Solid phase synthesis of Fmoc N-methyl amino acids: Application of the Fukuyama amine synthesis

Tetrahedron Letters

Volumn 38, Issue 42, 1997, Pages 7307-7310

  Yang, Lihu ^a   Chiu, Kuenley ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AMINE; AMINO ACID;

AMINO ACID SYNTHESIS; ARTICLE; DRUG PURIFICATION; DRUG SYNTHESIS; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; IN VITRO STUDY; METHODOLOGY; REACTION ANALYSIS;

EID: 0030820319     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0040-4039(97)01774-7     Document Type: Article

References (22)

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4. During the preparation of this manuscprit, a similar strategy for N-methylation of peptide has been presented: Miller, S. C.; Scanlan, T. S. J. Am. Chem. Soc. 1997, 119, 2301-2302
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14. Preloaded 2-Chlorotrityl resins are purchased from Novabiochem.
15. 3 powder (10 equiv.) also gave good results (DMF, 6 h). The deprotection can be carried out by draining the reaction and adding thiophenol (6 equiv.) and DMF. After 3 hours, the reaction was drained and the inorganic salt was removed by washing with a mixture of water and toluene.
16. a) Rano, T. A.; Chapman, K. T., Tetrahedron Lett., 1995, 36, 3789-3792.
17. b) Krchnak, V.; Flegelova, A.; Weichsel, A. S.; Lebl, M. Tetrahedron Lett., 1995, 36, 6193-6196. also Ref. 3.
18. It should be noted that replacing methanol with other alcohols such as ethanol and benzyl alcohol produced N-alkyl amino acid derivatives, providing an alternative way for reductive alkylation.
19. 3OD, ppm) for selected N-Methyl amino acid TFA salt: 1) N-Me-TrpOH: 7.60 (d, J=8 Hz, 1 H); 7.38 ((d, J=8 Hz, 1 H); 7.22 (s, 1H); 7.13-7.11 (m, 1 H); 7.07-7.04 (m, 1 H); 4.26 (t, J=5.9 Hz, 1 H); 3.48 (d, J=5.9 Hz, 2 H); 2.69 (s, 3 H). 2): N-Me-Trp(Boc)OH: 8.13 (d, J=8 Hz, 1H); 7.65 (s, 1H); 7.63 (d, 1H); 7.36-7.25 (m, 2H); 4.31 (t, J=5.9 Hz, 1H); 3.44 (ABq, 2H); 2.73 (s, 3H), 1.67 (s, 9H). 3): N-Me-Lys(Boc)OH: 3.94 (t, J=6.4 Hz, 1H); 3.05 (t, J=6.7 Hz, 2 H), 2.73 (s, 3 H); 1.97-1.92 (m, 2 H); 1.60-1.40 (m, 4 H); 1.42 (s, 9 H). 4): N-Me-Ser(t-Bu)OH: 4.09 (t, J=3.2 Hz, 1 H);3.93 (dd, J=3.2, 9.5 Hz, 1H); 3.85 (dd, J=3.2, 9.5 Hz, 1H), 2.73 (s, 3 H), 1.22 (s, 9 H). 5): N-Me-Asp(t-Bu)OH: 4.82 (t, J=4.2 Hz, 1 H); 3.01 (ABq, 2 H); 2.77 (s, 3 H); 1.22 (s, 9 H).
20. Analysis was performed using a Partisil ODS-3 RAC II column (100×4.6 mm, 5 μn) eluting with a linear gradient of 40-80% acetonitrile in water containing 0.1% TFA as buffer over 15 minutes at 1 mL/min., the HPLC is equipped with PDA detector and the results are plotted at 278 nm with band width of 8 nm.
21. MS was performed on Finnigan TSQ700 Mass SpectrometerElectrospray Ionization (ESI) in 82%ACCN: 18% aq 1.3mM TFA/1.3mM Ammonium Formate.
22. D-55 (c=2, ethanol), tested side by side with material obtained from Bachem).