Application of the Dakin-West Reaction for the Synthesis of Oxazole-Containing Dual PPARr/γ Agonists Alexander G. Godfrey,* Dawn A. Brooks, Lynne A. Hay, Mary Peters, James R. McCarthy, and David Mitchell Lilly Research Laboratories, Eli Lilly & Company, Lilly Corporate Center, Indianapolis, Indiana 46285 agg@lilly.com Received November 4, 2002 An improved method for the preparation of a series of oxazole-containing dual PPARR/γ agonists is described. A synthetic sequence utilizing a Dakin-West reaction was devised that allows for the introduction of the oxazole ring either late in the synthetic sequence via aminomalonate-derived chemistry or in pivotal SAR intermediates derived from aspartic acid. We have recently disclosed the structure of 1a, a dual PPARR/γ agonist, and demonstrated the compound’s preclinical beneficial impact on multiple facets of type 2 diabetes and the associated cardiovascular risk. 1 The peroxisome proliferator activated receptor (PPAR) family of nuclear hormone receptors has been identified as key modulators of metabolism since the first member of the receptor family was cloned a decade ago. 2 The profile of a dual PPARR/γ agonist appears well-suited as a treat- ment for type 2 diabetes 3 because of the insulin-sensitiz- ing/glucose-controlling potential of PPARγ agonists, the molecular target of the thiazolidine-2,4-diones (TZDs), 4 in combination with the positive lipid- and cholesterol- modulating activities of PPARR agonists, the molecular target of the fibrates. 5 Herein we describe the develop- ment of a practical synthesis of 1a and related analogues, utilizing the Dakin-West reaction 6 followed by Robin- son-Gabriel cyclodehydration 7 to install substitution at the 5-position of the oxazole ring. The versatility of these historic reactions is further demonstrated using acylated aspartic acid derivatives to prepare a variety of 2-sub- stituted oxazole analogues. Interest in compound 1a led to the development of a synthetic route amenable to large-scale execution. Previ- ous preparation of compound 1a, depicted in Scheme 1, utilized early oxazole ring formation through condensa- tion of butanedione monooxime with 4-bromobenzalde- hyde. 8 This route allowed preparation of 2-aryl analogues for structure-activity relationship studies by incorporat- ing straightforward coupling of tosylates of 5-methyl-2- aryl-4-oxazolylethanols (5) with 2-(4-hydroxyphenoxy)- 2-methylpropanoic acid ethyl ester. However, the sequence offers opportunities for process improvement to avoid several potentially hazardous reagents and intermedi- ates. These include potassium cyanide, diborane, an unstable N-oxide intermediate (2), and the explosive hazard associated with butanedione monooxime. 9 In addition, attempts to expand the SAR by condensation of the monooxime with certain halogen-substituted aro- matic aldehydes (particularly o-bromobenzaldehyde) were unsatisfactory. Results and Discussion In reviewing the literature for other methods to prepare oxazole-ethanols 6, the work of Meguro et al. and others 10 suggested aspartic acid  esters 8 could be (1) (a) Brooks, D. A.; Etgen, G. J.; Rito, C. J.; Shuker, A. J.; Dominianni, S. J.; Warshawsky, A. M.; Ardecky, A.; Paterniti, J. R.; Tyhonas, J.; Karanewsky, D. S.; Kauffman, R. F.; Broderick, C. L.; Oldham, B. A.; Montrose-Rafizadeh, C.; Winneroski, L. L.; Faul, M. M.; McCarthy, J. R. J. Med. Chem. 2001, 44, 2061. (b) Etgen, G. J.; Oldham, B. A.; Johnson, W. T., Broderick, C. L.; Brozinick, J. T.; Bean J. S.; Bensch, W. R.; Brooks, D. A.; Rito, C. J.; Shuker, A. J.; Kauffman, R. 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