and isolation and characterization of the intermediate saddle isomer

Götz

Schneider

Lützen

2019

Beilstein J. Org. Chem.

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The preparative resolution of a trifunctionalized C 3-symmetrical chiral cyclotriveratrylene derivative was achieved via high-performance liquid chromatography (HPLC) on a chiral stationary phase. This approach is a promising alternative to the previously reported resolution through formation of diastereomeric esters because it involves fewer synthetic steps and is less prone to thermal (re)racemization. During these studies an intermediate saddle conformer could also be isolated and characterized by 1H and 13C NMR spectroscopy. The HPLC separation method was further developed in order to allow investigations on the racemization behavior of the cyclotriveratrylene derivative.

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Section: Introductionmentioning

confidence: 99%

Efficient resolution of racemic crown-shaped cyclotriveratrylene derivatives and isolation and characterization of the intermediate saddle isomer

Götz

Schneider

Lützen

2019

Beilstein J. Org. Chem.

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“…All reported 111 derivatives to date 12,13 -none of them rimfunctionalized-were obtained by post-synthetic modification of 111, which itself is best synthesized by the S N 2-mediated dimerization of two units of cyclotriphenolene 3a using excess bromochloromethane (Scheme 1b, 46% optimized yield). 14 Unfortunately, despite recent progress, 15 the availability of 3a remains limited by the low yield (6-14%) synthesis of its methylated cyclotrianisylene precursor (2a) from 3-methoxybenzylalcohol (1a). We reasoned that synthesis of rim-functionalized 111 derivatives might be achieved more directly by the heterocapping of 3a with a pre-functionalized cyclotriphenolene, such as trisbromocyclotriphenolene (3b) or cyclotriguaiacylene (3c).…”

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confidence: 99%

“…Similarly also, close XeÁ Á ÁC(arene) intermolecular contacts are observed for the Xe@(MeO) 3 -111 complex, ranging from 3.64-4.35 Å (avg. = 3.91(19) Å) and exhibiting XeÁ Á Ácentroid(arene) distances averaging 3.65 (14) Å.…”

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confidence: 99%

Rim-functionalized cryptophane-111 derivatives via heterocapping, and their xenon complexes

et al. 2014

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“…However, even improved synthetic routes typically involve nine or more steps with low yields 5b. The preparation of separate connecting linkers and CTG units is time-consuming, and the hydroxyl functionalities must be protected to avoid side-products during the cryptophane synthesis.…”

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confidence: 99%

“…We have shown previously that 6a can undergo a copper(I)-catalyzed [3+2] cycloaddition with organic azides in nearly quantitative yields 13. This approach allows the introduction of one, two, or three different moieties on the cryptophane periphery in order to tune the biological and spectroscopic properties of the xenon biosensor 5a,14…”

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confidence: 99%

Shorter Synthesis of Trifunctionalized Cryptophane-A Derivatives

et al. 2011

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Efficient syntheses of trisubstituted cryptophane-A derivatives that are versatile host molecules for many applications are reported. Trihydroxy cryptophane was synthesized in six or seven steps with yields as high as 9.5%. By a different route, trihydroxy cryptophane modified with three propargyl, allyl, or benzyl protecting groups was synthesized with yields of 4.1-5.8% in just six steps. Hyperpolarized 129 Xe NMR chemical shifts of 57-65 ppm were measured for these trisubstituted cryptophanes.Cryptophane organic host molecules, constructed from two cyclotriguaiacylene (CTG) units connected by three alkane linkers, possess a hydrophobic cavity that can encapsulate a wide variety of guests. One important application involves xenon binding to cryptophane, which can be delivered to specific cellular targets for detection and resolution by 129 Xe magnetic resonance spectroscopy or imaging. 1 Currently, water-soluble cryptophane-A derivatives show the highest known xenon affinity with K A ≈ 30,000 M −1 in buffer at rt. 2 129 Xe can be hyperpolarized to generate ~10 5 NMR signal enhancements and provides a greater than 200 ppm 129 Xe NMR chemical shift window, with resonance frequencies that depend sensitively on the molecular environment. 3 Thus, cryptophane hosts functionalized with different recognition moieties allow the simultaneous detection of multiple targets (i.e., multiplexing), as is desirable for biomolecular imaging. 4 The importance of in vivo studies has motivated the development of synthetic routes capable of producing large quantities of functionalized cryptophane. 5 A previously described multi-step template strategy allowed the synthesis of diverse mono6 and tri-functionalized cryptophane-A derivatives2 ,7 as well as enantiopure (−)-cryptophane-A.8 However, even improved synthetic routes typically involve nine or more steps with low yields.5b The preparation of separate connecting linkers and CTG units is time-consuming, and the hydroxyl functionalities must be protected to avoid side-products during the cryptophane synthesis. Moreover, the two cyclization reactions to produce first CTG and finally cryptophane typically involve strong acid such as perchloric acid in methanol or formic acid.9 These conditions are incompatible with the synthesis of new CTG derivatives bearing acid-sensitive moieties, and very often dilute conditions are required to avoid polymerization, as in the case with propargyl groups.2 Recently, Brotin and coworkers * Corresponding author: Dmochowski, Ivan J., ivandmo@sas.upenn.edu. Supporting Information Available:Experimental procedures and characterization data for all synthesized compounds and 129 Xe NMR data. This material is available free of charge via the Internet at http://pubs.acs.org. reported cyclization reaction conditions using a milder reagent as Lewis acid, Sc(OTf) 3 . 10 Notably, in some cases even better yields were obtained, and the purification steps were made easier. NIH Public AccessBased on these observations, we developed a shorter, 6-step synt...

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Scalable Synthesis of Cryptophane-1.1.1 and its Functionalization

Cited by 39 publications

References 25 publications

Efficient resolution of racemic crown-shaped cyclotriveratrylene derivatives and isolation and characterization of the intermediate saddle isomer

Efficient resolution of racemic crown-shaped cyclotriveratrylene derivatives and isolation and characterization of the intermediate saddle isomer

Rim-functionalized cryptophane-111 derivatives via heterocapping, and their xenon complexes

Shorter Synthesis of Trifunctionalized Cryptophane-A Derivatives

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