Skip to main content
SpringerLink
Log in

Enantiospecific cyclization of methyl N-(tert-butoxycarbonyl)-N-(3-chloropropyl)-D-alaninate to 2-methylproline derivative via ‘memory of chirality’ in flow

  • Communications
  • Published:
Journal of Flow Chemistry Aims and scope Submit manuscript

Abstract

We report for the very first time a continuous-flow route to perform the intramolecular cyclization of haloalkyl-substituted α-amino esters via memory of chirality (MoC), using lithium bis(trimethylsilyl)amine as a base and methyl N-(tert-butoxycarbonyl)-N-(3-chloropropyl)-D-alaninate as a model reactant. The various reaction parameters, such as temperature, residence time, reactant stoichiometry, or type and concentration of the base were optimized to maximize the yield of the cyclized product and its enantiomeric excess. At the conditions identified, the reaction was eventually scaled up, reaching a productivity of 11 g h−1. Compared to the standard batch protocols available in the literature, the use of a microreactor enables a better control of the exothermicity associated with the addition of the organolithium reagent to the reaction mixture, resulting in operations at more practical temperatures, with high enantiospecificity and full conversion of the reactive amino ester within a few seconds of residence time.

ᅟ

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Scheme 1
Scheme 2
Scheme 3
Scheme 4
Fig. 1
Fig. 2
Fig. 3

Abbreviations

F 16 :

flow rate in mL min−1 of compound 16 in a solution of DMF

F base :

flow rate in mL min−1 of the base solution

T :

reaction temperature

Boc :

tert-butyloxycarbonyl

LC :

liquid chromatography

GC :

gas chromatography

MS :

mass spectrometry

NMR :

nuclear magnetic resonance

X :

conversion of 16

ee :

enantiomeric excess

References

  1. Park K-H, Kurth MJ (2002). Tetrahedron 58:8629

    Article  CAS  Google Scholar 

  2. Kano T, Sakamoto R, Mii H, Wang Y-G, Maruoka K (2010). Tetrahedron 66:4900

    Article  CAS  Google Scholar 

  3. Kawabata T, Yahiro K, Fuji K (1991). J. Am. Chem. Soc. 113:9694

    Article  CAS  Google Scholar 

  4. Zhao H, Hsu DC, Carlier PR (2005). Synthesis 1:1

    Google Scholar 

  5. Seebach D, Naef R (1981). Helv. Chim. Acta 64:2704

    Article  CAS  Google Scholar 

  6. Seebach D, Sting AR, Hoffmann M (1996). Angew. Chem. Int. Ed. 35:2708

    Article  CAS  Google Scholar 

  7. Branca M, Gori D, Guillot R, Alezra V, Kouklovsky C (2008). J. Am. Chem. Soc. 130:5864

    Article  CAS  PubMed  Google Scholar 

  8. Schmalz H-G, de Konig CB, Bernicke D, Siegel S, Pfletschinger A (1999). Angew. Chem. Int. Ed. 38:1620

    Article  CAS  Google Scholar 

  9. Buckmelter AJ, Kim AI, Rychnovsky SD (2000). J. Am. Chem. Soc. 122:9386

    Article  CAS  Google Scholar 

  10. Giese B, Wettsein P, Stähelin C, Barbosa F, Neuburger M, Zenher M, Wessig P (1999). Angew. Chem. Int. Ed. 38:2586

    Article  CAS  Google Scholar 

  11. Kolaczkowski L, Barnes DM (2007). Org. Lett. 9:3029

    Article  CAS  PubMed  Google Scholar 

  12. Hicks F, Hou Y, Langston M, McCarron A, O’Brien E, Ito T, Ma C, Matthews C, O’Bryan C, Provencal D, Zhao Y, Huang J, Yang Q, Heyang L, Johnson M, Sitang Y, Yuqiang L (2013). Org. Process. Res. Dev. 17:829

    Article  CAS  Google Scholar 

  13. Macharia J, Wambua V, Hong Y, Harris L, Hirschi JS, Evans GB, Vetticatt MJ (2017). Angew. Chem. Int. Ed. 56:8756

    Article  CAS  Google Scholar 

  14. Salmon AG, Kizer KW, Zeise L, Jackson RJ, Smith MT (1995). J. Toxicol. Clin. Toxicol. 33:115

    Article  CAS  PubMed  Google Scholar 

  15. Wu G, Huang M (2014). Org. Process. Res. Dev. 18:1192

    Article  CAS  Google Scholar 

  16. Kawabata T, Kawakami S, Majumdar S (2003). J. Am. Chem. Soc. 125:13012

    Article  CAS  PubMed  Google Scholar 

  17. Kawabata T, Wirth T, Yahiro K, Suzuki H, Fuji K (1994). J. Am. Chem. Soc. 116:10809

    Article  CAS  Google Scholar 

  18. Kawabata T, Matsuda S, Kawakami S, Monguchi D, Moriyama K (2006). J. Am. Chem. Soc. 128:15394

    Article  CAS  PubMed  Google Scholar 

  19. Kawabata T, Moriyama K, Kawakami S, Tsubaki K (2008). J. Am. Chem. Soc. 130:4153

    Article  CAS  PubMed  Google Scholar 

  20. Pastre JC, Browne DL, Ley SV (2013). Chem. Soc. Rev. 42:8849

    Article  CAS  PubMed  Google Scholar 

  21. Baumann M, Baxendale IR, Beilstein J (2015). Org. Chem. 11:1194

    CAS  Google Scholar 

  22. Vilé G, Richard-Bildstein S, Lhuillery A, Rueedi G (2018). ChemCatChem 10:3786–3794

  23. Abele S, Höck S, Schmidt G, Funel J-A, Marti R (2012). Org. Process. Res. Dev. 16:1114

    Article  CAS  Google Scholar 

  24. Amann F, Frank M, Rhodes M, Robinson A, Kesselgruber M, Abele S (2016). Org. Process. Res. Dev. 20:446

    Article  CAS  Google Scholar 

  25. Kockmann N, Thenée P, Fleischer-Trebes C, Laudadio G, Noël T (2017). React. Chem. Eng. 2:258

    Article  CAS  Google Scholar 

  26. Glasnov TN, Kappe CO (2011). Chem. Eur. J. 17:11956

    Article  CAS  PubMed  Google Scholar 

  27. Yoshida J, Takahashia Y, Nagaki A (2013). Chem. Commun. 49:9896

    Article  CAS  Google Scholar 

  28. Yoshida J, Kim H, Nagaki A (2017). J. Flow. Chem. 7:60

    Article  CAS  Google Scholar 

  29. For general methods to prepare 16, see: (i) Kachkovskyi G, Faderl C, Reiser O (2013). Adv. Synth. Catal. 355:2240; (ii) Anxionnat B, Robert B, George P, Ricci G, Perrin MA (2012). J. Org. Chem. 77:6087

  30. The chiral analysis of 16 was performed by analyzing the starting material using the method reported in the Supporting Information, and comparing this with a racemic mixture containing both 16 and ent -16

  31. Sapse AM, von Ragué Schleyer P (1995) Lithium Chemistry – a Theoretical and Experimental Overview. Wiley, New York, p 145

    Google Scholar 

  32. Hessel V, Kralisch D, Kockmann N, Noël T, Wang Q (2013). ChemSusChem 6:746

    Article  CAS  PubMed  Google Scholar 

  33. Wegner J, Ceylan S, Kirschning A (2012). Adv. Synth. Catal. 354:17

    Article  CAS  Google Scholar 

  34. Fogler, H. Elements of chemical reaction engineering 1992, 2nd edition. Prentice Hall, Upper Saddle River

  35. Singh R, Panda G (2013). RSC Adv. 3:19533

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to Dr. Simone Tortoioli for proof-reading the manuscript and for valuable comments. The authors would like to thank Julien Grimont for NMR support, as well as Claus Mueller and his team for analytical methods and chiral analyses. Finally, Dr. Thomas Weller is sincerely acknowledged for support and comments on the paper.

Author information

Authors and Affiliations

  1. Drug Discovery Chemistry, Idorsia Pharmaceuticals Ltd., Hegenheimermattweg 91, CH-4123, Allschwil, Switzerland

    Gianvito Vilé & Sylvia Richard-Bildstein

  2. Chemical Development, Idorsia Pharmaceuticals Ltd., Hegenheimermattweg 91, CH-4123, Allschwil, Switzerland

    Gunther Schmidt & Stefan Abele

Authors
  1. Gianvito Vilé
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gunther Schmidt
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sylvia Richard-Bildstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Stefan Abele
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gianvito Vilé.

Electronic supplementary material

ESM 1

(DOCX 407 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Vilé, G., Schmidt, G., Richard-Bildstein, S. et al. Enantiospecific cyclization of methyl N-(tert-butoxycarbonyl)-N-(3-chloropropyl)-D-alaninate to 2-methylproline derivative via ‘memory of chirality’ in flow. J Flow Chem 9, 19–25 (2019). https://doi.org/10.1007/s41981-018-0022-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s41981-018-0022-5

Keywords

Search

Navigation