Galan, M Carmen

Ghirardello, Mattia

Ledru, Helene

Sau, Abhijit

English

Rh/Al2O3 can be used as an effective chemo-selective reductive catalyst that combines the mild conditions of catalytic hydrogenation with high selectivity for azide moieties in the presence of other hydrogenolysis labile groups such as benzyl and benzyloxycarbonyl functionalities. The practicality of this strategy is exemplified with a range of azide-containing carbohydrate and amino acid derivatives.</p

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                          Ghirardello, M., Ledru, H., Sau, A., & Galan, M. C. (2020). Chemo-selectiveRh-catalysed hydrogenation of azides into amines. Carbohydrate Research,489, 107948. https://doi.org/10.1016/j.carres.2020.107948Publisher's PDF, also known as Version of recordLicense (if available):CC BYLink to published version (if available):10.1016/j.carres.2020.107948Link to publication record in Explore Bristol ResearchPDF-documentThis is the final published version of the article (version of record). It first appeared online via Elsevier athttps://doi.org/10.1016/j.carres.2020.107948 . Please refer to any applicable terms of use of the publisher.University of Bristol - Explore Bristol ResearchGeneral rightsThis document is made available in accordance with publisher policies. Please cite only the publishedversion using the reference above. Full terms of use are available:http://www.bristol.ac.uk/pure/about/ebr-termsContents lists available at ScienceDirectCarbohydrate Researchjournal homepage: www.elsevier.com/locate/carresChemo-selective Rh-catalysed hydrogenation of azides into aminesMattia Ghirardello, Helene Ledru, Abhijit Sau, M. Carmen Galan∗School of Chemistry, University of Bristol, Cantock's Close, BS8 3TS, UKA R T I C L E I N F OKeywords:Rhodium catalysisAzide reductionChemo-selective reductionProtecting groups manipulationAminoglycosidesA B S T R A C TRh/Al2O3 can be used as an effective chemo-selective reductive catalyst that combines the mild conditions ofcatalytic hydrogenation with high selectivity for azide moieties in the presence of other hydrogenolysis labilegroups such as benzyl and benzyloxycarbonyl functionalities. The practicality of this strategy is exemplified witha range of azide-containing carbohydrate and amino acid derivatives.1. IntroductionAmines are common functional groups present in many organiccompounds. In multistep organic synthesis, reactive amine groups oftenrequire temporary protection [1]. Azides are often used to mask amines,their chemical stability and orthogonal reactivity towards othercommon protecting groups makes them exceedingly versatile [2]. Theuse of azides in carbohydrate synthesis is also very prevalent sinceglycosyl azides are highly useful precursors for N-linked glycans [3].One of the most common ways to introduce azides in chemicalsynthesis consists in the displacement of halogens or other leavinggroups (e.g. tosyl and triflyl) by NaN3, other common protocols includeacid-catalysed addition of trimethylsilyl azide, amine substitution viasulfonylazides or the use of diazonium salts among others [4,5]. Re-duction of the azide moiety to an amine is also a synthetically importantstep, since many azides can be prepared with regio- and stereocontrol,their subsequent reduction permits controlled introduction of the aminegroup. To that end, the most common protocols for the reduction ofazides into amines involve Pd/C or PtO2-promoted catalytic hydro-genation [6], Staudinger reaction [7], or hydride reduction [8] (e.g.LiAlH4, PhSeH, tris(trimethylsilyl)silane, dithiol/Et3N), among manyothers [2].Despite the numerous methods available for the reduction of the N3group, selectivity issues often arise due to the presence of other non-orthogonal protecting groups or labile moieties on the same moleculewhich can't withstand the reaction conditions. While Pd-catalysed hy-drogenation is often non-selective for benzyl ethers and olefins, pre-vious examples of selective Pd-catalysed hydrogenation of azides inpresence of benzyl ethers have been reported [9]. Nonetheless, themethod does not allow for selective reduction of azides in the presenceof the more labile benzyloxycarbonyl (Cbz) protecting group. On theother hand, the Staudinger reaction requires the use of water, which isoften incompatible with hydrolytically labile groups; hydride-mediatedreductions (e.g. LiAlH4) are not selective towards N3 groups in thepresence of aldehydes or esters and in some instances the methods in-volve the use of toxic or/and malodourous reagents (e.g. selenols, thiols,tin hydrides) [2].Rh complexes have been successfully and extensively employed inorganometallic chemistry in for example metathesis reactions [10,11],hydrosilylation reactions [12], hydrogenation of olefins [13] and forreduction of nitriles to amines [14]. Rh-catalysed hydrogenation re-presents an alternative to the aforementioned azide reduction strate-gies, which has the potential to offer several advantages over moretraditional methods, in terms of chemical orthogonality.Herein we report the use of Rh as an effective and selective catalystfor the hydrogenolysis of azides. The applicability of the method isexemplified with a range of azide-containing carbohydrate and aminoacid derivatives. We demonstrate that Rh/Al2O3 may be used as aneffective reductive catalyst that combines the mild conditions used incatalytic hydrogenation with high selectivity for azide moieties in thepresence of other labile groups. To the best of our knowledge there areno reported applications of the use of Rh or its complexes for the cat-alytic reduction of azides in biological chemistry.2. Results and discussionInitial studies were aimed at evaluating the effectiveness of Rh as amild hydrogenation catalyst for the chemo-selective reduction of azidesin the presence of benzyl ethers, which are typically labile under Pd-catalysed hydrogenolysis conditions [15]. To that end, glycosyl azide 1https://doi.org/10.1016/j.carres.2020.107948Received 17 January 2020; Received in revised form 4 February 2020; Accepted 5 February 2020∗ Corresponding author.E-mail address: M.C.Galan@bristol.ac.uk (M.C. Galan).Carbohydrate Research 489 (2020) 107948Available online 06 February 20200008-6215/ © 2020 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/BY/4.0/).Twas chosen as a model substrate (Scheme 1a) and reacted with 10 mol%commercially available Rh/Al2O3 in presence of an excess of acetic acidto help stabilise the resulting amine product as the acetate salt [16].Pleasingly, the reduction of 1 to amine 2 was achieved in an excellentyield of 90% using mild conditions (H2, 1 atm, balloon and roomtemperature) without affecting the surrounding benzyl groups.To determine the efficiency of this reduction under different catalystloadings, a preliminary rate determination screen was performed using10, 5 and 1 mol% of Rh/Al2O3 under the same reaction conditions asbefore. Under these conditions and for each catalyst loading, the con-version between azide 1 to amine 2 was monitored by taking aliquots ofthe reaction at different time intervals and analysed via NMR spectro-scopy (Scheme 1b). The reduction at 10 mol% of Rh reached> 90%completion after 6 h. Similar results were achieved at 5 mol% of Rhafter 13 h, while at 1 mol% load of Rh the reaction was slower and gavea 17% conversion after 24 h.Solvent effects were then explored and the outcome of the modelreaction in different solvents was monitored in order to evaluate if thenature of the solvent would influence the efficiency of the reduction.The Rh-catalysed hydrogenation of 1 into 2 was tested in toluene,EtOAc, MeOH, THF, and CHCl3 under the same conditions (5 mol%catalytic load, H2 1 atm, 5 h, room temperature). No significant dif-ference was observed between the different solvents (Scheme 1c), ex-cept for CHCl3 that gave a much lower conversion probably due to thelower solubility of H2 in halogenated solvents [17]. Consequently, Itwas decided to carry out the Rh-catalysed hydrogenations in a 6:1 to-luene/EtOAc mixture, providing optimal solubility conditions for bothreagents and products.Encouraged by these initial results, the scope of the Rh-catalysedazide reduction was then explored on a range of glucosides containingeither primary, secondary or anomeric azides and bearing both acetyland benzyl ether protecting groups (Scheme 2) using the optimizedcatalytic conditions and toluene/EtOAc (6:1) as the reaction solvent.In most cases, the reductions proceeded smoothly in moderate togood yields at room temperature. In brief, glycosides bearing azide-groups at C2 as in 3 and 4 afforded the respective perbenzylated andperacetylated 2-aminoglycosides 5 and 6 in good yields of 63% and86% yield, after 3 and 6 h, respectively, at room temperature. Rh-cat-alysed reduction of 1-azido acetyl-protected glucoside 7 resulted in thecorresponding 1-amino glycoside 9 in 69% with no anomerization by-products observed. In the case of 1-azido benzyl-protected glucoside 8,a complex mixture of amino-containing derivatives including α/βanomeric mixtures of the 1-amino derivative were obtained under thisconditions, likely due to the electron donating nature of the benzylprotecting groups which makes the resulting hemiaminal product morereactive and thus more susceptible to anomerization and/or degrada-tion [18]. We, therefore resolved the product mixture via acetylation ofthe resulting reduced product using acetic acid and pyridine which leadto the isolation of the major product, β-1-N-acetyl glycoside 10 in 36%Scheme 1. (a) Rh-catalysed hydrogenation of 1,reagent and conditions: H2 1 atm, Rh/Al2O310 mol%, AcOH, toluene 6 h, room temperature,90%. (b) Plot of conversion of 1 into 2 at 1 mol%(blue ), 5 mol% (red ) and 10 mol% (grey ) ofRh/Al2O3 over time. (c) Relative conversion ratesbetween 1 into 2 in different solvent at 5 mol%Rh/Al2O3, H2 1 atm, AcOH, after 5 h.Scheme 2. Reagent and conditions: i) H2 1 atm, Rh/Al2O3 10 mol%, AcOH, to-luene/EtOAc (6:1), room temperature. ii) H2 1 atm, Rh/Al2O3 10 mol%, AcOH,toluene/EtOAc (6:1), 6 h, room temperature, then Py/Ac2O 1:1 16 h, roomtemperature.M. Ghirardello, et al. Carbohydrate Research 489 (2020) 1079482yield after 2 steps. On the other hand, reduction of glucoside 11,bearing a primary azide at C6, underwent reduction to the amine within8 h with concomitant acetate migration of the acetyl group at C4 toafford acetamide derivative 12 in a 83% yield. This was confirmed bythe proton shift associated for H4 (from δ 4.97 in 11 to δ 3.33 ppm foracetamide 12) and to the presence of a cross-peak in the COSY spectrumcorresponding to the broad OH signal and H4. To ascertain whetherother H2-cleavable protecting groups were amenable to the mild Rhreaction conditions, CbzN-protected glucoside 13 was also screened.Compound 13 was reduced to amide 14 in 63% yield, without loss ofthe carbamate protecting group. Similarly to the outcome observed for11, the primary amine undergoes intramolecular transacetylation af-fording the corresponding acetamide and leaving a free hydroxyl atposition C4 of the sugar. In order to elucidate whether the transacety-lation reaction occurs only for amines at position C6 of glycosidesfeaturing OAc groups at adjacent positions (e.g. C4) of the sugar moietyor due to the general stronger nucleophilicity of primary amines oversecondary or anomeric ones, the reduction of acetate containing gly-cosides 15 and 17, bearing a primary azide at different positions on thesugar, were performed. Amino-derivatives 16 and 18 were obtained ingood yields of 73% and 94%, respectively, without the formation oftransacetylated derivatives. These results confirm that the observedacetate migration appears to be a specific feature of C6-amine con-taining glycosides where acetate groups are present at C4 and can un-dergo intramolecular rearrangement via a 6-membered transition stategiving the corresponding acetamide, which is a common problem incarbohydrate chemistry [19].To evaluate the chemical selectivity and efficiency of Rh-catalysedhydrogenation in the presence of different protecting and functionalgroups, orthogonally protected glycoside 19, thioglycoside 21, nu-cleosides 23 and 25 and amino acid derivatives 27 and 29 containingfree amino and carboxylic acid groups, were subjected to the Rh-cata-lysed reduction (Scheme 3).Reduction of 19 gave amine 20 cleanly in 74% yield without clea-vage of the benzylidene acetal protecting group and without the needfor anhydrous conditions. On the other hand, Rh-catalysed reduction ofsulphur-bearing glycoside 21 only yielded starting material, despite oflong reaction times (24 h) with a 10 mol% of Rh, likely due to catalystpoisoning by the thioether [20,21]. Our reduction conditions were thenapplied to azido-containing uridine derivative 23 and adenosine 25 asmodel pyrimidine and purine nucleoside substrates. In the case of 23,complete reduction of the azido and double bond in the nucleobaseafforded dihydrouridine amine 24 as the major product. The lack ofchemo-selectivity in this instance is not completely unexpected asprevious work has demonstrated the applicability of Rh in the reductionof uridine bases [22–24]. However, selective azido reduction in ade-nosine 27 was successful and amine 28 was obtained in 65% yieldwithout affecting the nucleobase, in virtue of a stronger aromaticitycompared to the pyrimidine model 25. Finally, we also demonstratedthat Rh-catalysed hydrogenation of azides is compatible with the pre-sence of free acid or basic amine functions such as those found in aminoacid derivatives 27 and 29, which furnished the corresponding amines28 and 30 in excellent yields of 92% and 86% respectively, after sub-jecting the parent substrates to the Rh-catalysed conditions in methanolas the solvent for solubility purposes.3. ConclusionsIn conclusion, we have demonstrated that Rh/Al2O3 can be used asan effective and chemo-selective catalyst for the reduction of azides inthe presence of other hydrogen-labile functional groups such as O-Bnand N-Cbz protecting groups The method is mild and offers an ortho-gonal alternative to Pd- or Pt-catalysed hydrogenation where highspecificity for the azide moiety is required. Although the presence ofthiols as in thioglycosides appears to be incompatible with the protocol,in a similar way to hydrogenations carried out with Pd or Pt catalystswhere the catalysts are inactivated, the versatility of the protocol isexemplified in a range of glycosides and amino acid derivatives de-monstrating its compatibility with other commonly used orthogonalfunctional groups, setting the stage for novel applications of Rh-cata-lysed azide reduction in organic synthesis.Declaration of competing interestThe authors declare no conflict of interest.AcknowledgmentsThis project has been funded by the Industrial BiotechnologyCatalyst (Innovate UK, BBSRC, EPSRC) to support the translation, de-velopment and commercialisation of innovative IndustrialBiotechnology processes (BB/M028976/1). We also thank the EuropeanResearch Council (ERC-COG: 648239).Appendix A. Supplementary dataSupplementary data to this article can be found online at https://doi.org/10.1016/j.carres.2020.107948.Scheme 3. Reagent and conditions: i) H2 1 atm, Rh/Al2O3 10 mol%, AcOH,MeOH, 5 h, room temperature. ii) H2 1 atm, Rh/Al2O3 10 mol%, AcOH, to-luene/EtOAc (6:1), 24 h, room temperature. iii) H2 1 atm, Rh/Al2O3 10 mol%,AcOH, MeOH, 5 h, room temperature. iv) H2 1 atm, Rh/Al2O3 10 mol%, AcOH,MeOH, 2.5 h, room temperature.M. Ghirardello, et al. Carbohydrate Research 489 (2020) 1079483References[1] P.G.M. Wuts, T.W. Greene, Protecting Groups in Organic Synthesis, fourth ed., JohnWiley & Sons, Hoboken, New Jersey, 2007.[2] E.F.V. Scriven, K. Turnbull, Azides - their preparation and synthetic uses, Chem.Rev. 88 (1988) 297–368, https://doi.org/10.1021/cr00084a001.[3] H.S.G. Beckmann, V. Wittmann, V. Azides, S. Bräse, K. Banert (Eds.), CarbohydrateChemistry. In Organic Azides: Syntheses and Applications, John Wiley & Sons, Ltd,Chichester, UK, 2009, pp. 469–491.[4] Z. 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Chemo-selective Rh-catalysed hydrogenation of azides into amines

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Chemo-selective Rh-catalysed hydrogenation of azides into amines

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