Enantioselective Vinylogous Amination of 5-Alkyl-4-nitroisoxazoles

Letter Cite This: Org. Lett. 2018, 20, 429−432

pubs.acs.org/OrgLett

Enantioselective Vinylogous Amination of 5‑Alkyl-4-nitroisoxazoles with a Dipeptide-Based Guanidinium Phase-Transfer Catalyst Bo Zhu,†,‡,⊥ Richmond Lee,§,∥,⊥ Yanli Yin,† Fuyuan Li,† Michelle L. Coote,*,§ and Zhiyong Jiang*,† †

Key Laboratory of Natural Medicine and Immuno-Engineering, Henan University, Kaifeng, Henan, 475004, P. R. China School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan, 453007, P. R. China § ARC Centre of Excellence for Electromaterials Research & Research School of Chemistry, Australian National University, Canberra ACT, 2601, Australia ∥ Singapore University of Technology and Design, 8 Somapah Road, Singapore 487372, Singapore ‡

S Supporting Information *

ABSTRACT: An enantioselective vinylogous amination of 5-alkyl-4-nitroisoxazoles is reported. With a novel chiral dipeptidebased urea−amide−guanidinium as the phase-transfer catalyst, the reactions worked efficiently with NaOAc as the base, affording valuable and challenging-to-synthesize chiral isoxazole derivatives featuring a single stereocenter at the α-position in high yields and with excellent enantioselectivities. Theoretical studies with DFT predicted that cooperative multiple hydrogenbonding and ion pairing interactions of a nucleophile and NaOAc with the catalyst is crucial to deprotonation by reducing their HOMO−LUMO energy gap.

I

soxazoles are important structural motifs in synthetic and medicinal chemistry.1 Since the report by Adamo and coworkers in 2008 using 4-nitro-5-styrylisoxazoles in asymmetric Sharpless dihydroxylation,2 this class of electrophiles3,4 has been valuable for the construction of chiral isoxazole derivatives. In this regard, a number of elegant works have been demonstrated for conjugate addition3 and cycloaddition,4 leading to various optically pure functionalized analogs of isoxazoles featuring β-, β,γ-, and α,β-stereogenic C centers (Figure 1a). Recently, nucleophilic 5-alkyl-4-nitroisoxazoles were used by Zhang, Fan and co-workers in asymmetric vinylogous5 Michael reactions to α,β-unsaturated aldehydes with iminium catalysis,6 indicating how chiral isoxazolecontaining compounds with a β-stereocenter could be obtained with high enantioselectivities (Figure 1b). Given a wide range of available electrophiles, the synthesis of new chiral isoxazoles could be realized through such a complementary strategy, especially for the significant variants with an α-stereocenter, to which a catalytic synthetic approach is still undeveloped. Despite this, no examples have been reported to date. In recent years, we were focused on the development of novel asymmetric vinylogous reactions.7 Herein, we report an amination manifold with 5-alkyl-4-nitroisoxazoles as nucleophiles via asymmetric phase-transfer catalysis (PTC)8 by developing a new prototype of modular chiral organocatalysts that are dipeptide-based urea−amide−guanidiniums (DPUAGs, Figure 1c). Using the DP-UAG catalyst, the trans© 2018 American Chemical Society

Figure 1. Precedent and this work.

formations could be carried out effectively with an acetate base promoter, giving a number of valuable chiral isoxazoles featuring an α-amine-substituted stereocenter in high yield and enantiofacial selectivity. Theoretical studies provide a Received: December 3, 2017 Published: January 2, 2018 429

DOI: 10.1021/acs.orglett.7b03759 Org. Lett. 2018, 20, 429−432

Letter

Organic Letters

very low yield but with significantly boosted enantioselectivity (entry 5). Encouraged by this and given the failure of basification to the corresponding guanidine,12 we wondered if C5 would be rendered more reactive by adding inorganic base promoters (entries 6−8 and Table S1 in Supporting Information (SI)). It was discovered that these base promoters are indeed critical, while using sodium acetate presented the best results (84% yield and 80% ee, entry 8). Solvent screening was carried out next (entries 9−10 and Table S1), and the optimal CH2Cl2 solvent provided an enhanced ee of 84% (entry 10). An ethyl (C6) or benzyl (C7) N-substituent on the guanidinium gave a similar level of enantioselectivity (entries 11−12). Changing the guanidinium group from different diamines (C8−9) did little to improve ee’s (entries 13−14). Finally by changing the 3,5-substituent on the aryl group of the amide N-substituent, the yield improved slightly (C10, entry 15). Together with 5 Å molecular sieves (MS) as an additive and CPME as solvent, the optimal yield of 93% and ee of 91% was furnished (entry 16 and Table S1). Moreover, no reaction was observed without catalyst C10 (entry 16, footnote f). With the optimal reaction conditions in hand, we next explored the reaction scope (Table 2), and to summarize, all reactions completed within 36−60 h, leading to the amination products 3a−zi in 81−96% yield with 58−95% ee. 4Nitroisoxazoles derivatives with alkyl (3a), aryl-containing electron-withdrawing (3b−h) and electron-donating (3i−l) substituents on different positions of the aromatic ring, and heteroarene (e.g., thienyl, 3m) at the C3-position, gave uniformly high levels of enantioselectivity (entries 1−13). The reaction was tolerant of electron-rich (aza)arenes at the C3-position (3k−m, entries 11−13) and to variation of the substituents at the C5-position (3n−zg, entries 14−32), demonstrating the generality of this synthetic approach. The only exceptions were the azodicarboxylates with a sterically bulky alkyl group, e.g. tert-butyl (58% ee, 3zi, entry 32). To gain insight into the reaction mechanism, theoretical studies involving density functional theory, DFT, were undertaken. First, to examine the energetics, we calculated the HOMO−LUMO energies of acetate-nucleophile bound guanidium catalyst complexes, Cpx1a and Cpx1b, and compared that to a neutral complex, Cpx1c, consisting of isopropylamine, CH3COO−, and the nitroisoxazole. The HOMO−LUMO energy gaps, EHOMO−LUMO, for the guanidinium complexes Cpx1a and Cpx1b are 3.21 and 3.15 eV, respectively (Scheme S1), much smaller than Cpx1c of 3.96 eV and indicative that deprotonation of the nitroisoxazle would be kinetically more facile for the ion pair. From the HOMO energies, it could also be inferred that Cpx1b possesses the more reactive acetate. Indeed its smaller EHOMO−LUMO gap translates to a lower activation barrier for deprotonation, TS1b (ΔG‡ = 16.6 kcal/mol) compared to TS1a (ΔG‡ = 21.2 kcal/ mol). From this trend, we would also expect the activation barrier for deprotonation for Cpx1c to be highest, as this is the case for TS1c (ΔG‡ = 31.9 kcal/mol). The enhanced reactivity of the acetates in Cpx1a and Cpx1b correlates to more negatively charged O (Cpx1a and Cpx1b average Hirschfeld charges on acetate O is −0.32 versus −0.26 on Cpx1c), possibly attributed to the resonance stabilization of the positive charge over the entire CN3 moiety of the guanidinium group. To understand the chemistry of the ion pair consisting of guanidinium and acetate, three representative small catalysts guanidine, amidine, and iminewere selected to model how the stability of the catalyst’s base toward protonation

mechanistic understanding of how DP-UAG as a phase-transfer catalyst activates nucleophiles with the acetate and the origin of enantioselectivity. Asymmetric amination with azodicarboxylates is a simple yet powerful strategy to introduce a chiral amine moiety in molecules. Given the resulting chiral α-amine-substituted molecular architectures1f,g and the derivatives9 existing in many bioactive compounds and capable of serving as precursors3a of α-amino acids, we were convinced by these important factors to develop asymmetric vinylogous amination of 5-alkyl-substituted 4-nitroisoxazoles. We began our study with 3,5-diethyl-substituted 4-nitroisoxazole (1a) and diethyl azodicarboxylate (2a) as the model substrates. A variety of chiral tertiary amine catalysts7 C1−C4 derived from L-tertleucine were first assessed, but 3a was obtained in poor yield and enantioselectivity (Table 1, entries 1−4). The correspondTable 1. Optimization of the Reaction Conditionsa

entry

catalyst

base

solvent

yield (%)b

ee (%)c

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16d

C1 C2 C3 C4 C5 C5 C5 C5 C5 C5 C6 C7 C8 C9 C10 C10

− − − − − K3PO4 K2CO3 AcONa AcONa AcONa AcONa AcONa AcONa AcONa AcONa AcONa

toluene toluene toluene toluene toluene toluene toluene toluene Et2O CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CPME

20 29 42 24 8 90 91 84 90 96 83 85 80 82 92 93

15 23 18 49 80 58 60 80 73 84 82 83 83 82 86 91e,f

a

Reaction conditions: 1a (0.05 mmol), 2a (0.075 mmol), solvent (0.5 mL). Entries 1−6, 72 h; entries 7−16, 55 h. bYield of isolated product. cDetermined by HPLC analysis on a chiral stationary phase. d 25 mg of 5 Å molecular sieves (MS) were used. eWithout 5 Å MS, 3a was obtained in 92% yield with 88% ee. fNo reaction was observed without catalyst.

ing higher enantioselectivity for C2 and C4 (entries 2 and 4) suggests the suitability of the dipeptide scaffold and urea in the stereocontrol. To improve the reaction, we endeavored to replace the tertiary amine of C4 to the more basic guanidine,10 and the guanidinium11-based catalyst (DP-UAG) C5 was first conceived. Preliminary reaction with catalyst C5 gave 3a in 430

DOI: 10.1021/acs.orglett.7b03759 Org. Lett. 2018, 20, 429−432

Letter

Organic Letters Table 2. Substrate Scopea

entry

R1/R2/R3 (3)

t (h)

yield (%)b

ee (%)c

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34

Et/Me/Et (3a) Ph/Me/Et (3b) 4-CF3Ph/Me/Et (3c) 4-FPh/Me/Et (3d) 3-ClPh/Me/Et (3e) 4-ClPh/Me/Et (3f) 3-BrPh/Me/Et (3g) 4-BrPh/Me/Et (3h) 3-MePh/Me/Et (3i) 4-MePh/Me/Et (3j) 3-MeOPh/Me/Et (3k) 4-MeOPh/Me/Et (3l) 2-thienyl/Me/Et (3m) Ph/Et/Et (3n) Ph/nBu/Et (3o) Ph/decyl/Et (3p) Ph/PhCH2CH2/Et (3q) Ph/allyl/Et (3r) Ph/PhCH2/Et (3s) Ph/4-FPhCH2/Et (3t) Ph/3-FPhCH2/Et (3u) Ph/2-FPhCH2/Et (3v) Ph/4-ClPhCH2/Et (3w) Ph/3-ClPhCH2/Et (3x) Ph/4-BrPhCH2/Et (3y) Ph/3-BrPhCH2/Et (3za) Ph/2-BrPhCH2/Et (3zb) Ph/4-MePhCH2/Et (3zc) Ph/3-MePhCH2/Et (3zd) Ph/4-MeOPhCH2/Et (3ze) Ph/3-MeOPhCH2/Et (3zf) Ph/2-MeOPhCH2/Et (3zg) 2-thienyl/Me/iPr (3zh) 2-thienyl/Me/tBu (3zi)

55 60 45 45 45 45 36 36 52 60 60 60 50 60 63 63 55 53 60 48 48 48 36 36 48 48 52 48 48 48 48 60 48 52

93 87 96 93 92 93 92 91 88 87 85 92 95 89 90 87 90 92 88 92 93 92 93 92 89 84 92 81 94 91 90 87 91 90

91 93 92 93 93 94 95 93 91 91 92 94 93 94 92 93 91 91 92 93 92 92 94 95 91 93 93 92 92 93 93 92 90 58

After activating the nucleophile, subsequent addition of the nitroisoxazole to the azodicarbonate was calculated and the energetically preferred pathway (Scheme S1) is hypothesized through TS2a. In a bid to delve deeper into the origin of stereochemical preference, we carried out NCIplot13 on TS2a and TS2b. This analysis qualitatively describes the noncovalent interaction regions between the catalyst and substrates, and these mapped surfaces are color-coded in Blue-Green-Red to indicate the type of forces: attractive (blue), repulsive (red), and van der Waals (green) (see Figure 2, top). As we compare

Figure 2. Transition state (TS) structures for amination process TS2a and TS2b. Top: Noncovalent interactions plot (NCIplot) based on reduced density gradient with Blue-Green-Red surface mapping showing attractive (blue) and repulsive (red) regions. Bottom: TS with key bond lengths in Å.

the surface map on transition state structures TS2a and TS2b, it is apparent that the latter has a significant area of steric repulsion existing between the electrophile and the tert-butyl group of the catalyst. The blue attractive regions on both TSs correspond to H-bonding interactions between the catalyst and substrates (highlighted bond lengths ∼1.8 to 2.2 Å in Figure 2, bottom). In light of this, we suggest that in TS2a the nucleoand electrophile are bound more favorably to the catalyst via H-bonding interactions, and as a result more stable than TS2b. The DFT calculations predict that the S-configuration adduct Cpx4a is generated selectively, which is consistent with experiment. We then performed chemical transformations on the enantiopure α-functionalized vinylogous adducts to demonstrate the synthetic utility (Scheme 1). As a paradigm, the amination adduct 3t could be conveniently converted to acid 4 and then ester 5 in high yield and the subsequent reduction of 5 by LiBH4 afforded the corresponding alcohol 6 in 98% yield. As compound 6 was treated with Ac2O and SmI2 to functionalize the N−N bond, the protected amino alcohol 7 was obtained in satisfactory yield with 93% ee. In conclusion, we have developed the first catalytic enantioselective vinylogous amination of 5-alkyl-4-nitroisoxazoles. Through developing a new family of dipeptide-based urea−amide−guanidiniums (DP-UAGs) as the phase-transfer catalyst, the reaction worked smoothly with NaOAc as the

a

Reaction conditions: 1 (0.1 mmol), 2 (0.15 mmol), CH2Cl2 (0.1 mL). bYield of isolated product. cDetermined by HPLC analysis on a chiral stationary phase.

subsequently affects the reactivity of the acetate ion partner (Scheme S2). Optimization of the catalyst−acetic acid complexes of guanidine (Cpx5a) and amidine (Cpx5b) results in complete dissociation of the H from acetate to the N base, whereas for the imine complex Cpx5c the proton remains with acetate. Overall, partial charges on the acetate O for Cpx5a and Cpx5b are more negative than Cpx5c. Stabilization of the protonated catalyst depends on the number of adjacent amine groups which could contribute to one or two resonance forms. For guanidinium Cpx5a which is most stable via resonance effect, the calculated EHOMO is however more positive than Cpx5b or Cpx5c. This suggests that if the protonated cation could be stable, the corresponding acetate would be more reactive since ELUMO is constant for all, ∼2.7 eV. The acetate reactivity based on EHOMO follows this trend: Cpx5a > Cpx5b > Cpx5c. The activation free energy thus correlates to EHOMO−LUMO, i.e. a smaller gap and smaller barrier. 431

DOI: 10.1021/acs.orglett.7b03759 Org. Lett. 2018, 20, 429−432

Letter

Organic Letters

Career Award from SUTD. M.L.C. acknowledges Australian Research Council funding (CE140100012).

Scheme 1. Synthetic Applications

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(1) (a) Sperry, J. B.; Wright, D. L. Curr. Opin. Drug Disc. 2005, 8, 723. (b) Pinho e Melo, T. Curr. Org. Chem. 2005, 9, 925. (c) Liu, Y.; Cui, Z.; Liu, B.; Cai, B.; Li, Y.; Wang, Q. J. Agric. Food Chem. 2010, 58, 2685. (d) Yermolina, M. V.; Wang, J.; Caffrey, M.; Rong, L. L.; Wardrop, D. J. J. Med. Chem. 2011, 54, 765. (e) Heaney, F. Eur. J. Org. Chem. 2012, 2012, 3043. (f) Albrecht, B. K.; Audia, J. E.; Cote, A.; Gehling, V. S.; Harmange, J.-C.; Hewitt, M. C.; Leblanc, Y.; Naveschuk, C. G.; Taylor, A. M.; Vaswani, R. G. PCT Int. Appl., WO 2012075383 A2 20120607, 2012. (g) Abe, T.; Kawamoto, K.; Sasaki, T.; Terayama, T.; Moriwaki, A.; Hayashi, H.; Yamamoto, H. PCT Int. Appl., WO 2015129773 A1 20150903, 2015. (2) Adamo, M. F. A.; Nagabelli, M. Org. Lett. 2008, 10, 1807. (3) (a) Baschieri, A.; Bernardi, L.; Ricci, A.; Suresh, S.; Adamo, M. F. A. Angew. Chem., Int. Ed. 2009, 48, 9342. (b) Pei, Q.-L.; Sun, H.-W.; Wu, Z.-J.; Du, X.-L.; Zhang, X.-M.; Yuan, W.-C. J. Org. Chem. 2011, 76, 7849. (c) Zhang, J.; Liu, X.; Ma, X.; Wang, R. Chem. Commun. 2013, 49, 9329. (d) Disetti, P.; Moccia, M.; Illera, D. S.; Suresh, S.; Adamo, M. F. A. Org. Biomol. Chem. 2015, 13, 10609. (4) (a) Fiandra, C. D.; Piras, L.; Fini, F.; Disetti, P.; Moccia, M.; Adamo, M. F. A. Chem. Commun. 2012, 48, 3863. (b) Liu, X.-L.; Han, W.-Y.; Zhang, X.-M.; Yuan, W.-C. Org. Lett. 2013, 15, 1246. (c) Li, Y.; López-Delgado, F. J.; Jørgensen, D. K. B.; Nielsen, R. P.; Jiang, H.; Jørgensen, K. A. Chem. Commun. 2014, 50, 15689. (d) Chauhan, P.; Mahajan, S.; Raabe, G.; Enders, D. Chem. Commun. 2015, 51, 2270. (e) Liu, K.; Xiong, Y.; Wang, Z.-F.; Tao, H.-Y.; Wang, C.-J. Chem. Commun. 2016, 52, 9458. (5) (a) Chinchilla, R.; Nájera, C. Chem. Rev. 2000, 100, 1891. (b) Casiraghi, G.; Zanardi, F. Chem. Rev. 2000, 100, 1929. (c) Casiraghi, G.; Battistini, L.; Curti, C.; Rassu, G.; Zanardi, F. Chem. Rev. 2011, 111, 3076. (6) Zhang, Y.; Wei, B.; Lin, H.; Cui, W.; Zeng, X.; Fan, X. Adv. Synth. Catal. 2015, 357, 1299. (7) (a) Zhang, W.; Tan, D.; Lee, R.; Tong, G.; Chen, W.; Qi, B.; Huang, K.-W.; Tan, C.-H.; Jiang, Z. Angew. Chem., Int. Ed. 2012, 51, 10069. (b) Zhu, B.; Zhang, W.; Lee, R.; Han, Z.; Yang, W.; Tan, D.; Huang, K.-W.; Jiang, Z. Angew. Chem., Int. Ed. 2013, 52, 6666. (c) Bai, X.; Zeng, G.; Shao, T.; Jiang, Z. Angew. Chem., Int. Ed. 2017, 56, 3684. (8) (a) Ooi, T.; Maruoka, K. Angew. Chem., Int. Ed. 2007, 46, 4222. (b) Maruoka, K. Asymmetric Phase Transfer Catalysis; Wiley: Weinheim, Germany, 2008. (c) Shirakawa, S.; Maruoka, K. Angew. Chem., Int. Ed. 2013, 52, 4312. (9) (a) Baraldi, P. G.; Barco, A.; Benetti, S.; Pollini, G. P.; Simoni, D. Synthesis 1987, 1987, 857. (b) Evans, G. B.; Furneaux, R. H.; Gainsford, G. J.; Hanson, J. C.; Kicska, G. A.; Sauve, A. A.; Schramm, V. L.; Tyler, P. C. J. Med. Chem. 2003, 46, 155. (10) (a) Ishikawa, T. Superbases for Organic Synthesis: Guanidines, Amidines, Phosphazenes and Related Organocatalysts; Wiley: New Your, 2009. For selected reviews, see: (b) Leow, D.; Tan, C.-H. Chem. Asian J. 2009, 4, 488. (c) Coles, M. P. Chem. Commun. 2009, 3659. (d) Sohtome, Y.; Nagasawa, K. Chem. Commun. 2012, 48, 7777. (e) Krawczyk, H.; Dzięgielewski, M.; Deredas, D.; Albrecht, A.; Albrecht, Ł. Chem. - Eur. J. 2015, 21, 10268. (11) Zong, L.; Tan, C.-H. Acc. Chem. Res. 2017, 50, 842. (12) Basification of C5 using solid inorganic bases was attempted but failed. Decomposition was found when using strong inorganic bases, such as KOH and NaOH; the weaker bases, e.g. K2CO3 and K3PO4, could not basify C5 to the corresponding guanidine. (13) (a) Johnson, E. R.; Keinan, S.; Mori-Sanchez, P.; ContrerasGarcia, J.; Cohen, A. J.; Yang, W. J. Am. Chem. Soc. 2010, 132, 762. (b) Contreras-Garcia, J.; Johnson, E. R.; Keinan, S.; Chaudret, R.; Piquemal, J.-P.; Beratan, D. N.; Yang, W. J. Chem. Theory Comput. 2011, 7, 625.

promoter. A series of valuable chiral isoxazole derivatives were synthesized in high yields with excellent enantioselectivities, demonstrating an unprecedented example for the construction of a single α-stereocenter in the 4-nitroisoxazole molecular architecture. Quantum-chemical studies were carried out in conjunction, offering a mechanistic proposal that is DP-UAG activating the nucleophile with CH3COO− via cooperative noncovalent interactions, especially H-bonding, thus reducing their HOMO−LUMO gap and facilitating the crucial deprotonation. The stereochemical origins were also predicted computationally and were consistent with experiments.

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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.7b03759. General information, representative synthesis of catalysts, optimization, procedures, characterization data, determination of the absolute configuration, computational methods, and NMR spectra (PDF) Accession Codes

CCDC 1536277 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.

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REFERENCES

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Richmond Lee: 0000-0003-1264-4914 Michelle L. Coote: 0000-0003-0828-7053 Zhiyong Jiang: 0000-0002-6350-7429 Author Contributions ⊥

B.Z. and R.L. contributed equally.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Z.J. acknowledges the grants from NSFC (21672052) and SNPPIT (BX201700071). R.L. acknowledges a Faculty Early 432

DOI: 10.1021/acs.orglett.7b03759 Org. Lett. 2018, 20, 429−432