Hmb amino acid derivatives

The Hmb-substituted amino acids of non-functional and side-chain r-butyl/ Boc-protected derivatives are readily prepared from commercially available 2-hydroxy-4-methoxybenzaldehyde and amino acid residues by reductive amination Protocol 1). To date the following Hmb residues have been prepared Ala, Arg(Pmc), Asn(Trt), Asp(O Bu), Cys(Acm), Glu(O Bu), Gln(Trt), Gly, lie. Leu, Lys(Boc), Phe, Ser( Bu), Thr( Bu), Tyr( Bu), and Val. 

Protocol 1. Preparation of A/-(2-hydroxy-4-methoxybenzyl)amino acids 

Dissolve the amino acid (10 mmol) with stirring in water 10 ml) containing potassium hydroxide (10 mmol). Note that some of the more hydrophobic side-chain protected derivatives, e.g. Ot-butyl tyrosine, require the addition of ethanol to achieve fuli dissoiution. 

Add a soiution of 2-hydroxy-4-methoxybenzaldehyde (10 mmol) in ethanoi (10 ml) in a single portion and stir the resultant bright yellow solution at room temperature for 30 min. 

Add a soiution of sodium borohydride (10.1 mmol) in water (5 ml containing a few drops of 1 M NaOH) dropwise over 15 min, resulting in effervescence and some colour loss. 

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The incorporation of (Hmb)amino acid residues is conveniently achieved through 1-hydroxybenzotriazole activation of the Af,0-bis(Fmoc)-N-(Hmb)-protected pentafluorophenyl esters (Figure 4a). A number of groups have recently described the successful use of the N -Fmoc-iV-(Hmb)-amino acid derivatives (54, 55) in the synthesis of diflicult peptides. However, we have previously found that the monoFmoc derivatives of residues other than glycine or alanine couple slowly to resin-bound peptide chains (56). The slow coupling of these species is attributed to the formation of a relatively low... 

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