Templates for exploratory library preparation. Derivatization of a functionalized spirocyclic 3,6-dihydro-2H-pyran formed by ring-closing metathesis reaction

Journal of Combinatorial Chemistry

Volumn 4, Issue 2, 2002, Pages 125-130

  Walters, Michael A ^a   La, Frances ^a   Deshmukh, Prashant ^a   Omecinsky, Diana O ^a  

^a PFIZER INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ARTICLE;

EID: 0012086773     PISSN: 15204766     EISSN: None     Source Type: Journal    
DOI: 10.1021/cc0100215     Document Type: Article

References (40)

1. Inquiries regarding the structure determination of 16a and 16b should be directed to D.O.O. current address for P.D.: Department of Chemistry, Imperial College of Science, Technology and Medicine, London, England.
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7. The term "DEM" is roughly synonymous with the term "functional group". It is coined here because it is more fitting, in a retrocombinatorial sense, to recognize that groups can be considered to be more or less diversity-enabling. For example, although both are functional groups, an aromatic moiety does not carry with it as much diversity potential as does a carbonyl group.
8. Li, J.; Murray, C. W.; Waszkowycz, B.; Young, S. C. Targeted Molecular Diversity in Drug Discovery: Integration of Structure-Based Design and Combinatorial Chemistry. Drug Discovery Today 1998, 3, 105-112.
9. Several other combinatorial papers document the preparation of β-amino alcohols by the addition of amines to epoxides, hinting at the importance of these compounds in drug discovery. Solution-phase preparations include the following: (a) Hori, M.; Janda, K. D. A Soluble Polymer Approach to the "Fishing Out" Principle: Synthesis and Purification of β-Amino Alcohols. J. Org. Chem. 1998, 63, 889-894.
10. (b) Shuker, A. J.; Siegel, M. G.; Matthews, D. P.; Weigel, L. O. The Application of High-Throughput Synthesis and Purification to the Preparation of Ethanolamines. Tetrahedron Lett. 1997, 38, 6149-6152.
11. (c) Chng, B. L.; Ganesan, A. Solution-Phase Synthesis of a β-Amino Alcohol Combinatorial Library. Bioorg. Med. Chem. Lett. 1997, 7, 1511-1514.
12. (d) Maltais, R.; Poirier, D. A Solution-Phase Combinatorial Parallel Synthesis of 3β-Amido-3α-hydroxy-5α-androstane-17-ones. Tetrahedron Lett. 1998, 39, 4151-4154.
13. (e) Bolli, M. H.; Ley, S. V. Development of a Polymer Bound Wittig Reaction and Use in Multi-step Organic Synthesis for the Overall Conversion of Alcohols to β-Hydroxyamines. J. Chem. Soc., Perkin Trans. 1 1998, 2243-2246.
14. (f) Organ, M. G.; Kaldor, S. W.; Dixon, C. E.; Parks, D. J.; Singhfi, U.; Lavorato, D. J.; Isbestera, P. K.; Siegel, M. G. The Synthesis of Ethanolamine Libraries from Olefin Scaffolds. Tetrahedron Lett. 2000, 41, 8407-8411.
15. For the solid-phase, see the following: (g) Rosse, B.; Ouertani, F.; Schroder, H. Efficient Solid-Phase Synthesis of β-Aminosubstituted Piperidinols. J. Comb. Chem. 1999, 1, 397-401.
16. (h) Le Hetet, C.; David, M.; Carreaux, F.; Carboni, B.; Sauleau, A. Synthesis of Functionalized γ-and δ-Lactones via Polymer-Bound Epoxides. Tetrahedron Lett. 1997, 38, 5153-5156.
17. (i) Rotella, D. P. Solid Phase Synthesis of Olefin and Hydroxyethylene Peptidomimetics. J. Am. Chem. Soc. 1996, 118, 12246-12247.
18. For the reaction of an amino-functionalized polymer with an epoxide to generate a resin-linked amino alcohol, see the following: (j) Gauzy, L.; Le Merrer, Y.; Depezay, J.-C.; Clerc, F.; Mignani, S. Synthesis of Azepane Scaffolds on Solid Support for Combinatorial Chemistry. Tetrahedron Lett. 1999, 40, 6005-6008.
19. (a) Fürstner, A. Ruthenium-Catalyzed Metathesis Reactions in Organic Synthesis. Top. Organomet. Chem. 1998, 1, 37-72.
20. (b) Schuster, M.; Blechert, S. Application of Olefin Metathesis. Transition Met. Org. Synth. 1998, 1, 275-284.
21. (c) Randall, M. L.; Snapper, M. L. Selective Olefin Metatheses - New Tools for the Organic Chemist: A Review. J. Mol. Catal. A: Chem. 1998, 133, 29-40.
22. (d) Ivin, K. J. Some Recent Applications of Olefin Metathesis in Organic Synthesis: A Review. J. Mol. Catal. A: Chem. 1998, 133, 1-16.
23. (e) Grubbs, R. H.: Chang, S. Recent Advances in Olefin Metathesis and its Application in Organic Synthesis. Tetrahedron 1998, 54, 4413-4450.
24. (f) Phillips, A. J.; Abell, A. D. Ring-Closing Metathesis of Nitrogen-Containing Compounds: Applications to Heterocycles. Alkaloids, and Peptidomimetics. Aldrichim. Acta 1999, 32, 75-89.
25. Sannigrahi, M. Stereocontrolled Synthesis of Spirocyclics. Tetrahedron 1999, 55, 9007-9071.
26. A similar strategy involving RCM followed by epoxidation has recently been reported. (a) Pernerstorfer, J.; Schuster, M.; Blechert, S. A Solid-Phase Synthesis of Functionalized 6-. 7-, and 8-membered Azacycles via Olefin Metathesis. Synthesis 1999, 138-144.
27. (b) Schmidt, B. Base-Induced Rearrangement of Dihydropyran Oxides: A Novel Synthesis of Cyclic Enol Ethers with a Hydroxy-Function in the Allylic Position. Tetrahedron Lett. 1999, 40, 4319-4320.
28. While this work was in progress, several examples of the preparation of spirocyclic ethers using RCM methodology have been reported, (a) Holt, D. J.; Barker, W. D.; Jenkins, P. R.; Panda, J.; Ghosh, S. Stereoselective Preparation of Enantiomerically Pure Annulated Carbohydrates Using Ring-Closing Metathesis. J. Org. Chem. 2000, 65, 482-493.
29. (b) Holt, D. J.; Barker, W. D.; Jenkins, P. R.; Davies, D. L.; Garratt, S.; Fawcett, J.; Russell, D. R.; Ghosh, S. Ring-Closing Methathesis in Carbohydrate Annulation. Angew. Chem., Int. Ed. 1998, 37, 3298-330.
30. (c) Maier, M. E.; Bugl, M. Synthesis of Spiro Ethers by Ring Closing Metathesis. Synlett 1998, 1390-1392.
31. (d) van Hooft, P. A. V.; Leeuwenburgh, M. A.; Overkleeft, H. S.; van der Marel, G. A.; van Boeckel, C. A. A.; van Boom, J. H. A Novel and Flexible Synthesis of Pyranose Spiroacetal Derivatives. Tetrahedron Lett. 1998, 39, 6061-6064. An RCM process that features the addition of allylmagnesium bromide to imines was recently reported.
32. Wright, D. L.; Schulte, J. P.; Page, M. A. An Imine Addition/Ring-Closing Metathesis Approach to the Spirocyclic Core of Halichlorine and Pinnaic Acid. Org. Lett. 2000, 2, 1847-1850. None of these studies report the use of N-substituted ketones nor have any of these studies utilized the alkene formed in the process specifically in further parallel reactions.
33. Reference 6e reports the use of 25-100 equiv of volatile amines to effect epoxide opening.
34. Compounds 10, 16, and 18 were obtained as racemic mixtures. A single enantiomer of the major regioisomer is drawn.
35. Chini, M.; Crotti, P.; Gardelli, C.; Macchia, F. Regiochemical Control of the Ring Opening of 1,2-Epoxides by Means of Chelating Processes. 6. Opening Reactions of 3,4-Epoxytetrahydropyran. Tetrahedron 1994, 50, 1261-1274.
36. Chini, M.; Crotti, P.; Gardelli, C.; Macchia, F. Regiochemical Control of the Ring Opening of 1,2-Epoxides by Means of Chelating Processes. 7. Synthesis and Ring-Opening Reactions of cis-and trans-Oxides Derived from 2-(Benzyloxy)-3.6-dihydro-2H-pyran. J. Org. Chem. 1994, 59, 4131-4137.
37. 13C-ATP. gCOSY. and gHMQC spectroscopies; see Supporting Information.
38. Mikhailov, S. N.; Blaton, N.; Rozenski, J.; Balzarini, J.; De Clercq, E.; Herdewijn, P. Use of Cyclohexene Epoxides in the Preparation of Carbocyclic Nucleosides. Nucleosides Nucleotides 1996, 15, 867-878.
39. (a) Eliel, E. L.; Wilen, S. H.; Mander, L. N. In Stereochemistry of Organic Compounds, John Wiley & Sons: New York, 1994.
40. (b) Bordwell, F. G.; Frame, R. R.; Strong, J. G. Diaxial Ring Opening of 1,2-Oxidocyclohexanes. J. Org. Chem. 1968, 33, 3385-3388.