{"paper_id":"08fdf00e-612c-4db5-88b0-5055f52d19c7","body_text":"License and Terms: This document is copyright 2024 the Author(s); licensee Beilstein-Institut.\nThis is an open access work 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 and that individual graphics may be subject to special legal provisions.\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.2024.28.v1\nThis open access document is posted as a preprint in the Beilstein Archives at https://doi.org/10.3762/bxiv.2024.28.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 Towards an Asymmetric β-Selective Addition of Azlactones to\nAllenoates\nAuthors Behzad Nasiri, Ghaffar Pasdar, Paul Zebrowski, Katharina Röser,\nDavid Naderer and Mario Waser\nPublication Date 06 Mai 2024\nArticle Type Full Research Paper\nSupporting Information File 1 Supporting Information_azlactones_allenoates.pdf;  6.9 MB\nORCID® iDs Behzad Nasiri - https://orcid.org/0000-0002-5119-0356; Paul\nZebrowski - https://orcid.org/0000-0002-6154-7160; Mario Waser -\nhttps://orcid.org/0000-0002-8421-8642\n\n1 \nTowards an Asymmetric -Selective Addition of \nAzlactones to Allenoates  \nBehzad Nasiri, #1 Ghaffar Pasdar, #1 Paul Zebrowski, 1 Katharina Röser, 1 David \nNaderer,1 and Mario Waser*1 \n \nAddress: 1Institute of Organic Chemistry, Johannes Kepler University Linz, \nAltenbergerstrasse 69, 4040 Linz, Austria \nEmail: mario.waser@jku.at \n* Corresponding author \n# Equal contribution (in alphabetic order) \nAbstract \nWe herein report the asymmetric organocatalytic addition of azlactones to allenoates. \nUpon using chiral quaternary ammonium salt  catalysts, i.e. Maruoka’s binaphthyl-\nbased spirocyclic ammonium salts , the addition of various azlactones to allenoates \nproceeds in a -selective manner with moderate levels of enantioselectivities  (up to \n83:17 e.r.). Furthermore, the obtained products can be successfully engaged in \nnucleophilic ring opening reactions, thus giving highly functionalized -amino acid \nderivatives. \nKeywords \norganocatalysis; quaternary ammonium salt catalysis; azlactones; allenoates; amino \nacids \n\n2 \nIntroduction \nThe development of asymmetric syntheses routes to access non-natural amino acids \nhas for decades been one of the most heavily investigated tasks in organic synthesis \nand catalysis-oriented research [1-13]. As a consequence, a broad variety of \nconceptually orthogonal strategies to access differently functionalized non -natural -\namino acids (-AA) [2-7] as well as -amino acids (-AA) [8-13] have been introduced \nand there is still considerable interest in the development of new concepts and \nsyntheses approaches. Our group has a longstanding focus on the development of \nasymmetric organocatalytic methods to access non-natural chiral - and -AA [14-19]. \nHereby we are especially interested in utilizing simple (prochiral) starting materials and \ncarry out stereoselective -functionalizations by reacting them with suited C - or \nheteroatom electrophiles. -Amino acid-derived azlactones 1 are amongst the most \ncommonly utilized starting materials to access more diverse chiral -disubstituted \namino acids (Scheme 1A)  [20-22]. More specifically, these compounds can be \nengaged for a variety of asymmetric -carbo- and -heterofunctionalization reactions \nby utilizing different catalysis strategies  [20-22]. We have recently carried out \nsystematic investigations concerning the synthes es of advanced -AA by means of \nasymmetric -carbofunctionalization reactions and during these studies we also \nrealized that the masked -AA derivatives 2 undergo enantioselective -addition to \nallenoates 3 under chiral ammonium salt catalysis (Scheme 1B)  [18]. Interestingly, \nhereby we also found that the use of alternative catalyst systems (i.e. tert. phosphines) \nallows for  a -selective addition of 2 to the allenoate instead, thus resulting in tw o \ncomplementary catalyst -controlled pathways  [18]. Based on these previous results, \nand also the well -documented different reactivity trends of allenoates 3 when using \n\n3 \ndifferent organocatalysts and activation modes [23-27], we were thus wondering if we \ncould extend this  ammonium salt catalyzed -selective allenoate functionalization  \nstrategy to other amino acid classes. Azlactones 1 have previously been used for -\nselective additions to  allenoates under chiral phosphine catalysis  [28]. In addition, \nglycine Schiff base derivatives [ 29] as well as -amino acid based thiazol -ones [30] \nhave successfully been used for asymmetric -selective additions to allenoates when \nusing chiral ammonium salt catalysts or chiral organobase catalysts . However, to the \nbest of our knowledge the -selective asymmetric addition of azlactones 1 to allenoates \n3 delivering highly functionalized ,-disubstituted -amino acid derivatives 5 has so \nfar not been systematically addressed (for recent other -selective additions of enolate \nprecursors to allenoates please see Ref. [31-34]). Thus, we now became interested in \ntesting this transformation under asymmetric ammonium salt catalysis [35-38] and the \nresults of these investigations are outlined in this contribution (Scheme 1C). \n \n \n\n\n4 \nScheme 1: General use of azlactones 1 to access more advance  AA derivatives \n(A), our recently reported ammonium salt-catalyzed -selective addition of compounds \n2 to allenoates 3 (B), and the herein investigated -selective addition of azlactones 1 \nto allenoates 3 (C). \nResults and Discussion \nWe started our investigations by testing the quat. ammonium salt-catalyzed addition of \nazlactone 1a to allenoate 3a (Table 1 gives an overview of the most significant results \nobtained hereby). First experiments using Cinchona alkaloid -based quat. ammonium \nsalts A showed that the expected -addition product 5a can be accessed under typical \nphase-transfer conditions, but with low selectivities and yields only when using these \ncatalysts (entries 1-4, other Cinchona derivatives were tested too but did not allow for \nany improvement ). Using the established and commercially available Maruoka \ncatalysts B1 and B2 [39] next turned out to be more promising (entries 5-10). Testing \nthe bis-CF3-substitued B1 first allowed for 75:25 e.r., but with moderate yield only when \ncarrying out the reaction in toluene in the presence of 3 eq. of K2CO3 (entry 5). Lower \namounts of base (entry 6) or other solvents, as exemplified for CH2Cl2 (entry 7, similar \nnon-selective results were obtained when using THF), were found to be less -suited \nhowever. Testing the 3,4,5 -trifluorobenzene-decorated catalyst B2 with K 2CO3 in \ntoluene next (entry 8) allowed for a slightly higher selectivity but still gave a relatively \nlow yield only. Spirobiindane-based salts C emerged as promising alternative \nquaternary ammonium salt scaffolds recently [40,41] and were also the catalysts of \nchoice in our recen tly developed -selective allenoate addition of isoxazolidinones 2 \n(compare with Scheme 1B [18]). Unfortunately, these catalysts were found to be less-\nsuited for our azlactone protocol, as exemplified for derivative C1 (entry 9). \n\n5 \nAccordingly, we carried out our final optimization using Maruoka’s catalyst B2 (entries \n10-14). By testing different bases and lower temperatures as well as lower catalyst \nloadings we identified the use of 3 eq. Cs2CO3 in toluene (0.05 M) at room temperature \nas the best-suited conditions (entry 13), allowing for the synthesis of  5a in moderate \nyield (61%) and enantioselectivity (81:19 e.r.). \n \nTable 1: Optimization of the addition of azlactone 1a to allenoate 3aa. \n \nEntry Cat.  Base solvent T [°C] Yieldb e.r.c \n1 A1 K2CO3 toluene 25 41 58:42 \n2 A2 K2CO3 toluene 25 45 60:40 \n3 A3 K2CO3 toluene 25 40 58:42 \n4 A4 K2CO3 toluene 25 45 60:40 \n5 B1 K2CO3 toluene 25 55 75:25 \n6 B1 K2CO3 (1 eq.) toluene 25 20 72:28 \n7 B1 K2CO3 CH2Cl2 25 33 51:49 \n8 B2 K2CO3 toluene 25 50 80:20 \n9 C1 K2CO3 toluene 25 40 68:32 \n\n\n6 \n10 B2 K2CO3 toluene 0 45 80:20 \n11 B2 (5%) K2CO3 toluene 0 41 77:23 \n12 B2 K3PO4 toluene 25 55 81:19 \n13 B2 Cs2CO3 toluene 25 61 81:19 \n14 B2 Cs2CO3 toluene (0.1 M) 25 75 73:27 \na Unless otherwise stated, all reactions were carried out by stirring 1a (0.1 mmol), the \nallenoate (2 eq.), the indicated base and the catalyst, in the given solvent ( 0.05 M \nbased on 1a) at the given T for 24 h.  \nb Isolated yield. \nc Determined by HPLC using a chiral stationary phase  ((-)-5a was obtained as the \nmajor enantiomer when using the (R,R)-configurated catalysts B).  \n \nWith optimized conditions for the synthesis of enantioenriched (-)-5a at hand, we next \ninvestigated the generality of this protocol. As outlined in Scheme 2, differently \nsubstituted allenoates were reasonably well tolerated (see products 5a-d), albeit some \nerosion in enantioselectivity was observed when using a t-butyl ester  containing \nallenoate (product 5d). Various -arylmethyl-substituted azlactones 1 performed \nsimilarly as compared to the parent system 1a (products 5e-I), and analogous -alkyl-\nsubstituted derivatives were reasonably well accepted too (5j-o). When varying the aryl \nsubstituent in position 2 of the oxazolone core (compare products 5a, 5g, and 5p) we \nfound that increasing the steric bulk (5p) leads to a somewhat lower enantioselectivity, \nwhile the methoxy -substituent does not have a strong impact on the yield. It should \nhowever be stated that some of the methoxy -containing products, i.e. the -alkyl-\nsubstituted 5j and 5k tend to undergo partial nucleophilic ring opening by residual water \nduring column chromatography. \n\n7 \n \nScheme 2: Application scope (conditions as detailed in entry 13, Table 1). \n \nFinally, we also tested the suitability of products 5 to access acyclic -AA derivatives \nby means of nucleophilic azlactone-opening reactions. Gratifyingly primary amines can \nbe easily utilized under reflux conditions to access the amide derivatives 6a and 6b \nstraightforwardly (Scheme 3), thus demonstrating the versatility of compounds 5 to \naccess more complex acyclic -AA derivatives in a straightforward manner. \n \n  \nScheme 3: Azlactone opening reactions. \n \n\n\n8 \nConclusion \nThe development of novel catalytic methods for the asymmetric synthesis of non -\nnatural amino acid derivatives is a contemporary ta sk and we herein introduce an \norganocatalytic protocol for the -selective addition of various azlactones 1 to \nallenoates 3. Upon using Maruoka’s spirocyclic binaphthyl -based quaternary \nammonium salts B as catalysts this transformation can be achieved with \nenantioselectivities up to 83:17 e.r.. Furthermore, the herein accessed cyclic products \n5 could be successfully engaged in ring-opening reactions with different amines, thus \ngiving access to the acyclic -amino acid-based amides 6 straightforwardly.  \nExperimental \nGeneral details \n1H-,13C- spectra were recorded on a Bruker Avance III 300 MHz spectrometer with a \nbroad band observe probe. All NMR spectra were referenced on the solvent residual \npeak (CDCl3: δ 7.26 ppm for 1H NMR and δ 77.16 ppm for 13C NMR). NMR data are \nreported as follows: c hemical shift (δ ppm), multiplicity (s = singlet, d = doublet, t = \ntriplet, q = quartet, m = multiplet, dd = doublet of doublet), coupling constants (Hz). \nHigh resolution mass spectra were obtained using a Thermo Fisher Scientific LTQ \nOrbitrap XL with an I on Max API Source and analyses were made in the positive \nionization mode if not otherwise stated. \nHPLC was performed using a Shimadzu Prominence system with a diode array \ndetector with a CHIRALPAK AD-H, CHIRAL ART Amylose-SA, (250 × 4.6 mm, 5 µm) \nchiral st ationary phase. Optical rotations were recorded on a Schmidt + Haensch \nPolarimeter Model UniPol L1000 at 589 nm ([α]D values are listed in deg/(dm(g/cm3)); \nconcentration c is given in g/100 mL).  \n\n9 \nUnless otherwise stated, all chemicals were purchased from commercial suppliers and \nused without further purification. Dry solvents were obtained from an MBraun-SPS-800 \nsolvent purification system. All reactions were carried out under argon atmosphere \nunless stated otherwise. \nAzlactones 1 and allenoates 3 were synthesized according to previously published \nprocedures [18,42-44]. \n \nGeneral Procedure \nAn oven-dried Schlenk tube equipped with a stirring bar was charged with the \nazlactone 1 (0.05 – 0.1 mmol), catalyst B2 (10 mol% related to 1), and Cs2CO3 (3 eq.). \nThen the respective allenoate 3 (2 eq.) and toluene (0.05 M with respect to 1) were \nadded and the mixture was stirred at room temperature for 24 h (Ar atmosphere). The \ncrude product was passed through a short column of silicagel (rinsed with DCM and \nEtOAc), concentrated under reduced pressure , and subsequently purified by \npreparative TLC (silica gel, heptanes/EtOAc = 4/1) to obtain the products 2 in the given \nyields and enantiopurities. \n \nDetails for the parent compound 5a (details for the other targets can be found in the \nonline supporting information)  \nObtained as a colorless oil in 61% yield (81:19 e.r.) on 0.1 mmol scale. [ ]D22 = -11.4 \n(c 1.1, CHCl3); 1H-NMR (300 MHz, CDCl 3, 298.0 K): δ / ppm = 7.85 (2H, dd, J = 8.6, \n1.4 Hz), 7.54 (1H, t, J = 7.4 Hz), 7.43 (2H, t, J = 7.53 Hz), 7.24-7.11 (5H, m), 5.79 (1H, \ns), 5.37 (1H, s), 4.14-3.90 (2H, m), 3-52-3.16 (4H, m), 1.15 (3H, t, J = 7.1 Hz); 13C NMR \n(75 MHz, CDCl3, 298.0 K): δ / ppm = 177.4, 171.0, 160.3, 139.1, 133.8, 132.6, 130.5, \n128.6, 128.0, 127.8, 127.3, 125.6, 118.1, 75.9, 60.9, 44.9, 39.3, 13.9; HRMS (ESI) m/z: \ncalculated for [C 22H21NO4 + H] +: 364.1543; found: 364.1554, HPLC: (Chiralpak SA, \n\n10 \neluent: n-hexane:i-PrOH = 100/2, 0.5 mL· min-1, 20 °C,   = 254 nm) retention times: \ntmajor = 16.15 min , tminor = 17.00 min. \n \nSupporting Information  \nFull experimental and analytical details and copies of NMR spectra and HPLC traces \ncan be found in the online supporting information. \nAcknowledgements \nWe are grateful to Prof. Dr. Himmelsbach (Institute of Analytical Chemistry, JKU Linz) \nfor support with HRMS analysis. \n \nFunding \nThe used NMR spectrometers were acquired in collaboration with the University of \nSouth Bohemia (CZ) with financial support from the European Union through the EFRE \nINTERREG IV ETC-AT-CZ program (project M00146, \"RERI-uasb\").  \n \nReferences \n1. 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Žabka, M.; Kocian, A.; Bilka, S.; Andrejčák, S.; Šebesta, R. Eur. J. Org. Chem. \n2019, 6077.","source_license":"CC-BY-4.0","license_restricted":false}