A Novel Synthesis of a Key Intermediate for (+)-Biotin from l-Aspartic Acid

Abstract

The aldol reaction of an N-Cbz-3-amino-4-butanolide 4, derived from l-aspartic acid, with formaldehyde gave the trans-disubstituted 3-amino-4-butanolide 5 stereoselectively. Following protection of the hydroxyl group of 5, amidation and oxidation provided the β-substituted l-asparagine derivative 6. The Hofmann rearrangement of 6 with sodium hypochlorite in the presence of sodium hydroxide and subsequent hydrogenation gave the bicyclic lactone 11, which upon dibenzylation and thionation, gave the thiolactone 2, a key intermediate for the synthesis of (+)-biotin (1).

Key words

vitamins - stereoselective synthesis - amino acids - aldol reaction - rearrangement

References

• 1 du Vigneaud V. Hofmann K. Melvile DB. Rachele J. J. Biol. Chem.  1941,  140:  763 
• 2a Mistry PS. Dakshinamurti K. Vitam. Horm.  1964,  22:  1 
• 2b Coggeshall CJ. Heggers PJ. Robson CM. Baker H. Ann. N. Y. Acad. Sci.  1985,  447:  389 
• 2c Maebashi M. Makino Y. Furukawa Y. Ohinata K. Kimura S. Sato T. J. Clin. Biochem. Nutr.  1993,  14:  211 
• 3 For a review, see: Clercq PJD. Chem. Rev.  1997,  97:  1755 
• 4a Gerecke M. Zimmerman J.-P. Aschwanden W. Helv. Chim. Acta  1970,  53:  991 
• 4b Senuma M. Fujii T. Seto M. Okamura K. Date T. Kinumaki A. Chem. Pharm. Bull.  1990,  38:  882 
• 5 Iriuchijima S. Hasegawa K. Tsuchihashi G. Agric. Biol. Chem.  1982,  46:  1907 
• 6 Poetsch E. Casutt M. Chimia  1987,  41:  148 
• 7a Matsuki K. Inoue H. Takeda M. Tetrahedron Lett.  1993,  34:  1167 
• 7b Chen FE. Huang Y.-D. Fu H. Cheng Y. Zhang D.-M. Li Y.-Y. Peng Z.-Z. Synthesis  2000,  2004 
• 7c Choi C. Tian S.-K. Deng L. Synthesis  2001,  1737 
• For reviews on the utilization of aspartic acid to drug synthesis, see:
• 8a Matsumoto K. Seki M. J. Syn. Org. Chem. Jpn.  1991,  49:  26 
• 8b Seki M. Matsumoto K. Bioindustry  1995,  12:  5 
• 9 McGarvey GJ. Williams JM. Hiner RN. Matsubara Y. Oh T. J. Am. Chem. Soc.  1986,  108:  4943 
• 10 Yoda H. Nakagami Y. Takabe K. Tetrahedron: Asymmetry  1994,  5:  169 
• 11 For example, see: Seki M. Shimizu T. Matsumoto K. J. Org. Chem.  2000,  65:  1298 
• 12a Schneider F. Liebigs Ann. Chem.  1937,  529:  1 
• 12b Hayashi K. Nunami K. Kato J. Yoneda N. Kubo M. Ochiai T. Ishida R. J. Med. Chem.  1989,  32:  289 
• 15a Shimizu T. Seki M. Tetrahedron Lett.  2000,  41:  5099 
• 15b Shimizu T. Seki M. Tetrahedron Lett.  2001,  42:  429 
• 16 Schlosser M. Jenny T. Guggisberg Y. Synlett  1990,  704 

13

X-ray data for the compound 11 have been deposited at the Cambridge Crystallographic Data Centre.

14

The optical purity of the product 2 was determined to be >99% ee by HPLC.