An Enantioselective Formal Synthesis of Montelukast Sodium

• Published in: Journal of organic chemistry Vol. 80; no. 8; pp. 3891 - 3901
• Main Authors: Bollikonda, Satyanarayana, Mohanarangam, Saravanan, Jinna, Rajender Reddy, Kandirelli, Venkata Kiran Kumar, Makthala, Laxman, Sen, Saikat, Chaplin, David A, Lloyd, Richard C, Mahoney, Thomas, Dahanukar, Vilas Hareshwar, Oruganti, Srinivas, Fox, Martin E
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 17.04.2015; Amer Chemical Soc
• Subjects: Acetates - chemical synthesis; Acetates - chemistry; Anti-Asthmatic Agents - chemical synthesis; Anti-Asthmatic Agents - chemistry; Catalysis; Chemistry; Chemistry, Organic; Coordination Complexes - chemistry; Hydrogenation; Molecular Structure; Physical Sciences; Quinolines - chemical synthesis; Quinolines - chemistry; Ruthenium - chemistry; Science & Technology; Sodium - chemistry; Stereoisomerism; ANTAGONIST; REDUCTION; ALLYLIC ALCOHOLS; ARYL HALIDES; PALLADIUM-CATALYZED ARYLATION; INTERMEDIATE; ALDEHYDES; ASYMMETRIC HYDROGENATION; KETO ESTER; EFFICIENT
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/acs.joc.5b00197

A formal synthesis of the antiasthma drug montelukast sodium is described, wherein the key chiral diol intermediate was accessed with greater convergence of the C–C bond-forming steps as compared to previous routes. Improved synthetic efficiency was achieved by deploying homogeneous metal-based catalysis in two pivotal steps. In the first, a tandem Mizoroki–Heck reaction and double-bond isomerization between a previously known allyl alcohol intermediate and a hindered 2-(2-halophenyl)­propan-2-ol secured direct access to the 3-(2-(2-hydroxy­propan-2-yl)­phenyl)-1-phenyl­propan-1-one moiety in the product. In the second step, asymmetric hydrogenation of the ketone functionality in the Mizoroki–Heck reaction product provided a convenient method to introduce the benzylic alcohol chiral center and obtain the desired chiral diol precursor of montelukast sodium. A detailed catalyst screening led to the identification of ((R)-Xyl-BINAP)­((R,R)-DPEN)­RuCl2 as a catalyst that afforded an enantioselectivity of 99% ee in the hydrogenation step on a multigram lab scale at a molar substrate:catalyst loading of 5000:1.