Azetidin-2,3-dione Synthon for Stereoselective Synthesis of cis- and trans-C-3-Alkyl/Aryl Azetidin-2-ones

Abstract

1,4-Bis-(4-methoxyphenyl)azetidin-2,3-dione has been prepared and used as a synthon for the stereoselective synthesis of C-3-alkyl/aryl azetidin-2-ones. Some of these are well known for their cholesterol absorption inhibitor activity. A regioselective Grignard reaction at a keto-group followed by highly stereoselective removal of the hydroxyl group via reductive removal of the xanthate ester is a key step in this synthesis. Base-induced isomerization of cis-azetidin-2-ones to the thermodynamically stable trans-isomer was also studied.

Keywords

azetidin-2,3-diones - azetidin-2-ones - β-lactam - Grignard reaction - tributyltin hydride

References

• For reviews on β-lactam antibiotics, see:
• 1a Dürkheimer W. Blumbach J. Lattrell R. Scheunemann KH. Angew. Chem., Int. Ed. Engl.  1985,  24:  180 
• 1b Chemistry and Biology of β-Lactam Antibiotics   Vol. 1-3:  Morin RB. Gorman M. Academic; New York: 1982. 
• 1c Coulton S. Hunt E. In Recent Progress in the Chemical Synthesis of Antibiotics and Related Microbial Products   Vol. 2:  Lukacs G. Springer-Verlag; Berlin: 1993.  p.621 
• 1d Southgate R. Contemp. Org. Synth.  1994,  1:  417 
• 2 The Chemistry of β-Lactams   Page MI. Chapman and Hall; London: 1992. 
• For comprehensive general reviews, see:
• 3a Koppel GA. In Small Ring Heterocycles   Vol. 42:  Hasner A. Wiley; New York: 1983.  p.219 
• 3b Backes J. In Houben-Weyl, Methoden der organischen Chemie   Vol. E16B:  Klamann D. Thieme; Stuttgart: 1991.  p.31 
• 3c de Kimpe N. In Comprehensive Heterocyclic Chemistry II   Vol. 1B:  Katritzky AR. Rees CW. Scriven EFV. Padwa A. Pergamon; Oxford: 1996.  p.507 
• 4a Ojima I. In The Chemistry of β-Lactams   Georg GI. VCH; New York: 1993.  p.197 
• 4b Palomo C. Aizpurua J. Ganboa I. In Enantioselective Synthesis of β-Amino Acids   Juaristi E. Wiley-VCH; New York: 1997.  p.279 ; and references cited therein
• 4c For a review on this subject, see: Ojima I. Delaloge F. Chem. Soc. Rev.  1997,  26:  377 
• 4d Alcaide B. Almendros P. Chem. Soc. Rev.  2001,  30:  226 
• 4e Alcaide B. Almendros P. Synlett  2002,  381 
• 5a Burnett DA. Caplen MA. Davis HR. Burrier RE. Clader JW. J. Med. Chem.  1994,  37:  1733 
• 5b Burnett DA. Tetrahedron Lett.  1994,  35:  7339 
• 5c Rosenblum SB. Huynh T. Afonso A. Davis HR. Yumibe N. Clader JW. Burnett DA. J. Med. Chem.  1998,  41:  973 
• 6a Clader JW. Burnett DA. Caplen MA. Domalski MS. Dugar S. Vaccaro W. Sher R. Browne ME. Zhao H. Burrier RE. Salisbury B. Davis HR. J. Med. Chem.  1996,  39:  3684 
• 6b Dugar S. Kirkup MP. Clader JW. Lin SI. Rizvi R. Snow ME. Davis HR. McCombie SW. Bioorg. Med. Chem. Lett.  1995,  5:  2947 
• 7a Braun M. Galle D. Synthesis  1996,  819 
• 7b Kambara T. Tomioka K. J. Org. Chem.  1999,  64:  9282 
• 7c Shankar BB. Kirkup MP. McCombie SW. Clader JW. Ganguly AK. Tetrahedron Lett.  1996,  37:  4095 
• 7d Browne M. Burnett DA. Caplen MA. Chen L.-Y. Clader JW. Domalski M. Dugar S. Pushpavanam P. Sher R. Vaccaro W. Viziano M. Zhao H. Tetrahedron Lett.  1995,  36:  2555 
• 7e Chen L.-Y. Zaks A. Chackalamannil S. Dugar S. J. Org. Chem.  1996,  61:  8341 
• 7f Annunziata R. Benaglia M. Cinquini M. Cozzi F. Tetrahedron: Asymmetry  1999,  10:  4841 
• 7g Vaccaro WD. Sher R. Davis HR. Bioorg. Med. Chem. Lett.  1998,  8:  35 
• 7h Frick W. Bauer-Schäfer A. Bauer J. Girbig F. Corsiero D. Heuer H. Kramer W. Bioorg. Med. Chem. Lett.  2003,  11:  1639 
• 7i Mckittrick BA. Ma K. Huie K. Yumibe N. Davis H. Clader JW. Czarniecki M. J. Med. Chem.  1998,  41:  752 
• 8a Rosenblum SB. Huynh T. Afonso A. Davis HR. Tetrahedron  2000,  56:  5735 
• 8b For solid phase synthesis, see: Mata EG. Delpiccolo CML. Tetrahedron Lett.  2004,  45:  4085 ; and references cited therein
• 9 McKittrick BA. Ma K. Dugar S. Clader JW. Davis H. Czarniecki M. Bioorg. Med. Chem. Lett.  1996,  6:  1947 
• 10 Burnett DA. Curr. Med. Chem.  2004,  11:  1873 ; and references cited therein
• 11a Benfatii F. Cardilo G. Fabbroni F. Gentilucci L. Perciaccante R. Piccinelli F. Tolomelli A. Synthesis  2005,  61 
• 11b Alcaide B. Almendros P. Aragoncillo C. Rodriguez-Acebes R. J. Org. Chem.  2004,  69:  826 
• 11c Alcaide B. Almendros P. Aragoncillo C. Rodriguez-Acebes R. Synthesis  2003,  1163 
• 11d Alcaide B. Almendros P. Aragoncillo C. Rodriguez-Acebes R. J. Org. Chem.  2001,  66:  5208 
• 11e Paquette LA. Rothhaar RR. Isaac M. Rogers LM. Rogers RD. J. Org. Chem.  1998,  63:  5463 
• 11f Jayaraman M. Batista MT. Manhas MS. Bose AK. Heterocycles  1998,  49:  97 
• 11g Jayaraman M. Manhas MS. Bose AK. Tetrahedron Lett.  1997,  38:  709 
• 11h Palomo C. Aizpurua JM. Lopez MC. Aurrekoetxea N. Oiarbide M. Tetrahedron Lett.  1990,  31:  6425 
• 12a Jayaraman M. Deshmukh ARAS. Bhawal BM. Tetrahedron  1996,  52:  8989 
• 12b Jayaraman M. Puranik VG. Bhawal BM. Tetrahedron  1996,  52:  9005 
• 12c Srirajan V. Deshmukh ARAS. Puranik VG. Bhawal BM. Tetrahedron: Asymmetry  1996,  7:  2733 
• 12d Krishnaswamy D. Govande VV. Deshmukh ARAS. Synthesis  2003,  1903 
• 12e Deshmukh ARAS. Bhawal BM. Krishnaswamy D. Govande VV. Shinkre BA. Jayanthi A. Curr. Med. Chem.  2004,  11:  1889 ; and references cited therein
• 13a Zheng Y. Li Y. J. Org. Chem.  2003,  68:  1603 
• 13b Shingate BB. Hazra BG. Pore VS. Gonnade RG. Bhadbhade MM. Chem. Commun.  2004,  2194 
• 13c Jennings MP. Clemens RT. Tetrahedron Lett.  2005,  46:  2021 
• 14a Srirajan V. Deshmukh ARAS. Bhawal BM. Tetrahedron  1996,  52:  5585 
• 14b Joshi SN. Deshmukh ARAS. Bhawal BM. Tetrahedron: Asymmetry  2000,  11:  1477 
• 14c Shinkre BA. Puranik VG. Bhawal BM. Deshmukh ARAS. Tetrahedron: Asymmetry  2003,  14:  453 
• 14d Borer BC. Balogh DW. Tetrahedron Lett.  1991,  32:  1039 
• 15 Palomo C. Aizpurua JM. Ganboa I. Carreaux F. Cuevas C. Maneiro E. Ontoria JM. J. Org. Chem.  1994,  59:  3123