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Synthesis of 9-amino(9-deoxy)epi cinchona alkaloids, general chiral organocatalysts for the stereoselective functionalization of carbonyl compounds

Nature Protocols volume 8, pages 325–344 (2013)Cite this article

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Abstract

We describe two procedures for the synthesis of primary amines derived from 9-amino(9-deoxy)epi cinchona alkaloids, valuable catalysts used in the asymmetric functionalization of carbonyl compounds. The first approach allows the one-pot 5-g-scale syntheses of four cinchona-based analogs (1, 3, 5 and 7) from the alkaloids quinine (QN), quinidine (QD), dihydroquinine (DHQN) and dihydroquinidine (DHQD), respectively, performed by means of a Mitsunobu reaction to introduce an azide group, followed by reduction and hydrolysis. Demethylation of 1, 3, 5 and 7 with BBr3 provided direct access to the bifunctional aminocatalysts 2, 4, 6 and 8. A second approach, more convenient for scale-up (tested to a 20-g scale), is also provided. In this second procedure, the azides, formed from the O-mesylated derivatives of QN and QD, are selectively reduced with LiAlH4 to afford catalysts 1 and 3, whereas hydrogenation (Pd/C) provides 5 and 7. Demethylation of 1, 3, 5 and 7 using an alkylthiolate affords 2, 4, 6 and 8 in a process in which the less-expensive QN and QD are the only starting materials used.

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Figure 1
Figure 2
Figure 3: Reaction scheme for Approach 2: SN2-LiAlH4 or Pd/C-thiolate route.

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  • 25 January 2013

     In the version of this article initially published online, Fernando Bravo was not included as a corresponding author. Both Fernando Bravo and Paolo Melchiorre are corresponding authors for this manuscript. The error has been corrected in all versions of the article.

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Acknowledgements

We thank the ICIQ's NMR service for low-temperature 13C NMR, the ICIQ's Chemical Reaction Technologies Unit for technical support in performing pressurized hydrogenation reactions and the ICIQ's Chromatography, Thermal Analysis and Electrochemistry Unit for technical support in DSC analysis. Research support from the ICIQ Foundation, Ministerio de Ciencia e Innovación (MICINN) (grant no. CTQ2010-15513 and A Formación de Personal Investigador (FPI) predoctoral fellowship to C.C.) and the European Research Council (ERC starting grant agreement no. 278541 – ORGA-NAUT) is gratefully acknowledged.

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Author notes

  1. Carlo Cassani and Rafael Martín-Rapún: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Chemical Research of Catalonia (ICIQ), Tarragona, Spain

    Carlo Cassani, Elena Arceo & Paolo Melchiorre

  2. Catalyst Selection and Optimization Laboratory (CSOL), ICIQ, Tarragona, Spain

    Rafael Martín-Rapún & Fernando Bravo

  3. Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain

    Paolo Melchiorre

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Contributions

Synthetic work was carried out by C.C., R.M.-R. and F.B.; experimental procedure development and assembly of the manuscript was performed by C.C., R.M.-R., E.A., F.B. and P.M.

Corresponding authors

Correspondence to Fernando Bravo or Paolo Melchiorre.

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Competing interests

F.B., R.M-R. and P.M. have filed a patent application describing Approach 2 discussed in this protocol (application number EP12382291).

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1H NMR and 13C spectra of the products (PDF 1376 kb)

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Cassani, C., Martín-Rapún, R., Arceo, E. et al. Synthesis of 9-amino(9-deoxy)epi cinchona alkaloids, general chiral organocatalysts for the stereoselective functionalization of carbonyl compounds. Nat Protoc 8, 325–344 (2013). https://doi.org/10.1038/nprot.2012.155

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