Trifluoroacetic acid → 4-Pyrrolidinopyridine

HRID 1461682Notes

Reaction equation

HRID 1461682 reaction equation
CC(C[C@@H]1NC(=O)[C@H:34]2[N:30]([CH2:31][CH2:32][CH2:33]2)[C:28](=O)[C@H:27]([CH:38](C)C)NC(=O)C2=CSC(=N2)CNC(=O)C2=CSC(=N2)[C@H](CCC(N)=O)NC1=O)C.[NH:46]1CCC[C@H:47]1[C:48](OC)=O.FC(F)(F)C(O)=O.[OH-].[Na+].C1CCC(N=C=NC2CCCCC2)CC1.FC1C(O)=C(F)C(F)=C(F)C=1F>O1CCOCC1.COCCOC.CO.C(O)C.C(OCC)C.C(Cl)(Cl)Cl.C(OCC)(=O)C.CCCCCC>[N:30]1([C:28]2[CH:27]=[CH:38][N:46]=[CH:47][CH:48]=2)[CH2:31][CH2:32][CH2:33][CH2:34]1

Participants

13

Reactant 6

HCID 6422Trifluoroacetic acidHCID 10868DicyclohexylcarbodiimideHCID 13041PentafluorophenolHCID 14798Sodium HydroxideHCID 853477Methyl L-prolinateHCID 9852693Dolastatin 3

Product 1

HCID 755674-PyrrolidinopyridineYield 76%

Reagents, catalysts & solvents 6

HCID 887MethanolSolventHCID 6212ChloroformSolventHCID 80711,2-DimethoxyethaneSolventHCID 312751,4-DioxaneSolvent2×HCID 21226206Ethyl acetate hexaneSolventHCID 21585056Diethyl ether ethanolSolvent

Procedure

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.

Workup

  1. customwere prepared
  2. customSynthesis, 1987, 233-236
  3. customSchmidt et al, Synthesis, 1986, 992-998

Sources & evidence

ORD record
ord-0b0d51c7a3f445a09b947f116e6ebb06
Source dataset
uspto-grants-1991_12
Patent number
US05076973

Reaction notes

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