A-Ketoacids-hydroxylamine

Table 2 Cyclic peptides prepared by a-ketoacid-hydroxylamine amide-ligation...

Fukuzumi T, Ju L, Bode JW (2012) Chemoselective cyclization of unprotected linear peptides by a-ketoacid-hydroxylamine amide-ligation. Org Biomol Chem 10 5837-5844... 

The a-Ketoacid-Hydroxylamine (KAHA) Amide-FOTming Ligation. 16... 

Wu J, Ruiz-Rodrfguez J, Comstock JM, Dong JZ, Bode JW (2011) Synthesis of human GLP-1 (7-36) by chemoselective a-ketoacid- hydroxylamine peptide ligation of unprotected Iragments. Chem Sci 2 1976-1979... 

Fig. 10 General strategy for the preparation of vinprotected linear peptides with A-terminal hydroxylamine and C-terminal a-ketoacids for direct, reagent-less cyclizations...

Scheme 7 Our new research goals the synthesis of enantiopure, side-chain unprotected peptide a-ketoacids and hydroxylamines...

When we first disclosed the KAHA ligation, the general sentiment was that making the a-ketoacids would be the major problem. In contrast, most chemists did not feel that the peptide hydroxylamines would present a serious obstacle. This intuition was supported by the literature. There were only a few scattered reports of peptide ot-ketoacids but a respectable body of literature, including a Chemical Reviews article, on A-hydroxyamino acids and peptides [26]. 

At the time we took on this challenge, we had not yet developed our current methods for preparing the requisite N-terminal hydroxylamine or C-terminal a-ketoacids. If brought this problem today, it would take us no more than a few days to make the fragments and try the ligation. But in 2006 we had not yet even started doing solid-phase peptide synthesis in our laboratory ... 

The combination of our solid-phase methods for a-ketoacid and N-terminal hydroxylamine syntheses invited their application to the synthesis of macrocychc peptides by the cyclization of side-chain unprotected linear peptides. Cyclic peptide is an important and rapidly growing area of new therapeutics, and novel methods for their facile preparation are in great demand. We reasoned that our methods could be used to prepare suitably functionalized linear peptides that should cyclize simply upon warming them in an appropriate solvent. 

Takeo and Lei showed that it was indeed possible to use our methods for a-ketoacid and hydroxylamine synthesis to prepare several cyclic peptide namral products [34, 35]. No post-cyclization manipulatimis other than purification were required. The ability to perform the cyclization on unprotected side chains may... 

For reasons that we did not understand at the time, the ligation of a-ketoacids and 0-unsubstituted hydroxylamines, which we now call type 1 ligations, occurred best in polar aprotic solvents such as DMSO or DMF (Scheme 18). Water was detrimental to the reaction rates and tended to accelerate the decomposition of the peptide hydroxylamine. In contrast, we had identified a number of other variants of the KAHA ligation with 0-substituted hydroxylamines that occurred preferentially in water (type II ligations). Unfortunately, the most effective variants, 0-Bz hydroxylamines, cannot be used for a-peptides due to facile elimination [36]. 

The 4,5,6,7-tetrahydro-2,1-benzisoxazole group is the most reported category. The action of hydroxylamine on )3-diketones produced a mixture of 2,1- and 1,2-benzisoxazoles (Scheme 186). Ring opening gave )3-ketoacids which, under subsequent alkali treatment, degraded to diacids (67AHC(8)277). 

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