Methylthiomethyl, a new carboxyl protecting group in peptide synthesis (original) (raw)
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Synthesis of orthogonally protected thioamide dipeptides for use in solid-phase peptide synthesis
Tetrahedron Letters, 2016
Orthogonally protected thioamide-containing dipeptides were efficiently and cleanly prepared from the precursor dipeptides using Curphey's method (P4S10, hexamethyldisiloxane (HMDO), reflux, DCM) in 67-96% isolated yield. This was in contrast to the use of Lawesson's or Berzelius' reagents where significant issues with reaction noncompletion, decomposition and purification were observed. Subsequent clean removal of the dipeptides' t-butyl ester protecting groups gave thioamide dipeptide acids which were suitable for use in solid-phase peptide synthesis (SPPS).
The Journal of Organic Chemistry, 2008
Hydroxy acids were reacted with hexafluoroacetone and carbodiimides to give carboxy-activated sixmembered lactones in good yields. On reaction with amines, the corresponding amides were obtained. We demonstrate the following applications of this protecting/activating strategy: preparation of carboxamides in solution and on solid phase (both normal and reverse mode); recovery and reuse of the excess material in solid-phase synthesis; and convergent solid-phase peptide synthesis (CSPPS) with peptide segments bearing C-terminal Ser or Thr with very low levels of epimerization (<1%, HPLC).
Journal of Peptide Research, 1999
Reissmann, S. Synthesis of N-carboxyalkyl and Naminoalkyl functionalized dipeptide building units for the assembly of backbone cyclic peptides. Abstract: To improve the assembly of backbone cyclic peptides, N-functionalized dipeptide building units were synthesized. The corresponding N-aminoalkyl or N-carboxyalkyl amino acids were formed by alkylation or reductive alkylation of amino acid benzyl or tert-butyl esters. In the case of N-aminoalkyl amino acid derivatives the aldehydes for reductive alkylation were obtained from N,O-dimethyl hydroxamates of N-protected amino acids by reduction with LiAlH 4 . N-carboxymethyl amino acids were synthesized by alkylation using bromoacetic acid ester and the N-carboxyethyl amino acids via reductive alkylation using aldehydes derived from formyl Meldrums acid. Removal of the carboxy protecting group leads to free N-alkyl amino acids of very low solubility in organic solvents, allowing ef®cient puri®cation by extraction of the crude product. These N-alkyl amino acids were converted to their tetramethylsilane-esters by silylation with N,O-bis-(trimethylsilyl)acetamide and could thus be used for the coupling with Fmoc-protected amino acid chlorides or¯uorides. To avoid racemization the tert-butyl esters of N-alkyl amino acids were coupled with the Fmoc-amino acid halides in the presence of the weak base collidine. Both the N-aminoalkyl and N-carboxyalkyl functionalized dipeptide building units could be obtained in good yield and purity. For peptide assembly on the solid support, the allyl type protection of the branching moiety turned out to be most suitable. The Fmoc-protected N-functionalized dipeptide units can be used like any amino acid derivative under the standard conditions for Fmoc-solid phase synthesis.
The Journal of Organic Chemistry, 1992
and the oil was separated into three fractions (SiOz, EtOAc). Fraction 2 was separated further by HPLC (SiOz, EtOAc; CIE column, MeOH-H20, 141) to give 6b as an oil: [ a ] %~ +go (c 0.2, CHC1,); 'H NMR, see Figure 2. Anal. Found for C13HuN06: 274.1653 (M + H) (HRFABMS). Formation of 6b and Lactam 15. A sample of synthetic N-Boc-(~S,~R,~S)-IOE~ (37 mg) was hydrolyzed with 1 N NaOH (0.1 mL) in dioxane (1 mL) at rt for 2.5 h. Solvent was removed in vacuo, and the resulting oil was treated with TFA in CHzClz (0.1 mL) for 40 min. Excess solvent was removed under Nz, and the residual material was heated with MeOH-AcCl(401) at 65 O C for 25 min. MeOH and HC1 were removed in vacuo, and the oil was treated with AczO and CSHSN (0.2 mL each) at rt for 1 h. The product was passed through a small SiOz column (EtOAc) and then was subjected to HPLC @io2, EtOAc) to give 6b, the (200 MHz, CDClJ, Figure 2. The more polar fraction gave lactam 15 (4.2 mg, 15%): [ a I m~-5O (c 0.5, CHCl,); IR (film) 1740,1699 cm-'; ' H NMR, Table 11; FABMS m/z 200 (M + H); EIMS m/z (re1 intensity) 156 (6.4), 142 (loo), 111 (64.8),100 (36.6),82 (1001, 43 (24.0). Anal. Found for C1&8N03 (M + H): 200.1287 (HRFABMS). NOE Difference Experiment on Lactams 15 and 16. Solutions of lactams 15 (4.4 mg) and 16 (3.5 mg), each in CDCl, (0.5 mL), were degassed with dry Ar, and their qualitative NOE difference spectra were recorded with an XL-200 spectrometer: relaxation delay = 10 e; number of transients = 180 (Figure 13s). Preparation of N,O-Bis(trifluomacetyl)isostatine Methyl Esters. Synthetic samples of all eight Boc-ieostatine methyl ester isomers were treated individually with TFAA and TFA at 100 OC for 5 min. Excess acid was removed under Nz, and each product was purified by HPLC @ioz, hexane-EtOAc, 51) to give 6c-13c. Optical rotations and GC retention times are listed in Table IV. Acid Treatment of Boc-(3S,4SPS)-isostatine Ethyl Ester. Four samples (13-mg each) were treated with 6 N HC1 at 110 OC for 4,11, 24, and 38 h, respectively. Solvent was removed, and each residue was treated with MeOH-AcCl(101) at 110 OC for 15 min. The methanolic HC1 was removed, and the resulting oil was treated with TFAA and TFA at 110 OC for 5 min. Each product was dissolved in 2-propanol (1 mL) for GC analysis. Acid Treatment of Boc-(3R,4SPS)-isostine Ethyl Ester. Four samples (4-mg each) were treated with 6 N HC1 at 110 "C for 4,12,36, and 42 h, respectively. The products were converted le88 polar oil (4.6 mg, 11%): [ C I ]~D +1l0 (C 0.6, CHC13); ' H NMR to the TFA ethyl ester derivatives using the procedure described above. Each sample was dissolved in 2-propanol(l mL) for GC analysis. Synthesis of Boc-(4S,5S)-2,3-anhydroisostatine Methyl Ester (20). A mixture of Boc-(3S,4S,5S)-and Boc-(3R,4S,5S)-Ist-OMe (25 mg, 0.086 mmol) was treated with 6 N HCl(1 mL) at 110 OC for 20 h. Aqueous HCl was removed under Nz, and the residue was treated with mixture of MeOH-AcCl (101) and concentrated and then treated with Boc-ON (30 mg) and Et,N (20 pL) in CHZCl2 at rt for 10 h. Solvent was removed, and the product was purified by HPLC using a phenyl column and hexane-2-propanol (201) to give pure 20 (3.6 mg, 14%): needles, mp 60 O C ; [aImD +2O (c 0.03, CHC1,); 'H NMR, Figure 21s. _ _-Anal. Calcd for Cl4H%NO4: 272.1862 (M + H). Found: 272.1859 (M + H) (HRFABMS). Acid Tktment'of 20. Four L p l e s of 20 (0.7 mg each) were treated with 6 N HC1 at 110 OC for 4, 12, 24, and 36 h. The resulting hydrolyzates were converted to TFA methyl ester derivative 20a using the procedure described above for GC analyaea: