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Iodonitrene in Action: Direct Transformation of Amino Acids into Terminal Diazirines and N-Diazirines and their Application as Hyperpolarized Markers 15
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Thomas Glachet, Hamid MARZAG, Nathalie Saraiva Rosa, Johannes F. P. Colell, GUANNAN ZHANG, Warren S. Warren, Xavier Franck, Thomas Theis, and Vincent Reboul J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 02 Aug 2019 Downloaded from pubs.acs.org on August 2, 2019
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Journal of the American Chemical Society
Iodonitrene in Action: Direct Transformation of Amino Acids into Terminal Diazirines and 15N2-Diazirines and their Application as Hyperpolarized Markers Thomas Glachet,a Hamid Marzag,a Nathalie Saraiva Rosa,a Johannes F. P. Colell,b Guannan Zhang,b Warren S. Warren,b Xavier Franck,c Thomas Theisb,d* and Vincent Reboula* Normandie Univ, ENSICAEN, UNICAEN, CNRS, LCMT, 14000 Caen, France Duke University, Department of Chemistry, 124 Science Drive, Durham, NC27708, USA c Normandie Univ, CNRS, UNIROUEN, INSA Rouen, COBRA, 76000 Rouen, France d North Carolina State University, Department of Chemistry, 2620 Yarbrough Drive Raleigh, NC 27695 , USA a
b
ABSTRACT: A one-pot metal-free conversion of unprotected amino acids to terminal diazirines has been developed using phenyliodonium diacetate (PIDA) and ammonia. This PIDA mediated transformation occurs via three consecutive reactions and involves an iodonitrene intermediate. This method is tolerant to most functional groups found on the lateral chain of amino acids, it is operationally simple, and can be scaled up to provide multigram quantities of diazirine. Interestingly, we also demonstrated that this transformation could be applied to dipeptides without racemization. Furthermore, 14N2 and 15N2 isotopomers can be obtained, emphasizing a key trans-imination step when using 15NH3. In addition, we report the first experimental observation of 14N/15N isotopomers directly creating an asymmetric carbon. Finally, the 15N2-diazirine from L-tyrosine was hyperpolarized by a parahydrogen-based method (SABRE-SHEATH), demonstrating the products utility as hyperpolarized molecular tag.
INTRODUCTION Since the early 2010’s, transition metal-catalyzed nitrene transfer reactions1 to C=C, C-H and R–S–R group have become well established methods for the preparation of aziridines,2 amines3 or sulfilimines4 respectively (Figure 1). In addition to common reactions, recent studies have emerged and extended the scope of the synthetic nitrene chemistry.5 These methodologies typically require iminoiodinane N-protected nitrene species, easily generated from PIDA (phenyliodonium diacetate) or PhIO. Figure 1. Common Metal-Catalyzed Nitrene Transfer Reactions
Great improvements were recently described by Ess, Kürti and Falck groups, using homogeneous catalysis with rhodium based Dubois’s catalyst, with the direct stereospecific synthesis of NH-aziridines6 using O-(2,4-dinitrophenyl)-hydroxylamine (DPH) via a triplet state of the nitrene,7 and the primary amination reaction of arenes (Scheme 1a).8 At the same time, Luisi and Bull reported the first electrophilic metal-free NH transfer (Scheme 1b) during the synthesis of NH-sulfoximines
from sulfoxides, using PIDA and ammonia.9 In this reaction, two short-lived electrophilic intermediates were suggested: the iminoiodinane PhI=NH and the iodonitrene PhI(OAc)N. Simultaneously, during our mechanistic investigation of the NH-sulfoximination of sulfide using the same reagents, we proposed the formation of the nitrene species due to the observation of its fast dimerization into N2.10 In order to expand the reactivity and synthetic applications of nitrene species, we envisioned their use for the synthesis of terminal 3H-diazirines. Scheme 1. Direct NH Transfer Reactions via Nitrene Species
Diazirines, three-membered rings containing two nitrogen atoms and one carbon atom, were first identified as photoaffinity labeling groups by Knowles in the 1970’s,11 and remain widely used in chemical biology.12 Indeed, upon UVirradiation (360 nm), diazirines generate carbenes, which form
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covalent bonds with the nearest target protein via C–C, C–H or O–H insertion.13 A few years later, Richards introduced a trifluoromethyl group in aromatic series to further stabilize the carbene.14 Interestingly, the reactivity of halodiazirines15 was widely studied because they are easily prepared from nitriles using Graham’s method.16 In recent years, new practical applications for diazirines were disclosed; they were used as carbon radical traps in amination processes,17 as carbene sources for the formation of sulfur ylides,18 as electrophilic nitrogen sources in the synthesis of pyrazoles,19 and as reagents in the Pd-catalyzed cross-coupling reactions with aryl halides,20 or even in oxidative cross-coupling reactions with aryl boronic acid.21 Another recent promising application for substituted diazirines is the use of 15N2-diazirines in hyperpolarization, which enhances NMR signals by >10,000-fold. In this context, diazirines generate detectable signals that last for more than an hour.22 To date, the main obstacle for widespread utilization of diazirines is the lack of simple and efficient synthetic methods to prepare them. Indeed, their syntheses usually require at least 3 to 4 steps,23 generally using liquid ammmonia (at –78°C) with moderate reaction yields. For aliphatic diazirines, conventional methodologies involve treatment of carbonyl derivatives with NH3, subsequent reaction with hydroxylamine-O-sulfonic acid (HOSA) to form the corresponding diaziridines, and, finally, their oxidation into diazirines (Scheme 2).24 Unfortunately, the synthesis of terminal diazirines remains underexploited compared to their substituted counterparts.25 For trifluoromethylaryl diazirine synthesis, an additional step is needed to form the O-sulfonyl oxime. Recently, some improvements were made using resin-bound sulfonyl oximes,26 or t-BuOK as a dehydrogenating agent in a one-pot reaction.27 Scheme 2. Typical Synthesis of Diazirines from Carbonylated Compounds
In this study, we focused on the synthesis of terminal diazirines from unprotected amino acids via three consecutive one-pot reactions mediated by PIDA (Scheme 1c): 1) decarboxylation of the amino acid into the corresponding imine; 2) insertion of the iodonitrene to form a diaziridine; 3) its oxidation into the desired diazirine. The details for this new one-pot and metal-free reaction are reported herein.
RESULTS AND DISCUSSION Hypervalent iodine reagents are known to allow for oxidative decarboxylation of -amino acids28 resulting in an imine intermediate that in some cases, leads to the formation of nitrile (Scheme 3).29 The successful formation of diazirine depends on the (supposedly very fast) insertion reaction of the iodonitrene (formed from the reaction of PIDA and ammonia)9,10 on this imine30 leading to the corresponding diaziridine intermediate.31
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Scheme 3. Targeted and Side Reactions During the Decarboxylation Step.
Finally, its subsequent oxidation, with the release of iodobenzene and acetic acid, should lead to the expected diazirine.32 With this hypothesis in mind, we chose L-histidine (1a) as the model substrate (Table 1). First, we tested conditions used for the sulfoximination of sulfide,10 namely 2 equiv. of PIDA and 1.5 equiv. of ammonium carbamate (AC), in methanol at rt, with the addition of an extra equiv. of PIDA in order to perform the decarboxylation reaction. However, with these conditions (entry 1), only traces of expected diazirine 2a were detected by 1H NMR of the crude product and histidine 1a was recovered. In contrast, increasing the amount of AC (17.5 equiv) or switching to ammonia (entries 2-3), allowed for the isolation of diazirine 2a in 29% yield for both cases despite low conversion (
