Amides, from acid derivatives planarity

Incubation of SNAC 32 yielded no observable acylation of KSl, suggesting that the amide substrate should be derived from an a-amino acid. Equally, no acylation was detected with SNAC 33 indicating that the distal carbonyl is not a factor in substrate viability. Previous work by Claderone et al. revealed that the reduction of the 2-keto-4-methylpentanoyl intermediate to the 2-hydroxy-analogue is performed by the KR domain of module 3 (Scheme 4.1) [6]. This unorthodox reduction step is believed to occur post-KSl elongation, therefore suggesting that the oxidation level of SNAC 27 is correct, and therefore a substrate mimic for KSl. To probe this issue further, a 2-hydroxy-4-methyl-pentanoyl SNAC (34) was synthesised. Upon incubation of SNAC 34 with KSl, a slight reduction in acylation rate was observed ( 20 %) compared to SNAC 27. The reduction in acylation rate may be due to unfavourable loss of planarity in the substrate, or decreased intrinsic reactivity of the thioester (Fig. 4.4). 

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