New Approaches to the Design and Synthesis of Inhibitors of Acetyl-CoA Carboxylase

Optimization of Manganese Coupling Reaction for Kilogram-Scale Preparation of Two Aryl-1,3-dione Building Blocks

“…It was envisioned that the aryl-1,3-diones 3 and 4 could be obtained by semi-pinacol rearrangement of the corresponding epoxy-ketones 15 and 16 . , Our previous experience of this rearrangement showed that it is a relatively general method favoring aryl-1,3-diones, over the isomeric 1,2-diones, through a preferential acyl transfer mechanism under protic or Lewis acid catalysis . The required epoxide starting materials (compounds 15 and 16 , Scheme ) could in turn be synthesized by condensation of furanone 10 with aldehydes 17 or 18 followed by epoxidation or alternatively by Darzens reaction of bromo-furanone 19 and the corresponding aldehyde (Scheme ).…”

“…Unfortunately, direct arylation of building block 12 using palladium catalyzed conditions proved only moderately successful, probably due to high steric hindrance of both dione and aryl bromide coupling partners. The most robust method for the direct coupling of ortho-substituted aryls was found to be an unusual aryl lead cross coupling reaction using conditions reported by Morgan and Pinhey. , Aryl lead reagents had to be prepared from the corresponding aryl boronic acid using lead tetraacetate and catalytic mercury­(II) acetate in chloroform . The arylation itself was performed using a large excess of N , N -dimethyl-4-aminopyridine in a 4:1 chloroform/toluene mixture.…”

“…The most robust method for the direct coupling of ortho-substituted aryls was found to be an unusual aryl lead cross coupling reaction using conditions reported by Morgan and Pinhey. 7,8 Aryl lead reagents had to be prepared from the corresponding aryl boronic acid using lead tetraacetate and catalytic mercury(II) acetate in chloroform. 7 The arylation itself was performed using a large excess of N,Ndimethyl-4-aminopyridine in a 4:1 chloroform/toluene mixture.…”

“…9,10 Our previous experience of this rearrangement showed that it is a relatively general method favoring aryl-1,3-diones, over the isomeric 1,2-diones, through a preferential acyl transfer mechanism under protic or Lewis acid catalysis. 8 The required epoxide starting materials (compounds 15 and 16, Scheme 3) could in turn be synthesized by condensation of furanone 10 with aldehydes 17 or 18 followed by epoxidation or alternatively by Darzens reaction of bromofuranone 19 and the corresponding aldehyde (Scheme 3). 8 Accordingly, our first goal was to find an efficient synthesis of aldehyde building blocks 17 and 18.…”

“…8 The required epoxide starting materials (compounds 15 and 16, Scheme 3) could in turn be synthesized by condensation of furanone 10 with aldehydes 17 or 18 followed by epoxidation or alternatively by Darzens reaction of bromofuranone 19 and the corresponding aldehyde (Scheme 3). 8 Accordingly, our first goal was to find an efficient synthesis of aldehyde building blocks 17 and 18. To this end we focused on an interesting manganese coupling reaction which was supported by literature precedent.…”