We synthesized the extremely polar acetyl-CoA and malonyl-CoA analogs using the strategy in scheme 1, similar to our previous synthesis of methylmalonyl-CoA analogs, with details in the supplemental information. Acetonide protected oxa(dethia)pantetheine (7) and aza(dethia)pantetheine ( ) were generated as previously published. The acetonide pantetheine analogs 7/8 were treated with acetic anhydride and triethylamine to give acetyl-oxa(dethia)pantetheine acetonide ( ) and acetylaza(dethia)pantetheine acetonide (10), respectively. Malonyloxa(dethia)pantetheine acetonide (11) and malonyl-aza(dethia)pantetheine acetonide (12) were generated through heating 7/8 with Meldrum's acid for 4 hours, respectively. Decarboxylation of 11/12 to 9/10 was detected if the reactions were left refluxing for extended times. The acetonides 7-12 were deprotected with formic acid in water and chemoenzymatically converted to the CoA analogs 1-6 using an acetate kinase ATP regeneration system. The deprotection of esters 9 and 11 required careful addition of formic acid to a pH of 2.2 and careful neutralization to avoid ester hydrolysis.