Trifluoroacetic acid → 4-Pyrrolidinopyridine

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Reaction Steps

Synthesis of dolastatin 3 is accomplished by one L-amino acid unit additions from L-Pro-OMe employing diethyl phosphorocyanidate (DEPC)-triethylamine for peptide bond formation and N-Boc-protection (trifluoroacetic acid cleavage). The thiazole amino acid components used herein were prepared as described by Schmidt et al (Synthesis, 1987, 233-236; Schmidt et al, Synthesis, 1986, 992-998; Kelly et al, J. Org. Chem., 1986, 51, 4590-4594; Houssin et al, J. Org. Chem., 1985, 50, 2787-2788; and Holzapfel et al, J. Org. Chem., 1985, 50, 2323-2327). By these means, Boc-L-Leu--L-(gln)Thz-(gly)Thz-L-Val-L-Pro-OMe, mp 125°-126° from ethyl acetate-hexane, [α]D25.8 -74.9 (c=3.73, CHCl3) was obtained in 71% overall yield. After successive hydrolysis [1N NaOH, dioxane 3N HCl→mp 168°-170° from ethanol-diethyl ether, [α]D22 -37.7 (c=1.64, CH3OH), conversion (DCCI, DME, pentafluorophenol) to the OPfp active ester, Boc cleavage, and cyclization in dioxane containing 4% t-butanol and 4 -pyrrolidinopyridine (at 95° C., 76% yield), synthetic (-)-dolastatin 3, a colorless amorphous solid from ethanol-ethyl acetate, mp 170°-173°, [α]D25 -53.3 (c=0.94 in CHCl3), 1H- and 13C-NMR was realized in 41% overall yield.

Provenance & Evidence