HIV Protease Inhibitor Part 1: Use of Evans’ Oxazolidinone in Intermolecular Diels-Alder Reaction en route to 3,4-Substituted Cyclohexanones

Abstract

α,β-Unsaturated chiral oxazolidinone 10 can be smoothly obtained from the corresponding aldehyde 14 under Masamune-Roush conditions. Oxazolidinone 10 reacts diastereoselectively with diene 14 under lewis acid catalysis which allows the synthesis of 3,4-substituted cyclohexanone 16 and its derivatives 20, 21, and 22 in good overall yields from ester 4. These compounds can be converted to the corresponding hydroxyethylamine derivatives, analogues of Saquinavir 1, which are known to have antiviral activity.

Key words

oxazolidinone - Diels-Alder - cyclohexanone - cyclohexane - HIV protease inhibitor

References

• 2 Roberts NA. Martin JA. Kinchington D. Broadhurst AV. Craig JC. Duncan IB. Galpin SA. Handa BK. Kay J. Krohn A. Lambert RW. Merrtt JH. Mills JS. Parkes KEB. Redshaw S. Ritchie AJ. Taylor DL. Thomas GJ. Machin PJ. Science  1990,  248:  358 
• 3 Gareth TJ. Bushnell DJ. Martin JA. Bioorg. Med. Chem. Lett.  1994,  4:  2759 
• 4 Parkes KEB. Bushnell DJ. Crackett PH. Dunsdon SJ. Freeman AC. Gunn MP. Hopkins RA. Lambert RW. Martin JA. J. Org. Chem.  1994,  59:  3656 
• 5 Hashimoto S. Furukawa I. Kuroda T. Tetrahedron Lett.  1980,  21:  2857 
• 6 Devine PN. Oh T. J. Org. Chem.  1992,  57:  396 
• 7a Jung ME. McCombs CA. Tetrahedron Lett.  1976,  2935 
• 7b See also: Jung ME. McCombs CA. Org. Synth., Coll. Vol. VI   Wiley; New York: 1988.  p.445 
• 8 Danishefsky S. Kitahara T. J. Am. Chem. Soc.  1974,  96:  7807 
• 9 Kan T. Ohfune Y. Tetrahedron Lett.  1995,  36:  943 
• 10 Evans DA. Chapman KT. Bisaha J. J. Am. Chem. Soc.  1988,  110:  1238 
• See for example:
• 11a Damon RE. Coppola GM. Tetrahedron Lett.  1990,  31:  2849 
• 11b Some success has been obtained using α,β-unsaturated oxazolidinones as dienophiles at r.t. under high pressure in the presence of chiral Lewis acids: Knol J. Meetsma A. Feringa BL. Tetrahedron: Asymmetry  1995,  6:  1069 ; and references cited therein
• 12a Evans DA. Black WC. J. Am. Chem. Soc.  1992,  114:  2260 
• 12b Evans DA. Black WC. J. Am. Chem. Soc.  1993,  115:  4497 
• 12c For examples of intramolecular Diels-Alder reactions using hindered substrates see: Morimoto Y. Iwahashi M. Nishida K. Hayashi Y. Shirahama H. Angew. Chem., Int. Ed. Engl.  1996,  35:  904 
• 12d Evans DA. Johnson JS. J. Org. Chem.  1997,  62:  786 
• 13 Martinelli MJ. J. Org. Chem.  1990,  55:  5065 
• 14a The oxazolidinone derived from phenylalanine is known to give better selectivity in Diels-Alder reactions, see: Evans DA. Chapman KT. Tan Hung D. Kawaguchi AT. Angew. Chem., Int. Ed. Engl.  1987,  26:  1184 
• 14b For a large scale synthesis, see: Pridgen LN. Prol J. Alexander B. Gillyard L. J. Org. Chem.  1989,  54:  3231 
• 15 Evans DA. Weber AE. J. Am. Chem. Soc.  1986,  108:  6757 
• 16 Blanchette MA. Choy W. Davis JT. Essenfeld AP. Masamune S. Roush WR. Sakai T. Tetrahedron Lett.  1984,  25:  2183 
• 18 Brown HC. Krishnamurthy S. J. Am. Chem. Soc.  1972,  94:  7159 
• 19 Evans DA. Britton TC. Ellman JA. Tetrahedron Lett.  1987,  28:  6141 
• 20 Gemal AL. Luche J.-L. J. Am. Chem. Soc.  1981,  103:  5454 
• 21a In all cases only one isomer was observed in the NMR spectrum (after removal of the Boc group) or by HPLC. Reductive amination of cyclic ketones in these conditions is usually not selective: Hutchins RO. Su W.-Y. Sivakumar R. Cistone F. Stercho YP. J. Org. Chem.  1983,  48:  3412 
• 21b For stereoselective reduction of protected imines see: Hutchins RO. Adams J. Rutledge MC. J. Org. Chem.  1995,  60:  7396 
• 21c See also: Hutchins RO. Rao SJ. Adams J. Hutchins MK. J. Org. Chem.  1998,  63:  8077 

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Present address: GlaxoSmithKline. The Frythe, Welwyn, AL6 9AR Hertfordshire, UK.

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CCDC No. 217034 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html [or from the CCDC 12 Union Road Cambridge CB2 1EZ UK; fax: [phone]; e-mail: [e-mail]].