Abstract
The solid phase synthesis of 2,4,5-trisubstituted thiomorpholin-3-ones is described. Starting from a resin-bound protected cysteine, and employing reductive alkylation and amide formation, thiomorpholin-3-one derivatives have been synthesized through intramolecular thioether formation in good yield and high purity.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 3671-3674 |
| Number of pages | 4 |
| Journal | Tetrahedron Letters |
| Volume | 39 |
| Issue number | 22 |
| DOIs | |
| State | Published - May 28 1998 |
| Externally published | Yes |
Bibliographical note
Funding Information:ACKNOWLEDGMENTS We thank Eileen Weiler for editorial assistance. This work was funded in part by National Science Foundation Grant No. CHE-9520142 (Houghten) and by Trega Biosciences, Inc. REFERENCES AND NOTES 1. Nefzi, A.; Ostresh, J. M.; Houghten, R. A. Chem. Rev. 1997, 97, 449. 2. Thompson, L. A.; Ellman, J. A. Chem. Rev. 1996, 96, 555. 3. Fruchtel, J. S.; Jung, G. ChemRev. 1996, 35, 17. 4. Merrifield, R. B. Science. 1986, 232, 341. 5. Ho, P. T.; Chang, D.; Zhong, J. W. X.; Musso, G. F. Pep. Res. 1993, 6, 10. 6. Carpino, L. A.; E1-Faham, A.; Minor, C. A.; Albericio, F. J. Chem. Soc.; Chem. Commun. 1994, 201. 7. Typical procedure for the individual synthesis ofthiomorpholin-3-one 5:100 mg p-methylbenzhydrylamine (MBHA) resin (0.81 meq/g, 100-200 mesh) was contained within a sealed polypropylene mesh packet. Reactions were carried out in a 10 ml polyethylene bottle. Following neutralization with 5% DIEA in DCM, the resin was washed with DCM. Fmoc-Cys(Trt)-OH was coupled using the conventional reagents HOBt and DICI. Following removal of the Trt group with TFA/(iBu)3SiH/DCM (5:5:90), the resin was treated overnight with 15-fold excess of ct-bromo, (x-alkyl carboxylic acid derivatives in DMF in the presence of NMM. Following the removal of Fmoc with 20% piperidine in DMF, benzaldehyde (5 eq, 0.07M) was added in 1% AcOH in DMF, followed immediately by the addition of NaBH3CN (5 eq). The mesh packet was shaken overnight in a solution of HATU (5eq) and DIPEA (5eq) in DMF. Following cleavage from the resin with anhydrous HF in the presence of anisole, ~° the desired product 5 was extracted, lyophilized and analyzed. 8. Nefzi, A.; Ostresh, J. M.; Houghten, R. A. Tedrahedron Lett. 1997, 38, 4943. 9. Nefzi, A.; Ostresh, J. M.; Meyer, J-P.; Houghten, R. A. TedrahedronLett. 1997, 38, 931. 10. Houghten, R. A.; Bray, M. K.; DeGraw, S. T.; Kirby, C.J. Int. J. Pep. Prot. Res. 1986, 27, 673.