Borane → 2,6,6-Trimethylbicyclo[3.1.1]heptane-1,2-diol

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Reaction Steps

Scheme 12 illustrates the preparation of boronic acid analogs containing a substituted cyclohexyl ring in the P1 site. Cyclohexadione monoethylene ketone 38 was converted to the alkene 39 using a Wittig reaction. 39 was hydroboronated using diiisopinocamphyl borane and converted to the boronic acid ethyl ester using the general procedure described by Brown et al. J. Org. Chem. 47, 5065, 1982. Transesterification with pinanediol gave 40. The α-chloro compound 41 was prepared by the homologation reaction of 40 with the anion of methylene chloride using the procedure of Matteson et al. J. Am. Chem. Soc. 105, 2077, 1983. Nucleophillic displacement of the α-chloride with the lithium salt of hexamethyldisilazane gave the bis-silyl protected amine 42. The trimethylsilyl protecting groups were removed by treatment with anhydrous HCl. The α-amino group was coupled to either an acyl group or N-protected peptide or amino acid using the mixed anhydride or other standard peptide coupling reaction conditions. The peptide 43 was treated with an aqueous suspension of a sulfonic acid substituted ion exchange resin to yield the side chain ketone which was converted to the amino cyclohexylpeptide 44 by reductive amination using ammonium acetate and sodium cyanoborohydride. ##STR35##

Provenance & Evidence