{"paper_id":"0ddb2042-fd42-4ae8-959e-c7ee6a7b981f","body_text":"License and Terms: This document is copyright 2020 the Author(s); licensee Beilstein-Institut.\nThis is an open access publication under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0). Please note that the reuse,\nredistribution and reproduction in particular requires that the author(s) and source are credited.\nThe license is subject to the Beilstein Archives terms and conditions: https://www.beilstein-archives.org/xiv/terms.\nThe definitive version of this work can be found at https://doi.org/10.3762/bxiv.2020.118.v1\nThis open access document is posted as a preprint in the Beilstein Archives at https://doi.org/10.3762/bxiv.2020.118.v1 and is\nconsidered to be an early communication for feedback before peer review. Before citing this document, please check if a final,\npeer-reviewed version has been published.\nThis document is not formatted, has not undergone copyediting or typesetting, and may contain errors, unsubstantiated scientific\nclaims or preliminary data.\nPreprint Title Direct synthesis of anomeric tetrazolyl iminosugars from sugar-\nderived lactams\nAuthors Michał M. Więcław and Bartłomiej Furman\nPublication Date 12 Okt. 2020\nArticle Type Full Research Paper\nSupporting Information File 1 CCDC-2001372.cif; 799.4 KB\nSupporting Information File 2 CCDC-2001373.cif;  1.5 MB\nSupporting Information File 3 esi beilstein 08.10.2020.pdf;  6.9 MB\nORCID® iDs Michał M. Więcław - https://orcid.org/0000-0001-7884-8982;\nBartłomiej Furman - https://orcid.org/0000-0001-5459-8026\n\n1 \nDirect synthesis of anomeric tetrazolyl iminosugars from \nsugar-derived lactams \nMichał M. Więcław∗ and Bartłomiej Furman∗ \nInstitute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 \nWarsaw, Poland \nMichał M. Więcław - mwieclaw@icho.edu.pl;  Bartłomiej Furman - bfurman@icho.edu.pl \nAbstract \nHerein we present the direct asymmetric synthesis of tetrazole-functionalized 1 -\ndeoxynojirimycin derivatives from simple sugars via a Schwartz’s reagent -mediated \nreductive amide functionalization followed by a variant of the Ugi-azide multi-component \nreaction. The anomeric configurations of two products were  unambiguously confirmed \nby X -ray analysis. This work also describes examples of interesting further \ntransformations of the title products. Finally, some surprising observations regarding the \nmechanism of their formation were made. \nKeywords: amide functionalization; iminosugars; Schwartz’s reagent; tetrazole \nIntroduction \nTransformation of an amide into another chemical moiety in a controlled manner is \nnot a trivial task. Although the Vilsmeier -Haack reaction1 or amide reduction with LiAlH4 \nare textbook examples that easily come to mind, there are not many other methods \navailable. Simple alkyl and aryl amides, unlike other carbonyl compounds, typically do \nnot undergo direct addition by a nucleophile, including active organom etallic \n\n2 \ncompounds. For this rea son, it has been chemists’ long -lasting ambition to develop a \nreliable, mild, and selective methodology for amide functionalization. 2 Even though a \ntremendous amount of work has been already done towards this matter, it is still a \nhighly active field of research. Several review articles have been written about this topic, \nenclosing most of the advances made to date.3–5 \nA fascinating subset of these transformations encompass the reduction of amides to \nimines, with direct subsequent functionalization. One of th e methodologies for such a \nmodification was developed by Charette et al  . In their procedure the combination of \ntriflic anhy dride and pyridine 6 (or its 2 -fluoro derivative 7) was used as an activating \nagent to transform amides into reactive iminium complexes. Another stoichiometric \napproach was presented by Georg et al. by utilization of zirconocene chloride hydride, \nknown as Schwartz’s reagent. 8 This reduces an amide moiety,  giving a complex that \ncan be readily transformed into an imine or iminium cation.9 \nThere have also been some catalytic protocols developed for the reduction of \namides to imines. The most notable examples incorporate iridium complexes and \nsilanes.10,11 Cheng and Brookhart showed that the chlorobis(cyclooctene)iridium dimer \n([Ir(coe)2Cl]2) can act as the catalyst in combination with Et 2SiH2.12 Surprisingly, they \nwere able to obtain imines as well as amines using this methodology. Ba sed on the \nworks of Nagashima, 13 an iridium-based protocol for tertiary amides was introduced by \nDixon14–16 and Huang. 17,18 Adolfsson expanded this by use of molybdenum -based \ncatalysts.19 The reductive ap proach allows the issues associated with nucleophilic \naddition to amide carbonyl groups to be overcome and as such is finding its place in a \ngrowing number of synthetic applications.20 \n\n3 \nEmployment of these methods for modification of lactams is a challenge in its own \nright — there are hardly any examples of such transformations available in the \nliterature.21 Our group was the first to surmount this challenge by means of Schwartz’s \nreagent-mediated reductive functionalization. Since then, we have performed a number \nof diff erent functionalizations of such cyclic systems with various complexity, and with a \nparticular focus on the modification of sugar -derived lactams. As summarized in \nScheme 1, this includes simple nuclephile addition to in situ  generated imines, 21 the \nconsecutive one-pot Mannich/Michael sequence lead ing to oligocyclic compounds, 22 \nand employment in subsequent Joulié-Ugi multi-component reactions.23 \n \nScheme 1:  Our previous e fforts in the field of functionalization of sugar -derived \nlactams. \nThis work is an extension of these e ff orts and seeks to inves tigate the possibility of \nincorporating the Ugi -azide multi -component reaction in this workflow. A molecule \nincorporating both an iminosugar an d a tetrazole fragment is of particular interest, due \nto the interesting properties of both moieties (Figure 1) . It is probably hard to \noverestimate the importance of sugar sca ff olds in nature, and we believe that it speaks \nfor itself, however a significance of iminosugar derivatives may be less obvious. Several \npharmaceuticals are based on this sca ff old including the glucose -derived nojirimycin, \nan antibiotic and glycosidase inhibitor 24 and 1-deoxygalactonojirimycin, known under a \n\n4 \ntrade name Galafold ®, which is utilized for the treatment of Fabry disease, a rare \ngenetic condition. 25 On the other hand, the tetrazole moiety is known to have a \nbioisosteric relationship to carboxylic acids 26, which also makes them suitable for usage \nas bi ologically active compounds. Moreover, there are numerous reports of the \norganocatalytic activity of chiral aminotriaz oles and aminotetrazoles in num ber of \nreactions, such as the aldol reaction, 27 Michael addition, 28 Mannich reaction, 29 and \nhydrogenation.30 \n \nFigure 1: Key concepts behind the goal of this work. 31 \nResults and Discussion \nQuite recently Xie and Dixon showed that it is possible to synthesize α-tetrazolo \namines from simple and linear tertiary amides using an iridium -based catalytic \nprotocol.16 They have, however, only reported one example of lactam functionalization \nwhich only proceeded with moderate e fficiency (1-tert -butyl-azepan-2-one, 41 % yield \nof des ired product). Unfor tunately, this approach cannot be utilized for the \nfunctionalization of secondary amides, like sugar -derived lactams, due to the afore -\nmentioned method’s limitation to tertiary amides. Our previous work shows that \nCharette’s methodology  is also not applicable in this case, as it does not lead to the \nformation of an imine. 21 Luckily, we we re able to use a formerly estab lished strategy \nbased on Georg’s procedure with standard Ugi -azide32–36 reaction conditions in a one-\n\n5 \npot, tandem process. Subjecting glucose-derived lactam 1 to such a procedure gave the \ndesired product in good yield, but with virtually no diastereoselectivity, as shown in \nScheme 2. \n \nScheme 2: Preliminary experiment in search of a procedure for the synthesis of 2 -(1H-\ntetrazol-5-yl)-iminosugars. \nOptimization and scope \nAn initial optimization study for the proton donor for TMSN 3 activation (shown in \nTable 1) using commo nly encountered reagents for such reactions was performed. To \nour surprise, we observed the formation of the Ugi-azide product even in the absence of \na protic additive . Moreover, the aprotic conditions proved to provide the highest yield \nand diastereoselectivity, thus were chosen as optimal (Table 1, entry 9.). We also tried \nto isolate the imine after the reduction step and carry out the second step in a solvent \ncommonly used for the Ugi -azide reaction alone. For this,  we observed a significant \ndecrease in overall yield and suspect that the low stability of imines of type 2 may be \nthe reason for this behaviour. \nTable 1:  Optimization of 2 -(1H-tetrazol-5-yl)-iminosugar synthesis via Schwartz’s \nreagent-mediated reduction of amides and Ugi-azide reaction. \n\n6 \n \n№ Additive Solvent Yield /% d.r. a \n1. MeOH b THF 65 43:57 \n2. CF3CO2H THF 24 43:57 \n3. AcOH THF 47 80:20 \n4. Et3N · HCl THF 45 74:26 \n5. H2O THF 34 >95:5 \n6. (CF3)2CHOH THF 35 >95:5 \n7. none MeOH 19 c >95:5 \n8. none DCM 36 c >95:5 \n9. none THF 73 >95:5 \nA: 1.6 equiv. Cp 2Zr(H)Cl in THF under argon atmosphere; B: 1.6 equiv. of additive (if \napplicable), 1.1 equiv. CyNC, and 1.1 equiv. TMSN 3. a 2-(R) to 2-(S), isolated. b Additive \nused in excess. c Imine was isolated after reduction. \nThe established optimal conditions were applied for the synthesis of selected \nexamples of various 2 -(1H -tetrazol-5-yl)-iminosugars (Table 2). Attempts at using this \nmethodology to synthesize pentose -derived 2 -(tetrazol-5-yl)-iminosugars, using 2,3,5 -\ntri-O-benzyl-D-ribo-furanose- and -arabinofuranose-derived lactams as substrates were \nmade. Very unexpectedly,  we failed to isolate such products although we did observe \ntheir formation via mass spec trometry of the reaction mixtures. Employing alternative \nprocedures did not help, and none  of the desired products were observed at all when \napplying iridium complexes- or triflic anhydride-based methods. \nTable 2: Synthesis of 2-(1H -tetrazol-5-yl)-iminosugars using optimized conditions. \nReaction yield and d.r. are given.  \n\n7 \n \n№ Product -R2 Yield /% d.r.a \n1. 3a Cy 73 >95:5 \n2. 3b CH2CO2Et 49 >95:5 \n3. 3c Bn 18 >95:5 \n4. 3d PMP 29 79:21 \n5. 3e PMB 42 >95:5 \n6. 3f tert-Bu 40 >95:5 \n7. 3g tert-Oct 48 >95:5 \n8. 5a Cy 33 >95:5 \n9. 5b CH2CO2Et 16 >95:5 \na 2-(R) to 2-(S), isolated. \nThe methodology described here provides a pathway to new, interesting \ncompounds, containing both an iminosugar and tetrazole  moiety. Such compounds \nhave not been seen  to date, and their accessibility creates exciting synthetic \nopportunities. Here we present two  examples of possible further transformations of the \nproducts obtained over the course of this  research directed towar ds novel, attractive \nmolecules. \nCompound 3b underwent a cyclization reaction in the presence of benzoic acid at \nan elevated temperature yielding lactam 6 almost quantitatively. Deoxygenative \nreduction of this compound turned out to be challenging, as the ty pical procedure using \nLiAlH4 proved ine ff ective. We were able to obtain 7 using a Schwartz’s reagent -\nmediated amide activation methodology followed by NaBH 4 reduction. This structure \nwith three condensed rings can be seen as a new class of unnatural, chiral alkaloid \nscaff old, potentially exhibiting pharmacological activity (Scheme 3).37 \n\n8 \n \nScheme 3:  Synthesis of a new class of alkaloid sca ffold using the presented \nmethodology. \nVarious unsuccessful attempts were made to deprotect compound 3e. \nUnexpectedly, however, one of those experiments resulted in rearrangement in the \ntetrazole ring, as shown in Scheme 4. We were able to obtain the desired \naminotetrazole 9 by treating 3g with dry HCl at elevated temperature (Scheme 5). The \nresulting compound is particularly appealing, as similar sca ffolds are widely  used as \norganocatalysts. Such moieties are employed in a number of important synthetic \ntransformations, including the aldol reaction, 27 Michael addition, 28 Mannich reaction, 29 \nand hydrogenation.30 We plan to test these possibilities in the near future. \n \nScheme 4: Rearrangement of 3e under acidic conditions. \n \nScheme 5:  Synthesis of a new, chiral 2 -(tetrazol-5-yl)-iminosugar based potential \norganocatalyst. \n\n9 \nStereochemistry and configuration of products \nAs presented in Table 2, only one diastereomer of the desir ed iminosugar is \nobtained in almost all cases. This outstanding selectivity has been observed before and \nis described in our previous works devoted to the functionalization of sugar -derived \nlactams.21–23 We explain it in light of Woerpel’s model, which characterizes the direction \nof nucleophilic addition to oxo carbenium ions. 38–40 According to this concept,  the \nconformational stability of the compound in question is the key property to consider \nwhen predicting the reaction’s stereoselectivity. \nWhen the oxocarbenium ion is substituted, two diastereomeric half-chair conformers \nare possible: 3H4 and 4H3 (shown for a 4 -substituted pyranose cation in Scheme 6). \nBoth may undergo attack by a nucleophile in two ways: on the axial trajectory from the \ntop or the bottom face. Such an event would result in the formation of the product as a \nchair (1C4, 4C1) or a skew-boat (1S3, 3S1) conformer, of which the former is favored, as it \nproceeds via the lower-energetic chair-like transition state. The favored path of action \nwill result in addition syn or anti to the substituent in position 4, depending on the \nstarting conformer. Therefore,  once the ground conformer of the oxocarbenium ion is \nestablished, this logic may be used to predict the reaction’s stereochemistry.  \n \n\n10 \nScheme 6:  Principle behind Woerpel’s model for pred iction of the direction of \nnucleophile addition to oxocarbenium cations. \nThe same principle may be successfully applied to reactions of iminium cations. We \nhave previously shown that in the case of glucose - and galactose-derived, O -benzyl-\nprotected iminos ugars the addition syn to the substituent in position 3 is favored \n(Scheme 7). This work proves no di ff erent, as the isolated major products were in such \nconfiguration. The experimental determination of this, however, was not straig htforward \nin all cases. \n \nScheme 7:  Diff erence in conformational stability of glucose - and galactose -derived \niminium cations and the major product of nucleophile attack according to Woerpel’s \nmodel.22 \nWe were able to determine the structure of compounds 3a and 3e unambiguously \nby means of X -ray analysis, as shown in Figure 2. The configuration of the remaining \nglucose based products 3 was easily determined by the analysis of 1H–1H coupling \nconstants and NOE e ff ects. Unfortunately, the same approach was not possible in the \ncase of compounds 5, as 1H NMR spectroscopy showed indefinite results. In compound \n5a the coupling constant between protons H 2 and H3 has a value of 8.5 Hz. This cannot \n\n11 \nbe associated with a particular relative configuration without comparison with the \ncorresponding coupling constant in 2-epi-5a. But, alas, this value is unknown, due to of \noverlapping and broadening of the relevant  signals in the 1H NMR spectrum of the \ncompound in question. For the same reasons NOE e ffects present in 2-epi-5a cannot \nbe accurately interpreted. However, analysis of NOE e ffects in 5a, particularly a small \neff ect between protons H 2 and H 7 suggest that it may be the diastereomer 2 -(R), as \nshown in Figure 3 . This result would be in accordance with the previously mentioned  \nWoerpel’s model. \n \nFigure 2: ORTEP structures of compounds 3a and 3e obtained by X -ray analysis. \nHydrogen atoms and benzyl groups are omitted for clarity.  Full crystallographic data \navailable in Supplementary Information File 2 and 3, and in  Cambridge Crystallographic \nDatabase under CCDC-2001373 and CCDC-2001372 numbers respectively. \n \n\n\n12 \nFigure 3: Proposed absolute configuration (2-(R)) of compound 5a with selected carbon \natoms numbered. \nWe made an attempt at resolving this problem by means of  the electronic circular \ndichroism (ECD) technique. We recorded an ECD spectrum of both compounds and \ncompared it with simulated spectra, generated for both possible diastereomers (2 -(R) \nand 2-(S)) using computational chemistry software. Unfortunately, we were not able to \nfit any of the se simulations to the experimental data with sufficient certainty. For the \ninquisitive readers, this work is fully described in the supporting information section. \nMechanism of reaction \nAs mentioned previously, we observed Ugi-azide products, despite the absence of a \nproton donor in the reaction mixture. Intriguingly, this behaviour is inconsistent with the \ngenerally accepted mechanism of this transformation, which assumes hydrolysis of \nTMSN3 to HN 3 and activation of the imine species by protonation. Scheme 8 presents \nour proposal for the possible course of the Ugi -azide reaction variant described in this \nwork. We suppose that after reduction of amide I by Schwartz’s reagent, complex II \nundergoes a slow, spontaneous decomposition, y ielding imine III. III then reacts with \nTMSN3, which acts as both, an imine activator and an azide anion source. Complex IV \nundergoes a subsequent addition of an isocyanide moiety (intermediate V), followed by \nan azide anion addition. Intermediate VI undergoes a cyclization, producing VII, a \nsilylated derivative of the expected product. The hydrolysis of VII most likely occurs \nduring the reaction’s work-up. \n\n13 \n \nScheme 8: Proposed reaction mechanism for the described Ugi-azide reaction variant. \nPreliminary DTF calculations were performed on a simplified model to provisionally \nvalidate this proposed mechanism. The geometry of the intermediate species were \noptimized with Gaussian 09 software 41, using the B3LYP/LANL2DZ theory leve l for Zr \nand B3LYP/6 -31G(d,p) for other atoms, with GD3 empirical dispersion correction. \nOptimization was followed by a single-point energy calculation using the larger basis set \nDef2TZVP with a PCM solvatation model for THF, as implemented in the Gaussian  \nsoftware. Energy values reported are a sum of electronic and zero-point energies. \nScheme 9 shows possible pathways for the spontaneous  decomposition of \nzirconium com plex INT-1-A to free imine species INT-3. This process is much more \nlikely to occur via the 5-memberd cyclic transition state TS-1-A than the alternative TS-\n1-B, as the energy barrier of 60.1 kcal·mol−1 is definitely too high for the reaction to take \nplace, even at an elevated temperature. Path A with a barrier of 22.6 kcal·mol−1 is \ncertainly more feasible. We assume that the Cp 2Zr(OH)Cl species just leaves the initial \ncomplex, as this seems to be the simplest possibility in absence of any Lewis acid \nwhich could catalyze this decomposition. \n\n14 \n \nScheme 9: Possible pathway for spontaneous imine formation. Values reported are in \nkcal·mol−1. \nScheme 10 shows the energy diff erences in the subsequent steps of the examined \nreaction. The reported energy barriers are reasonably high for a slow process taking \nplace at room temperature. The overall barrier is not considerably di ff erent to those \npreviously published for typical mechanisms o f tetrazole formation by azide addition to \nnitriles.42 It is important  to note that the computational investigation of this reaction’s \nmechanism was not a primary goal of this work. That said, we consiser this simple, \ncrude DFT research to support our model of the transformation described herein. \n\n15 \n \nScheme 10: A possible path for tetrazole formation in the described conditions. Values \nreported are in kcal·mol−1. \nConclusions \nDuring the course of this research we have developed a methodology for the \nsynthesis of sugar -derived α-tetrazolyl amines. Such compounds — incorporating both \niminosugar and tetrazole fragments — are particularly interesting, thanks to the well -\nknown biological and catalytic activity of these moieties. This work is the first example of \nusing Schwartz’s reagent -mediated partial reduction of lactams and the Ugi -azide \nmulticomponent reacition in a tandem pro cess. Yields of the described products are \nmoderate to good, a satisfying result for such a multi-step process. We have shown that \nsuch a reaction does not necessarily requires protic conditions, in opposition to what is \n\n16 \ngenerally agreed upon for these type of reactions. An alternative reaction mechanism is \nproposed and provision ally confirmed with DFT calcula tions. Moreover, selected α-\ntetrazolyl iminosugars were subjected to further transformations, yielding new, \npotentially biologically active and organocatalytic compounds. \nExperimental \nExperimental procedures and other data are available in Supporting Information File 1. \nSupporting Information \nSupporting Information  File 1: ESI; pdf; Experimental data and additional details; \nexperimental procedures, characterisation of compounds, ECD analyses for compounds \n5a and 2-epi-5a, calculations of appropriate ECD and UV spectra, crystallographic data \nfor compounds 3a and 3e, atomic coordinates, energies, and number of imaginary \nfrequencies for computed stationary points, and copies of 1H NM R and 13C NMR \nspectra. \nSupporting Information File 2: CCDC-2001373; cif; X-ray crystallographic data for  \ncompound 3a. \nSupporting Information File 2: CCDC-2001372; cif; X-ray crystallographic data for  \ncompound 3e. \nAcknowledgements \nWe would like to thank Magdalena Jawiczuk for her invaluable tips and guidance in \nthe field of chemical computations. \n\n17 \nFounding \nWe would like to thank National Science Centre of Poland for the financial support \nprovided with grant PRELUDIUM № 2017/25/N/ST5/00079 (in the fie lds of  synthesis \nand analysis). 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