Crystallization Does It All: An Alternative Strategy for Stereoselective

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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Crystallization Does It All: An Alternative Strategy for Stereoselective Aza-Henry Reaction Michaela Marcě kova,́ † Peter Gerža,† Michal Š oral,† Jań Moncol,† Dušan Berkeš,† Andrej Kolarovic,̌ ‡ and Pavol Jakubec*,† †

Faculty of Chemical and Food Technology, Slovak University of Technology, Radlinského 9, 812 37 Bratislava, Slovakia Department of Chemistry, Faculty of Education, Trnava University, Priemyselná 4, 918 43 Trnava, Slovakia

‡

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S Supporting Information *

ABSTRACT: An efficient and experimentally straightforward method for the stereoselective synthesis of a variety of β-nitroα-amino carboxylic acids via aza-Henry (nitro-Mannich) reaction of aldimines is disclosed, yielding either anti- or a rarely reported syn-configuration. The reaction operates directly on free glyoxylic acid and generates imine species in situ. Crystallization-controlled diastereoselectivity enables isolation of the target compounds in high enantio- and diastereomeric purities by a simple filtration.

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severalfold excess,1 thus hampering applications to more complex and expensive nitro derivatives. Isolation and purification of the reaction products constitute a problem on their own and can be laborious and costly, bringing a significant environmental burden. Selective crystallization of the desired product followed by filtration greatly simplifies the reaction workup and constitutes an attractive separation option.14 Moreover, crystallization can play a pivotal role in the overall direction of the reaction course, as is the case in crystallization-induced diastereoselective transformations (CIDT).15 Recently, we have demonstrated that reversible reactions, which yield the amino acid functionality, are suitable for exploration as a platform for CIDT.16 On the basis of the knowledge that amino acid formation makes crystallization of the product presumable, we envisioned that this concept might be further expanded to the aza-Henry reaction (Scheme 1D). The aza-Henry reaction can be reversible and often yields stereoisomeric mixtures.17 Besides a simple separation, several useful strategies toward a more effective product isolation have been employed, e.g., a dynamic kinetic resolution cascade,18 a selective extraction of a single diastereomer in combination with Et3N-catalyzed epimerization of the solid residue,3c or a base-catalyzed epimerization associated with CIDT.19 We aimed to develop an innovative multicomponent procedure that would take advantage of the reaction reversibility and, under a simple reaction setup, would yield crystalline α-aminoβ-nitro acids in excellent stereoisomeric purities. As a key design feature, we envisioned the use of glyoxylic acid.20

za-Henry reaction, often titled as a nitro-Mannich reaction,1 belongs to a family of synthetically useful multicomponent reactions. It allows for an effective carbon− carbon bond formation between nitroalkanes and imines, potentially formed in situ, and is associated with a simultaneous construction of up to two stereogenic centers. The resulting β-nitro-α-amino compounds bear two different nitrogen functionalities, which allow diverse chemoselective manipulations toward complex nitrogen-containing structures.2,3 Despite its potential usefulness, the aza-Henry reaction remained relatively unexplored for a long time, and an intensified interest in the method was sparked in 1998 by Anderson’s pioneering work on diastereoselectivity of acyclic reactions.4 Very soon it was followed by its first catalytic enantioselective variant,5 and ever since, numerous asymmetric protocols based on chiral auxiliaries,6 metal catalysis,7 or organocatalysis8−10 have been reported (Scheme 1A−C). In general, the most remarkable examples of stereoselective azaHenry reactions involving aldimines are based on catalytic protocols. Nevertheless, relatively high loadings of complex ligands or catalysts (10−20 mol %) are often required.1 In response to that, more effort has been put into the development of reusable supported catalysts, with several interesting applications to the aza-Henry reaction.11 While impressive advancements have been made in the field over the last two decades, some issues remain to be addressed. The vast majority of the reported methodologies describe syntheses of β-nitroamino structures in the anti-configuration, and only very few efficient protocols toward syn-stereoisomers are known.7b,12 Preformed imines bearing a protecting group, e.g., N-Boc or N-PMP, are typically required, which brings about an extra reaction step.13 For the sake of satisfactory reaction yields, nitroalkanes are commonly used in a © XXXX American Chemical Society

Received: April 29, 2019

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DOI: 10.1021/acs.orglett.9b01489 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Scheme 1. Examples Illustrating Current State-of-the-Art Stereoselective Aza-Henry Reactions of Aldimines

Scheme 2. Initial Studies of Aza-Henry Reaction

The efficiency and beauty of this stereoselective transformation intrigued us to further explore its applicability on sterically hindered α,α-disubstituted nitro compounds. We were pleased to find that the reaction had a broad scope and smoothly afforded the corresponding conformationally constrained amino acids 6−10 in very high stereochemical purities and good yields (Figure 1).

At the outset of our investigation, the most simple nitroalkane, nitromethane (1), was chosen as a model substrate (Scheme 2). Introductory screening experiments with four different amine auxiliaries and 10 solvents disclosed21 that (R)-1phenylethylamine (3) in combination with iPrOH provided superior results. To our delight, under the optimized conditions, the reaction mixture gradually formed a thick white suspension. As further revealed by HPLC analyses, a diastereomeric composition of the mixture was changing over time and (2S,1′R)-4, initially dominant, was gradually transformed in favor of (2R,1′R)-4. A final filtration removed most of the residual minor diastereomer and (2R,1′R)-4 was obtained in excellent diastereomeric purity 99:1 and a good yield of 59%. It is important to note that experiments conducted with 1 equiv of (R)-3 failed to crystallize, yielding low drs of 65:35, and thus, use of 2 equiv of (R)-3 was vital for the success of the reaction. The stereochemistry of the configurationally labile acid (2R,1′R)-4 was locked by a catalytic reduction to provide a highly crystalline α,β-diamino acid 5, suitable for X-ray crystallography (Scheme 2).

Figure 1. Reaction scope for α,α-disubstituted nitro compounds.

Notably, the use of organic solvents could have been completely avoided in this set of reactions and water served as a suitable medium. We succeeded in finding experimental conditions for a selective reduction of amino acid 9 to derivative 11, yielding crystals suitable for X-ray analysis, and the (R)-configuration of the newly built stereogenic center was confirmed. Elucidation of stereochemistry in structures 5 (Scheme 2) and 11 led us to an assumption that amino acids B

DOI: 10.1021/acs.orglett.9b01489 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

Figure 2. Reaction scope for α-prochiral nitro compounds. The dr composition is reported in the order of elution on HPLC.

iPrOH were most suitable and allowed for a fine tune up of the reaction medium properties. The reaction progress was carefully monitored by means of HPLC. Remarkably, concerning the diastereomeric composition, the measured reaction profiles exhibited two distinct patterns: it has always been either the first (D1) or the last (D4) signal of the arisen set of diastereomers intensity of which grew over time, thus reflecting its gradual deposition in the form of crystals. Two representatives of each of these groups, 13 and 16 for D1 and 20 and 28 for D4, were analyzed by X-ray crystallography. The obtained data disclosed three stereochemical trends that appear to be general: (a) (R)-1-phenylethylamine 3 and (R)1-(1-naphthyl)ethylamine induce an (R)-configuration on C2 (X-ray analyses of 5 and 11 provide an additional experimental support, vide supra); (b) the diastereomers labeled as D1, that are eluted first by reversed-phase HPLC, bear an anticonfiguration; (c) consequently, the diastereomers labeled as D4, that are eluted last, exhibit a syn relationship. On the other hand, it appears that there is no distinct structural feature of the nitro substrates that would allow for any conclusive

of the whole series, i.e., 4 and 6−10, prefer to crystallize in a (2R,1′R)-configuration. This judgment is in conclusive accordance with our findings related to more complex derivatives (vide infra). Encouraged by the feasibility of crystallization-driven azaHenry reaction using a variety of symmetrical nitroalkanes, we set out to evaluate the generality of this method on more challenging nitro compounds bearing a prochiral carbon in the α-position. As shown in Figure 2, a rich array of alkyl-, alkenyl-, and aryl-substituted nitro derivatives were successful substrates and underwent highly stereoselective conversions to the corresponding salts of α-amino-β-nitro amino acids 12−27.22 Nevertheless, owing to the broad structural scope, the previously employed reaction conditions (Scheme 2 and Figure 1) had to be further optimized. We found out that in terms of the product crystallinity and the overall reaction performance, (R)-1-(1-naphthyl)ethylamine was superior to the previously utilized phenyl-substituted analogue 3. Additional adjustment was needed for the used solvents on a case by case basis. Generally, aqueous mixtures with MeCN or C

DOI: 10.1021/acs.orglett.9b01489 Org. Lett. XXXX, XXX, XXX−XXX

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(2) (a) Lucet, D.; Le Gall, T.; Mioskowski, C. The Chemistry of Vicinal Diamines. Angew. Chem., Int. Ed. 1998, 37, 2580−2627. (b) Ballini, R.; Petrini, M. The Nitro to Carbonyl Conversion (Nef reaction): New Perspective for a Classical Transformation. Adv. Synth. Catal. 2015, 357, 2371−2402. (3) For illustrative examples of aimed syntheses featuring aza-Henry reaction as one of the key steps, see: (a) Jakubec, P.; Hawkins, A.; Felzmann, W.; Dixon, D. J. Total Synthesis of Manzamine A and Related Alkaloids. J. Am. Chem. Soc. 2012, 134, 17482−17485. (b) Clark, P. G. K.; Vieira, L. C. C.; Tallant, C.; Fedorov, O.; Singleton, D. C.; Rogers, C. M.; Monteiro, O. P.; Bennett, J. M.; Baronio, R.; Müller, S.; Daniels, D. L.; Méndez, J.; Knapp, S.; Brennan, P. E.; Dixon, D. J. LP99: Discovery and Synthesis of the First Selective BRD7/9 Broandersonmodomain Inhibitor. Angew. Chem., Int. Ed. 2015, 54, 6217−6221. (c) Lin, L.-Z.; Fang, J.-M. Total Synthesis of Anti-Influenza Agents Zanamivir and Zanaphosphor via Asymmetric Aza-Henry Reaction. Org. Lett. 2016, 18, 4400−4403. (4) Adams, H.; Anderson, J. C.; Peace, S.; Pennell, A. M. K. The Nitro-Mannich Reaction and Its Application to the Stereoselective Synthesis of 1,2-Diamines. J. Org. Chem. 1998, 63, 9932−9934. (5) Yamada, K.-i.; Harwood, S. J.; Gröger, H.; Shibasaki, M. The First Catalytic Asymmetric Nitro-Mannich-Type Reaction Promoted by a New Heterobimetallic Complex. Angew. Chem., Int. Ed. 1999, 38, 3504−3506. (6) For illustrative examples, see: (a) Ruano, J. L. G.; Topp, M.; López-Cantarero, J.; Alemán, J.; Remuiñań , M. J.; Cid, M. B. Asymmetric Aza-Henry Reactions from N-p-Tolylsulfinylimines. Org. Lett. 2005, 7, 4407−4410. (b) Pindi, S.; Kaur, P.; Shakya, G.; Li, G. N-Phosphinyl Imine Chemistry (I): Design and Synthesis of Novel NPhosphinyl Imines and their Application to Asymmetric aza-Henry Reaction. Chem. Biol. Drug Des. 2011, 77, 20−29. (c) Yun, H.-S.; Lee, H.-J.; Chang, D.-H.; Lee, S.-J.; Kim, S. H.; Kim, J. S.; Cho, C.-W. Asymmetric Synthesis of Chiral 2-Alkyl-3,3-Dinitro-1-Tosylazetidines. Bull. Korean Chem. Soc. 2015, 36, 1524−1527. (7) For representative examples, see: (a) Nishiwaki, N.; Knudson, K. R.; Gothelf, K. V.; Jörgensen, K. A. Catalytic Enantioselective Addition of Nitro Compounds to Imines − A Simple Approach for the Synthesis of Optically Active β-Nitro-α-Amino Esters. Angew. Chem., Int. Ed. 2001, 40, 2992−2995. (b) Handa, S.; Gnanadesikan, V.; Matsunaga, S.; Shibasaki, M. syn-Selective Catalytic Asymmetric Nitro-Mannich Reactions Using a Heterobimetalic Cu-Sm-Schiff Base Complex. J. Am. Chem. Soc. 2007, 129, 4900−4901. (c) Choudhary, M. K.; Tak, R.; Kureshy, R. I.; Ansari, A.; Khan, N.-u. H.; Abdi, S. H. R.; Bajaj, H. C. Enantioselective aza-Henry reaction for the synthesis of (S)-levamisole using efficient recyclable chiral Cu(II)-amino alcohol derived complexes. J. Mol. Catal. A: Chem. 2015, 409, 85− 93. (d) Dudek, A.; Mlynarski, J. Iron-Catalyzed Asymmetric NitroMannich Reaction. J. Org. Chem. 2017, 82, 11218−11224. (e) Liu, S.; Gao, W.-C.; Miao, Y.-H.; Wang, M.-C. Dinuclear Zinc-AzePhenol Catalyzed Asymmetric Aza-Henry Reaction of N-Boc Imines and Nitroalkanes under Ambient Conditions. J. Org. Chem. 2019, 84, 2652−2659. (8) Illustrative examples: (a) Fini, F.; Sgarzani, V.; Pettersen, D.; Herrera, R. P.; Bernardi, L.; Ricci, A. Phase-Transfer-Catalyzed Asymmetric Aza-Henry Reaction Using N-Carbamoyl Imines Generated In Situ from α-Amido Sulfones. Angew. Chem., Int. Ed. 2005, 44, 7975−7978. (b) Wang, C.-J.; Dong, X.-Q.; Zhang, Z.-H.; Xue, Z.-Y.; Teng, H.-L. Highly anti-Selective Asymmetric NitroMannich Reactions Catalyzed by Bifunctional Amine-ThioureaBearing Multiple Hydrogen-Bonding Donors. J. Am. Chem. Soc. 2008, 130, 8606−8607. (c) Takada, K.; Nagasawa, K. Enantioselective Aza-Henry Reaction with Acyclic Guanidine-Thiourea Bifunctional Organocatalyst. Adv. Synth. Catal. 2009, 351, 345−347. (d) Davis, T. A.; Wilt, J. C.; Johnston, J. N. Bifunctional Asymmetric Catalysis: Amplification of Brønsted Basicity Can Orthogonally Increase the Reactivity of a Chiral Brønsted Acid. J. Am. Chem. Soc. 2010, 132, 2880−2882. (e) Anderson, J. C.; Koovits, P. J. An enantioselective tandem reduction/nitro-Mannich reaction of nitroalkenes using a simple thiourea organocatalyst. Chem. Sci. 2013, 4,

prediction of the product syn/anti-stereochemistry, and broader crystallographic investigations might be needed. On the basis of the obtained data, a preferential crystallization in syn-configuration seems to be more presumable. In summary, we have discovered a highly stereoselective crystallization-driven aza-Henry reaction, applicable to a broad range of substrates. The target compounds are readily isolated by filtration. The method features imine species generated in situ, eliminating the need for preparation of these moisturesensitive compounds in an extra step. In contrast with most of the previous records, only 1 equiv of the nitro compound was sufficient to obtain the corresponding β-nitroamines in satisfactory yields. The method is applicable to sterically demanding α,α-disubstituted nitro compounds as well as αprochiral substrates, yielding either syn- or anti-stereoisomers in high purities. Moreover, synthesis of β-nitroamines with a syn-configuration has scarcely been reported, and we believe that the protocol described herein provides an attractive synthetic tool that fills this gap and holds promise for various future applications.

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b01489. Experimental details, characterization data, copies of NMR spectra (PDF) Crystallographic data for 5, 11·1.5H2O, 13, 16, 20, and 28·H2O (PDF) Accession Codes

CCDC 1908404−1908409 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Ján Moncol: 0000-0003-2153-9753 Andrej Kolarovič: 0000-0001-8533-0743 Pavol Jakubec: 0000-0001-8872-3817 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the Slovak Research and Development Agency under Contract No. APVV-16-0258. The crystal structures were solved with the support of the project “University Science Park of STU Bratislava” (ITMS Project No. 26240220084) cofounded by the European Regional Development Fund.

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REFERENCES

(1) For a recent review, see: Noble, A.; Anderson, J. C. NitroMannich Reaction. Chem. Rev. 2013, 113, 2887−2939. D

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Organic Letters 2897−2901. (f) Lu, N.; Bai, F.; Fang, Y.; Wei, Z.; Cao, J.; Liang, D.; Lin, Y.; Duan, H. Bifunctional Phase-Transfer Catalysts Catalyzed Diastereo- and Enantioselective Aza-Henry Reaction of β,γ-Unsaturated Nitroalkenes With Amidosulfones. Adv. Synth. Catal. 2017, 359, 4111−4116. (9) For an interesting example of organocatalysis mediated by an iridium(III) complex, see: Ma, J.; Ding, X.; Hu, Y.; Huang, Y.; Gong, L.; Meggers, E. Metal-templated chiral Brønsted base organocatalysis. Nat. Commun. 2014, 5, 4531. (10) Studies related to ketimines, α-nitroesters, α-nitrophosphonates, or cascade reactions are beyond the scope of this article and are not quoted in the literature survey. (11) (a) Pedrosa, R.; Andrés, J. M.; Á vila, D. P.; Ceballos, M.; Pindado, R. Chiral Ureas and Thioureas Supported on Polystyrene for Enantioselective Aza-Henry Reaction in Solvent-free conditions. Green Chem. 2015, 17, 2217−2225. (b) Miao, Z.; Qi, C.; Wang, L.; Wensley, A. M.; Luan, Y. The synthesis of metal-organic framework Al-MIL-53-derived Brønsted acid catalyst and its application in the Mannich reaction. Appl. Organomet. Chem. 2017, 31, No. e3569. For an example of immobilized catalysts in ketimine chemistry, see: (c) Goldys, A. M.; Núñez, M. G.; Dixon, D. J. Creation through Immobilization: A New Family of High Performance Heterogenous Bifunctional Iminophosphorane (BIMP) Superbase Organocatalysts. Org. Lett. 2014, 16, 6294−6297. (12) (a) Palomo, C.; Oiarbide, M.; Laso, A.; López, R. Catalytic Enantioselective Aza-Henry Reaction with Broad Substrate Scope. J. Am. Chem. Soc. 2005, 127, 17622−17623. (b) Wang, X.; Chen, Y.-F.; Xu, P.-F. Diastereo- and Enantioselective Aza-MBH-Type Reaction of Nitroalkenes to N-Tosylimines Catalyzed by Bifunctional Organocatalysts. Org. Lett. 2009, 11, 3310−3313. (c) Kundu, D.; Debnath, R. K.; Majee, A.; Hajra, A. Zwitterionic-type molten salt-catalyzed synselective aza-Henry reaction: solvent-free one-pot synthesis of βnitroamines. Tetrahedron Lett. 2009, 50, 6998−7000. (d) Wei, Y.; He, W.; Liu, Y.; Liu, P.; Zhang, S. Highly Enantioselective Nitro-Mannich Reaction Catalyzed by Cinchona Alkaloids and N-Benzotriazole Derived Ammonium Salts. Org. Lett. 2012, 14, 704−707. (13) For an illustrative example of aza-Henry reaction involving imine formed in situ, see: Cruz-Acosta, F.; de Armas, P.; GarcíaTellado, F. Chem. - Eur. J. 2013, 19, 16550−16554. (14) (a) Tung, H.-H. Industrial Perspectives of Pharmaceutical Crystallization. Org. Process Res. Dev. 2013, 17, 445−454. For an appealing combination of an intermittent-flow aza-Henry reaction and a product crystallization, see: (b) Tsukanov, S. V.; Johnson, M. D.; May, S. A.; Rosemeyer, M.; Watkins, M. A.; Kolis, S. P.; Yates, M. H.; Johnston, J. N. Development of an Intermittent-Flow Enantioselective Aza-Henry Reaction Using an Arylnitromethane and Homogeneous Brønsted Acid-Base Catalyst with Recycle. Org. Process Res. Dev. 2016, 20, 215−226. (15) For a review on CIDT, see: Brands, K. M. J.; Davies, A. J. Crystallization-Induced Diastereomer Transformations. Chem. Rev. 2006, 106, 2711−2733. (16) Sivák, I.; Toběrný, M.; Kyselicová, A.; Caletková, O.; Berkeš, D.; Jakubec, P.; Kolarovič, A. Stereoselective Synthesis of Functionalized α-Amino Acids Isolated by Filtration. J. Org. Chem. 2018, 83, 15541−15548. (17) (a) Anderson, J. C.; Stepney, G. J.; Mills, M. R.; Horsfall, L. R.; Blake, A. J.; Lewis, W. Enantioselective Conjugate Addition NitroMannich Reactions: Solvent Controlled Synthesis of Acyclic anti- and syn-β-Nitroamines with Three Contiguous Stereocenters. J. Org. Chem. 2011, 76, 1961−1971. For a recent mechanistic study of a retro-aza-Henry reaction, see: (b) Kallitsakis, M. G.; Tancini, P. D.; Dixit, M.; Mpourmpakis, G.; Lykakis, I. N. Mechanistic Studies on the Michael Addition of Amines and Hydrazines To Nitrostyrenes: Nitroalkane Elimination via a Retro-aza-Henry-Type Process. J. Org. Chem. 2018, 83, 1176−1184. (18) Cheng, T.; Meng, S.; Huang, Y. A Highly Diastereoselective and Enantioselective Synthesis of Polysubstituted Pyrrolidines via an Organocatalytic Dynamic Kinetic Resolution Cascade. Org. Lett. 2013, 15, 1958−1961.

(19) Xu, F.; Corley, E.; Zacuto, M.; Conlon, D. A.; Pipik, B.; Humphrey, G.; Murry, J.; Tschaen, D. Asymmetric Synthesis of a Potent, Aminopiperidine-Fused Imidazopyridine Dipeptidyl Peptidase IV Inhibitor. J. Org. Chem. 2010, 75, 1343−1353. (20) Glyoxylic acid is reported to react in aza-Henry reaction, in aqueous KOH: Coghlan, P. A.; Easton, C. J. A one-pot threecomponent synthesis of β-nitro-α-amino acids and their N-alkyl derivatives. J. Chem. Soc., Perkin Trans. 1 1999, 2659−2660. (21) Screened amines: (R)-2-phenylglycinamide, (S)-2-phenylglycinol, (S)-1-(4-methoxyphenyl)ethylamine, (R)-1-phenylethylamine (3); solvents: H2O, MeOH, EtOH, iPrOH, MeCN, 1,4dioxane, THF, Et2O, CH2Cl2, toluene. (22) For examples of less successful α-prochiral substrates, see the Supporting Information.

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DOI: 10.1021/acs.orglett.9b01489 Org. Lett. XXXX, XXX, XXX−XXX