Catalytic Asymmetric Reactions of α-Isocyanoacetates and meso

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

pubs.acs.org/OrgLett

Catalytic Asymmetric Reactions of α‑Isocyanoacetates and mesoAziridines Mediated by an in-Situ-Generated Magnesium Catalytic Method Dan Li,†,§ Linqing Wang,†,§ Haiyong Zhu,† Lutao Bai,† Yuling Yang,† Minmin Zhang,† Dongxu Yang,*,† and Rui Wang*,†,‡ †

Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, China ‡ State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou 730000, China

Downloaded by BETHEL UNIV at 17:00:30:342 on May 30, 2019 from https://pubs.acs.org/doi/10.1021/acs.orglett.9b01599.

S Supporting Information *

ABSTRACT: A catalytic asymmetric ring-opening reaction between αisocyanoacetates and meso-aziridines has been realized by developing an in-situ-generated magnesium catalytic method. Chiral oxazoline−OH ligands were employed in the magnesium catalyst and diphenylphosphinamide was improved as a powerful achiral additive in this reaction. The ring-opening products of the desired reaction were obtained in good chemical yields and enantioselectivities. Moreover, these enantioenriched adducts can be smoothly transformed into tetrahydropyrimidines mediated by a silver salt under mild conditions. α-Isocyanoacetates have been widely utilized as useful synthons and applied in many enantioselective reactions to build important enantio-enriched skeletons, including highly functionalized enantio-enriched heterocyclic rings.1 In recent years, seminal works concerning with isonitriles have been established in asymmetric Ugi, Passerini, and other types of cyclization reactions.2−4 However, there is still no report on αisocyanoacetates participating in asymmetric ring-opening reactions with aziridines, despite the fact that aziridines are increasingly being exploited as versatile building blocks in organic synthesis,5 especially in enantioselective pathways to build continuous stereocenters in one C−C bond-formation step. To date, only racemic versions of the reaction between αisocyanoacetates and aziridines have been reported.6 Recently, Zhao, Wong, and co-workers reported an elegant work on building 1,4,5,6-tetrahydropyrimidine derivatives by utilizing α-isocyanoacetates and enantiopure aziridines.7 Moreover, the Ghorai group also reported a case that described the synthesis of chiral 1,4,5,6-tetrahydropyrimidines by using activated enantiopure aziridines and α-acidic isocyanides as initial materials.8 However, the catalytic asymmetric method of the reaction between α-isocyanoacetates and aziridines is still not established. Here, by developing an efficient in-situ-generated magnesium catalytic method,9,10 we realized the catalytic asymmetric reaction between α-isocyanoacetates and mesoaziridines under mild conditions. Furthermore, the obtained ring-opening products can be smoothly transformed to highly functionalized tetrahydropyrimidines after treatment with silver salts (see Scheme 1). © XXXX American Chemical Society

Scheme 1. Mg(II)-Mediated Enantioselective Reaction between α-Isocyanoacetates and meso-Aziridines

Our initial experiments focused on screening of simple chiral oxazoline−OH ligands in the Mg(II)-mediated asymmetric ring-opening reactions of meso-aziridine 2a with α-isocyanoacetate 1a (see Scheme 2). The screening process did not give satisfactory results in the current desymmetrization reaction. The final choice of chiral oxazoline−OH ligand L6 only led to a moderate result: 47% ee and 2.2:1 dr value (Scheme 2, L6). We speculate that the disappointing selectivity might be caused by the linear structure of α-isocyanoacetate 1a, which creates a discrimination problem regarding the substituted groups around the center carbon of the substrate. To accomplish highly desirable enantio-enriched ringopening products in the current desymmetrization reaction, we tried to utilize some simple nonchiral molecules to regulate the enantioselectivities and diastereoselectivities of the reaction.11 As illustrated in Table 1, pyridine derivatives, which might coordinate to the magnesium center and alter the chiral environment of the catalyst, did not give more-promising Received: May 6, 2019

A

DOI: 10.1021/acs.orglett.9b01599 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

to be a highly potential nonchiral additive, dramatically leading to the desymmetrization product 3a to 94% ee and 5.3:1 diastereomeric ratio (dr) (Table 1, entry 5). Next, we screened a series of analogues of easily accessed amide and discovered that the introduction of Cbz-NH2 or Boc-NH2 has similar effects on the diastereoselectivity of the reaction (Table 1, entries 6 and 7). The screening process further revealed that diphenylphosphinamide A8 is a more-efficient nonchiral additive, while phosphinamide A9 gave a relatively lower dr value (Table 1, entries 8 and 9). In addition, the selection progress on detail conditions proved that the magnesium catalyst could be decreased to 10 mol % without obviously affecting the catalytic efficiency (Table 1, entry 10). The in-situ-generated magnesium catalytic method using diphenylphosphinamide A8 as an effective additive then was applied to the ring-opening reaction of a wide range of mesoaziridines (see Scheme 3). Aziridines containing five-, six-, and

Scheme 2. Initial Optimization of the Reaction by Screening of Chiral Ligands

Scheme 3. Substrate Scope, with Respect to meso-Aziridinea Table 1. Further Optimization of the Reaction

entrya

A

yield (%)

diastereomeric ratio, dr

enantiomeric ratio, ee (%)

1 2 3 4 5 6 7 8 9 10b

A1 A2 A3 A4 A5 A6 A7 A8 A9 A8

85 61 51 59 90 82 80 92 92 91

2.2:1 1.6:1 1.4:1 1.3:1 5.3:1 2.7:1 7.2:1 >20:1 8.3:1 >20:1

49 44 30 34 94 57 93 97 97 96

a

a

Reactions were performed with 1a (0.60 mmol) and 2a (0.20 mmol) in the presence of L6 (10 mol %, 0.02 mmol) A8 (10 mol %, 0.02 mmol), and Bu2Mg (10 mol %, 0.02 mmol) in toluene (1.0 mL) at 40 °C for 24 h.

results (Table 1, entries 1 and 2). The introduction of phenol A3 or amino alcohol A4 decreased the ee values and did not have obvious effects on the diastereoselectivities (Table 1, entries 3 and 4). Further selection processes found benzamide

seven-membered cyclic skeletons were all tolerable under the current efficient catalytic system, leading to the corresponding desymmetrization products in high yields and good to excellent diastereoselectivities and enantioselectivities (Scheme 3, 3a− 3e). Acyclic aziridines containing alkyl or aryl groups were further tested under the optimized reaction conditions, also obtaining the desired desymmetrization products with satisfactory results (Scheme 3, 3f−3h). Next, the scope of α-isocyanoacetates was investigated using the in-situ-generated Mg(II) catalyst with the powerful additive A8, and the results are illustrated in Scheme 4. The introduction of different electronic groups to the phenyl rings

Reactions were performed with 1a (0.12 mmol) and 2a (0.10 mmol) in the presence of chiral ligands (20 mol %, 0.02 mmol), achiral additives (20 mol %, 0.02 mmol) and Bu2Mg (20 mol %, 0.02 mmol) in toluene (1.0 mL) at room temperature overnight. Isolated yields are given in the table, dr values were determined by 1H NMR NMR studies, and ee values were analyzed by stationary-phase highperformance liquid chromatography (HPLC). bReactions performed under a 10 mol % magnesium catalytic system at 40 ̊C by using 3.0 equiv of 1a on a 0.2 mmol scale, and performed for 24 h.

B

DOI: 10.1021/acs.orglett.9b01599 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Scheme 4. Substrate Scope of the Desymmetrization Reaction

Scheme 5. Transformation of the Product to Highly Functionalized Pyrimidines

Scheme 6. Transformation of the Product by a Deprotection Process

namide A8 was selected as an effective additive to improve the diastereoselectivities and enantioselectivities of the reaction. Although the detailed mechanism of this reaction is still unclear, the initial control experiments, electrospray ionization mass spectrometry (ESI-MS), nuclear magnetic resonance (NMR), and nonlinear effects studies were conducted to study the important role of the diphenylphosphinamide.12 Furthermore, the enantio-enriched ring-opening adducts can be smoothly transferred into highly functionalized tetrahydropyrimidines under mild conditions. Further investigations of insitu-generated magensium catalysis and related asymmetric reactions are underway in our laboratory.

of isocyanoacetates did not have obvious negative effects on the results of the desymmetrization reaction (Scheme 4, 3i− 3m). Isocyanoacetates with hetereocyclic rings equipped were also tolerable, leading to the corresponding ring-opening products in high yields and selectivities (Scheme 4, 3n, 3o). In addition, these isocyanoacetates were also compatible with different cyclic or acyclic meso-aziridines. However, it is notable that α-alkyl isocyanoacetates were not effective substrates under the current Mg(II) catalysis, which might be due to the relatively weak acidity of the α-proton of this type of substrate, and the introduction of more steric hindrance groups would also frustrate the transformation (Scheme 4). Given the wide existence and important role of substitiuted pyrimidines in medical-grade drugs and pharmacologic studies, the obtained desymmetrization products were transferred into multisubstituted tetrahydropyrimidines that contained several variable groups with a silver catalyst under mild conditions (see Scheme 5). Finally, the ring-opening product 3d was converted to a lactam product 6 by simply treating it with sodium hydroxide under reflux conditions. The bicyclic adduct was obtained in a moderate yield (see Scheme 6). In summary, we have developed an in-situ-generated magnesium catalytic method and realized the asymmetric ring-opening reactions between α-isocyanoacetates and mesoaziridines. After a careful screening process, diphenylphosphi-

■

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b01599. Experimental procedures including spectroscopic and analytical data of new compounds (PDF) Accession Codes

CCDC 1499073 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 [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

■

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] (D. Yang). *E-mail: [email protected] (R. Wang). C

DOI: 10.1021/acs.orglett.9b01599 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters ORCID

Chem. Soc. 2006, 128, 6312−6313. (d) Arai, K.; Lucarini, S.; Salter, M. M.; Ohta, K.; Yamashita, Y.; Kobayashi, S. J. Am. Chem. Soc. 2007, 129, 8103−8111. (e) Rowland, E. B.; Rowland, G. B.; Rivera-Otero, E.; Antilla, J. C. J. Am. Chem. Soc. 2007, 129, 12084−12085. (f) Peruncheralathan, S.; Teller, H.; Schneider, C. Angew. Chem., Int. Ed. 2009, 48, 4849−4852. (g) Xu, Y.-J.; Lin, L.-Q.; Kanai, M.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2011, 133, 5791− 5793. (h) Kalow, J. A.; Schmitt, D. E.; Doyle, A. G. J. Org. Chem. 2012, 77, 4177−4183. (i) Hayashi, M.; Shiomi, N.; Funahashi, Y.; Nakamura, S. J. Am. Chem. Soc. 2012, 134, 19366−19369. (j) Ohmatsu, K.; Hamajima, Y.; Ooi, T. J. Am. Chem. Soc. 2012, 134, 8794−8797. (k) Li, J.; Liao, Y.; Zhang, Y.; Liu, X.; Lin, L.; Feng, X. Chem. Commun. 2014, 50, 6672−6274. (l) Yang, D.; Wang, L.; Han, F.; Li, D.; Zhao, D.; Cao, Y.; Ma, Y.; Kong, W.; Sun, Q.; Wang, R. Chem. - Eur. J. 2014, 20, 16478−16483. (m) Yang, D.; Wang, L.; Han, F.; Li, D.; Zhao, D.; Wang, R. Angew. Chem., Int. Ed. 2015, 54, 2185−2189. (n) Li, D.; Wang, L.; Yang, D.; Zhang, B.; Wang, R. ACS Catal. 2015, 5, 7432−7436. (o) Li, D.; Wang, K.; Wang, L.; Wang, Y.; Wang, P.; Liu, X.; Yang, D.; Wang, R. Org. Lett. 2017, 19, 3211−3214. (p) Shiomi, N.; Yamamoto, K.; Nagasaki, K.; Hatanaka, T.; Funahashi, Y.; Nakamura, S. Org. Lett. 2017, 19, 74−77. (q) Shiomi, N.; Kuroda, M.; Nakamura, S. Chem. Commun. 2017, 53, 1817−1820. (r) Zhang, J.; Xiao, W.; Hu, H.; Lin, L.; Liu, X.; Feng, X. Chem. - Eur. J. 2018, 24, 13428−13431. (6) Zheng, D.; Wu, J. Eur. J. Org. Chem. 2014, 2014, 767−771. (7) Kok, G. P. Y.; Yang, H.; Wong, M. W.; Zhao, Y. Org. Lett. 2018, 20, 5112−5115. (8) Bhattacharyya, A.; Shahi, C. K.; Pradhan, S.; Ghorai, M. K. Org. Lett. 2018, 20, 2925−2928. (9) For a recent review, see: (a) Yang, D.; Wang, L.; Li, D.; Wang, R. Chem. 2019, 5, 1108−1166. For examples on in-situ-generated magnesium catalysts, see: (b) Evans, D. A.; Nelson, S. G. J. Am. Chem. Soc. 1997, 119, 6452−6453. (c) Du, H.; Zhang, X.; Wang, Z.; Bao, H.; You, T.; Ding, K. Eur. J. Org. Chem. 2008, 2008, 2248−2254. (d) Yoshino, T.; Morimoto, H.; Lu, G.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 17082−17083. (e) Trost, B. M.; Malhotra, S.; Fried, B. A. J. Am. Chem. Soc. 2009, 131, 1674−1675. (f) Hatano, M.; Horibe, T.; Ishihara, K. Org. Lett. 2010, 12, 3502− 3505. (g) Hatano, M.; Horibe, T.; Ishihara, K. Angew. Chem., Int. Ed. 2013, 52, 4549−4553. (h) Hatano, M.; Horibe, T.; Yamashita, K.; Ishihara, K. Asian J. Org. Chem. 2013, 2, 952−956. (i) Hatano, M.; Nishikawa, K.; Ishihara, K. J. Am. Chem. Soc. 2017, 139, 8424−8427. (10) (a) Yang, D.; Wang, L.; Han, F.; Zhao, D.; Zhang, B.; Wang, R. Angew. Chem., Int. Ed. 2013, 52, 6739−6742. (b) Wang, L.; Yang, D.; Han, F.; Li, D.; Zhao, D.; Wang, R. Org. Lett. 2015, 17, 176−179. (c) Yang, D.; Wang, L.; Kai, M.; Li, D.; Yao, X.; Wang, R. Angew. Chem., Int. Ed. 2015, 54, 9523−9527. (d) Wang, L.; Li, D.; Yang, D.; Wang, K.; Wang, J.; Wang, P.; Su, W.; Wang, R. Chem. - Asian J. 2016, 11, 691−695. (e) Wang, K.; Wang, L.; Liu, X.; Li, D.; Zhu, H.; Wang, P.; Liu, Y.; Yang, D.; Wang, R. Org. Lett. 2017, 19, 4351−4354. (f) Wang, L.; Yang, D.; Li, D.; Liu, X.; Wang, P.; Wang, K.; Zhu, H.; Bai, L.; Wang, R. Angew. Chem., Int. Ed. 2018, 57, 9088−9092. (11) For reviews on additives effects in asymmetric reactions, see: (a) Vogl, E. M.; Gröger, H.; Shibasaki, M. Angew. Chem., Int. Ed. 1999, 38, 1570−1577. (b) Hong, L.; Sun, W.; Yang, D.; Li, G.; Wang, R. Chem. Rev. 2016, 116, 4006−4123. (12) See the Supporting Information for the initial studies of the current reaction mechanism.

Linqing Wang: 0000-0001-5922-1332 Rui Wang: 0000-0002-4719-9921 Author Contributions §

These authors contributed equally.

Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS This work was supported by the NSFC (Nos. 21602091, 21432003, 81473095), and the Fundamental Research Funds for the Central Universities (Nos. lzujbky-2018-kb11, lzujbky2017-19, lzujbky-2017-118).

■

REFERENCES

(1) (a) Dömling, A. Chem. Rev. 2006, 106, 17−89. (b) Gulevich, A. V.; Zhdanko, A. G.; Orru, R. V. A.; Nenajdenko, V. G. Chem. Rev. 2010, 110, 5235−5331. (c) Giustiniano, M.; Basso, A.; Mercalli, V.; Massarotti, A.; Novellino, E.; Tron, G. C.; Zhu, J. Chem. Soc. Rev. 2017, 46, 1295−1357. (d) Wang, Q.; Wang, D.-X.; Wang, M.-X.; Zhu, J. Acc. Chem. Res. 2018, 51, 1290−1300. (2) (a) Denmark, S. E.; Fan, Y. J. Am. Chem. Soc. 2003, 125, 7825− 7827. (b) Kusebauch, U.; Beck, B.; Messer, K.; Herdtweck, E.; Dömling, A. Org. Lett. 2003, 5, 4021−4024. (c) Andreana, P. R.; Liu, C. C.; Schreiber, S. L. Org. Lett. 2004, 6, 4231−4233. (d) Wang, S.-X.; Wang, M.-X.; Wang, D.-X.; Zhu, J. Org. Lett. 2007, 9, 3615−3618. (e) Wang, S.-X.; Wang, M.-X.; Wang, D.-X.; Zhu, J. Angew. Chem., Int. Ed. 2008, 47, 388−391. (f) Yue, T.; Wang, M.-X.; Wang, D.-X.; Zhu, J. Angew. Chem., Int. Ed. 2008, 47, 9454−9457. (g) Mihara, H.; Xu, Y.; Shepherd, N. E.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 8384−8385. (h) Zeng, X.; Ye, K.; Lu, M.; Chua, P. J.; Tan, B.; Zhong, G. Org. Lett. 2010, 12, 2414−2417. (i) Zhang, J.; Lin, S.-X.; Cheng, D.-J.; Liu, X.-Y.; Tan, B. J. Am. Chem. Soc. 2015, 137, 14039− 14042. (3) (a) Pan, S. C.; List, B. Angew. Chem., Int. Ed. 2008, 47, 3622− 3625. (b) Yue, T.; Wang, M.-X.; Wang, D.-X.; Masson, G.; Zhu, J. Angew. Chem., Int. Ed. 2009, 48, 6717−6721. (c) Hashimoto, T.; Kimura, H.; Kawamata, Y.; Maruoka, K. Angew. Chem., Int. Ed. 2012, 51, 7279−7281. (d) Zhao, W.; Huang, L.; Guan, Y.; Wulff, W. D. Angew. Chem., Int. Ed. 2014, 53, 3436−3441. (e) Zhang, Y.; Ao, Y.-F.; Huang, Z.-T.; Wang, D.-X.; Wang, M.-X.; Zhu, J. Angew. Chem., Int. Ed. 2016, 55, 5282−5285. (f) Li, D.; Yang, D.; Wang, L.; Liu, X.; Wang, K.; Wang, J.; Wang, P.; Liu, Y.; Zhu, H.; Wang, R. Chem. - Eur. J. 2017, 23, 6974−6978. (4) (a) Guo, C.; Xue, M.-X.; Zhu, M.-K.; Gong, L.-Z. Angew. Chem., Int. Ed. 2008, 47, 3414−3417. (b) Sladojevich, F.; Trabocchi, A.; Guarna, A.; Dixon, D. J. J. Am. Chem. Soc. 2011, 133, 1710−1713. (c) Kim, H. Y.; Oh, K. Org. Lett. 2011, 13, 1306−1309. (d) Ortín, I.; Dixon, D. J. Angew. Chem., Int. Ed. 2014, 53, 3462−3465. (e) Zhao, M.-X.; Bi, H.-L.; Jiang, R.-H.; Xu, X.-W.; Shi, M. Org. Lett. 2014, 16, 4566−4569. (f) Shao, P.-L.; Liao, J.-Y.; Ho, Y. A.; Zhao, Y. Angew. Chem., Int. Ed. 2014, 53, 5435−5439. (g) Hayashi, M.; Iwanaga, M.; Shiomi, N.; Nakane, D.; Masuda, H.; Nakamura, S. Angew. Chem., Int. Ed. 2014, 53, 8411−8415. (h) de la Campa, R.; Ortín, I.; Dixon, D. J. Angew. Chem., Int. Ed. 2015, 54, 4895−4898. (i) Liao, J.-Y.; Shao, P.L.; Zhao, Y. J. Am. Chem. Soc. 2015, 137, 628−631. (j) Nakamura, S.; Yamaji, R.; Iwanaga, M. Chem. Commun. 2016, 52, 7462−7465. (k) Kok, G. P. Y.; Shao, P.-L.; Liao, J.-Y.; Ismail, S. N. F. B. S.; Yao, W.; Lu, Y.; Zhao, Y. Chem. - Eur. J. 2018, 24, 10513−10520. (l) Xu, B.; Zhang, Z.-M.; Zhou, L.; Zhang, J. Org. Lett. 2018, 20, 2716−2719. (m) Zheng, S.-C.; Wang, Q.; Zhu, J. Angew. Chem., Int. Ed. 2019, 58, 1494−1498. (5) (a) Li, Z.; Fernandez, M.; Jacobsen, E. N. Org. Lett. 1999, 1, 1611−1613. (b) Mita, T.; Fujimori, I.; Wada, R.; Wen, J.- F.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2005, 127, 11252−11253. (c) Fukuta, Y.; Mita, T.; Fukuda, N.; Kanai, M.; Shibasaki, M. J. Am. D

DOI: 10.1021/acs.orglett.9b01599 Org. Lett. XXXX, XXX, XXX−XXX