Facile N-Urethane-Protected α-Amino/Peptide Thioacid Preparation Using EDC and Na₂S

Abstract

We report herein an efficient protocol for the synthesis of N-urethane-protected α-amino/peptide thioacids from their corresponding acids mediated by EDC and Na₂S. The fast reaction under mild conditions enabled the process to be completed in shorter duration with good yield circumventing column purification. The chemistry is compatible with a wide variety of urethane protecting groups, side-chain functionalities, and sterically hindered amino ­acids.

N-urethane-protected α-amino thioacids - carbodiimides - sodium sulfide

References and Notes

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27a

General Procedure for the Preparation of Peptide Acids
A solution of N^α-protected amino acid (1 mmol) in dry CH₂Cl₂ (5 mL) was cooled to 0 ˚C, EDC (1 mmol), HOBt (1.2 mmol), and O,N-bis-TMS-amino acid (1.5 mmol) were added. The reaction mixture was stirred for 3-4 h (TLC analysis), and then evaporation of the solvent and acidification with 1 M HCl furnished pure peptide acid.

27b For the preparation of O,N-bis-TMS-amino acids, see: Tantry SJ. Vasanthakumar G.-R. Sureshbabu VV. Lett. Pept. Sci.  2003,  10:  51 

28

General Procedure for the Synthesis of Amino/Peptide Thioacids
To a DMF solution of an acid (1.0 mmol), EDC (1.1 equiv) was added at 0 ˚C under a nitrogen atmosphere. After stirring for 10 min, finely ground Na₂S (3 equiv) was added to the reaction mixture which was allowed for stir for 3-4 h until the disappearance of the starting material (TLC analysis). The residue was dissolved in EtOAc (15 mL), and the solution was then carefully acidified at 0 ˚C to a pH of 3 by using 1 M KHSO₄. The organic layer was then immediately separated and removed under reduced pressure. The crude product was triturated with Et₂O or recrystallized with THF-H₂O to obtain pure thioacid.

29

Fmoc-Ile-COSH
Yellow solid; mp 81-83 ˚C. IR (KBr): ν_max = 1689, 1739, 2550, 3342 cm^-¹. R _f  = 0.39 (EtOAc-n-hexane = 60:40). RP-HPLC: t _R = 15.2 (60-100% MeCN, 30 min). ESI-HRMS: m/z calcd for C₂₁H₂₃NO₃S: 392.1296 [M + Na]⁺; found: 392.1290. ^¹H NMR (400 MHz, CDCl₃): δ = 0.88 (t, J = 5.6 Hz, 3 H), 0.98 (d, J = 3.8 Hz, 3 H), 1.12-1.24 (m, 2 H), 2.38-2.47 (m, 1 H), 4.28 (d, J = 6.7 Hz, 1 H), 4.37 (d, J = 7.1 Hz, 1 H), 4.61 (d, J = 4.4 Hz, 2 H), 5.91 (br s, 1 H), 7.43 (br s, 1 H), 7.26-7.84 (m, 8 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 10.8, 14.3, 24.1, 37.0, 46.4, 65.9, 72.8, 125.9, 127.3, 128.6, 128.9, 139.2, 142.6, 155.2, 197.2.

30

Fmoc-Ala-Phe-COSH
White solid; mp 126-128 ˚C. IR (KBr): ν_max = 1681, 1748, 1768, 2549, 3328 cm^-¹. R _f  = 0.53 (CHCl₃-MeOH = 80:20). RP-HPLC: t _R = 11.4 (60-100% MeCN, 30 min). ESI-HRMS: m/z calcd for C₂₇H₂₆N₂O₄S: 497.1511 [M + Na]⁺; found: 497.1501. ^¹H NMR (400 MHz, CDCl₃): δ = 1.2 (d, J = 4.8 Hz, 3 H), 2.6 (d, J = 5.6 Hz, 2 H), 2.8 (br s, 1 H), 3.38 (t, J = 7.4 Hz, 1 H), 3.6 (br s, 1 H), 3.9 (t, J = 6.9 Hz, 2 H), 4.1 (m, 1 H), 4.3 (m, 1 H), 6.32 (br s, 1 H), 7.1 (br s, 1 H), 7.2-7.9 (m, 13 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 17.2, 37.4, 46.8, 51.2, 67.9, 69.7, 125.7, 126.8, 127.2, 127.9, 128.4, 128.9, 131.2, 139.1, 141.4, 143.2, 155.7, 172.1, 197.2.

31

Chiral-HPLC analyses were carried out employing Chiralpak IA, 250 × 4.6 mm; solvent: hexane-EtOH (7:3); flow rate: 1.0 mL/min.