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Synfacts 2005(0): 0015-0015
DOI: 10.1055/s-2005-865353
DOI: 10.1055/s-2005-865353
Synthesis of Natural Products and Drugs
© Georg Thieme Verlag Stuttgart · New York
Asymmetric Synthesis of L-869,298, a Potent PDE4 Inhibitor
Contributor(s): Philip KocienskiP. D. O’Shea*, C. Chen*, W. Chen, P. Dageneau, L. F. Frey, E. J. J. Grabowski, K. M. Marcantonio, R. A. Reamer, L. Tan, R. D. Tillyer, A. Roy, X. Wang, D. Zhao
Merck Frosst Centre for Therapeutic Research, Quebec, Canada; Merck Research Laboratories, Rahway, USA
Practical Asymmetric Synthesis of a Potent PDE4 Inhibitor via Stereoselective Enolate Alkylation of a Chiral Aryl-Heteroaryl Secondary Tosylate
J. Org. Chem. 2005, 70: 3021-3030
Merck Frosst Centre for Therapeutic Research, Quebec, Canada; Merck Research Laboratories, Rahway, USA
Practical Asymmetric Synthesis of a Potent PDE4 Inhibitor via Stereoselective Enolate Alkylation of a Chiral Aryl-Heteroaryl Secondary Tosylate
J. Org. Chem. 2005, 70: 3021-3030
Further Information
Publication History
Publication Date:
20 July 2005 (online)
Key words
asymmetric hydrogenation - -
Significance
The target molecule inhibits phosphodiesterase-4 (PDE4), an enzyme that hydrolyzes cAMP. It is a potential drug for the treatment of asthma and chronic obstructive pulmonary disease.
Comment
Noyori asymmetric hydrogenation gave the most efficient reduction of A. The unstable tosylate B underwent substitution with the lithium enolate of pyridine N-oxide C to give D in 92% yield with no loss of enantiopurity. The cyclopropyl ether was synthesized on a 21.5 mol scale by reaction of a phenolic vinyl ether with Et2Zn and CH2I2.