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Sulfo-Click Reaction Via in Situ Generated Thioacids and Its Application in Kinetic Target-Guided Synthesiswz

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Sulfo-Click Reaction Via in Situ Generated Thioacids and Its Application in Kinetic Target-Guided Synthesiswz View Online / Journal Homepage / Table of Contents for this issue ChemComm Dynamic Article Links Cite this: Chem. Commun., 2012, 48, 1526–1528 www.rsc.org/chemcomm COMMUNICATION Sulfo-click reaction via in situ generated thioacids and its application in kinetic target-guided synthesiswz Niranjan Kumar Namelikonda and Roman Manetsch* Received 31st July 2011, Accepted 15th August 2011 DOI: 10.1039/c1cc14724b Herein, we describe a practical, one-pot variant of the sulfo-click straightforward although various synthetic protocols are reaction, in which 9-fluorenylmethyl-protected thioesters are available.9 Reliable protocols have been reported, in which rapidly deprotected and reacted further with sulfonylazides to protected thioacids are deprotected prior to the amidation give N-acyl sulfonamides. step. For example, 2,4,6-trimethoxybenzyl (Tmob) thiol and trityl thiol were used to prepare the corresponding thioesters In the last decade, various click chemistry approaches mani- from carboxylic acids.10 These Tmob or trityl thioesters were fested themselves as simple yet reliable tools for material and then selectively deprotected and reacted with sulfonylazides in life sciences.1 Other bioorthogonal transformations known as the presence of 2,6-lutidine to arrive at the N-acyl sulfonamides.10 the thiol-click reaction or the sulfo-click reaction emerged as The generation of the thioacids from these thioesters, however, alternatives though they are slightly limited in their reactivity requires prolonged exposure to an excess of trifluoroacetic profile and substrate scope.2,3 Herein, we report a rapid, one- acid for complete deprotection and an aqueous workup to pot sulfo-click reaction taking advantage of an in situ activation remove the residual acid, since the sulfo-click reaction is of thioesters into thioacids followed by the amidation step. optimally conducted under slightly basic conditions. Adoption of these reaction conditions furthermore eliminated Crich and coworkers recently developed an amidation the major limitation of our developed sulfo-click-based kinetic reaction between 2,4-dinitrobenzenesulfonamides and thioacids, target-guided synthesis approach4 improving it to fully in which the thioacids have been prepared starting from complement the established in situ click chemistry approach.5 corresponding 9-fluorenylmethyl (Fm) thioesters with 20% Though N-acyl sulfonamides are known for more than a piperidine in DMF.11 Analogously, we envisioned a strategy Downloaded by University of Sussex on 26 September 2012 century, in recent years they gained great attention in medicinal in which corresponding thioacids are rapidly generated and 6 directly used without any workup and purification in a sulfo- Published on 05 September 2011 http://pubs.rsc.org | doi:10.1039/C1CC14724B chemistry. Commonly, N-acyl sulfonamides are synthesized via reactions between sulfonamides and carboxylic acids with click amidation. However, Williams et al. reported that the carbodiimide reagents or between acid halides and sulfo- sulfo-click reaction with piperidine generates piperidine namides under basic conditions. Recently there have been amides of the corresponding thioacids, sulfonamides and only reports on the preparation of N-acyl sulfonamides by a copper small amounts of targeted N-acyl sulfonamides.3b Because the catalyzed reaction between sulfonylazides and alkynes.7 An- nucleophilic piperidine attacks the carbonyl carbon and out- other modern approach entails the reaction between sulfonyl- competes the intramolecular S-acyl transfer, the unwanted azides and thioacids3 or sulfonylazides and selenocarboxylates8 piperidine amide is generated as one of the two main products. (Scheme 1). Especially, the amidation with thioacids stands To start the optimization of a one-pot deprotection/amidation out by its ease and bioorthogonality and thus was later named reaction, various thioesters were prepared from corresponding sulfo-click reaction by Liskamp.3c carboxylic acids and FmSH following the reported procedures.12 Though the sulfo-click reaction has been proven to be In search of a non-nucleophilic base which would rapidly reliable in various applications, it is currently underutilized deprotect the Fm thioester and promote the amidation, due to limitations with respect to the preparation and handling 1,8-diazabicycloundec-7-ene (DBU) has served the purpose. of thioacids. In general, thioacids are nucleophilic, readily A convenient procedure was attained, which performs well dimerize, and suffer from storage and stability issues. The with diverse thioacids and sulfonylazides after screening the synthesis and purification of thioacids are also not always different proportions of DBU from 5% to 3% DBU in DMF. Optimal deprotection was achieved in one minute at room temperature by a mixture of 3.5% DBU/DMF and subsequent Department of Chemistry, University of South Florida, 4202 E Fowler Ave., Tampa, FL 33620, USA. E-mail: [email protected]; Tel: +1 8139747306 w This article is part of the ChemComm ‘Emerging Investigators 2012’ themed issue z Electronic supplementary information (ESI) available: Experimental section and spectral data of the compounds. See DOI: 10.1039/ Scheme 1 Reaction between sulfonylazides and thioacids or sulfonyl- c1cc14724b azides and selenocarboxylates to yield N-acyl sulfonamides. 1526 Chem. Commun., 2012, 48, 1526–1528 This journal is c The Royal Society of Chemistry 2012 View Online Scheme 2 Sulfo-click reaction between sulfonylazides and thioacids generated from 9-fluorenylmethyl-protected thioesters. amidation with 1 equivalent of sulfonylazide was completed in another minute to obtain N-acyl sulfonamide along with DBF 4 (Scheme 2). All products were purified and isolated in good to excellent yields. Representative examples of this rapid depro- Scheme 3 Preparation of a semi-synthetic derivative of the natural tection/amidation reaction are shown in Table 1. Reactions product artemisinin. between aromatic or aliphatic azides and aromatic or aliphatic confirmed by the doublet at d 4.8 ppm with a vicinal equatorial- thioacids performed well in the one-pot two-reaction sequence. axial coupling constant of H-10 with H-9 and only one Functional groups like an acetamide 3i, a hydroxyl 3f and an singlet at d 5.38 ppm, which corresponds to H-12. ether 3e and 3f were tolerated in the reaction. Heterocycles like As a second example, a peptidic N-acyl sulfonamide has caffeine 3h, thiazole 3b and 3i, piperazine 3g, and tetrahydroi- been synthesized. After Boc deprotection of Fm thioester 9, soquinoline 3c were also compatible with the reaction conditions. the resulting amine was reacted with Boc-Ala-OH under This reaction was also examined in high dilutions of thioacids standard peptide coupling conditions providing the dipeptidic and sulfonylazides. At 20 mM concentration of thioester and Fm thioester 10 (Scheme 4). The sulfo-click reaction between sulfonylazide, the reaction attained completion at room the Fm thioester 10 and p-chlorobenzenesulfonyl azide temperature in 12 hours. It is noteworthy that the deprotection/ with 3.5% DBU/DMF resulted in two minutes in the amidation reaction worked similarly well with Cs CO with 2 3 N-acyl sulfonamide 11 in good yields without detectable good yields. First the deprotection completed with 5 equivalents epimerization. of Cs CO in DMF in 90 minutes and after the addition of the 2 3 The use of Fm thioesters in the sulfo-click reaction is also sulfonylazide, the N-acyl sulfonamide was formed cleanly in compatible with applications requiring bioorthogonal conditions. 30 minutes at room temperature. Previously, we developed similar to in situ click chemistry a The good yields and the high chemoselectivity of the kinetic target-guided synthesis (TGS) approach, in which amidation reaction are especially useful for the preparation the sulfo-click reaction between thioacids and sulfonyl- of highly complex biomolecules. First, artelinic acid, a semi- azides was used for the screening of compounds with biological synthetic derivative of the natural product artemisinin, has activity.4 In kinetic TGS, the biological target is engaged in the been successfully derivatized with a fluorescent dansyl moiety assembly of its own inhibitory bidentate ligand from a pool of using the new amidation reaction conditions. Commercially complementary reacting fragments. In proof-of-concept available dihydroartemisinin 5 was reacted under known Downloaded by University of Sussex on 26 September 2012 studies, we demonstrated that incubation of the protein target Lewis acid conditions with the thioester of the p-hydroxy- Bcl-X with a library of thioacids and sulfonylazides leads to methyl benzoic acid 1j resulting in the thioester of artelinic L Published on 05 September 2011 http://pubs.rsc.org | doi:10.1039/C1CC14724B the selective formation of four hit N-acyl sulfonamides acid (Scheme 3).13 The major product obtained was the displaying inhibitory activity towards Bcl-X .4b Although 10b isomer 6 along with trace amounts of the 10a isomer 7. L the initial proof-of-concept study underlines the potential of Next, the sulfo-click reaction of the isomeric mixture contain- kinetic TGS, the issues related to the preparation and handling ing 6 and 7 was deprotected with 3.5% DBU/DMF and of the thioacid fragments restrict the kinetic TGS approach to reacted with dansylazide to provide the dansyl analogue 8 of a minor degree. artelinic acid in excellent yields after the trace amounts of the Inspired from the success of the rapid one-pot
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