Brönsted-Acid-Catalyzed Asymmetric Three-Component Reaction of

Letter Cite This: Org. Lett. 2018, 20, 317−320

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Brönsted-Acid-Catalyzed Asymmetric Three-Component Reaction of Amines, Aldehydes, and Pyruvate Derivatives. Enantioselective Synthesis of Highly Functionalized γ‑Lactam Derivatives Xabier del Corte, Aitor Maestro, Javier Vicario, Edorta Martinez de Marigorta, and Francisco Palacios* Departamento de Química Orgánica I, Facultad de Farmacia, University of the Basque Country, UPV/EHU Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain S Supporting Information *

ABSTRACT: Chiral phosphoric acids are efficient organocatalysts for the asymmetric three-component reaction of amines, aldehydes, and pyruvate derivatives. Simultaneous condensation of amines with both carbonylic compounds followed by a hydrogen bonding activated nucleophilic addition of enamines to imines affords densely functionalized enantioenriched 1,5-dihydro-2H-pyrrol-2-ones. These substrates can be used in subsequent diastereoselective transformations to afford enantiopure γ-lactam derivatives.

P

of 3-amino-1,5-dihydro-2H-pyrrol-2-ones II plays an important role in rational drug design. On the other hand, multicomponent reactions (MCRs)9 are valuable synthetic processes in organic chemistry affording structures with a high degree of molecular diversity for biomedical research. Consequently, MCRs are very powerful tools in diversity oriented synthesis10 with a huge potential in the field of medicinal chemistry.11 The biological activity of chiral drugs in general is known to be strongly dependent on the absolute configuration of their stereocenters.12 For that reason, the development of asymmetric approaches for the synthesis of enantiopure organic molecules is an imperative task in science, and in this matter, asymmetric MCRs (AMCRs) are particularly interesting instruments.13 Several synthetic procedures for the preparation of dihydropyrrol-2-ones have been reported.2,14 In particular, some years ago we reported an acid-catalyzed three-component reaction of aldehydes 1, ethyl pyruvate 2a, and amines 3 to afford 3-amino1,5-dihydro-1H-pyrrol-2-ones 4 (Scheme 1).15 This reaction consists of an initial Mannich reaction between aldimines 5 and enamines 6, both generated by a concomitant condensation of

yrrole and pyrrolidine derivatives occur in numerous pharmaceutically active natural and unnatural products.1 1,5-Dihydro-2H-pyrrol-2-ones2 I (Figure 1) contain the γ-

Figure 1. Dihydro-pyrrol-2-ones I and II and biologically active 3amino-dihydro-pyrrol-2-one structures III and IV.

lactam ring and are the core structures in the skeleton of many bioactive natural products, such as cytotoxic polyketides Myceliothermophins E, C, and D,3a the endothelin receptor antagonist Oteromicyn,3b and antibiotic Pyrrocides A and B.3c Moreover, 1,5-dihydro-2H-pyrrol-2-one structure is present in a wide range of drug candidates with assorted pharmacological activities such as FPR1 antagonists,4a antivirals HIV-1,4b antitumorals,4c or anticancer VEGF-R enzyme inhibitors.4d Furthermore, the ring conjugate system of these functionalized lactams contributes to its high regio- and stereoselectivity and favors its potential as intermediates in synthetic chemistry.5 In addition, when an amino substituent is present at the 3position, these heterocycles II (Figure 1) are also cyclic enamines and, therefore, excellent synthetic intermediates.6 These cyclic dehydro α,β-amino acid derivatives II7 contain an essential moiety of the dithiopyrrolone group antibiotics Holothin, Holomycin, Thiolutin, Aureothricin IIIa−d (Figure 1), or Thiomarinol A−F,8a and they are key intermediates for the synthesis of Amarillidaceae and Sceletium alkaloids.8b,c Additionally, 3-amino dihydro-pyrrol-2-one skeleton IV is also present in many new bioactive ingredients (Figure 1) such as antimicrobials8d with antibiofilm activity,8e caspase-3 inhibitors,8f antipyretics,8g or analgesics.8h Accordingly, the synthesis © 2017 American Chemical Society

Scheme 1. Three-Component Reaction of Aldehydes 1, Ethyl Pyruvate 2, and Amines 3

Received: October 31, 2017 Published: December 28, 2017 317

DOI: 10.1021/acs.orglett.7b03397 Org. Lett. 2018, 20, 317−320

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Organic Letters

Having identified a suitable catalyst for the enantioselective multicomponent reaction, next we performed a study on the influence of the solvent on the enantioselectivity of the process using the most promising phosphoric acid catalyst VI. The results observed for the organocatalytic three-component reaction of p-toluidine 1a, ethyl pyruvate 2a, and p-nitrobenzaldehyde 3a in different solvents are summarized in Table 2. The normalized molar electronic translation energies (ETN)23 are used as an indicator of the polarity of the solvent.

amines 3 with aldehydes 1 and ethyl pyruvate 2a, respectively, followed by an intramolecular formation of an amide bond in adduct 7 due to the addition of the resulting amine to the carboxylic group (Scheme 1). Some modifications of our synthetic procedure have been described later, such as the uncatalyzed16 or solvent-free17 reaction or the use of recyclable catalysts.18 It has been also established that such a reaction can be performed under organocatalysis.19 Although in this latter case good yields can be achieved, only one example is reported for the asymmetric reaction of ethyl pyruvate, benzaldehyde, and panisidine using several chiral Brönsted acids as catalyst, and unfortunately, the enantiomeric excesses are not higher than 44%.19 Continuing with the interest of our research group in the preparation of functionalized heterocyles20 and in the asymmetric synthesis of amino acid and amino phosphonic acid derivatives,21,22 we report here a highly enantioselective threecomponent reaction (AMCR) of several amines, aldehydes, and pyruvate derivatives to afford densely functionalized γ-lactam derivatives, using chiral phosphoric acids as organocatalysts. Initially we chose phosphoric acids V−XII (Figure 2) as Brönsted acid catalysts for the three-component reaction of p-

Table 2. Screening of the Solventa

entry

solvent

ETN (kcal/mol)

conv. (%)

ee (%)b

1 2 3 4 5 6 7 8 9

toluene Pr2O Et2O MTBE THF DME CH2Cl2 MeCN Et2O/CH2Cl2

0.099 0.105 0.117 0.124 0.207 0.231 0.309 0.460 -

100 100 100 100 100 100 100 100 100

82 78 96 85 58 66 67 89 95

i

a

Reaction conditions: p-nitrobenzaldehyde 1a (1 equiv), ethyl pyruvate 2a (3 equiv), and p-toluidine 3a (2 equiv) were stirred at rt in the presence of MgSO4 and catalyst VI (0.1 equiv). bDetermined by chiral HPLC.

Figure 2. Brönsted acid catalysts tested in this study.

nitrobenzaldehyde 1a with 3 equiv of ethyl pyruvate 2a and 2 equiv of p-toluidine 3a in the presence of MgSO4. The results are summarized in Table 1.

With respect to noncoordinating solvents, in comparison with dichloromethane (Table 2, entry 7), toluene showed a slight improvement in the enantioselectivity (Table 2, entry 1). Surprisingly, when the reaction was performed using diethyl ether as solvent, a dramatic increase in the enantioselectivity was observed (Table 2, entry 3). Although this type of solvent effect is normally attributed to a dependence of the energy of activation of ionic transition states with the polarity of the solvent, in our case, we thought that this effect could be explained by a participation of the solvent in the transition state as described for other reactions.24 This idea is supported by the fact that similar enantiomeric excess is obtained when the reaction is performed in a mixture of dichloromethane/diethyl ether 10:1 (Table 2, entry 9). This result may suggest a participation of the ether molecule in the transition state for the initial hydrogen bonding assisted nucleophilic addition of enamine to imine intermediate by means of a coordination of the heteroatom with the organocatalyst. Following this idea, several ethers were tested as solvents in the multicomponent reaction; however, disparate results were observed, and lower enantiomeric excesses were obtained using di(iso)-propylether, methyl-(tert)-butylether, tetrahydrofuran, or dimethoxyethane (Table 2, entries 2−6). In addition, the reaction performed in acetonitrile showed also a good enantioselectivity (Table 2, entry 8). In order to check whether the Mg2+ cation from drying agent had any influence on the enantioselectivity of the reaction, two control experiments were conducted where MgSO4 was replaced by Na2SO4 or molecular sieves. Since no significant changes were observed in the reactivity or enantioselectivity we conclude that Mg does not play any role in the catalytic system. Moreover, while the same enantiomeric excess was obtained when the catalyst loading was

Table 1. Screening of the Catalysta

entry

cat.

time (h)

conv. (%)

ee (%)b

1 2 3 4 5 6 7 8

V VI VII VIII IX X XI XII

18 18 18 18 18 18 18 18

100 100 100 100 100 100 100 100

1 67 61 5 11 3 45 2

a

Reaction conditions: p-nitrobenzaldehyde 1a (1 equiv), ethyl pyruvate 2a (3 equiv), and p-toluidine 3a (2 equiv) in CH2Cl2 were stirred at rt in the presence of MgSO4 and catalyst V−XII (0.1 equiv). bDetermined by chiral HPLC.

Phosphoric acids V−XII proved to be efficient catalysts, and the reaction of the amine, aldehyde, and pyruvate proceeded in full conversion in a few hours showing disparate enantioselectivity (Table 1, entries 1−8). Importantly, good enantiomeric excesses were observed when triphenylsilyl and 2,4,6-triisopropylphenyl-substituted BINOL derived phosphoric acids VI and VII were used in a 10% ratio with respect to the aldehyde (Table 1, entries 2−3) 318

DOI: 10.1021/acs.orglett.7b03397 Org. Lett. 2018, 20, 317−320

Letter

Organic Letters

meta-substituted aromatic aldehydes in the three-component reaction led to the formation of lactams 4l−m in good yields. In these cases, while a good ee is observed when m-nitrobenzaldehyde is used as substrate, the use of less electrophilic m-tolualdehyde requires heating of the reaction which results in a drop in the ee (Figure 3). The reaction can be also extended to the use of other aliphatic aldehydes 1 as electrophiles, such as cinnamaldehyde or ethyl glyoxalate (Figure 3, 4n−o), as well as enolizable aldehydes as iso-butyraldehyde, or cyclohexanecarboxaldehyde (Figure 3, 4p−q) with acceptable enantioselectivities. Finally, when heteroaromatic aldehydes were used as substrates, the three-component reaction only afforded lactams 4 upon heating. Although heating the reaction results in a substantial drop in the enantioselectivity, 2-thiophene-substituted lactam 4r can be obtained with a reasonably good ee. In order to further broaden the possibilities of the reaction, pnitrobenzaldehyde 1a, some substituted pyruvate substrates, and p-toluidine 3a were stirred under reflux in methyl-(tert)butylether in the presence of Brönsted acid catalyst VII. Although good yields were obtained for tetrasubstituted lactam derivatives 4s−t, lower enantioselectivities were observed, which may be possibly again attributed to the necessity of performing the reaction at higher temperature (Figure 3). It should be also noted that when the reaction was performed in 0.5 mmol scale for the synthesis of lactam 4h same enantiomeric excess was obtained. The absolute configuration of γ-lactams 4 could not be directly determined since these compounds did not provide suitable monocrystals for X-ray diffraction. To overcome that obstacle and additionally explore the synthetic use of these pyrrolidones 4, we used freshly prepared γ-lactam 4h as enamine reagent in a formal [3 + 3] annulation reaction26 with α,β-unsaturated ketoester 8 in the presence of ytterbium triflate to afford bicyclic azaheterocycles 9 (Scheme 2). Only the cis diastereoisomer was detected by 1H NMR, and no racemization was observed

increased to 20% with respect to the aldehyde, a substantial drop of the enantioselectivity was observed when the catalyst loading was reduced to 5%. Once the optimal conditions for the enantioselective threecomponent reaction were established, the synthetic protocol was generalized to the use of several aldehydes 1 and amines 3 using substituted BINOL-derived phosphoric acids V−XII. The result for the best catalyst is reported in Figure 3 (see SI for optimization for each substrate).

Figure 3. Scope of the three-component reaction. Reaction conditions: aldehyde 1 (1 equiv), pyruvate derivative 2 (3 equiv), amine 3 (2 equiv), and phosphoric acid catalyst VI−IX (0.1 equiv) in Et2O at rt (4a−l and 4n−q) or MTBE at 55 °C (4m and 4r−t).

Scheme 2. Diastereoselective Reactions of γ-Lactam 4h

With respect to the amine substrate, very good enantiomeric excesses are obtained when weak activating or deactivating groups such as p-methyl, p-bromo, or o-fluor are present in the aromatic substituent of the amine 3 (Figure 3, compounds 4a− c). Very good enantioselectivity is also observed when a strong activated aromatic amine such as p-anisidine is used (Figure 3, 4d), but a slower reaction is observed in this case, which may be due to a higher deactivation of the imine electrophile 5 with respect to the activation of enamine nucleophile 6. Although a substantial drop in the enantioselectivity is observed using amines with strong electron-withdrawing groups as substituents in the aromatic ring such as m-trifluoromethylaniline25 (Figure 3, 4e), the reaction using m-chloroaniline affords lactam 4f with excellent enantioselectivity. A slower reaction is observed again in these cases, which may be due to a higher deactivation of the enamine nucleophile 6 with respect to the activation of imine 5. Regarding the aldehyde component 1, the reaction can be performed in the same conditions and with good enantioselectivities using the less electrophilic benzaldehyde instead of pnitrobenzaldehyde (Figure 3, 4g−h). Good reactivity and enantioselectivity are also obtained using other electron-poor aldehydes such as p-trifluoromethylbenzaldehyde (Figure 3, 4i− j). However, a substantial drop in the enantiomeric excess together with an increase in the reaction time was observed when p-fluorobenzaldehyde was used as substrate (Figure 3, 4k). Moreover, although ortho substitution is not allowed in the aldehyde substrate, which may be due to sterical issues, using

Bicyclic compound 9 can also be prepared in a one-pot procedure starting from the three-component reaction, without isolating the intermediate lactam 4h with an overall yield of 80% and 90% ee. Monocrystals of the major enantiomer of bicycle 9 were isolated after several crystallizations, and a 4S, 5R absolute configuration of the stereocenters was determined from its X-ray diffraction spectrum (see SI). Therefore, a 5S configuration of the stereocenter formed in γ-lactam 4h through the asymmetric three-component reaction was established. Moreover, in order to demonstrate the potential of the asymmetric threecomponent reaction of amines, pyruvate derivatives, and aldehydes, the reduction of γ-lactam derivative 4h was performed under hydrogen pressure and in the presence of palladium as catalyst. After a few hours, saturated γ-lactam 10 was obtained in very good yield, with an excellent diaster319

DOI: 10.1021/acs.orglett.7b03397 Org. Lett. 2018, 20, 317−320

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Organic Letters

Takanashi, N.; Nagano, T.; Suizu, H.; Suzuki, T.; Kobayashi, S. Org. Lett. 2012, 14, 4886. (4) (a) Kirpotina, L. N.; Schepetkin, I. A.; Khlebnikov, A. I.; Ruban, O. I.; Ge, Y.; Ye, R. D.; Kominsky, D. J.; Quinn, M. T. Biochem. Pharmacol. 2017, 142, 120. (b) Ma, K.; Wang, P.; Fu, W.; Wan, X.; Zhou, L.; Chu, Y.; Ye, D. Bioorg. Med. Chem. Lett. 2011, 21, 6724. (c) Zhuang, C.; Miao, Z.; Zhu, L.; Dong, G.; Guo, Z.; Wang, S.; Zhang, Y.; Wu, Y.; Yao, J.; Sheng, C.; Zhang, W. J. Med. Chem. 2012, 55, 9630. (d) Peifer, C.; Selig, R.; Kinkel, K.; Ott, D.; Totzke, F.; Schaechtele, C.; Heidenreich, R.; Roecken, M.; Schollmeyer, D.; Laufer, S. J. Med. Chem. 2008, 51, 3814. (5) Chatzimpaloglou, A.; Kolosov, M.; Eckols, T. K.; Tweardy, D. J.; Sarli, V. J. Org. Chem. 2014, 79, 4043. (6) For selected contributions: (a) Liu, Q.-J.; Wang, L.; Kang, Q.-K.; Zhang, X. P.; Tang, Y. Angew. Chem., Int. Ed. 2016, 55, 9220. (b) Bures, J.; Armstrong, A.; Blackmond, D. G. Acc. Chem. Res. 2016, 49, 214. (7) Hekking, K. F. W.; Waalboer, D. C. J.; Moelands, M. A. H.; van Delft, F. L.; Rutjes, F. P. J. T. Adv. Synth. Catal. 2008, 350, 95. (8) (a) Li, B.; Wever, W. J.; Walsh, C. T.; Bowers, A. A. Nat. Prod. Rep. 2014, 31, 905. (b) Rigby, J. H.; Hughes, R. C.; Heeg, M. J. J. Am. Chem. Soc. 1995, 117, 7834. (c) Lewis, J. R. Nat. Prod. Rep. 1994, 11, 329. (d) Khalaf, A. I.; Waigh, R. D.; Drummond, A. J.; Pringle, B.; McGroarty, I.; Skellern, G. G.; Suckling, C. J. J. Med. Chem. 2004, 47, 2133. (e) Ye, Y.; Fang, F.; Li, Y. Bioorg. Med. Chem. Lett. 2015, 25, 597. (f) Zhu, Q.; Gao, L.; Chen, Z.; Zheng, S.; Shu, H.; Li, J.; Jiang, H.; Liu, S. Eur. J. Med. Chem. 2012, 54, 232. (g) Gein, V. L.; Popov, A. V.; Kolla, V. E.; Popova, N. A.; Potemkin, K. D. Pharm. Chem. J. 1993, 27, 343. (h) Gein, V. L.; Popov, A. V.; Kolla, V. E.; Popova, N. A. Pharmazie 1993, 8, 107. (9) Multicomponent Reactions in Organic Synthesis; Zhu, J., Wang, Q., Wang, M.-X., Eds.; Wiley-VCH: Weinheim, 2015. (10) Schreiber, S. L. Science 2000, 287, 1964. (11) de Moliner, F.; Kielland, N.; Lavilla, R.; Vendrell, M. Angew. Chem., Int. Ed. 2017, 56, 3758 and references therein. (12) Kasprzyk-Hordern, B. Chem. Soc. Rev. 2010, 39, 4466. (13) Ramón, D. J.; Yus, M. Angew. Chem., Int. Ed. 2005, 44, 1602. (14) For recent contributions, see: (a) Shymanska, N. V.; Pierce, J. G. Org. Lett. 2017, 19, 2961. (b) Ghorbani-Vaghei, R.; Davood, A.; Daliran, S.; Oveisi, A. R. RSC Adv. 2016, 6, 29182 and references therein. (15) Palacios, F.; Vicario, J.; Aparicio, D. Eur. J. Org. Chem. 2006, 2006, 2843. (16) Shaterian, H. R.; Ranjbar, M. Res. Chem. Intermed. 2014, 40, 2059. (17) Niknam, K.; Mojikhalifeh, S. Mol. Diversity 2014, 18, 111. (18) Qian, J.; Yi, W.; Cai, C. Tetrahedron Lett. 2013, 54, 7100. (19) Li, X.; Deng, H.; Luo, S.; Cheng, J.-P. Eur. J. Org. Chem. 2008, 2008, 4350. (20) (a) Vélez del Burgo, A.; Ochoa de Retana, A. M.; de los Santos, J. M.; Palacios, F. J. Org. Chem. 2016, 81, 100. (b) Alonso, C.; González, M.; Fuertes, M.; Rubiales, G.; Ezpeleta, J. M.; Palacios, F. J. Org. Chem. 2013, 78, 3858. (d) Alonso, C.; González, M.; Palacios, F.; Rubiales, G. J. Org. Chem. 2017, 82, 6379. (21) (a) Palacios, F.; Vicario, J. Org. Lett. 2006, 8, 5405. (b) Vicario, J.; Ezpeleta, J. M.; Palacios, F. Adv. Synth. Catal. 2012, 354, 2641. (c) Vicario, J.; Ortiz, P.; Ezpeleta, J. M.; Palacios, F. J. Org. Chem. 2015, 80, 156. (22) Palacios, F.; Alonso, C.; de los Santos, J. M. Chem. Rev. 2005, 105, 899. (23) Reichardt, C. Chem. Rev. 1994, 94, 2319. (24) Some examples: (a) Fukaya, H.; Morokuma, K. J. Org. Chem. 2003, 68, 8170. (b) Gajewski, J. J. J. Am. Chem. Soc. 2001, 123, 10877. (25) Alonso, C.; Martinez de Marigorta, E.; Rubiales, G.; Palacios, F. Chem. Rev. 2015, 115, 1847. (26) (a) A review: Wang, X.-Na; Yeom, H.-S.; Fang, L.-C.; He, S.; Ma, Z.-X.; Kedrowski, B. L.; Hsung, R. P. Acc. Chem. Res. 2014, 47, 560. (b) Yi, L.; Zhang, Z.-F.; Sun, D.; Ye, S. Org. Lett. 2017, 19, 2286.

eoselectivity and without racemization (Scheme 2). The 3S, 5S absolute configuration of the stereocenters in γ-lactam 10 was determined indirectly by nuclear Overhauser effect (see SI). These 1H NMR data showed a cis relative configuration, which is the result, as expected, from a syn addition of hydrogen that approaches to the double bond from the less hindered face, that is, opposite to the phenyl substituent. Compound 10 can also be prepared in a one-pot procedure starting from the three components 1b, 2a, and 3d, without isolating the intermediate lactam 4h and with an overall yield of 95% and 90% ee. In conclusion, we report here the first highly enantioselective three-component reaction of pyruvate derivatives, amines, and aldehydes to efficiently afford 3-amino-1,5-dihydro-2H-pyrrol2-ones. The reaction has been generalized to several aromatic amines, aromatic and aliphatic aldehydes, and some substituted pyruvate derivatives, allowing the asymmetric synthesis of highly functionalized γ-lactam derivatives. Moreover, enantioenriched lactam derivatives can be used in subsequent diastereoselective transformations, such as formal [3 + 3] annulation and hydrogenation of the double bond.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b03397. Thermal ellipsoid plot for 8 and full experimental details, characterization, and copies of 1H and 13C NMR spectra for compounds 4, 8, and 9 (PDF) Accession Codes

CCDC 1581117 contains 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 data_ [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

*Fax: (+34) 945 013049. E-mail: [email protected]. ORCID

Javier Vicario: 0000-0002-8976-0991 Francisco Palacios: 0000-0001-6365-0324 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial support from the Ministerio de Economı ́a, Industria y Competitividad (MINECO, CTQ-2015-67871R), and Gobierno Vasco (GV, IT 992-16) is gratefully acknowledged. We also thank SGIker (UPV/EHU) technical support for NMR spectra (MINECO, GV/EJ, and European Social Found).

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REFERENCES

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DOI: 10.1021/acs.orglett.7b03397 Org. Lett. 2018, 20, 317−320