Efficient Activation of Zinc: Application of the Blaise Reaction to an Expedient Synthesis of a Statin Intermediate

Abstract

Efficient and practical in situ zinc activation was accomplished by treatment with catalytic amount of an organic acid. The protocol was applied successfully to the Blaise reaction of various nitriles. Noteworthy is the excellent Blaise transformation of (S)-4-chloro-3-trimethylsilyloxybutyronitrile (2b) into tert-butyl (S)-6-chloro-5-hydroxy-3-oxohexanoate (1), a key intermediate for the preparation of HMG-CoA reductase inhibitors (statins).

Key words

in situ zinc activation - Blaise reaction - statin intermediate

References

• 1a Blaise EE. C. R. Acad. Sci.  1901,  132:  478 
• 1b Blaise EE. C. R. Acad. Sci.  1901,  132:  978 
• 1c Carson J. Rinehart KL. Thornton SD. J. Org. Chem.  1953,  18:  1594 
• 1d Kagan HB. Suen Y.-H. Bull. Chim. Soc. Fr.  1966,  1819 
• 1e Konrad J. Jezo I. Chem. Zvesti.  1980,  34:  125 ; Chem. Abstr. 1980, 93, 150172
• 2 Hannick SM. Kishi Y. J. Org. Chem.  1983,  48:  3833 
• 3a For the Blaise reaction, see: Narkunan K. Uang B.-J. Synthesis  1998,  1713 
• 3b For the Reformatsky reaction, see: Han B.-H. Boudjouk P. J. Org. Chem.  1982,  47:  5030 
• 4 Lee AS.-Y. Cheng R.-Y. Pan O.-G. Tetrahedron Lett.  1997,  38:  443 
• 5a

  In the literature, iodine and 1,2-dibromoethane were used as in situ zinc activators. However, iodine and 1,2-dibromoethane were found to be deleterious for the Blaise reaction of benzonitrile with ethyl bromoacetate. Only 30% and 18% of respective conversion were observed.

• 5b For the use of iodine, see: Zitsman J. Johnson PY. Tetrahedron Lett.  1971,  12:  4201 
• 5c For the use of 1,2-dibromoethane, see: Gaudemar M. Tetrahedron Lett.  1983,  24:  2749 
• 6a

  About 7-8 mol% of trimethylsilyl chloride was used for the activation of zinc. Under these conditions, complete conversion of the Blaise reaction of benzonitrile with ethyl bromoacetate was observed.

• 6b For the Reformatsky reaction, see: Picotin G. Miginiac P. J. Org. Chem.  1987,  52:  4796 
• 6c For the reaction with ethyl formate, see: Gawronski JK. Tetrahedron Lett.  1984,  25:  2605 
• 7 Istvan ES. Deisenhofer J. Nature  2001,  292:  1160 
• 8a Nishiyama A, and Inoue K. inventors; US Patent  6340767.  ; Chem. Abstr. 2001, 134, 41920
• 8b Kizaki N, Yamada Y, Yasohara Y, Nishiyama A, Miyazaki M, Mitsuda M, Kondo T, Ueyama N, and Inoue K. inventors; WO  2000008011.  ; Chem. Abstr. 2000, 132, 166230
• 8c Mitsuda M, Miyazaki M, and Inoue K. inventors; US Patent  6344569.  ; Chem. Abstr. 1999, 131, 310642
• 8d Thottathil JK, Pendri Y, Li W.-S, and Kronenthal DR. inventors; US Patent  5278313.  ; Chem. Abstr. 1994, 120, 217700
• 8e Scheffler J.-L. Bette V.-B. Mortreux A. Nowogrocki G. Carpentier J.-F. Tetrahedron Lett.  2002,  43:  2679 
• 9a Wolberg M. Hummel W. Wandrey C. Muller M. Angew. Chem. Int. Ed.  2000,  39:  4306 
• 9b Wolberg M. Hummel W. Wandrey C. Muller M. Chem.-Eur. J.  2001,  7:  4562 
• 9c Wolberg M, Muller M, and Hummel W. inventors; WO  2000036134.  ; Chem. Abstr. 2000, 133, 42239
• 10a Iranpoor N. Shekapriz M. Synth. Commun.  1999,  29:  2249 
• 10b Mitchell D. Koenig TM. Tetrahedron Lett.  1992,  33:  3281 
• 10c Culvenor CCJ. Davies W. Haley FG. J. Chem. Soc.  1950,  3123 
• 11 Langer SH. Connell S. Wender I. J. Org. Chem.  1958,  23:  50 
• 12a

  The activation method was applied successfully to the Reformatsky reactions of benzaldehyde and nonanal with ethyl bromoacetate (1.3 equiv) in benzene to provide 79% and 78% of the corresponding β-hydroxy esters, respectively. For the Reformatsky reaction, benzene was found to be the choice of solvent. Use of THF has resulted in low yield.

• 12b For similar conditions of the Reformatsky reaction except zinc activation method, see: Frankenfeld JW. Werner JJ. J. Org. Chem.  1969,  34:  3689 
• 13a Spitzmiller ER. J. Am. Chem. Soc.  1947,  69:  2013 
• 13b Wolf H. Matzel U. Brunke E.-J. Klein E. Tetrahedron Lett.  1979,  20:  2339 
• 14a Capozzi G. Roelens S. Talami S. J. Org. Chem.  1993,  58:  7932 
• 14b Schinzer D. Abel U. Jones PG. Synlett  1997,  633 
• 15 Balaji BS. Chanda BM. Tetrahedron  1998,  54:  13237