Towards an Asymmetric β-Selective Addition of Azlactones to Allenoates

We herein report the asymmetric organocatalytic addition of azlactones to allenoates. Upon using chiral quaternary ammonium salt catalysts, i.e. Maruoka’s binaphthyl- based spirocyclic ammonium salts , the addition of various azlactones to allenoates proceeds in a -selective manner with moderate levels of enantioselectivities (up to 83:17 e.r.). Furthermore, the obtained products can be successfully engaged in nucleophilic ring opening reactions, thus giving highly functionalized -amino acid derivatives.

organocatalysis; quaternary ammonium salt catalysis; azlactones; allenoates; amino acids 2

The development of asymmetric syntheses routes to access non-natural amino acids has for decades been one of the most heavily investigated tasks in organic synthesis and catalysis-oriented research [1-13]. As a consequence, a broad variety of conceptually orthogonal strategies to access differently functionalized non -natural - amino acids (-AA) [2-7] as well as -amino acids (-AA) [8-13] have been introduced and there is still considerable interest in the development of new concepts and syntheses approaches. Our group has a longstanding focus on the development of asymmetric organocatalytic methods to access non-natural chiral - and -AA [14-19]. Hereby we are especially interested in utilizing simple (prochiral) starting materials and carry out stereoselective -functionalizations by reacting them with suited C - or heteroatom electrophiles. -Amino acid-derived azlactones 1 are amongst the most commonly utilized starting materials to access more diverse chiral -disubstituted amino acids (Scheme 1A) [20-22]. More specifically, these compounds can be engaged for a variety of asymmetric -carbo- and -heterofunctionalization reactions by utilizing different catalysis strategies [20-22]. We have recently carried out systematic investigations concerning the synthes es of advanced -AA by means of asymmetric -carbofunctionalization reactions and during these studies we also realized that the masked -AA derivatives 2 undergo enantioselective -addition to allenoates 3 under chiral ammonium salt catalysis (Scheme 1B) [18]. Interestingly, hereby we also found that the use of alternative catalyst systems (i.e. tert. phosphines) allows for a -selective addition of 2 to the allenoate instead, thus resulting in tw o complementary catalyst -controlled pathways [18]. Based on these previous results, and also the well -documented different reactivity trends of allenoates 3 when using 3 different organocatalysts and activation modes [23-27], we were thus wondering if we could extend this ammonium salt catalyzed -selective allenoate functionalization strategy to other amino acid classes. Azlactones 1 have previously been used for - selective additions to allenoates under chiral phosphine catalysis [28]. In addition, glycine Schiff base derivatives [ 29] as well as -amino acid based thiazol -ones [30] have successfully been used for asymmetric -selective additions to allenoates when using chiral ammonium salt catalysts or chiral organobase catalysts . However, to the best of our knowledge the -selective asymmetric addition of azlactones 1 to allenoates 3 delivering highly functionalized ,-disubstituted -amino acid derivatives 5 has so far not been systematically addressed (for recent other -selective additions of enolate precursors to allenoates please see Ref. [31-34]). Thus, we now became interested in testing this transformation under asymmetric ammonium salt catalysis [35-38] and the

of these investigations are outlined in this contribution (Scheme 1C). 4 Scheme 1: General use of azlactones 1 to access more advance AA derivatives (A), our recently reported ammonium salt-catalyzed -selective addition of compounds 2 to allenoates 3 (B), and the herein investigated -selective addition of azlactones 1 to allenoates 3 (C).

and Discussion We started our investigations by testing the quat. ammonium salt-catalyzed addition of azlactone 1a to allenoate 3a (Table 1 gives an overview of the most significant results obtained hereby). First experiments using Cinchona alkaloid -based quat. ammonium salts A showed that the expected -addition product 5a can be accessed under typical phase-transfer conditions, but with low selectivities and yields only when using these catalysts (entries 1-4, other Cinchona derivatives were tested too but did not allow for any improvement ). Using the established and commercially available Maruoka catalysts B1 and B2 [39] next turned out to be more promising (entries 5-10). Testing the bis-CF3-substitued B1 first allowed for 75:25 e.r., but with moderate yield only when carrying out the reaction in toluene in the presence of 3 eq. of K2CO3 (entry 5). Lower amounts of base (entry 6) or other solvents, as exemplified for CH2Cl2 (entry 7, similar non-selective results were obtained when using THF), were found to be less -suited however. Testing the 3,4,5 -trifluorobenzene-decorated catalyst B2 with K 2CO3 in toluene next (entry 8) allowed for a slightly higher selectivity but still gave a relatively low yield only. Spirobiindane-based salts C emerged as promising alternative quaternary ammonium salt scaffolds recently [40,41] and were also the catalysts of choice in our recen tly developed -selective allenoate addition of isoxazolidinones 2 (compare with Scheme 1B [18]). Unfortunately, these catalysts were found to be less- suited for our azlactone protocol, as exemplified for derivative C1 (entry 9). 5 Accordingly, we carried out our final optimization using Maruoka’s catalyst B2 (entries 10-14). By testing different bases and lower temperatures as well as lower catalyst loadings we identified the use of 3 eq. Cs2CO3 in toluene (0.05 M) at room temperature as the best-suited conditions (entry 13), allowing for the synthesis of 5a in moderate yield (61%) and enantioselectivity (81:19 e.r.). Table 1: Optimization of the addition of azlactone 1a to allenoate 3aa. Entry Cat. Base solvent T [°C] Yieldb e.r.c 1 A1 K2CO3 toluene 25 41 58:42 2 A2 K2CO3 toluene 25 45 60:40 3 A3 K2CO3 toluene 25 40 58:42 4 A4 K2CO3 toluene 25 45 60:40 5 B1 K2CO3 toluene 25 55 75:25 6 B1 K2CO3 (1 eq.) toluene 25 20 72:28 7 B1 K2CO3 CH2Cl2 25 33 51:49 8 B2 K2CO3 toluene 25 50 80:20 9 C1 K2CO3 toluene 25 40 68:32 6 10 B2 K2CO3 toluene 0 45 80:20 11 B2 (5%) K2CO3 toluene 0 41 77:23 12 B2 K3PO4 toluene 25 55 81:19 13 B2 Cs2CO3 toluene 25 61 81:19 14 B2 Cs2CO3 toluene (0.1 M) 25 75 73:27 a Unless otherwise stated, all reactions were carried out by stirring 1a (0.1 mmol), the allenoate (2 eq.), the indicated base and the catalyst, in the given solvent ( 0.05 M based on 1a) at the given T for 24 h. b Isolated yield. c Determined by HPLC using a chiral stationary phase ((-)-5a was obtained as the major enantiomer when using the (R,R)-configurated catalysts B). With optimized conditions for the synthesis of enantioenriched (-)-5a at hand, we next investigated the generality of this protocol. As outlined in Scheme 2, differently substituted allenoates were reasonably well tolerated (see products 5a-d), albeit some erosion in enantioselectivity was observed when using a t-butyl ester containing allenoate (product 5d). Various -arylmethyl-substituted azlactones 1 performed similarly as compared to the parent system 1a (products 5e-I), and analogous -alkyl- substituted derivatives were reasonably well accepted too (5j-o). When varying the aryl substituent in position 2 of the oxazolone core (compare products 5a, 5g, and 5p) we found that increasing the steric bulk (5p) leads to a somewhat lower enantioselectivity, while the methoxy -substituent does not have a strong impact on the yield. It should however be stated that some of the methoxy -containing products, i.e. the -alkyl- substituted 5j and 5k tend to undergo partial nucleophilic ring opening by residual water during column chromatography. 7 Scheme 2: Application scope (conditions as detailed in entry 13, Table 1). Finally, we also tested the suitability of products 5 to access acyclic -AA derivatives by means of nucleophilic azlactone-opening reactions. Gratifyingly primary amines can be easily utilized under reflux conditions to access the amide derivatives 6a and 6b straightforwardly (Scheme 3), thus demonstrating the versatility of compounds 5 to access more complex acyclic -AA derivatives in a straightforward manner. Scheme 3: Azlactone opening reactions. 8

The development of novel catalytic methods for the asymmetric synthesis of non - natural amino acid derivatives is a contemporary ta sk and we herein introduce an organocatalytic protocol for the -selective addition of various azlactones 1 to allenoates 3. Upon using Maruoka’s spirocyclic binaphthyl -based quaternary ammonium salts B as catalysts this transformation can be achieved with enantioselectivities up to 83:17 e.r.. Furthermore, the herein accessed cyclic products 5 could be successfully engaged in ring-opening reactions with different amines, thus giving access to the acyclic -amino acid-based amides 6 straightforwardly. Experimental General details 1H-,13C- spectra were recorded on a Bruker Avance III 300 MHz spectrometer with a broad band observe probe. All NMR spectra were referenced on the solvent residual peak (CDCl3: δ 7.26 ppm for 1H NMR and δ 77.16 ppm for 13C NMR). NMR data are reported as follows: c hemical shift (δ ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublet), coupling constants (Hz). High resolution mass spectra were obtained using a Thermo Fisher Scientific LTQ Orbitrap XL with an I on Max API Source and analyses were made in the positive ionization mode if not otherwise stated. HPLC was performed using a Shimadzu Prominence system with a diode array detector with a CHIRALPAK AD-H, CHIRAL ART Amylose-SA, (250 × 4.6 mm, 5 µm) chiral st ationary phase. Optical rotations were recorded on a Schmidt + Haensch Polarimeter Model UniPol L1000 at 589 nm ([α]D values are listed in deg/(dm(g/cm3)); concentration c is given in g/100 mL). 9 Unless otherwise stated, all chemicals were purchased from commercial suppliers and used without further purification. Dry solvents were obtained from an MBraun-SPS-800 solvent purification system. All reactions were carried out under argon atmosphere unless stated otherwise. Azlactones 1 and allenoates 3 were synthesized according to previously published procedures [18,42-44]. General Procedure An oven-dried Schlenk tube equipped with a stirring bar was charged with the azlactone 1 (0.05 – 0.1 mmol), catalyst B2 (10 mol% related to 1), and Cs2CO3 (3 eq.). Then the respective allenoate 3 (2 eq.) and toluene (0.05 M with respect to 1) were added and the mixture was stirred at room temperature for 24 h (Ar atmosphere). The crude product was passed through a short column of silicagel (rinsed with DCM and EtOAc), concentrated under reduced pressure , and subsequently purified by preparative TLC (silica gel, heptanes/EtOAc = 4/1) to obtain the products 2 in the given yields and enantiopurities. Details for the parent compound 5a (details for the other targets can be found in the online supporting information) Obtained as a colorless oil in 61% yield (81:19 e.r.) on 0.1 mmol scale. [ ]D22 = -11.4 (c 1.1, CHCl3); 1H-NMR (300 MHz, CDCl 3, 298.0 K): δ / ppm = 7.85 (2H, dd, J = 8.6, 1.4 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, s), 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 (75 MHz, CDCl3, 298.0 K): δ / ppm = 177.4, 171.0, 160.3, 139.1, 133.8, 132.6, 130.5, 128.6, 128.0, 127.8, 127.3, 125.6, 118.1, 75.9, 60.9, 44.9, 39.3, 13.9; HRMS (ESI) m/z: calculated for [C 22H21NO4 + H] +: 364.1543; found: 364.1554, HPLC: (Chiralpak SA, 10 eluent: n-hexane:i-PrOH = 100/2, 0.5 mL· min-1, 20 °C,  = 254 nm) retention times: tmajor = 16.15 min , tminor = 17.00 min. Supporting Information Full experimental and analytical details and copies of NMR spectra and HPLC traces can be found in the online supporting information.

We are grateful to Prof. Dr. Himmelsbach (Institute of Analytical Chemistry, JKU Linz) for support with HRMS analysis. Funding The used NMR spectrometers were acquired in collaboration with the University of South Bohemia (CZ) with financial support from the European Union through the EFRE INTERREG IV ETC-AT-CZ program (project M00146, "RERI-uasb").

1. Hughes A. (Ed.) Amino Acids, Peptides and Proteins in Organic Chemistry, Vol 1-5; Wiley-VCH: Weinheim, 2009. 2. Soloshonok, V. A.; Izawa K. (Eds) Asymmetric Synthesis and Application of - Amino Acids; American Chemical Society, Washington DC, 2009. 11 3. O’Donnell, M. J. (Ed.) -Amino Acid Synthesis, Tetrahedron Symposia-in-Print, No. 33; Pergamon, Oxford, 1988. 4. Najera, C.; Sansano, J. M. Chem. Rev. 2007, 107, 4584. 5. Metz, A. E.; Kozlowski, M. C, J. Org. Chem. 2015, 80, 1. 6. Vogt, H.; Bräse, S. Org. Biomol. Chem. 2007, 5, 406. 7. Cativiela, C.; Ordonez, M. Tetrahedron: Asymmetry, 2009, 20, 1. 8. Juaristi, E.; Lopez-Ruiz, H Curr. Med. Chem. 1999, 6, 983. 9. Abele, S.; Seebach, D. Eur. J. Org. Chem. 2000, 1. 10. Juaristi, E.; Soloshonok, V. A. (Eds.), Enantioselective Synthesis of -Amino Acids, Second Edition; John Wiley & Sons, 2005. 11. Weiner, B.; Szymanski, W.; Janssen, D. B.; Minnaard, A. J.; Feringa, B. L. Chem. Soc. Rev. 2010, 39, 1656. 12. Ashfaq, M.; Tabassum, R.; Ahmad, M. M.; Hassan, N. A.; Oku, H.; Rivera, G. Med. Chem. 2015, 5, 295. 13. Noda, H.; Shibasaki, M. Eur. J. Org. Chem. 2020, 2350. 14. Tiffner, M.; Novacek, J.; Busillo, A.; Gratzer, K.; Massa, A.; Waser, M. RSC Adv. 2015, 5, 78941. 15. Eitzinger, A.; Winter, M.; Schörgenhumer, J.; Waser, M. Chem. Commun. 2020, 56, 579. 16. Zebrowski, P.; Eder, I.; Eitzinger, A.; Mallojjala, S. C.; Waser, M. ACS Org. Inorg. Au 2022, 2, 34. 17. Haider, V.; Zebrowski, P.; Michalke, J.; Monkowius, U.; Waser, M. Org. Biomol. Chem. 2022, 20, 824. 18. Zebrowski, O.; Röser, K.; Chrenko, D.; Pospisil, J.; Waser, M. Synthesis 2023,55, 1706. 12 19. Stockhammer, L.; Craik, R.; Monkowius, U.; Cordes, D. B.; Smith, A. D.; Waser, M. ChemistryEurope 2023 1, e202300015. 20. Alba, A.-N. R.; Rios, R. Chem. Asian J. 2011, 6, 720. 21. de Castro, P. P.; Carpanez, A. G.; Amarante, G. W. Chem. Eur. J. 2016, 22, 10294. 22. Marra, I. F. S.; de Castro, P. P.; Amarante, G. W. Eur. J. Org. Chem. 2019, 5830. 23. Li, X.; Zhang, C.; Xu, Z. Acc. Chem. Res., 2001, 34, 535. 24. Cowen, B. J.; Miller, S. J. Chem. Soc. Rev. 2009, 38, 3102. 25. Yu, S.; Ma, S. Angew. Chem., Int. Ed. 2012, 51, 3074. 26. Fan, Y. C.; Kwon, O. Chem. Commun., 2013, 49, 11588. 27. Wang, Z.; Xu, X.; Kwon, O. Chem. Soc. Rev. 2014, 43, 2927. 28. Wang, T.; Yu, Z.; Hoon, D. L.; Phee, C. Y.; Lan, Y.; Lu, Y. J. Am. Chem. Soc. 2016, 138, 265. 29. Elsner, P.; Bernardi, L.; Dela Salla, G.; Overgaard, J.; Jørgensen, K. A. J. Am. Chem. Soc. 2008, 130, 4897. 30. Uraguchi, D.; Kawai, Y.; Sasaki, H.; Yamada, K.; Ooi, T. Chem. Lett. 2018, 47, 594. 31. Shu, L.; Wang, P.; Gu, C.; Liu, W.; Alabanza, L. M.; Zhang, Y. Org. Process Res. Dev. 2013, 17, 651. 32. Jin, N.; Misaki, T.; Sugimura, T. Chem. Lett. 2013, 42, 894. 33. Vaishanv, N. K.; Zaheer, M. K.; Kant, R.; Mohanan, K. Eur. J. Org. Chem. 2019, 6138. 34. Liu, Y.-Y.; Wang, X.-P.; Wei, J.; Li, Y. Tetrahedron 2022, 103, 132577. 35. Shirakawa, S.; Maruoka, K. Angew. Chem., Int. Ed., 2013, 52, 4312. 36. Qia, D.; Sun, J. Chem. Eur. J. 2019, 25, 3740. 13 37. Albanese, D. C. M.; Penso, M. Eur. J. Org. Chem. 2023, 26, e202300224 38. Otevrel, J.; Waser, M. ‘Asymmetric Phase-Transfer Catalysis- From Classical Applications to New Concepts’ in ‘Asymmetric Organocatalysis: New Strategies, Catalysts, and Opportunities’ Albrecht, L.; Albrecht, A.; Dell'Amico, L. (Eds.) 2023, 71-120, Wiley-VCH. 39. Lee, H.-J.; Maruoka, K. Chem. Rec. 2023, 23, e202200286. 40. Xu, C.; Qi, Y.; Yang, X.; Li, X.; Li, Z.; Bai, L. Org. Lett. 2021, 23, 2890. 41. Xu, C.; Yang, X., Synlett 2022, 33, 664. 42. Macovei, C.; Vicennati, P.; Quinton, J.; Nevers, M. -C.; Volland, H.; Créminon, C.; Taran, F. Chem. Commun. 2012, 48, 4411. 43. de Mello, A. C.; Momo, P. B.; Burtoloso, A. C. B.; Amarante, G. W. J. Org. Chem. 2018, 83, 11399. 44. Žabka, M.; Kocian, A.; Bilka, S.; Andrejčák, S.; Šebesta, R. Eur. J. Org. Chem. 2019, 6077.