Letter Cite This: Org. Lett. 2018, 20, 4499−4503
pubs.acs.org/OrgLett
N‑Heterocyclic Carbene-Catalyzed Enantioselective Synthesis of Spiro-glutarimides via α,β-Unsaturated Acylazoliums Santigopal Mondal,†,§ Arghya Ghosh,‡ Subrata Mukherjee,†,§ and Akkattu T. Biju*,‡ †
Organic Chemistry Division, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411008, India Academy of Scientific and Innovative Research (AcSIR), New Delhi 110020, India ‡ Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, India §
Org. Lett. 2018.20:4499-4503. Downloaded from pubs.acs.org by DURHAM UNIV on 08/04/18. For personal use only.
S Supporting Information *
ABSTRACT: NHC-catalyzed enantioselective [3 + 3] spiro-annulation of α,β-unsaturated aldehydes with cyclic β-ketoamides allowing the preparation of synthetically and biologically important spiro-glutarimide derivatives has been reported. The interception of the ketoamides with catalytically generated chiral α,β-unsaturated acylazoliums proceeds in a Michael addition− intramolecular amidation pathway to deliver the spirocyclic products with good yield, diastereoselectivity, and enantioselectivity. The generation of α,β-unsaturated acylazolium is one of the nonumpolung modes of NHC reactivity.7 1,3-Bisnucleophiles such as 1,3-dicarbonyl compounds and enamines undergo a formal [3 + 3] annulation reaction with catalytically generated α,β-unsaturated acylazoliums from enals (under oxidative conditions), 2-bromoenals, ynals, and carboxylic acid derivatives to give dihydropyranones and dihydropyridinones (eq 1).8,9 In 2014, Studer and co-workers demonstrated the organocascade transformation involving the reaction of α,βunsaturated acylazoliums with α-substituted malonate derivatives for the highly stereoselective synthesis of cyclopentane-fused β-lactones under oxidative NHC catalysis (eq 2).10 Simultaneously, our group has developed the NHCcatalyzed reaction of malonate derivatives bearing a γ-aroyl moiety with 2-bromoenals leading to the enantioselective synthesis of functionalized cyclopentenes (eq 3).11 Moreover, the reaction of catalytically generated α,β-unsaturated acylazoliums with malonates bearing a Michael acceptor moiety at the α-position was disclosed by the groups of Studer,12 Ye,13 and Chi.14 In the context of our interest in the use of α-substituted β-dicarbonyl compounds as a coupling partner for α,β-unsaturated acyl azoliums,9 we envisioned that the interception of the cyclic β-ketoamides with α,β-unsaturated acylazoliums could result in the
G
lutarimides are an important class of structural motif and are frequently found in various natural products and biologically relevant molecules. For instance, alonimid is a tetralone-fused spiro-glutarimide derivative mainly known for sedative and hypnotic activity,1 and thalidomide is a widely used drug for the treatment of cancer (Figure 1).2
Figure 1. Selected biologically active glutarimide compounds.
Moreover, actiketal is a glutarimide ring containing natural product used as an antibiotic,3 and glutethimide is a hypnotic sedative, which is used for the treatment of insomnia.4 In addition, the glutarimide ring is present in a large number of medicinally important molecules.5 Due to the widespread biological importance of the glutarimide family of compounds, the development of efficient and enantioselective synthetic routes of these targets is highly desirable. Organocatalysis using NHC catalysis has emerged as one of the popular fields in organic chemistry in the last two decades.6 NHCs are widely used for catalytic transformations proceeding via various umpolung or nonumpolung modes. © 2018 American Chemical Society
Received: June 9, 2018 Published: July 26, 2018 4499
DOI: 10.1021/acs.orglett.8b01799 Org. Lett. 2018, 20, 4499−4503
Letter
Organic Letters
intramolecular proton transfer−cyclization sequence. It may be noted that related spirocyclic compounds from cyclic βketoamides using organocatalysis was developed by the group of Rodriguez15a and Rios.15b The present study was initiated by the treatment of the cyclic β-ketoamide 1a with α-bromocinnamaldehyde 2a in the presence of triazolium salt A and DBU as a base in CH3CN solvent. Interestingly, the expected spiro-glutarimide derivative 3a was formed in 17% yield with 6:1 dr (Table 1, entry 1). When the reaction was carried out in the presence of NHC generated from the chiral triazolium salt B and C, the product 3a was formed in improved yield and dr with high er (entries 2 and 3). Further optimization studies were performed with triazolium salt C.16 A rapid solvent screening revealed that in THF, the product 3a formed in 56% yield but with reduced selectivity (entry 4), whereas other solvents such as toluene and chloroform furnished inferior results (entries 5 and 6). Among the various bases screened using CH3CN solvent, DABCO, i-Pr2NEt, and KOt-Bu afforded 3a in moderate yield with high selectivity (entries 7−9). Gratifyingly, employing Na2CO3 as base furnished 3a in an improved yield of 80% preserving the high dr and er values (entry 10). For further improvement in the efficiency and selectivity, we considered the use of various additives. The use of 50 mol % of LiCl and 4 Å MS did not give further improvement in reactivity/selectivity (entries 11 and 12). Finally, performing the reaction at 0 °C and gradually warming to room temperature in Na2CO3 base and CH3CN solvent furnished 3a in 81% yield, 12:1 dr, and 96:4 er (entry 13).17 With the optimized reaction conditions in hand, we then examined the scope and limitations of this spiro-annulation reaction. First, we examined the variation of the 2-bromoenal moiety (Scheme 1). The parent β-phenyl-α-bromoenal and the electronically different substituents at the 4-position of the β-aryl ring underwent a smooth spiro-annulation reaction and the corresponding spiro-glutarimide derivatives are formed with good yield, dr, and er values (3a−i). In the case of product 3d, the structure and stereochemistry were confirmed by single-crystal X-ray analysis. Moreover, the substitution at the 3-position as well as disubstitution at the β-aryl ring did not affect the reaction outcome, and the desired product was formed in moderate to good yield and selectivity (3j−l). Next, we focused on the scope of the β-ketoamide component (Scheme 2). The N-phenyl β-ketoamide and various β-ketoamides with electron-donating and electronwithdrawing groups at the 4-position of N-aryl ring are well tolerated, and the desired product was formed in good yield and enantioselectivity with moderate diastereoselectivity (3m−q). Moreover, the pentafluoroaniline-derived β-ketoamide- and cyclopentane-derived β-ketoamide furnished the corresponding product in good yield and selectivity (3r,s). Additionally, the indanone-derived β-ketoamide afforded the corresponding product in moderate yield and enantioselectivity with a 1:1 mixture of diastereomers (3t). Additionally, the β-ketoamide synthesized from α-tetralone underwent a smooth annulation reaction leading to the formation of the desired products in high yield and enantioselectivity with a 2:1 diastereomeric ratio (3u−w). Mechanistically, the reaction proceeds via the generation of the free carbene from the chiral triazolium salt under basic reaction conditions, which undergoes nucleophilic attack on
synthesis of spirocyclic compounds. Herein, we report the NHC-catalyzed enantioselective synthesis of spiro-glutarimides by the reaction of modified enals and cyclic βketoamides (eq 4).15 This selective, formal [3 + 3] annulation reaction proceeds via the generation of the chiral α,β-unsaturated acylazoliums and the desired product is formed by a cascade reaction involving a Michael addition− Table 1. Optimization of the Reaction Conditionsa
entry
cat.
base
solvent
yield 3ab (%)
drc
erd
1 2 3 4 5 6 7 8 9 10 11e 12f 13g
A B C C C C C C C C C C C
DBU DBU DBU DBU DBU DBU DABCO i-Pr2NEt KOt-Bu Na2CO3 Na2CO3 Na2CO3 Na2CO3
CH3CN CH3CN CH3CN THF toluene CHCl3 CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN
17 24 34 56 20 18 40 50 32 80 79 75 81
6:1 8:1 10:1 3:1 3:1 2:1 10:1 10:1 12:1 10:1 14:1 12:1 12:1
86:14 96:4 86:14 82:18 92:8 95:5 95:5 92:8 94:6 93:7 95:5 96:4
a
Conditions: 1a (0.10 mmol), 2a (0.12 mmol), cat. (10 mol %), base (1.0 equiv), solvent (1.5 mL), 25 °C, and 24 h. bThe yields were determined by 1H NMR analysis of crude product using CH2Br2 as the internal standard. cDiastereomeric ratio was determined by 1H NMR spectroscopy prior to purification. dEnantiomeric ratio was determined by HPLC analysis on a chiral column. eUse of 50 mol % of LiCl as an additive. fUse of 4 Å MS as an additive. gReaction performed at 0 °C to rt. 4500
DOI: 10.1021/acs.orglett.8b01799 Org. Lett. 2018, 20, 4499−4503
Letter
Organic Letters Scheme 2. Substrate Scope: Variation of the βKetoamidesa
Scheme 1. Substrate Scope: Variation of the 2Bromoenalsa
a
General reaction conditions: 1 (0.25 mmol), 2a (0.30 mmol), C (10 mol %), Na2CO3 (1.0 equiv), CH3CN (4.0 mL), 0 °C to rt and 24 h. Combined yield of both diastereomers are given. bThe reaction mixture stirred for 48 h. cGiven are the er values of both diastereomers.
a
General reaction conditions: 1a (0.25 mmol), 2 (0.30 mmol), C (10 mol %), Na2CO3 (1.0 equiv), CH3CN (4.0 mL), 0 °C to rt and 24 h. Yields of isolated products are given. The dr value was determined by 1 H NMR spectroscopy of crude reaction mixture, and the er value was determined by HPLC analysis on a chiral column. bThe reaction mixture stirred for 48 h.
Scheme 3. Proposed Mechanism of the Reaction
2-bromoenal 2 followed by a proton transfer generating the nucleophilic Breslow intermediate (I)18 or the homoenolate intermediate (II) (Scheme 3). The debromination from intermediate I generated the chiral α,β-unsaturated acylazolium intermediate (III). Michael addition of the enolate generated from 1 onto intermediate III leads to the formation of the NHC-bound enolate intermediate IV.19 An intramolecular proton transfer followed by cyclization of the intermediate V results in the formation of the desired product 3. When the NHC-catalyzed reaction of β-ketoamide 1a was performed with aliphatic bromoenals under the optimized reaction conditions, the desired product was obtained in poor yield and selectivity. Then, we switched the reaction to oxidative conditions using enals.17 Interestingly, the reaction of pentenal 4a with 1a in the presence of carbene generated from C under oxidative conditions using the bisquinone oxidant 620 resulted in the formation of the spiro-glutarimide derivative 5a in 93% yield, 11:1 dr and 88:12 er (Scheme 4). Analogous spiro-annulation was observed with crotonal and decenal, and the desired product was formed with high yield and dr and moderate er values (5b,c). Finally, functionalization of the spiro-glutarimides was also carried out (Scheme 5). Treatment of 3a with m-CPBA under basic conditions afforded the ring-expanded spiro δlactone 7a in 42% (70% brsm) yield and high selectivity. Moreover, in the presence of excess Lawesson’s reagent,21 monothionation of compound 3a at the less hindered imide carbonyl took place to furnish 8a in 95% yield.
In conclusion, we have developed the NHC-catalyzed enantioselective synthesis of spiro-glutarimide derivatives containing two contiguous stereocenters including one allcarbon quaternary spirocenter by the reaction of modified enals with cyclic β-ketoamides. The interception of the ketoamides with catalytically generated chiral α,β-unsaturated acylazoliums proceeds in a Michael addition−proton transfer−cyclization sequence. Given the importance of the chiral glutarimide derivatives in biological systems, the method 4501
DOI: 10.1021/acs.orglett.8b01799 Org. Lett. 2018, 20, 4499−4503
Letter
Organic Letters Scheme 4. Reaction of Aliphatic Enalsa
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS Generous financial support from the Indian Institute of Science (start-up grant for A.T.B) is gratefully acknowledged. Sa.M. and Su.M. thank UGC for fellowships, and A.G. thanks CSIR for the fellowship. We thank Mr. Rupak Saha (IPC, IISc) for the X-ray data and Dr. Santhivardhana Reddy Yetra (CSIR-NCL) for fruitful discussions.
■
(1) (a) Dictionary of Drugs; Elks, J., Ganellin, C. R., Eds.; Chapman and Hall: London, 1990; p 32 (A-00142). (b) Carr, A. A.; Meyer, D. R. Ger. Pat. 2,035,636, 1971; Chem. Abstr. 1971, 74, 99895h. (2) Bartlett, J. B.; Dredge, K.; Dalgleish, A. G. Nat. Rev. Cancer 2004, 4, 314. (3) Kiyota, H.; Shimizu, Y.; Oritani, T. Tetrahedron Lett. 2000, 41, 5887. (4) Hoffmann, K.; Tagmann, E. US Patent 2673205, Mar 23, 1954. (5) (a) Li, W.; Georg, G. I. Chem. Commun. 2015, 51, 8634. (b) Ota, E.; Takeiri, M.; Tachibana, M.; Ishikawa, Y.; Umezawa, K.; Nishiyama, S. Bioorg. Med. Chem. Lett. 2012, 22, 164. (c) Lecomte, N.; Njardarson, J. T.; Nagorny, P.; Yang, G.; Downey, R.; Ouerfelli, O.; Moore, M. A. S.; Danishefsky, S. J. Proc. Natl. Acad. Sci. U. S. A. 2011, 108, 15074. See also: (d) Nabet, B.; Roberts, J. M.; Buckley, D. L.; Paulk, J.; Dastjerdi, S.; Yang, A.; Leggett, A. L.; Erb, M. A.; Lawlor, M. A.; Souza, A.; Scott, T. G.; Vittori, S.; Perry, J. A.; Qi, J.; Winter, G. E.; Wong, K.-K.; Gray, N. S.; Bradner, J. E. Nat. Chem. Biol. 2018, 14, 431. (e) Winter, G. E.; Buckley, D. L.; Paulk, J.; Roberts, J. M.; Souza, A.; Dhe-Paganon, S.; Bradner, J. E. Science 2015, 348, 1376. (6) For recent reviews on NHC organocatalysis, see: (a) Murauski, K. J. R.; Jaworski, A. A.; Scheidt, K. A. Chem. Soc. Rev. 2018, 47, 1773. (b) Wang, M. H.; Scheidt, K. A. Angew. Chem., Int. Ed. 2016, 55, 14912. (c) Menon, R. S.; Biju, A. T.; Nair, V. Beilstein J. Org. Chem. 2016, 12, 444. (d) Flanigan, D. M.; Romanov-Michailidis, F.; White, N. A.; Rovis, T. Chem. Rev. 2015, 115, 9307. (e) Menon, R. S.; Biju, A. T.; Nair, V. Chem. Soc. Rev. 2015, 44, 5040. (f) Yetra, S. R.; Patra, A.; Biju, A. T. Synthesis 2015, 47, 1357. (g) Hopkinson, M. N.; Richter, C.; Schedler, M.; Glorius, F. Nature 2014, 510, 485. (h) De Sarkar, S.; Biswas, A.; Samanta, R. C.; Studer, A. Chem. Eur. J. 2013, 19, 4664. (i) Ryan, S. J.; Candish, L.; Lupton, D. W. Chem. Soc. Rev. 2013, 42, 4906. (j) Fevre, M.; Pinaud, J.; Gnanou, Y.; Vignolle, J.; Taton, D. Chem. Soc. Rev. 2013, 42, 2142. (k) Vora, H. U.; Wheeler, P.; Rovis, T. Adv. Synth. Catal. 2012, 354, 1617. (l) Cohen, D. T.; Scheidt, K. A. Chem. Sci. 2012, 3, 53. (m) Bugaut, X.; Glorius, F. Chem. Soc. Rev. 2012, 41, 3511. (n) Izquierdo, J.; Hutson, G. E.; Cohen, D. T.; Scheidt, K. A. Angew. Chem., Int. Ed. 2012, 51, 11686. (o) Biju, A. T.; Kuhl, N.; Glorius, F. Acc. Chem. Res. 2011, 44, 1182. (p) Nair, V.; Menon, R. S.; Biju, A. T.; Sinu, C. R.; Paul, R. R.; Jose, A.; Sreekumar, V. Chem. Soc. Rev. 2011, 40, 5336. (q) Enders, D.; Niemeier, O.; Henseler, A. Chem. Rev. 2007, 107, 5606. (7) For recent reviews on α,β-unsaturated acyl azoliums, see: (a) Zhang, C.; Hooper, J. F.; Lupton, D. W. ACS Catal. 2017, 7, 2583. (b) Mahatthananchai, J.; Bode, J. W. Acc. Chem. Res. 2014, 47, 696. (8) For selected reports, see: (a) Zhao, C.; Guo, D.; Munkerup, K.; Huang, K.-W.; Li, F.; Wang, J. Nat. Commun. 2018, 9, 611. (b) Li, G.-T.; Li, Z.-K.; Gu, Q.; You, S.-L. Org. Lett. 2017, 19, 1318. (c) Yi, L.; Zhang, Y.; Zhang, Z.-F.; Sun, D.; Ye, S. Org. Lett. 2017, 19, 2286. (d) Wu, X.; Liu, B.; Zhang, Y.; Jeret, M.; Wang, H.; Zheng, P.; Yang, S.; Song, B.-A.; Chi, Y. R. Angew. Chem., Int. Ed. 2016, 55, 12280. (e) Zhang, Z.; Zeng, X.; Xie, D.; Chen, D.; Ding, L.; Wang, A.; Yang, L.; Zhong, G. Org. Lett. 2015, 17, 5052.
a
General reaction conditions: 1a (0.25 mmol), 4 (0.50 mmol), 6 (0.50 mmol), C (10 mol %), Na2CO3 (20 mol %), DCM (4.0 mL), 25 °C, and 24 h. Yields of isolated products are given.
Scheme 5. Functionalization of Spiro-glutarimides
described herein is likely a practical way to access these molecules.
■
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b01799. Details on experimental procedures, characterization, NMR spectra, and HPLC traces of spiro-glutarimide derivatives (PDF) Accession Codes
CCDC 1840626 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.
■
REFERENCES
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Akkattu T. Biju: 0000-0002-0645-8261 4502
DOI: 10.1021/acs.orglett.8b01799 Org. Lett. 2018, 20, 4499−4503
Letter
Organic Letters (f) Gao, Z.-H.; Chen, X.-Y.; Zhang, H.-M.; Ye, S. Chem. Commun. 2015, 51, 12040. (g) Xie, D.; Yang, L.; Lin, Y.; Zhang, Z.; Chen, D.; Zeng, X.; Zhong, G. Org. Lett. 2015, 17, 2318. (h) Mahatthananchai, J.; Zheng, P.; Bode, J. W. Angew. Chem., Int. Ed. 2011, 50, 1673. (i) Wanner, B.; Mahatthananchai, J.; Bode, J. W. Org. Lett. 2011, 13, 5378. (j) De Sarkar, S.; Studer, A. Angew. Chem., Int. Ed. 2010, 49, 9266. (k) Sun, F.-G.; Sun, L.-H.; Ye, S. Adv. Synth. Catal. 2011, 353, 3134. (l) Zhu, Z.-Q.; Xiao, J.-C. Adv. Synth. Catal. 2010, 352, 2455. (m) Kaeobamrung, J.; Mahatthananchai, J.; Zheng, P.; Bode, J. W. J. Am. Chem. Soc. 2010, 132, 8810. (n) Ryan, S. J.; Candish, L.; Lupton, D. W. J. J. Am. Chem. Soc. 2009, 131, 14176. (o) Maki, B. E.; Chan, A.; Phillips, E. M.; Scheidt, K. A. Org. Lett. 2007, 9, 371. (p) Zeitler, K. Org. Lett. 2006, 8, 637. (9) For reports from our group, see: (a) Mukherjee, S.; Ghosh, A.; Marelli, U. K.; Biju, A. T. Org. Lett. 2018, 20, 2952. (b) Yetra, S. R.; Mondal, S.; Mukherjee, S.; Gonnade, R. G.; Biju, A. T. Angew. Chem., Int. Ed. 2016, 55, 268. (c) Yetra, S. R.; Mondal, S.; Suresh, E.; Biju, A. T. Org. Lett. 2015, 17, 1417. (d) Yetra, S. R.; Bhunia, A.; Patra, A.; Mane, M. V.; Vanka, K.; Biju, A. T. Adv. Synth. Catal. 2013, 355, 1089. (e) Yetra, S. R.; Roy, T.; Bhunia, A.; Porwal, D.; Biju, A. T. J. Org. Chem. 2014, 79, 4245. (f) Yetra, S. R.; Kaicharla, T.; Kunte, S. S.; Gonnade, R. G.; Biju, A. T. Org. Lett. 2013, 15, 5202. (10) Bera, S.; Samanta, R. C.; Daniliuc, C. G.; Studer, A. Angew. Chem., Int. Ed. 2014, 53, 9622. (11) Mondal, S.; Yetra, S. R.; Patra, A.; Kunte, S. S.; Gonnade, R. G.; Biju, A. T. Chem. Commun. 2014, 50, 14539. (12) Bera, S.; Daniliuc, C. G.; Studer, A. Org. Lett. 2015, 17, 4940. (13) Liang, Z.-Q.; Wang, D.-L.; Zhang, H.-M.; Ye, S. Org. Lett. 2015, 17, 5140. (14) Fu, Z.; Wu, X.; Chi, Y. R. Org. Chem. Front. 2016, 3, 145. (15) (a) Goudedranche, S.; Bugaut, X.; Constantieux, T.; Bonne, D.; Rodriguez, J. Chem. - Eur. J. 2014, 20, 410. (b) Zhang, K.; Meazza, M.; Dočekal, V.; Light, M. E.; Veselý, J.; Rios, R. Eur. J. Org. Chem. 2017, 1749. (16) Struble, J. R.; Bode, J. W. Org. Synth. 2010, 87, 362. (17) For details, see the Supporting Information. (18) Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719. (19) Alternatively, the enolate generated from 1 could undergo 1,2addition to III forming the hemiacetal, which could undergo [3,3] sigmatropic rearrangement to furnish IV. For details, see ref 8m. (20) Kharasch, M. S.; Joshi, B. S. J. Org. Chem. 1957, 22, 1439. (21) For a review, see: Ozturk, T.; Ertas, E.; Mert, O. Chem. Rev. 2007, 107, 5210.
4503
DOI: 10.1021/acs.orglett.8b01799 Org. Lett. 2018, 20, 4499−4503
