Asymmetric cross-aldol reactions of α-keto hydrazones and α,β-unsaturated γ-keto hydrazones with trifluoromethyl ketones

Depósito de investigación de la Universidad de Sevilla https://idus.us.es/ “This is an Accepted Manuscript of an article published in CHEMICAL COMMUNICATIONS on 18 November 2021, available at https://doi.org/10.1039/d1cc05014a .” COMMUNICATION Please do not adjust margins Please do not adjust margins Received 00th January 20xx, Accepted 00th January 20xx DOI: 10.1039/x0xx00000x Asymmetric cross-aldol reaction of α-keto hydrazones and α,βunsaturated γ-keto hydrazones with trifluoromethyl ketones Saúl Alberca,a Esteban Matador,a Javier Iglesias-Sigüenza,a Mª de Gracia Retamosa,*,a,b Rosario Fernández,*,a José M. Lassaletta*,c and David Monge,*,a α-Keto hydrazones and α,β-unsaturated γ-keto hydrazones are suitable pro-nucleophiles for the asymmetric cross-aldol reaction with trifluoromethyl ketones via aza-di(tri)enamine-type intermediates. Quinidine-derived primary amine catalyst affords tertiary trifluoromethylated alcohols in good-to-excellent yields and high enantioselectivities. Subsequent transformations of hydrazono moieties yield appealing fluorinated carboxylic acids, 1,4-dicarbonyls and γ-keto acids. Fluorinated compounds play a pivotal role in different fields, including pharmaceutical,1 agricultural2 and material science.3 In particular, tertiary alcohols bearing CF3 groups in combination with other functionalities appear as key building blocks for accessing biologically active targets. The structures shown in Figure 1, including reverse transcriptase inhibitors such as approved Efavirenz A4 and related anti-VIH drugs such as B or C,5 a platelet-activating factor antagonist D6 and nonsteroidal glucocorticoid agonist E7 are just a set of selected examples. Accordingly, considerable efforts have been made to access precursors of these trifluoromethylated tertiary alcohols in a catalytic enantioselective way.8 Straightforward approaches to build up such molecular scaffolds rely on the asymmetric cross-aldol reactions of simple ketone pronucleophiles with trifluoromethyl ketones.9 However, the range of compatible donors is still limited to aliphatic ketones, 9a-c aryl ketones,9e,g o-hydroxyaryl ketones,9f allyl arylketones9h and a few others.10 In order to expand the synthetic repertoire, the N O Ph CF3 OH N NMe N D: PAF antagonist F3C O N HO Cl OH O F3C O N HO Cl A:Efavirenz,anti-VIH F3C O N HO MeO OH B:Anti-VIH C:Anti-VIH E: Glucocorticoid agonist N H OH F3C NC O SO2Me Fig . 1. Selected bioactive trifluoromethyl tertiary alcohols. incorporation of ready-to-functionalize ketones as enamine precursors was envisioned as an appealing strategy. During years, we have exploited hydrazones as versatile reagents in organic synthesis;11 acting as carbon πnucleophiles12 or iminetype electrophiles,13 enabling distinctive transformations. Enalderived hydrazones, reacting as aza-dienes or C3-nucleophiles, offer an appealing platform to introduce easy-to-modify carbon skeletons in diverse substrates, albeit with relatively scarce implementation in asymmetric catalysis.14 As a complementary approach, we have recently reported on α-keto hydrazones 1 as precursors of β-amino aza-dienamine intermediates (Int-1, scheme 1), formed upon activation by multifunctional primary amine catalysts, and their 1,4-addition to nitroalkenes.15 Regarding the reagent design, it was demonstrated that the N,N-di(alkyl/aryl)amino group served as reactivity modulator (conjugative effect and control of conformational space), influencing also the stereochemical outcome of the process through steric effects and secondary non-covalent interactions with the catalysts. In this communication, we present our results on the asymmetric cross-aldol addition of α-keto hydrazones 1 to trifluoromethyl ketones 2 for the synthesis of densely functionalized trifluoromethyl alcohols 3, useful intermediates for diversity- and target-oriented synthesis. a.Departamento de Química Orgánica, Universidad de Sevilla and Centro de Innovación en Química Avanzada (ORFEO−CINQA), C/ Prof. García González, 1, 41012 Sevilla, Spain. E-mail: [email protected], [email protected] b.Departamento de Química Orgánica e Instituto de Síntesis Orgánica, Universidad de Alicante 03080-Alicante, Spain. Centro de Innovación en Química Avanzada (ORFEO-CINQA). E-mail: [email protected] c. Instituto de Investigaciones Químicas (CSIC-US) and Centro de Innovación en Química Avanzada (ORFEO−CINQA), Avda. Américo Vespucio, 49, 41092 Sevilla, Spain. E-mail: [email protected] † Electronic Supplementary Information (ESI) available: Experimental procedures, optimization experiments, characterization data, NMR spectra for new compounds and HPLC traces. CCDC 2098150, 2098151, 2098152, 2098153. For ESI and crystallographic data in CIF or other electronic format see: DOI: 10.1039/x0xx00000x Page 1 of 4 ChemComm ChemComm Accepted Manuscript Published on 15 October 2021. Downloaded by Universidad de Alicante on 10/21/2021 2:13:03 PM. View Article Online DOI: 10.1039/D1CC05014A COMMUNICATION Journal Name 2 | J. Name., 2012, 00, 1-3 This journal is © The Royal Society of Chemistry 20xx Please do not adjust margins Please do not adjust margins N N O R1 R2R3CF3 O R3 CF3 OH O N N R2 R1 Primary amine N N HN R1 R2 R 1 2 3 Int-1 Reactivity/selectivity modulator Synthetically useful intermediates catalysis Scheme 1. Cross-aldol reaction of α-keto hydrazones 1 with trifluoromethyl ketones 2. The cross-aldol reaction of (E)-1-(piperidin-1-ylimino)propan-2- one (1A) with 2,2,2-trifluoroacetophenone (2a) in toluene at room temperature was initially investigated (see the ESI†). A variety of proline derivatives and primary amines were evaluated as catalysts in combination with benzoic acid (BA) as co-catalyst. Quinine-derived Ia (20 mol%) allowed up to 65% conversion to the aldol product 3Aa in 82% ee after 48 hours (Table 1, entry 1). Cupreine-derived Ib showed a low catalytic activity (entry 2) while quinidine-derived II provided similar conversion than Ia in higher 90% ee (entry 3).16 The solvent had a significant impact in the reaction outcome (see the ESI†). Remarkably, in pure water the aldol reaction proceeded in full conversion after 36 hours, albeit in slightly lower 84% ee (entry 4).17 Further optimizations of the reaction conditions at 0.2 mmol scale led to the use of salicylic acid (SA) as co-catalyst (40 mol%) in toluene/H2O (8:1) as the optimal solvent mixture to afford 3Aa in full conversion and 92% ee (entry 5). Moreover, the catalyst loading could be reduced to 10 mol% of the preformed, crystalline and easy-to-handle, II(SA)2 salt without compromising conversion or enantioselectivity (entry 6). Table 1. Optimization of a model reaction.a Cat* (20 mol%) Solvent (1M), rt N N O +Ph CF3 ON O Ph CF3 OH 2a N 1A 3Aa N RO N H2N N MeO N H2N Ia: R = Me Ib: R = H PhCOOH (20 mol%) Cat* = II Entry Catalyst Solvent time (h) Conv. (%)b ee (%)c 1 Ia Toluene 48 65 82 2 Ib Toluene 48 <10 66 3 II Toluene 48 55 90 4 II H2O 36 >95 84 5 d,e II Toluene/H2Of 48 >95 92 6 d,g II Toluene/H2Of 48 >95 92 a Reactions conditions: 1A (0.2 mmol), 2a (0.1 mmol), catalyst I-II (20 mol%) and benzoic acid (20 mol%) in solvent (1M) at room temperature. b Estimated by 1H- NMR. c Determined by HPLC on chiral stationary phases. d 0.2 mmol scale. e SA (40 mol%). f Toluene/H2O (8:1). g II(SA)2 salt (10 mol%). Next, the influence of the amino group (NR1R2) of the α-keto hydrazone 1 was examined (Scheme 2). Morpholine-derived reagent 1B was slightly better than 1A, affording the aldol adduct 3Ba in excellent 98% yield and 93% ee. (S)-3Ha: R = Ph 99%, 88% ee, 2 d (S)-5b 98%, 86% ee, 3 d N N O Ph CF3 OH BnO (S)-7 92%, 79% ee O Ph CF3 OH MeO OMe N X (S)-3Aa: X = CH2 94%, 92% ee, 2 d (S)-3Ba: X = O 98%, 93% ee, 2 d N Me Me (S)-3Cab 99%, 83% ee, 7 d (S)-3Da:bn = 1 94%, 89% ee, 7 d (S)-3Ea:bn = 3 99%, 83% ee, 7 d N Ph Ph (S)-3Fab 99%, 78% ee, 3 d Z = O MeO OMe 6 N Ph R (S)-3Ga: R = CH3 98%, 92% ee, 2 d II(SA)2 (10 mol%) Toluene/H2O 8:1 rt, time (d) N Z O +Ph CF3 ON O Ph CF3 OH 2a Z 1A-H: Z = NR1R2 4: Z = OBn 3Aa-Ha: Z = NR1R2 5: Z = OBn n II(SA)2 (20 mol%) Toluene/H2O 8:1 rt, 3 d +Ph CF3 O 2a Scheme 2. Evaluation of different pro-nucleophiles. a Reactions conditions: 1A-H, 4 or 6 (0.4 mmol), 2a (0.2 mmol), II(SA)2 salt (10 mol%) in toluene/H2O (8:1, 1M) at room temperature. b II(SA)2 salt (20 mol%). Yields (isolated products after flash column chromatography), enantiomeric excesses (ee, determined by HPLC analysis) and reaction times shown for each product. However, reagents 1C (bearing two methyl groups at positions 2 and 5 of the piperidine ring), or five- and seven-membered ring 1D and 1E, respectively, showed a reduced reactivity, requiring 20 mol% of catalyst loading and 7 days to generate aldol adducts 3Ca-Ea in 94-99% yields, also in lower enantioselectivities (83-89% ee). Dibenzyl hydrazine derived 1F also required 20 mol% of catalyst to provide, after 3 days, 3Fa in 99% yield, albeit with the lowest enantioselectivity of the series (78% ee). Finally, hydrazones containing at least one phenyl group at the amino nitrogen, 1G (NPhMe) and 1H (NPh2), were as reactive than six-membered ring reagents 1A and 1B, providing alcohols 3Ga and 3Ha in excellent yields and up to 92% ee for 3Ga. These results confirmed the influence by the different amino groups in the reactivity and enantioselectivity of the process. The amino group in the α-keto hydrazone could be also replaced by a benzyloxy group as in reagent 4, providing a level of reactivity similar to that observed for N,N- dibenzylamino derivative 1F: employing 20 mol% of catalyst, product 5 was isolated after 3 days in 98% yield and 86% ee. A comparative experiment performed with commercially available pyruvic aldehyde dimethyl acetal 618 and 20 mol% of catalyst II(SA)2 afforded the expected product 7 in 92% yield and 79% ee after 3 days. This result confirms that optimal α-keto hydrazones 1A,B,G,H clearly outperform ketone 6 as pronucleophiles in this context. The scope of the reaction was then investigated with α-keto hydrazones 1A,B,G and diverse trifluoromethyl ketones 2a-i (Scheme 3). In general, the aldol reaction proceeded smoothly and the expected alcohols 3 were obtained in good yields (83-99%) and high enantioselectivities (85-95% ee). The reaction rates correlate with the electronic and steric properties of the starting ketones. Page 2 of 4ChemComm ChemComm Accepted Manuscript Published on 15 October 2021. Downloaded by Universidad de Alicante on 10/21/2021 2:13:03 PM. View Article Online DOI: 10.1039/D1CC05014A Journal Name COMMUNICATION This journal is © The Royal Society of Chemistry 20xx J. Name., 2013, 00, 1-3 | 3 Please do not adjust margins Please do not adjust margins II(SA)2(10 mol%) 8:1 Toluene/H2O rt, time (d) N N O N O R3 CZF2 OH N 3A,B,G +R3CZF2 O 1A,B,G 2b-j, Z = F 2k, Z = H (S)-3Ab: X = CH2, Y = F, 93%, 94% ee (1 d) (S)-3Bb: X = O, Y = F, 98%, 94% ee (1 d) (S)-3Ac: X = CH2, Y = Me, 93%, 92% ee (3 d) (S)-3Bc: X = O, Y = Me, 94%, 92% ee (2 d) (S)-3Bd: X = O, Y = OMe, 96%, 95% eeb(3 d) (S)-3Ae: X = CH2, 83%, 90% eeb (5 d) (R)-3Ah: X = CH2, 90%, 87% eeb(5 d) (R)-3Bf: X = O, 94%, 83% ee (2 d) (S)-3Bg: X = O, 85%, 91% ee (2 d) (S)-3Bk: 98%, 88% eeb(2 d) N N O Ph CHF2 OH O (S)-3Gb: Y = F, 92%, 95% ee (1 d) (S)-3Gc: Y = Me, 99%, 90% ee (2 d) (S)-3Ge: 92%, 92% eeb(5 d) (R)-3Gi: 81%, 87% eeb (7 d) N N O R3 CF3 OH X O iPr iPr S N N O R3 CF3 OH Ph Me Y R3= R1 R2 R1 R2 Y R3= O iPr iPr Scheme 3. Scope of the reaction.a Reaction conditions: 1A,B; 1G (0.4 mmol), 2 (0.2 mmol), II(SA)2 salt (10 mol%) in toluene/H2O (8:1, 1M) at room temperature. b II(SA)2 salt (20 mol%). Substrate 2b, carrying an electron-poor aryl group, reacted faster than 2a, while substrates 2c,d, carrying electron-rich aryl groups, required longer times for completion (2-3 days). A challenging allyl-protected propofol19 derivative 2e was also tolerated, although 20 mol% of II(SA)2 and a longer reaction time (5 days) were required. Interestingly, 2-furyl and alkenylsubstituted trifluoromethyl ketones 2f and 2g were also suitable substrates, yielding 3Bf and 3Bg in 83% and 91% ee, respectively. Alkyl-substituted trifluoromethyl ketones 2h-i underwent the aldol reaction slower than aryl substituted trifluoromethyl ketones (5-to-7 days), requiring 20 mol% of catalyst loading to get 3Ah and 3Gi in good yields and enantioselectivities up to 87% ee. Unfortunately, a secondary (isopropyl) group in ketone 2j kills the reactivity (<10% conv. after 7 days, with 1A). Finally, employing 20 mol% of catalyst loading, the methodology could be also extended to the less reactive difluoromethylketone 2k, affording 3Bk in 98% yield and 88% ee. Finally, the influence of an additional C=C bond between the hydrazone moiety and the keto group was investigated. A first set of α,β-unsaturated γ-keto hydrazones 8A-E, bearing the most representative N,N-dialkyl(aryl)amino groups (piperidine, morpholine, NBn2, NMePh and NPh2) was synthesized by chemoselective mono-condensation of the corresponding hydrazines with (E)-4-oxopent-2-enal, obtained from commercially available 2-methylfuran, in good overall yields (see the ESI†). Under optimal conditions, the cross-aldol reaction of π-extended hydrazones 8A-E with 2a was studied (Scheme 4). Interestingly, the collected results showed up a (S)-9Ea: R = Ph 94%, 90% ee, 2 d N X(S)-9Aa:bX = CH2 26%, 89% ee, 7 d (S)-9Ba:bX =O 58%, 88% ee, 3 d N Ph Ph (S)-9Ca 94%, 90% ee, 2 d NR1R2= N Ph R (S)-9Da: R = Me 75%, 86% ee, 2 d + Ph CF3 O 2a 9Aa-Ea N N O Ph CF3 OH R1 R2 8A-E N N O R1 R2II(SA)2 (10 mol%) Toluene/H2O 8:1 rt, time (d) Scheme 4. Cross aldol reactions with π-extended α,β-unsaturated γ-keto hydrazones. a Reaction conditions: 8A-E (0.4 mmol), 2a (0.2 mmol), II(SA)2 salt (10 mol%) in toluene/H2O (8:1, 1M) at room temperature. b II(SA)2 salt (20 mol%). different reactivity trend in comparison with the previous αketohydrazones: piperidine- and morpholine-derived hydrazones 8A,B were the least reactive among this series, requiring 20 mol% of catalyst loading and longer reaction times (3-to-7 days) to afford adducts 9Aa and 9Ba in low-to-moderate yields, albeit in good enantioselectivities (88-89% ee). On the contrary, dibenzyl hydrazine-derived 8C, and aromatic derivatives 8D (NPhMe) and 8E (NPh2) provided comparable results, requiring just 10 mol% of catalyst loading to afford, in 2 days, the aldol adducts 9Ca-Ea in good yields (75-94%) and enantioselectivities (86-90% ee). To further demonstrate the synthetic value of the methodology, the syntheses of 3Aa (99%, 92% ee), 3Ba [98%, 92% ee; (47%, >99% ee after a single recrystallization)], 3Ga (84%, 93% ee), 9Ca (97%, 90% ee), and 9Ea (97%, 90% ee) were performed on 2 mmol scale under optimal reaction conditions. The structure of products (S)-3Ba, (S)-3Ga and (S)-9Ea was elucidated by XRD analysis, unequivocally confirming the absolute S configuration of the newly created stereogenic center, while those of other adducts 3 and 9 was assigned by analogy, assuming a uniform reaction pathway. The absolute configuration of (S)-7 was assigned by chemical correlation.18 Products 3 and 9 are valuable building blocks for diversity-oriented synthesis en route to biologically active molecules. Making use of the versatility of the hydrazono group, subsequent transformations were performed to access appealing trifluoromethylated compounds (Scheme 5). Oxidative cleavage of the 1,2-(aza)dicarbonylic moieties provides α-hydroxy α-trifluoromethyl carboxylic acids. Thus, morpholine-derived hydrazone (S)-3Ba was oxidized with the Jones reagent to afford the known carboxylic acid (S)-10, valuable building block for the synthesis of antagonist PAF D.6 α,β-Unsaturated γ-keto hydrazones (S)-9Ca and (S)-9Ea served as masked 1,4-dicarbonyl precursors. A 2-step C=C bond chemoselective hydrogenation/ hydrolysis of (S)-9Ca using SnCl2 as the reagent20 afforded γ-keto aldehyde (S)-11 in good overall yield (91%) and without erosion of enantioselectivity (90% ee). Starting from (S)-9Ea, Raney Ni-catalyzed C=C bond hydrogenation followed by oxidation afforded γ-keto acid (S)- 12 in good overall yield, also without racemization. Additionally, the same hydrogenation intermediate was subjected to C(sp2)- Page 3 of 4 ChemComm ChemComm Accepted Manuscript Published on 15 October 2021. Downloaded by Universidad de Alicante on 10/21/2021 2:13:03 PM. View Article Online DOI: 10.1039/D1CC05014A COMMUNICATION Journal Name 4 | J. Name., 2012, 00, 1-3 This journal is © The Royal Society of Chemistry 20xx Please do not adjust margins Please do not adjust margins CH trifluoromethylation employing Togni’s reagent under copper chloride catalysis21 to afford (bis)-trifluoromethylated hydrazone (E)-(S)-13 in good yield (73%, 2-steps) and 90% ee. (S)-9Ea, 90% ee (S)-9Ca, 90% ee N O Ph CF3 OH (S)-11, 91%, 90% ee O O Ph CF3 OH N O Ph CF3 OH i) H2, Raney Ni ii) Togni’s reagent CuCl (20 mol%) CHCl3, rt (E)-(S)-13, 73%, 90% ee NNPh2 O Ph CF3 OH F3C SnCl2(6 eq.) HCl (6M), THF, 0 °C N O Ph CF3 OH N O (S)-3Ba, 99% ee (S)-10, 58%, 99% ee HO O Ph CF3 OH ref 6b i) H2, Raney Ni ii) Jones Oxidation (S)-12, 63%, 90% ee O O Ph CF3 OH HO Jones Oxidation D Bn2N Ph2N N O Ph CF3 OH N NMe N Scheme 5. Synthetic transformations of hydrazones 3,9 In summary, α-keto hydrazones and α,β-unsaturated γ-keto hydrazones are suitable pro-nucleophiles for the asymmetric cross-aldol reaction with trifluoromethyl ketones. A quinidinederived primary amine/salicylic acid (1/2) salt in a watercontaining reaction media efficiently catalyzes this reaction, affording densely functionalized trifluoromethylated alcohols in good-to-excellent yields and enantioselectivities. Noteworthy, the nature of the amino group in the hydrazone moiety has a significant impact in the reactivity and stereochemical outcome of the process, highlighting the suitability of this tool for further reagent designs. This work was supported by the Spanish MICINN (grants PID2019-106358GB-C21, PID2019-106358GB-C22, and predoctoral fellowship to S.A), European FEDER funds and the Junta de Andalucía (Grants US-1262867, P18-FR-644, P18-FR- 3531). We also thank general NMR/MS/X-Ray services of the University of Sevilla. Conflicts of interest There are no conflicts to declare. Notes and references 1 (a) Y. Zhou, J. Wang, Z. Gu, S. Wang, W. Zhu, J. L. Aceña, V. A. Soloshonok, K. Izawa and H. Liu, Chem. Rev. 2016, 116, 422. (b) S. Purser, P. R. Moore, S. Swallow and V. Gouverneur, Chem. Soc. Rev. 2008, 37, 320. (c) I. Ojima, Fluorine in Medicinal Chemistry and Chemical Biology, Wiley-Blackwell: Chichester, U.K., 2009. 2 T. Hiyama, in Organofluorine Compounds: Chemistry and Applications; H. Yamamoto, Ed., Springer: New York, 2000. 3 R. Berger, G. Resnati, P. Metrangolo, E. Weber and J. Hulliger, Chem. Soc. Rev. 2011, 40, 3496. 4 S. Staszewski, J. Morales-Ramirez, K. T. Tashima, A. Rachlis, D. Skiest, J. Stanford, R. Stryker, P. Johnson, D. F. Labriola, D. Farina, D. J. Manion and N. M. Ruiz, N. Engl. J. Med. 1999, 341, 1865. 5 J. Valdez, PCT Appl. 2005, WO 2005062979 A2 20050714. 6 (a) E. Carceller, M. Merlos, M. Giral, C. Almansa, J. Bartrolí, J. García-Rafanell and J. Forn, J. Med. Chem. 1993, 36, 2984. (b) For a racemic synthesis, see: W. Jingjing, L. Feng, X. Yan, W. Juan, W. Ziyan, Y. Chengyu and L. Lantao, Chin. J. Org. Chem. 2018, 38, 1155. 7 R. Betageri, T. Gilmore, D. Kuzmich, T. M. Kirrane, J. Bentzien, D. Wiedenmeyer, J. Regan, A. J. Kukulka, T. N. Fadra, R. M. Nelson, L. Zuvela-Jelaska, D. Souza, J. Pelletier, J. Proudfoot, R. Dinallo, M. Panzenbeck, C. Torcellini, H. Lee, E. Pack, C. Harcken, G. Nabozny and D. S. Thomson, Bioorg. Med. Chem. Lett. 2011, 21, 6842. 8 Y. Zhu, J. Han, J. Wang, N. Shibata, M. Sodeoka, V. A. Soloshonok, J. A. S. Coelho and F. D. Toste, Chem. Rev. 2018, 118, 388. 9 Selected examples, via enamine: (a) L. H. Qiu, Z. X. Shen, C. Q. Shi, Y. H. Liu and Y. W. Zhang, Chin. J. Chem. 2005, 23, 584. (b) C. G. Kokotos, J. Org. Chem. 2012, 77, 1131. (c) H. Zong, H. Huang, G. Bian and L. Song, J. Org. Chem. 2014, 79, 11768. (d) Z. Jing, X. Bai, W. Chen, G. Zhang, B. Zhu and Z. Jiang, Org. Lett. 2016, 18, 260. (e) M. Lutete, T. Miyamoto, and T. Ikemoto, Tetrahedron Letters 2016, 57, 1220. (f) P. Wang, H.-F. Li, J.-Z. Zhao, Z.-H. Du and C.-S. Da, Org. Lett. 2017, 19, 2634; via enolate: (g) C. J. Thomson, D. M. Barber and D. J. Dixon, Angew. Chem. Int. Ed. 2020, 59, 5359. 10 J. H. Park, J. H. Sim and C. E. Song, Org. Lett. 2019, 21, 4567. 11 For reviews, see: (a) R. Brehme, D. Enders, R. Fernández and J. M. Lassaletta, Eur. J. Org. Chem. 2007, 5629. (b) M. de G. Retamosa, E. Matador, D. Monge, J. M. Lassaletta, R. Fernández, Chem. Eur. J. 2016, 22, 13430. 12 (a) R. P. Herrera, D. Monge, E. Martín-Zamora, R. Fernández, and J. M. Lassaletta, Org. Lett. 2007, 9, 3303. (b) A. Crespo- Peña, D. Monge, E. Martín-Zamora, E. Álvarez, R. Fernández, J. M. Lassaletta, J. Am. Chem. Soc. 2012, 134, 12912. (c) E. Matador, J. Iglesias-Sigüenza, D. Monge, P. Merino, R. Fernández and J. M. Lassaletta, Angew. Chem. Int. Ed., 2021, 60, 5096. 13 M. Velázquez, S. Alberca, J. Iglesias-Sigüenza, R. Fernández, J. M. Lassaletta and D. Monge, Chem. Commun., 2020, 56, 5823. 14 Some examples: (a) T. Hashimoto, H. Kimura and K. Maruoka, Angew. Chem. Int. Ed. 2010, 49, 6844. (b) H. Zhang, Q. Yao, W. Cao, S. Ge, J. Xu, X. Liu and X. Feng, Chem. Commun. 2018, 54, 12511. 15 E. Matador, M. G. Retamosa, D. Rohal'ová, J. Iglesias- Sigüenza, P. Merino, R. Fernández, J. M. Lassaletta and D. Monge, Org. Chem. Front. 2021, 8, 3446. 16 P. Melchiorre, Angew. Chem. Int. Ed. 2012, 51, 9748. 17 (a) A. P. Brogan, T. J. Dickerson and K. D. Janda, Angew. Chem. Int. Ed. 2006, 45, 8100; (b) Y. Hayashi, Chem. Int. Ed. 2006, 45, 8103 and references therein. 18 Employing 20 mol% of a primary-tertiary diamine/TfOH salt, 7 was isolated after 2 days in 95% yield and 59% ee. See: S. Luo, H. Xu, L. Chen, and J.-P. Cheng, Org. Lett. 2008, 10, 1775. 19 D. S. Stewart, P. Y. Savechenkov, Z. Dostalova, D. C. Chiara, R. Ge, D. E. Raines, J. B. Cohen, S. A. Forman, K. S. Bruzik and K. W. Miller, J. Med. Chem. 2011, 54, 8124. 20 T. Severin, R. Adam and H. Lerche, Chem. Ber. 1975, 108, 1756. 21 A. Prieto, M. Landart, O. Baudoin, N. Monteiro and D. Bouyssia, Adv. Synth. Catal. 2015, 357, 2939. Page 4 of 4ChemComm ChemComm Accepted Manuscript Published on 15 October 2021. Downloaded by Universidad de Alicante on 10/21/2021 2:13:03 PM. View Article Online DOI: 10.1039/D1CC05014A