Amidation Backbone oxidation

Alternatively, sulfonamides can also be prepared by oxidation of sulfinamides with periodate (Entry 3, Table 8.8) or with MCPBA [125]. Polystyrene-bound sulfonyl chlorides, which can be prepared from polystyrene-bound sulfonic acids by treatment with PCI5, SOCI2 [126-129], CISO3H [130], or SO2CI2/PPI13 [131], react smoothly with amines to yield the corresponding sulfonamides (Entry 4, Table 8.8). Support-bound carbamates of primary aliphatic or aromatic amines can be N-sulfonylated in the presence of strong bases, and can therefore be used as backbone amide linkers for sulfonamides (Entries 5 and 6, Table 8.8). 

The discovery route20 21,29 to aliskiren targeted three key intermediates, a-aminoaldehyde 11, the isopropyl-substituted propane unit 12, and the P-aminopropan amide 13. The union of 11 and the Grignard reagent derived from 12 establishes the full contiguous carbon backbone of aliskiren and the C4 stereocenter. Following oxidation-state manipulation, P-aminopropanamide 13 is introduced by a peptide coupling. 

The early substrate series had P,-residues which incorporated a para-nitroanilide in place of the normal scissile amide bond. This feature allowed the kinetics of the hydrolyses to be easily followed spectrophotometrically [95]. As a result, these studies focused on the 8,-85 subsites. 8ome of these substrates, for example (3-4)-(3-6), were based on the sequence of the reactive centre of a,-PI. It was shown that substrate (3-3) which contains a P,-Val is a better substrate than (3-4) which contains the P,-Met found in a,-PI (see Table 2.2). As in a,-PI, oxidation of the P,-Met resulted in a decrease in enzyme recognition, for example, compare (3-4) and (3-5). One of the compounds (3-3) prepared in the course of this work is an excellent, specific substrate for HLE and also has better aqueous solubility than other related substrates. As a result of this combination of properties, compound (3-3) has been used as the standard low-molecular-weight substrate for much of the kinetic analyses of HLE inhibitors, and its peptide backbone has been incorporated into several low-molecular-weight inhibitors. 

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