Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Generation and exploitation of acyclic azomethine imines in chiral Brønsted acid catalysis

Abstract

Successful implementation of a catalytic asymmetric synthesis strategy to produce enantiomerically enriched compounds requires the adoption of suitable prochiral substrates. The combination of an azomethine imine electrophile with various nucleophiles could give straightforward access to a number of synthetically useful chiral hydrazines, but is used rarely. Here we report the exploitation of acyclic azomethine imines as a new type of prochiral electrophile. They can be generated in situ by the condensation of N′-benzylbenzoylhydrazide with a variety of aldehydes in the presence of a catalytic amount of an axially chiral dicarboxylic acid. By trapping these electrophiles with alkyl diazoacetate or (diazomethyl)phosphonate nucleophiles, we produced a diverse array of chiral α-diazo-β-hydrazino esters and phosphonates with excellent enantioselectivities.

Your institute does not have access to this article

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Classification and reactivity of azomethine imines.
Figure 2: Influence of the catalyst structure on the reaction pathway.
Figure 3: Applications of axially chiral dicarboxylic acid catalysed reaction of acyclic azomethine imines.

References

  1. Miller, E. D., Kauffman, C. A., Jensen, P. R. & Fenical, W. Piperazimycins: cytotoxic hexadepsipeptides from a marine-derived bacterium of the genus Streptomyces. J. Org. Chem. 72, 323–330 (2006).

    Google Scholar 

  2. Li, W., Gan, J. & Ma, D. Total synthesis of piperazimycin A: a cytotoxic cyclic hexadepsipeptide. Angew. Chem. Int. Ed. 48, 8891–8895 (2009).

    CAS  Google Scholar 

  3. Bold, G. et al. New aza-dipeptide analogues as potent and orally absorbed HIV-1 protease inhibitors: candidates for clinical development. J. Med. Chem. 41, 3387–3401 (1998).

    CAS  PubMed  Google Scholar 

  4. Pyrko, P. et al. HIV-1 protease inhibitors nelfinavir and atazanavir induce malignant glioma death by triggering endoplasmic reticulum stress. Cancer Res. 67, 10920–10928 (2007).

    CAS  PubMed  Google Scholar 

  5. Ragnarsson, U. Synthetic methodology for alkyl substituted hydrazines. Chem. Soc. Rev. 30, 205–213 (2001).

    CAS  Google Scholar 

  6. Nair, V., Biju, A. T., Mathew, S. C. & Babu, B. P. Carbon–nitrogen bond-forming reactions of dialkyl azodicarboxylate: a promising synthetic strategy. Chem. Asian J. 3, 810–820 (2008).

    CAS  PubMed  Google Scholar 

  7. Küchenthal, C-H. & Maison, W. Synthesis of cyclic hydrazino α-carboxylic acids. Synthesis 2010, 719–740 (2010).

    Google Scholar 

  8. Friedstad, G. K. Chiral N-acylhydrazones: versatile imino acceptors for asymmetric amine synthesis. Eur. J. Org. Chem. 2005, 3157–3172 (2005).

    Google Scholar 

  9. Sugiura, M. & Kobayashi, S. N-Acylhydrazones as versatile electrophiles for the synthesis of nitrogen-containing compounds. Angew. Chem. Int. Ed. 44, 5176–5186 (2005).

    CAS  Google Scholar 

  10. Denmark, S. E. & Nicaise, O. J-C. in Comprehensive Asymmetric Catalysis Vol. 2 (eds Jacobsen, E. N., Pfaltz, A. & Yamamoto, H.) Ch. 26.2 (Springer, 1999).

    Google Scholar 

  11. Hashimoto, T. & Maruoka, K. in Handbook of Cyclization Reactions Vol. 1 (ed. Ma, S.) Ch. 3 (Wiley, 2009).

    Google Scholar 

  12. Pellissier, H. Asymmetric 1,3-dipolar cycloadditions. Tetrahedron 63, 3235–3285 (2007).

    CAS  Google Scholar 

  13. Stanley, L. M. & Sibi, M. P. Enantioselective copper-catalyzed 1,3-dipolar cycloadditions. Chem. Rev. 108, 2887–2902 (2008).

    CAS  PubMed  Google Scholar 

  14. Kawai, H., Kusuda, A., Nakamura, S., Shiro, M. & Shibata, N. Catalytic enantioselective trifluoromethylation of azomethine imines with trimethyl(trifluoromethyl)silane. Angew. Chem. Int. Ed. 48, 6324–6327 (2009).

    CAS  Google Scholar 

  15. Shintani, R., Soh, Y-T. & Hayashi, T. Rhodium-catalyzed asymmetric arylation of azomethine imines. Org. Lett. 12, 4106–4109 (2010).

    CAS  PubMed  Google Scholar 

  16. Hashimoto, T., Maeda, Y., Omote, M., Nakatsu, H. & Maruoka, K. Catalytic enantioselective 1,3-dipolar cycloaddition of C,N-cyclic azomethine imines with α,β-unsaturated aldehydes. J. Am. Chem. Soc. 132, 4076–4077 (2010).

    CAS  PubMed  Google Scholar 

  17. Hashimoto, T., Omote, M. & Maruoka, K. Asymmetric inverse-electron-demand 1,3-dipolar cycloaddition of C,N-cyclic azomethine imines: an umpolung strategy. Angew. Chem. Int. Ed. 50, 3489–3492 (2011).

    CAS  Google Scholar 

  18. Oppolzer, W. Ein neuer, flexibler augang zu pyrazolidinen und pyrazolinen. Tetrahedron Lett. 11, 2199–2204 (1970).

    Google Scholar 

  19. Oppolzer, W. Intramolekulare cycloadditionen von azomethiniminen, teil I: reaktion von ungesaettigten aldehyden mit N-acyl-N ′-alkylhydraziden. Tetrahedron Lett. 11, 3091–3094 (1970).

    Google Scholar 

  20. Oppolzer, W. Intramolekulare cycloadditionen von azomethiniminen, teil II: reaktionen von ungesaettigten hydraziden mit aldehyden. Tetrahedron Lett. 13, 1707–1710 (1972).

    Google Scholar 

  21. Oppolzer, W. & Peter Weber, H. Die thermolyse von quecksilber-bis (N,N-dimethyl-N ′-phenacetylhydrazin) in gegenwart dipolarophiler olefine. Tetrahedron Lett. 13, 1711–1714 (1972).

    Google Scholar 

  22. Jacobi, P. A., Brownstein, A., Martinelli, M. & Grozinger, K. A mild procedure for the generation of azomethine imines. Stereochemical factors in the intramolecular 1,3-dipolar addition of azomethine imines and a synthetic approach to saxitoxin. J. Am. Chem. Soc. 103, 239–241 (1981).

    CAS  Google Scholar 

  23. Jacobi, P. A., Martinelli, M. J. & Polanc, S. Total synthesis of (±)-saxitoxin. J. Am. Chem. Soc. 106, 5594–5598 (1984).

    CAS  Google Scholar 

  24. Nilsson, B. L., Overman, L. E., Read de Alaniz, J. & Rohde, J. M. Enantioselective total syntheses of nankakurines A and B: confirmation of structure and establishment of absolute configuration. J. Am. Chem. Soc. 130, 11297–11299 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Kanemasa, S., Tomoshige, N., Wada, E. & Tsuge, O. Triethylamine-mediated generation of a synthetic equivalent of parent azomethine imine by condensation of ethyl 3-benzylcarbazate with paraformaldehyde. Bull. Chem. Soc. Jpn 62, 3944–3949 (1989).

    CAS  Google Scholar 

  26. Tamura, Y., Minamikawa, J-I., Miki, Y., Okamoto, Y. & Ikeda, M. The synthesis and properties of N-acylimino-3,4-dihydroisoquinolinium betaines. Yakugaku Zasshi 93, 648 (1973).

    CAS  PubMed  Google Scholar 

  27. Portlock, D. E., Naskar, D., West, L. & Li, M. Petasis boronic acid–Mannich reactions of substituted hydrazines: synthesis of α-hydrazinocarboxylic acids. Tetrahedron Lett. 43, 6845–6847 (2002).

    CAS  Google Scholar 

  28. Akiyama, T. Stronger Brønsted acids. Chem. Rev. 107, 5744–5758 (2007).

    CAS  PubMed  Google Scholar 

  29. Terada, M. Chiral phosphoric acids as versatile catalysts for enantioselective transformations. Synthesis 2010, 1929–1982 (2010).

    Google Scholar 

  30. Hashimoto, T. & Maruoka, K. Design of axially chiral dicarboxylic acid for asymmetric Mannich reaction of arylaldehyde N-Boc imines and diazo compounds. J. Am. Chem. Soc. 129, 10054–10055 (2007).

    CAS  PubMed  Google Scholar 

  31. Hashimoto, T. & Maruoka, K. Design of an axially chiral dicarboxylic acid and its application in syntheses of optically active β-amino acids and β-amino phosphonic acid derivatives. Synthesis 2008, 3703–3706 (2008).

    Google Scholar 

  32. Hashimoto, T., Hirose, M. & Maruoka, K. Asymmetric imino aza-enamine reaction catalyzed by axially chiral dicarboxylic acid: use of arylaldehyde N,N-dialkylhydrazones as acyl anion equivalent. J. Am. Chem. Soc. 130, 7556–7557 (2008).

    CAS  PubMed  Google Scholar 

  33. Hashimoto, T., Uchiyama, N. & Maruoka, K. Trans-selective asymmetric aziridination of diazoacetamides and N-Boc imines catalyzed by axially chiral dicarboxylic acid. J. Am. Chem. Soc. 130, 14380–14381 (2008).

    CAS  PubMed  Google Scholar 

  34. Hashimoto, T., Kimura, H. & Maruoka, K. Enantioselective formal alkenylations of imines catalyzed by axially chiral dicarboxylic acid using vinylogous aza-enamines. Angew. Chem. Int. Ed. 49, 6844–6847 (2010).

    CAS  Google Scholar 

  35. Ramón, D. J. & Yus, M. Asymmetric multicomponent reactions (AMCRs): the new frontier. Angew. Chem. Int. Ed. 44, 1602–1634 (2005).

    Google Scholar 

  36. Uraguchi, D., Sorimachi, K. & Terada, M. Organocatalytic asymmetric direct alkylation of α-diazoester via C−H bond cleavage. J. Am. Chem. Soc. 127, 9360–9361 (2005).

    CAS  PubMed  Google Scholar 

  37. Maruoka, K., Itoh, T., Shirasaka, T. & Yamamoto, H. Asymmetric hetero-Diels–Alder reaction catalyzed by a chiral organoaluminum reagent. J. Am. Chem. Soc. 110, 310–312 (1988).

    CAS  Google Scholar 

  38. Hashimoto, T., Takagaki, T., Kimura, H. & Maruoka, K. Modular synthesis of axially chiral 3,3′-disilyl dicarboxylic acids by silalactones. Chem. Asian J. DOI: 10.1002/asia.201100172.

    CAS  Google Scholar 

  39. Zelenin, K. N. et al. Synthesis of 5-hydroxy- and 5-acylhydrazinopyrazolidines by the reaction of β-substituted hydrazides with α,β-unsaturated aldehydes and their biological activity. Chem. Heterocycl. Compd 20, 529–536 (1984).

    Google Scholar 

  40. Tanaka, K., Kato, T., Fujinami, S., Ukaji, Y. & Inomata, K. Asymmetric 1,3-dipolar cycloaddition of azomethine imines to homoallylic alcohols. Chem. Lett. 39, 1036–1038 (2010).

    CAS  Google Scholar 

  41. Palacios, F., Alonso, C. & de los Santos, J. M. Synthesis of β-aminophosphonates and -phosphinates. Chem. Rev. 105, 899–932 (2005).

    CAS  PubMed  Google Scholar 

  42. Ding, H. & Friestad, G. K. Trifluoroacetyl-activated nitrogen−nitrogen bond cleavage of hydrazines by samarium(II) iodide. Org. Lett. 6, 637–640 (2004).

    CAS  PubMed  Google Scholar 

  43. Córdova, A. The direct catalytic asymmetric Mannich reaction. Acc. Chem. Res. 37, 102–112 (2004).

    PubMed  Google Scholar 

  44. Ting, A. & Schaus, S. E. Organocatalytic asymmetric Mannich reactions: new methodology, catalyst design, and synthetic applications. Eur. J. Org. Chem. 5797–5815 (2007).

  45. Verkade, J. M. M., van Hemert, L. J. C., Quaedflieg, P. J. L. M. & Rutjes, F. P. J. T. Organocatalysed asymmetric Mannich reactions. Chem. Soc. Rev. 37, 29–41 (2008).

    CAS  PubMed  Google Scholar 

  46. Kobayashi, S., Mori, Y., Fossey, J. S. & Salter, M. M. Catalytic enantioselective formation of C−C bonds by addition to imines and hydrazones: a ten-year update. Chem. Rev. 111, 2626–2704 (2011).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was partially supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan. T.H. thanks a Grant-in-Aid for Young Scientists (B).

Author information

Authors and Affiliations

Authors

Contributions

T.H. conceived the study and wrote the manuscript. H.K. principally performed the experiments. Y.K. assisted preliminary experiments. K.M. organized the research. All authors contributed to designing the experiments, analysing data and editing the manuscript.

Corresponding author

Correspondence to Keiji Maruoka.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information

Supplementary information (PDF 19785 kb)

Supplementary information

Crystallographic data for compound 7o (CIF 43 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Hashimoto, T., Kimura, H., Kawamata, Y. et al. Generation and exploitation of acyclic azomethine imines in chiral Brønsted acid catalysis. Nature Chem 3, 642–646 (2011). https://doi.org/10.1038/nchem.1096

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nchem.1096

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing