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Stereodefined trisubstituted enolates as a unique entry to all-carbon quaternary stereogenic centers in acyclic systems

Abstract

This protocol describes a new approach for the preparation of stereodefined trisubstituted chiral enolate species, avoiding conventional asymmetric enolization of carbonyl compounds. This protocol was developed as a single-flask synthetic sequence and therefore does not require isolation or purification of intermediate compounds. The sequence starts from a regioselective carbocupration reaction of readily accessible chiral ynamides; this is followed by oxidation of the generated vinylcuprate with a commonly available oxidizing reagent (tert-butyl hydroperoxide) in order to generate an enolate that completely retains its configuration. This synthetic protocol has been applied to the preparation of aldol and Mannich-type adducts. The procedure reported here requires a simple reaction setup commonly available in all synthetic laboratories and takes 6 h for completion and 2 h for isolation and purification. Final products are valuable diastereomerically and enantiomerically enriched building blocks for organic synthesis containing all-carbon quaternary stereocenters in acyclic systems.

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Figure 1: The general method developed for the construction of all-carbon quaternary stereogenic centers in acyclic systems starting from ynamides 3.

References

  1. 1

    Hawner, C. & Alexakis, A. Metal-catalyzed asymmetric conjugate addition reaction: formation of quaternary stereocenters. Chem. Commun. 46, 7295–7306 (2010).

    CAS  Article  Google Scholar 

  2. 2

    Das, J.P. & Marek, I. Enantioselective synthesis of all-carbon quaternary stereogenic centers in acyclic systems. Chem. Commun. 47, 4593–4623 (2011).

    CAS  Article  Google Scholar 

  3. 3

    Wender, P.A. & Miller, B. L. Synthesis at the molecular frontier. Nature 460, 197–201 (2009).

    CAS  Article  Google Scholar 

  4. 4

    Newhouse, T., Baran, P.S. & Hoffmann, R.W. The economies of synthesis. Chem. Soc. Rev. 38, 3010–3021 (2009).

    CAS  Article  Google Scholar 

  5. 5

    Baran, P.S., Maimone, T.J. & Richter, J.M. Total synthesis of marine natural products without using protecting groups. Nature 446, 404–408 (2007).

    CAS  Article  Google Scholar 

  6. 6

    Seebach, D. Organic synthesis—where now? Angew. Chem. Int. Ed. Engl. 29, 1320–1367 (1990).

    Article  Google Scholar 

  7. 7

    Tietze, L.F. Domino reactions in organic synthesis. Chem. Rev. 96, 115–136 (1996).

    CAS  Article  Google Scholar 

  8. 8

    Scott, H.K. & Aggarwal, V.K. Highly enantioselective synthesis of tertiary boronic esters and their stereospecific conversion to other functional groups and quaternary stereocentres. Chem. Eur. J. 17, 13124–13132 (2011).

    CAS  Article  Google Scholar 

  9. 9

    Marek, I. A shift in retrosynthetic paradigm. Chem. Eur. J. 14, 7460–7468 (2008).

    CAS  Article  Google Scholar 

  10. 10

    Sklute, G. & Marek, I. Multicomponent approach for the creation of chiral quaternary centers in the carbonyl allylation reactions. J. Am. Chem. Soc. 128, 4642–4649 (2006).

    CAS  Article  Google Scholar 

  11. 11

    Dutta, B., Gilboa, N. & Marek, I. Highly diastereoselective preparation of homoallylic alcohols containing two contiguous quaternary stereocenters in acyclic systems from simple terminal alkynes. J. Am. Chem. Soc. 132, 5588–5589 (2010).

    CAS  Article  Google Scholar 

  12. 12

    Carreira, E.M. Aldol reaction: methodology and stereochemistry. in Modern Carbonyl Chemistry (ed. Otera, J.) Ch. 8 227–248 (Wiley- VCH, 2001).

  13. 13

    Yamago, S., Machii, D. & Nakamura, E. Simple diastereoselectivity of the aldol reaction of persubstituted enolates. Stereoselective construction of quaternary centers. J. Org. Chem. 56, 2098–2106 (1991).

    CAS  Article  Google Scholar 

  14. 14

    Manthorpe, J.M. & Gleason, J.L. Stereoselective generation of E- and Z-disubstituted amide enolates. Reductive enolate formation from bicyclic thioglycolate lactams. J. Am. Chem. Soc. 123, 2091–2092 (2001).

    CAS  Article  Google Scholar 

  15. 15

    Kummer, D.A., Chain, W.J., Morales, M.R., Quiroga, O. & Myers, A.G. Stereocontrolled alkylative construction of quaternary carbon centers. J. Am. Chem. Soc. 130, 13231–13233 (2008).

    CAS  Article  Google Scholar 

  16. 16

    Morales, M.R., Mellem, K.T. & Myers, A.G. Pseudoephenamine: a practical chiral auxiliary for asymmetric synthesis. Angew. Chem. Int. Ed. 51, 4568–4571 (2012).

    CAS  Article  Google Scholar 

  17. 17

    Medley, J.W. & Movassaghi, M. A concise and versatile double-cyclization strategy for the highly stereoselective synthesis and arylative dimerization of aspidosperma alkaloids. Angew. Chem. Int. Ed. 51, 4572–4576 (2012).

    CAS  Article  Google Scholar 

  18. 18

    Qin, Y.-C., Stivala, C.E. & Zakarian, A. Acyclic stereocontrol in the Ireland-Claisen rearrangement of α-branched esters. Angew. Chem. Int. Ed. 46, 7466–7469 (2007).

    CAS  Article  Google Scholar 

  19. 19

    Gu, Z., Herrmann, A.T., Stivala, C.E. & Zakarian, A. Stereoselective construction of adjacent quaternary chiral centers by the Ireland-Claisen rearrangement: stereoselection with esters of cyclic alcohols. Synlett 2010 1717–1722 (2010).

    Article  Google Scholar 

  20. 20

    Evans, D.A., Bartroli, J. & Shih, T.L. Enantioselective aldol condensations. Erythroselective chiral aldol condensations via boron enolates. J. Am. Chem. Soc. 103, 2127–2129 (1981).

    CAS  Article  Google Scholar 

  21. 21

    Chechik-Lankin, H., Livshin, S. & Marek, I. Regiocontrolled carbometalation reactions of ynamides. Synlett 2005, 2239–2241 (2005).

    Google Scholar 

  22. 22

    DeKorver, K.A. et al. Ynamides: a modern functional group in the new millennium. Chem. Rev. 110, 5064–5106 (2010).

    CAS  Article  Google Scholar 

  23. 23

    Evano, G., Coste, A. & Jouvin, K. Ynamides: versatile tools in organic synthesis. Angew. Chem. Int. Ed. 49, 2840–2859 (2010).

    CAS  Article  Google Scholar 

  24. 24

    Das, J.P., Chechik, H. & Marek, I. A unique approach to aldol products for the creation of all-carbon quaternary stereocentres. Nat. Chem. 1, 128–132 (2009).

    CAS  Article  Google Scholar 

  25. 25

    Panek, E.J., Kaiser, L.R. & Whitesides, G.M. Vinylic radicals are intermediates in the oxidation of vinylic lithium reagents to lithium enolates by dioxygen, but not by lithium tert-butyl peroxide. J. Am. Chem. Soc. 99, 3708–3713 (1977).

    CAS  Article  Google Scholar 

  26. 26

    Zhang, D. & Ready, J.M. Tandem carbocupration/oxygenation of terminal alkynes. Org. Lett. 7, 5681–5683 (2005).

    CAS  Article  Google Scholar 

  27. 27

    Wendlandt, A.E., Suess, A.M. & Stahl, S.S. Copper-catalyzed aerobic oxidative C-H functionalizations: trends and mechanistic insights. Angew. Chem. Int. Ed. 50, 11062–11087 (2011).

    CAS  Article  Google Scholar 

  28. 28

    DeBergh, J.R., Spivey, K.M. & Ready, J.M. Preparation of substituted enol derivatives from terminal alkynes and their synthetic utility. J. Am. Chem. Soc. 130, 7828–7829 (2008).

    CAS  Article  Google Scholar 

  29. 29

    Minko, Y., Pasco, M., Lercher, L., Botoshansky, M. & Marek, I. Forming all-carbon quaternary stereogenic centres in acyclic systems from alkynes. Nature 490, 522–526 (2012).

    CAS  Article  Google Scholar 

  30. 30

    Zhang, Y., Hsung, R.P., Tracey, M.R., Kurtz, K.C.M. & Vera, E.L. Copper sulfate-pentahydrate-1,10-phenanthroline catalyzed amidations of alkynyl bromides. synthesis of heteroaromatic amine substituted ynamides. Org. Lett. 6, 1151–1154 (2004).

    CAS  Article  Google Scholar 

  31. 31

    Yao, P.-Y., Zhang, Y., Hsung, R.P. & Zhao, K. A sequential metal-catalyzed C-N bond formation in the synthesis of 2-amido-indoles. Org. Lett. 10, 4275–4278 (2008).

    CAS  Article  Google Scholar 

  32. 32

    Buissonneaud, D. & Cintrat, J.C. Highly regio- and stereocontrolled synthesis of β-substituted α-tributylstannyl enamides. Tetrahedron Lett. 47, 3139–3143 (2006).

    CAS  Article  Google Scholar 

  33. 33

    Sagamanova, I.K., Kurtz, K.C.M. & Hsung, R.P. Practical synthesis of a chiral ynamide: (R)-4-phenyl-3-(2-triisopropylsilyl-ethynyl)oxazolidin-2-one. Org. Synth. 84, 359–367 (2009).

    Google Scholar 

Download references

Acknowledgements

This research was supported by the Israel Science Foundation (administered by the Israel Academy of Sciences and Humanities (140/12)) and by the Fund for Promotion of Research at the Technion. L.L. thanks the Bayer-Stiftung for financial support. I.M. is the holder of the Sir Michael and Lady Sobell Academic Chair.

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Y.M., M.P. and L.L. planned, conducted and analyzed the experiments. I.M. conceived and directed the project and wrote the manuscript with contributions from Y.M. and M.P. All authors contributed to discussions.

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Correspondence to Ilan Marek.

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Minko, Y., Pasco, M., Lercher, L. et al. Stereodefined trisubstituted enolates as a unique entry to all-carbon quaternary stereogenic centers in acyclic systems. Nat Protoc 8, 749–754 (2013). https://doi.org/10.1038/nprot.2013.036

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