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Solid-phase asymmetric synthesis using a polymer-supported chiral Evans'-type oxazolidin-2-one

Nature Protocols volume 8, pages 1890–1906 (2013)Cite this article

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Abstract

This protocol describes the synthesis of (S)-4-(4-hydroxybenzyl)-oxazolidin-2-one, its attachment to a Merrifield-Cl resin and its use for asymmetric synthesis. The chiral auxiliary is prepared in four steps from N-Boc-L-tyrosine on a multigram scale in high yield and attached to Merrifield-Cl resin via its phenolic group to afford a solid-supported chiral auxiliary for asymmetric synthesis that takes ∼7 d to prepare. A procedure for its N-acylation is reported and a method for carrying out diastereoselective solid-supported Evans' syn-aldol reactions is described, with aldol products being cleaved from the polymer by either hydrolysis or reduction. The use of the supported auxiliary for two sequential 'on-bead' reactions has been demonstrated for the synthesis of a chiral cyclopropane aldol and a γ-lactone in a >95:5 diastereomeric ratio. These polymer-supported reactions are carried out in IRORI Kan resin capsules to protect the polymer support from mechanical degradation, thus allowing multiple on-bead reactions to be performed.

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Figure 1: Synthetic route to Merrifield-supported (S)-4-(4-hydroxybenzyl)-oxazolidin-2-one 6.
Figure 2: Directed reactions using γ,δ-unsaturated N-acyl oxazolidin-2-ones.
Figure 3: Solid-supported Evans' syn-aldol reactions using an IRORI Kan to encapsulate the polymer.
Figure 4: Solid-supported Evans' syn-aldol reaction followed by a directed cyclopropanation reaction and reductive cleavage to afford chiral diol 13.
Figure 5: Solid-phase syn-aldol reaction followed by an epoxidation/lactonization sequence to afford chiral lactone 14.
Figure 6: Cross-section diagram of resin capsule assembly.
Figure 7: Photographs of the different steps used to assemble and use the capsule for carrying out solid-supported synthesis.

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References

  1. Chung, C.W.Y. & Toy, P.H. Chiral auxiliaries in polymer-supported organic synthesis. Tetrahedron: Asymmetry 15, 387–399 (2004).

    Article  CAS  Google Scholar 

  2. Solid-Supported Combinatorial and Parallel Synthesis of Small-Molecular-Weight Compound Libraries (eds. Obrecht, D. & Villalgordo, J.M.) 1–339 (Pergamon Press, 1998); http://www.amazon.com/Solid-Supported-Combinatorial-Synthesis-Small-Molecular-Weight-Tetrahedron/dp/0080432581.

  3. Kerrigan, N.J., Hutchison, P.C., Heightman, T.D. & Procter, D.J. Development of a solid-phase 'asymmetric resin-capture-release' process: application of an ephedrine chiral resin in an approach to γ-butyrolactones. Org. Biomol. Chem. 2, 2476–2482 (2004).

    Article  CAS  Google Scholar 

  4. El-Shehawy, A.A. Efficient dual catalytic enantioselective diethylzinc addition to the exocyclic C=N double bond of some 1,2,4-N-triazinylarylimines using polymer-supported chiral β-amino alcohols derived from norephedrine. Tetrahedron 63, 5490–5500 (2007).

    Article  CAS  Google Scholar 

  5. McGhee, A.M., Kizirian, J.C. & Procter, D.J. Synthesis and evaluation of a new polymer-supported pseudoephedrine auxiliary for asymmetric alkylations on solid phase. Org. Biomol. Chem. 5, 1021–1024 (2007).

    Article  CAS  Google Scholar 

  6. Zech, G. & Kunz, H. Synthesis of a polymer-bound galactosylamine and its application as an immobilized chiral auxiliary in stereoselective syntheses of piperidine and amino acid derivatives. Chem. Eur. J. 10, 4136–4149 (2004).

    Article  CAS  Google Scholar 

  7. Kim, H.J., Shin, E.K., Chang, J.Y., Kim, Y. & Park, Y.S. Dynamic kinetic resolution of α-chloro esters in asymmetric nucleophilic substitution using diacetone-D-glucose as a chiral auxiliary. Tetrahedron Lett. 46, 4115–4117 (2005).

    Article  CAS  Google Scholar 

  8. Schuster, C., Knollmueller, M. & Gaertner, P. Chiral linker. Part 2: Synthesis and evaluation of a novel, reusable solid-supported open chain chiral auxiliary derived from m-hydrobenzoin for the diastereoselective reduction of α-keto esters. Tetrahedron: Asymmetry 16, 3211–3223 (2005).

    Article  CAS  Google Scholar 

  9. Broeker, J., Knollmueller, M. & Gaertner, P. Chiral linker. Part 3: Synthesis and evaluation of aryl substituted m-hydrobenzoins as solid supported open chain chiral auxiliaries for the diastereoselective reduction of α-keto esters. Tetrahedron: Asymmetry 17, 2413–2429 (2006).

    Article  CAS  Google Scholar 

  10. Senanayake, C.H., Krishnamurthy, D., Lu, Z.H., Han, Z.X. & Gallou, I. Enantiopure sulfoxides and sulfinamides: recent developments in their stereoselective synthesis and applications to asymmetric synthesis. Aldrichimica Acta. 38, 93–104 (2005).

    CAS  Google Scholar 

  11. Gais, H.-J., Babu, G.S., Günter, M. & Das, P. Asymmetric synthesis of cycloalkenyl and alkenyloxiranes from allylic sulfoximines and aldehydes and application to solid-phase synthesis. Eur. J. Org. Chem. 1464–1473 (2004).

  12. Zhang, Y., Wang, Y.Q. & Dai, W.M. Efficient remote axial-to-central chirality transfer in enantioselective Sml2-mediated reductive coupling of aldehydes with crotonates of atropisomeric 1-naphthamides. J. Org. Chem. 71, 2445–2455 (2006).

    Article  CAS  Google Scholar 

  13. Songis, O., Geant, P.Y., Sautrey, G., Martinez, J. & Calmes, M. Asymmetric Diels-Alder reaction of aminodienes with a nonracemic acrylate bound to rink resin: a comparison of these reactions with their solution-state analogues. Eur. J. Org. Chem. 308–318 (2008).

  14. Quynh, P.B.N., Kim, J.N. & Kim, T.H. Solid-phase asymmetric alkylation reactions using 2-imidazolidinone chiral auxiliary. Tetrahedron Lett. 50, 4015–4018 (2009).

    Article  Google Scholar 

  15. Lazny, R. & Nodzewska, A. N,N-Dialkylhydrazones in organic synthesis. from simple N,N-dimethylhydrazones to supported chiral auxiliaries. Chem. Rev. 110, 1386–1434 (2009).

    Article  Google Scholar 

  16. Ager, D.J., Prakash, I. & Schaad, D.R. 1,2-Amino alcohols and their heterocyclic derivatives as chiral auxiliaries in asymmetric synthesis. Chem. Rev. 96, 835–876 (1996).

    Article  CAS  Google Scholar 

  17. Purandare, A.V. & Natarajan, S. Synthesis of chiral α-substituted β-hydroxy acid derivatives on solid support. Tetrahedron Lett. 38, 8777–8780 (1997).

    Article  CAS  Google Scholar 

  18. Burgess, K. & Lim, D. Resin type can have important effects on solid phase asymmetric alkylation reactions. Chem. Commun. 785–786 (1997).

  19. Winkler, J.D. & McCoull, W. Diels-Alder reaction on solid supports using polymer-bound oxazolidinones. Tetrahedron Lett. 39, 4935–4936 (1998).

    Article  CAS  Google Scholar 

  20. Faita, G., Paio, A., Quadrelli, P., Rancati, F. & Seneci, P. Solid supported chiral auxiliaries in asymmetric synthesis. Part 2: Catalysis of 1,3-dipolar cycloadditions by Mg(II) cation. Tetrahedron 57, 8313–8322 (2001).

    Article  CAS  Google Scholar 

  21. Faita, G., Paio, A., Quadrelli, P., Rancati, F. & Seneci, P. (4S)-p-Hydroxybenzyl-1,3-oxazolidin-2-one as a solid-supported chiral auxiliary in asymmetric 1,3-dipolar cycloadditions. Tetrahedron Lett. 41, 1265–1269 (2000).

    Article  CAS  Google Scholar 

  22. Kotake, T. et al. Design and synthesis of a new polymer-supported Evans-type oxazolidinone: an efficient chiral auxiliary in the solid-phase asymmetric alkylation reactions. Tetrahedron 61, 3819–3833 (2005).

    Article  CAS  Google Scholar 

  23. Phoon, C.W. & Abell, C. Solid phase aldol and conjugate addition reactions using Evans' oxazolidinone chiral auxiliary. Tetrahedron Lett. 39, 2655–2658 (1998).

    Article  CAS  Google Scholar 

  24. Davies, I.R. et al. Efficient asymmetric synthesis of chiral hydroxy-γ-butyrolactones. Org. Lett. 11, 2896–2899 (2009).

    Article  CAS  Google Scholar 

  25. Green, R., Merritt, A.T. & Bull, S.D. A cleavable linker strategy for optimising enolate alkylation reactions of a polymer-supported Evans' oxazolidin-2-one. Chem. Commun. 508–510 (2008).

  26. Ganguly, A.K. et al. Solution- and solid-phase synthesis of enantiomerically pure spiro oxindoles. Tetrahedron Lett. 43, 8981–8983 (2002).

    Article  CAS  Google Scholar 

  27. Davies, S.G. et al. An oxidatively-activated safety-catch linker for solid-phase synthesis. Org. Biomol. Chem. 6, 1625–1634 (2008).

    Article  CAS  Google Scholar 

  28. Hu, F.-Q., Xia, D.-X., Lu, C.-F., Chen, Z.-X. & Yang, G.-C. A new non-cross-linked polystyrene supported 2-phenylimino-2-oxazolidine chiral auxiliary: synthesis and application in asymmetric alkylation reactions. Eur. J. Org. Chem. 2010, 5552–5554 (2010).

    Article  Google Scholar 

  29. Lu, C., Li, D., Wang, Q., Yang, G. & Chen, Z. Stereoselective synthesis of sex pheromone (R)-4-methyl-1-nonanol: non-cross-linked polystyrene supported oxazolidinone as a chiral auxiliary. Eur. J. Org. Chem. 1078–1081 (2009).

  30. Desimoni, G. et al. A soluble polymer-bound Evans' chiral auxiliary: synthesis, characterization and use in cycloaddition reactions. Tetrahedron: Asymmetry 13, 333–337 (2002).

    Article  CAS  Google Scholar 

  31. Sudharshan, M. & Hultin, P.G. An improved preparation of oxazolidin-2-one chiral auxiliaries. Synlett 171–172 (1997).

  32. Green, R. et al. A practical synthesis of enantiopure (S)-4-(4-hydroxybenzyl)-oxazolidin-2-one. Tetrahedron: Asymmetry 14, 2619–2623 (2003).

    Article  CAS  Google Scholar 

  33. Cruz, A. & Rivero, I.A. Preparation and supporting on solid phase of chiral auxiliary (S)-4-(4-hydroxybenzyl)oxazolidin-2-one from L-tyrosinol assisted by microwaves. J. Mex. Chem. Soc. 53, 120–125 (2009).

    CAS  Google Scholar 

  34. Jung, M.E. & Lazarova, T.I. Efficient synthesis of selectively protected L-dopa derivatives from L-Tyrosine via Reimer-Tiemann and Dakin reactions. J. Org. Chem. 62, 1553–1555 (1997).

    Article  CAS  Google Scholar 

  35. Hallman, K., Macedo, E., Nordström, K. & Moberg, C. Enantioselective allylic alkylation using polymer-supported palladium catalysts. Tetrahedron: Asymmetry 10, 4037–4046 (1999).

    Article  CAS  Google Scholar 

  36. Niyadurupola, D.G., Davies, I.R., Wisedale, R. & Bull, S.D. A temporary stereocentre approach for the stereodivergent synthesis of either enantiomer of α-methyloctanal. Eur. J. Org. Chem. 5487–5491 (2007).

  37. Aitken, D.J. et al. An expedient asymmetric synthesis of N-protected (S,S)-2-aminomethyl-1-cyclopropanecarboxylic acid. Synlett 2729–2732 (2010).

    Article  Google Scholar 

  38. Cheeseman, M. & Bull, S.D. An efficient asymmetric synthesis of cascarillic acid. Synlett 7, 1119–1121 (2006).

    Google Scholar 

  39. Cheeseman, M., Davies, I.R., Axe, P., Johnson, A.L. & Bull, S.D. A temporary stereocentre approach for the asymmetric synthesis of chiral cyclopropane-carboxaldehydes. Org. Biomol. Chem. 7, 3537–3548 (2009).

    Article  CAS  Google Scholar 

  40. Cheeseman, M., Feuillet, F.J.P., Johnson, A.L. & Bull, S.D. A novel strategy for the asymmetric synthesis of chiral cyclopropane carboxaldehydes. Chem. Commun. 2372–2374 (2005).

  41. Davies, I.R., Cheeseman, M., Niyadurupola, D.G. & Bull, S.D. An efficient synthesis of semiplenamide C. Tetrahedron Lett. 46, 5547–5549 (2005).

    Article  CAS  Google Scholar 

  42. Green, R., Cheeseman, M., Duffill, S., Merritt, A. & Bull, S.D. An efficient asymmetric synthesis of grenadamide. Tetrahedron Lett. 46, 7931–7934 (2005).

    Article  CAS  Google Scholar 

  43. Peed, J. et al. Asymmetric synthesis of chiral δ-lactones containing multiple contiguous stereocenters. Org. Lett. 13, 3592–3595 (2011).

    Article  CAS  Google Scholar 

  44. Peed, J. et al. Dihydroxylation-based approach for the asymmetric syntheses of hydroxy-γ-butyrolactones. J. Org. Chem. 77, 543–555 (2012).

    Article  CAS  Google Scholar 

  45. Danda, H., Hansen, M.M. & Heathcock, C.H. Acyclic stereoselection. 48. Reversal of stereochemistry in the aldol reactions of a chiral boron enolate. J. Org. Chem. 55, 173–181 (1990).

    Article  CAS  Google Scholar 

  46. Ho, G.-J. & Mathre, D.J. Lithium-initiated imide formation. A simple method for N-acylation of 2-oxazolidinones and bornane-2,10-sultam. J. Org. Chem. 60, 2271–2273 (1995).

    Article  CAS  Google Scholar 

  47. Nakata, T. et al. Peptide synthesis in aqueous solution. 5. Properties and reactivities of (p-hydroxyphenyl)benzylmethylsulfonium salts for direct benzyl esterification of N-acylpeptides. Bull. Chem. Soc. Jpn. 69, 1099–1106 (1996).

    Article  CAS  Google Scholar 

  48. Spaltenstein, A., Carpino, P.A., Miyake, F. & Hopkins, P.B. New approaches to the synthesis of trans-alkene isosteres of dipeptides. J. Org. Chem. 52, 3759–3766 (1987).

    Article  CAS  Google Scholar 

  49. Vandraanen, N.A., Arseniyadis, S., Crimmins, M.T. & Heathcock, C.H. Protocols for the preparation of each of the four possible stereoisomeric α-alkyl-β-hydroxy carboxylic acids from a single chiral aldol reagent. J. Org. Chem. 56, 2499–2506 (1991).

    Article  CAS  Google Scholar 

  50. Fécourt, F., Lopez, G., Van Der Lee, A., Martinez, J. & Dewynter, G. Cyclosulfamide as a chiral auxiliary: application to efficient asymmetric synthesis (alkylation/aldolization). Tetrahedron: Asymmetry 21, 2361–2366 (2010).

    Article  Google Scholar 

  51. Ghosh, A.K. & Kim, J.H. Chelation-controlled ester-derived titanium enolate aldol reaction: diastereoselective syn-aldols with mono- and bidentate aldehydes. Tetrahedron Lett. 43, 5621–5624 (2002).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank GlaxoSmithKline (R.G.), the Engineering and Physical Sciences Research Council (R.G.) and the University of Bath (J.P., R.A.R.B. and J.E.T.) for funding. We also thank M. Topham from Plastok Meshes and Filtration for his help in designing and manufacturing the plastic components required to prepare the permeable resin capsules used for solid-phase synthesis.

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Authors and Affiliations

  1. Department of Chemistry, University of Bath, Bath, UK

    Rachel Green, Jennifer Peed, James E Taylor, Richard A R Blackburn & Steven D Bull

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Contributions

R.G., J.P. and J.E.T. carried out the synthesis of the polymer-supported oxazolidin-2-one and synthesis of authentic samples of chiral compounds in solution phase and compound characterization. R.G. and R.A.R.B. carried out the polymer-supported asymmetric synthesis. S.D.B. conceived and supervised the work. J.E.T., J.P. and S.D.B. contributed toward the manuscript preparation.

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Correspondence to Steven D Bull.

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Green, R., Peed, J., Taylor, J. et al. Solid-phase asymmetric synthesis using a polymer-supported chiral Evans'-type oxazolidin-2-one. Nat Protoc 8, 1890–1906 (2013). https://doi.org/10.1038/nprot.2013.025

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