An improved method for the preparation of desoxopeffides—reductions of endothiopeptides

New efficient enantioselective synthesis of 2-oxopiperazines: a practical access to chiral 3-substituted 2-oxopiperazines

“…Finally, thioamide reduction using sodium borohydride in the presence of nickel chloride affords the aminoalcohol (R)-7 in 93% yield. 23 However, two additional steps are necessary to access to 2-oxopiperazine (1 0 R)-2, this modification of our previously described synthetic route is still so long. A shorter, more efficient route should be feasible.…”

“…Subsequently, this compound was converted to methyl ester (R)-21 using methyl orthoformiate in acid conditions. The treatment of alcohol (R)-21 with triflic anhydride, in toluene, furnished the corresponding triflate intermediate which immediately underwent an N-Boc-piperazine SN 2 substitution to afford piperazine (S)-22 {½a 23 D ¼ À16 (c 0.5, EtOH)} with a good yield of 98% and an ees superior to 95%. No epimerization at the stereogenic carbon was observed, as determined by chiral HPLC analysis, using the opposite enantiomer as a standard {(piperazine (R)-22: ½a 23 D ¼ þ16 (c 0.5, EtOH)}.…”

“…In our synthesis, oxidation was accomplished in the presence of catalytic amounts of ruthenium dioxide in a double layer (ethyl acetate/water) with an additional oxidant, sodium periodate, to re-oxidize the transiently formed ruthenium dioxide and thus completing the catalytic cycle. This reaction led to the 2-oxopiperazine (S)-12 {½a 23 D ¼ À12 (c 0.3, EtOH)} with an excellent regioselectivity in 58% yield. The final ester reduction step of compound 12 gave the desired 2-oxopiperazine (1 0 R)-2 in 73% yield.…”

“…½a Following the same procedure for (S)-12, the compound (R)-12 was prepared (0.93 g, 58%) and was afforded as a yellow oil. ½a 23 D ¼ þ12 (c 0.3, EtOH). Spectroscopic data of (R)-12 were identical with those of (S)-12.…”

Peptide Backbone Modifications

“…Guziec and coworkers described the desulfurization of thionated dipeptides (157) yielding desoxypeptides (Scheme 54) [72], an interesting class of peptidomimetics. Either Raney nickel or nickel boride were used as reducing agent, whereas boride tolerated the Z-protective group, which was cleaved by catalytic hydrogenation using Raney nickel.…”