Synlett 2012; 23(10): 1516-1522
DOI: 10.1055/s-0031-1290683
letter
© Georg Thieme Verlag Stuttgart · New York

A Simple Approach for the Synthesis of Thio-, Dithio- and Selenothiocarbamate-Tethered Peptidomimetics

H. S. Lalithamba
#109, Peptide Research Laboratory, Department of Studies in Chemistry, Central College Campus, Bangalore University, Dr. B. R. Ambedkar Veedhi, Bangalore 560001, India, Email: hariccb@hotmail.com   Email: hariccb@gmail.com
,
T. M. Vishwanatha
#109, Peptide Research Laboratory, Department of Studies in Chemistry, Central College Campus, Bangalore University, Dr. B. R. Ambedkar Veedhi, Bangalore 560001, India, Email: hariccb@hotmail.com   Email: hariccb@gmail.com
,
M. Samarasimha Reddy
#109, Peptide Research Laboratory, Department of Studies in Chemistry, Central College Campus, Bangalore University, Dr. B. R. Ambedkar Veedhi, Bangalore 560001, India, Email: hariccb@hotmail.com   Email: hariccb@gmail.com
,
Vommina V. Sureshbabu*
#109, Peptide Research Laboratory, Department of Studies in Chemistry, Central College Campus, Bangalore University, Dr. B. R. Ambedkar Veedhi, Bangalore 560001, India, Email: hariccb@hotmail.com   Email: hariccb@gmail.com
› Author Affiliations
Further Information

Publication History

Received: 23 February 2012

Accepted after revision: 09 April 2012

Publication Date:
25 May 2012 (online)


Abstract

A simple and efficient method is described for the synthesis of thio-, dithio- and selenothiocarbamate-linked peptidomimetics. The nucleophilic addition of enantiopure N α-protected amino alkyl thiols to isocyanates, isothiocyanates or isoselenocyanates obtained from amino acid esters proceeds smoothly in the presence of catalytic amount of DMAP. The protocol was further extended for the synthesis of N,N′-orthogonally protected thio-, dithio- and selenothiocarbamate-linked peptidomimetics. The reaction is mild, free from racemization, and the products were obtained in good yield.

 
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  • 24 General Procedure for the Synthesis of Thio-, Dithio- and Selenothiocarbamate-Linked Peptidomimetics: To a solution of PgNH-CHR-ψ-[CH2SH] (10.0 mmol) in anhyd CH2Cl2 (10.0 mL), isocyanato derivatives (10.0 mmol) and DMAP (0.2 equiv) were added. The reaction mixture was stirred for 30–50 min at r.t. After the completion of the reaction (TLC), the organic layer was washed with H2O (10 mL), brine (10 mL) and dried over Na2SO4. The organic phase was evaporated under vacuo and the crude was recrystallized (Et2O–THF) or purified through column chromatography using EtOAc–n-hexane (20:80) as eluent. Spectral data for compounds: Compound 5a: 1H NMR (300 MHz, CDCl3): δ = 0.98 (d, 6 H, J = 6.1 Hz), 1.59 (d, 3 H, J = 5.5 Hz), 2.90–3.11 (m, 3 H), 3.60 (s, 3 H), 3.91 (m, 1 H), 4.28 (m, 1 H), 4.20 (t, 1 H, J = 4.6 Hz), 5.01 (d, 2 H, J = 5.1 Hz), 5.16 (br, 2 H), 7.22–7.77 (m, 8 H). 13C NMR (100 MHz, CDCl3): δ = 19.6, 20.1, 30.9, 37.4, 45.7, 47.1, 51.9, 58.3, 66.6, 126.8, 127.3, 128.2, 128.9, 141.4, 143.2, 155.7, 164.5, 171.8. HRMS: m/z [M + Na]+ calcd for C25H30N2O5S: 493.1773; found: 493.1775. Compound 5b: 1H NMR (300 MHz, CDCl3): δ = 2.70–3.02 (m, 2 H), 3.21–3.30 (m, 4 H), 3.62 (s, 3 H), 4.20 (m, 1 H), 4.83 (m, 1 H), 5.16 (br, 2 H), 5.32 (s, 2 H), 7.19–7.25 (m, 15 H). 13C NMR (100 MHz, CDCl3): δ = 34.1, 36.2, 43.3, 52.3, 53.1, 56.5, 64.3, 126.1, 126.3, 126.8, 127.0, 127.2, 127.4, 127.8, 128.2, 129.0, 138.1, 139.0, 140.1, 155.2, 164.2, 171.7. HRMS: m/z [M + Na]+ calcd for C28H30N2O5S: 529.1773; found: 529.1770. Compound 5c: 1H NMR (300 MHz, CDCl3): δ = 0.94 (t, 3 H, J = 6.0 Hz), 1.02 (d, 3 H, J = 5.7 Hz), 1.22 (m, 2 H), 2.24 (m, 1 H), 2.92–3.24 (m, 4 H), 3.61 (s, 3 H), 3.75 (m, 2 H), 3.78 (m, 1 H), 4.81 (m, 1 H), 5.18 (br, 2 H), 5.32 (s, 2 H), 7.18–7.20 (m, 10 H). 13C NMR (100 MHz, CDCl3): δ = 12.1, 15.0, 24.1, 32.2, 33.3, 39.0, 40.0, 52.1, 53.9, 55.7, 65.4, 126.4, 127.2, 128.1, 128.3, 128.5, 128.9, 137.4, 141.3, 155.8, 165.2, 171.8. HRMS: m/z [M + Na]+ calcd for C26H34N2O5S2: 541.1807; found: 541.1805. Compound 5d: 1H NMR (300 MHz, CDCl3): δ = 2.20–2.30 (m, 4 H), 3.13 (d, 2 H, J = 5.2 Hz), 3.43–3.60 (m, 3 H), 3.63 (s, 3 H), 4.20 (t, 1 H, J = 3.5 Hz), 4.91 (d, 2 H, J = 5.8 Hz), 5.15 (br, 2 H), 5.21 (s, 2 H), 7.19–7.72 (m, 13 H). 13C NMR (100 MHz, CDCl3): δ = 25.2, 28.3, 37.4, 40.6, 47.2, 51.8, 55.2, 68.1, 68.9, 126.2, 126.9, 127.5, 128.0, 128.4, 128.6, 129.0, 141.2, 143.2, 157.0, 171.1, 173.2, 196.2. HRMS: m/z [M + Na]+ calcd for C31H32N2O6S2: 615.1599; found: 615.1595. Compound 5e: 1H NMR (300 MHz, CDCl3): δ = 0.90 (d, 6 H, J = 6.3 Hz), 1.25 (d, 3 H, J = 5.8 Hz), 1.70–1.75 (m, 3 H), 2.12–3.20 (m, 2 H), 3.63 (s, 3 H), 3.66 (m, 1 H), 3.85 (m, 1 H), 4.28 (t, 1 H, J = 4.8 Hz), 4.91 (d, 2 H, J = 6.7 Hz), 5.15 (br, 2 H), 7.26–7.78 (m, 8 H). 13C NMR (100 MHz, CDCl3): δ = 18.5, 19.6, 20.7, 40.5, 43.8, 47.0, 47.5, 50.9, 52.4, 66.0, 126.7, 127.5, 128.0, 128.6, 141.4, 143.2, 154.7, 173.2, 195.7. HRMS: m/z [M + Na]+ calcd for C26H32N2O4S2: 523.1701; found: 523.1705. Compound 5f: 1H NMR (300 MHz, CDCl3): δ = 0.95 (d, 6 H, J = 5.2 Hz), 2.15 (s, 3 H), 2.23–2.47 (m, 5 H), 2.95 (d, 2 H, J = 5.8 Hz), 3.45 (m, 1 H), 3.62 (s, 3 H), 3.86 (m, 1 H), 5.17 (br, 2 H), 5.22 (s, 2 H), 7.19–7.22 (m, 5 H). 13C NMR (100 MHz, CDCl3): δ = 16.2, 17.3, 17.5, 29.0, 31.1, 33.2, 36.5, 52.1, 56.2, 58.4, 65.4, 126.1, 127.6, 128.3, 142.1, 155.7, 171.2, 197.0. HRMS: m/z [M + Na]+ calcd for C20H30N2O4S3: 481.1265; found: 481.1261. Compound 5g: 1H NMR (300 MHz, CDCl3): δ = 1.33 (d, 3 H, J = 4.6 Hz), 2.96–3.02 (m, 2 H), 3.04–3.31 (m, 2 H), 3.50 (s, 3 H), 3.81 (m, 1 H), 4.10 (m, 1 H), 4.12 (t, 1 H, J = 4.9 Hz), 4.99 (d, 2 H, J = 6.4 Hz), 5.22 (br, 2 H), 7.12–7.81 (m, 13 H). 13C NMR (100 MHz, CDCl3): δ = 19.1, 36.2, 37.1, 47.2, 48.2, 52.0, 58.7, 67.2, 125.1, 126.7, 127.5, 127.9, 128.0, 128.2, 128.6, 139.0, 141.1, 143.4, 155.7, 171.2, 205.7. 77Se NMR (76 MHz, Me2Se–CDCl3): δ = 322.0. HRMS: m/z [M + Na]+ calcd for C29H30N2O4SSe: 605.0989; found: 605.0984. Compound 5h: 1H NMR (300 MHz, CDCl3): δ = 0.95 (d, 6 H, J = 5.6 Hz), 2.30 (m, 1 H), 2.73–2.95 (m, 2 H), 2.98–3.21 (m, 2 H), 3.61 (s, 3 H), 3.80 (m, 1 H), 4.10 (m, 1 H), 4.21 (t, 1 H, J = 4.2 Hz), 4.80 (d, 2 H, J = 6.4 Hz), 5.21 (br, 2 H), 5.30 (s, 2 H), 7.12–7.81 (m, 13 H). 13C NMR (100 MHz, CDCl3): δ = 17.2, 17.4, 32.9, 34.3, 37.4, 47.2, 51.8, 52.1, 58.3, 67.1, 69.2, 125.3, 126.2, 127.2, 127.3, 128.0, 128.3, 128.6, 141.3, 142.1, 143.7, 155.1, 171.2, 173.2, 203.4. 77Se NMR (76 MHz, Me2Se–CDCl3): δ = 322.0. HRMS: m/z [M + Na]+ calcd for C33H36N2O6SSe: 691.1357; found: 691.1352. Compound 5i: 1H NMR (300 MHz, CDCl3): δ = 0.94 (t, 3 H, J = 5.8 Hz), 1.01 (d, 3 H, J = 6.1 Hz), 1.37 (m, 2 H), 2.51 (m, 1 H), 2.60–2.81 (m, 2 H), 2.94–3.23 (m, 2 H), 3.41 (m, 1 H), 3.59 (s, 3 H), 4.21 (m, 1 H), 5.19 (br, 2 H), 5.29 (s, 2 H), 7.12–7.20 (m, 10 H). 13C NMR (100 MHz, CDCl3): δ = 12.2, 15.2, 36.2, 37.1, 42.2, 51.2, 55.3, 58.9, 66.3, 125.4, 126.5, 127.4, 128.0, 128.3, 128.7, 139.1, 141.4, 155.2, 171.3, 202.4. 77Se NMR (76 MHz, Me2Se–CDCl3): δ = 322.0. HRMS: m/z [M + Na]+ calcd for C25H32N2O4SSe: 559.1146; found: 559.1149. Compound 7a: 1H NMR (300 MHz, CDCl3): δ = 0.97 (d, 6 H, J = 6.0 Hz), 1.31 (d, 3 H, J = 5.4 Hz), 1.43 (m, 2 H), 1.76 (m, 1 H), 2.90–3.21 (m, 2 H), 3.01–3.35 (m, 2 H), 4.01–4.21 (m, 2 H), 4.25 (t, 1 H, J = 4.0 Hz), 5.01 (d, 2 H, J = 7.2 Hz), 5.31 (s, 2 H), 5.88 (br, 3 H), 7.19–7.82 (m, 13 H). 13C NMR (100 MHz, CDCl3): δ = 20.2, 22.1, 23.4, 37.5, 42.2, 45.2, 47.0, 47.8, 48.9, 65.2, 67.2, 127.2, 127.4, 127.8, 128.1, 128.5, 128.8, 129.4, 141.2, 141.5, 143.1, 155.7, 163.1. HRMS: m/z [M + Na]+ calcd for C33H39N3O5S: 612.2508; found: 612.2505. Compound 7b: 1H NMR (300 MHz, CDCl3): δ = 1.21 (d, 3 H, J = 6.6 Hz), 1.25–1.60 (m, 6 H), 2.90–3.20 (m, 4 H), 3.25–3.45 (m, 2 H), 3.75 (m, 1 H), 5.01 (m, 1 H), 4.23 (t, 1 H, J = 4.5 Hz), 5.21 (d, 2 H, J = 6.1 Hz), 5.32 (s, 4 H), 5.81 (br, 4 H), 7.16–7.79 (m, 18 H). 13C NMR (100 MHz, CDCl3): δ = 17.7, 22.4, 29.2, 33.8, 35.0, 47.1, 47.4, 49.2, 49.4, 49.8, 67.4, 68.2, 68.5, 126.1, 126.3, 126.9, 127.2, 127.4, 127.7, 128.2, 128.6, 128.9, 129.4, 141.1, 141.4, 141.8, 143.4, 155.3, 155.7, 156.2, 167.5. HRMS: m/z [M + Na]+ calcd for C41H46N4O7S: 761.2985; found: 761.2980. Compound 7c: 1H NMR (300 MHz, CDCl3): δ = 1.02 (d, 6 H, J = 5.2 Hz), 1.49 (m, 2 H), 1.81 (m, 1 H), 3.01–3.32 (m, 4 H), 3.69 (m, 2 H), 4.32 (m, 1 H), 4.31 (t, 1 H, J = 5.2 Hz), 4.83 (d, 2 H, J = 6.2 Hz), 5.32 (s, 2 H), 5.80 (br, 3 H), 7.19–7.81 (m, 13 H). 13C NMR (100 MHz, CDCl3): δ = 22.1, 22.4, 23.3, 32.5, 39.0, 41.7, 46.3, 47.2, 47.5, 64.2, 68.2, 126.2, 127.6, 127.3, 128.2, 128.7, 128.9, 129.4, 141.3, 141.8, 143.5, 155.2, 156.3, 169.1. HRMS: m/z [M + Na]+ calcd for C32H37N3O5S: 598.2352; found: 598.2350. Compound 7d: 1H NMR (300 MHz, CDCl3): δ = 0.95 (d, 6 H, J = 5.6 Hz), 1.20 (s, 9 H), 1.72 (m, 3 H), 2.40–2.49 (m, 4 H), 2.51 (d, 2 H, J = 4.9 Hz), 3.48 (m, 1 H), 3.99 (m, 1 H), 4.22 (t, 1 H, J = 4.2 Hz), 4.91 (d, 2 H, J = 6.7 Hz), 5.92 (br, 3 H), 7.21–7.78 (m, 13 H). 13C NMR (100 MHz, CDCl3): δ = 20.1, 22.9, 27.7, 38.4, 40.1, 41.6, 46.9, 47.8, 49.1, 51.5, 65.7, 82.3, 127.5, 127.8, 127.9, 128.2, 128.6, 128.9, 129.5, 141.7, 142.3, 143.4, 155.6, 156.3, 194.5. HRMS: m/z [M + Na]+ calcd for C36H45N3O4S2: 670.2749; found: 670.2745. Compound 7e: 1H NMR (300 MHz, CDCl3): δ = 0.99 (d, 6 H, J = 5.6 Hz), 1.40 (m, 2 H), 1.80 (m, 1 H), 2.74–3.10 (m, 6 H), 3.80 (m, 1 H), 4.19 (m, 1 H), 4.35 (t, 1 H, J = 4.2 Hz), 4.87 (d, 2 H, J = 6.7 Hz), 5.33 (s, 2 H), 5.82 (br, 3 H), 7.23–7.81 (m, 18 H). 13C NMR (100 MHz, CDCl3): δ = 22.1, 23.1, 23.3, 39.4, 41.9, 42.3, 47.0, 47.8, 49.5, 55.5, 65.1, 67.4, 126.5, 126.8, 127.1, 127.5, 127.9, 128.2, 128.5, 128.7, 129.5, 139.2, 141.2, 143.3, 155.2, 155.8, 198.4. HRMS: m/z [M + Na]+ calcd for C39H43N3O4S2: 704.2593; found: 704.2595. Compound 7f: 1H NMR (300 MHz, CDCl3): δ = 0.91 (t, 3 H, J = 5.6 Hz), 1.08 (d, 3 H, J = 5.1 Hz), 1.32 (m, 2 H), 2.23 (m, 1 H), 2.81–3.32 (m, 6 H), 3.80 (m, 1 H), 4.37 (t, 1 H, J = 5.2 Hz), 4.99 (d, 2 H, J = 6.7 Hz), 5.30 (s, 2 H), 5.82 (br, 3 H), 7.20–7.78 (m, 13 H). 13C NMR (100 MHz, CDCl3): δ = 12.2, 16.1, 25.5, 35.3, 40.2, 41.0, 43.2, 47.1, 54.2, 66.1, 68.4, 126.6, 127.4, 127.8, 128.5, 128.7, 129.0, 129.5, 141.0, 141.5, 144.3, 155.6, 156.0, 198.4. HRMS: m/z [M + Na]+ calcd for C32H37N3O4S2: 614.2123; found: 614.2126. Compound 7g: 1H NMR (300 MHz, CDCl3): δ = 0.97 (d, 6 H, J = 5.4 Hz), 1.31 (d, 3 H, J = 5.8 Hz), 1.12 (s, 9 H), 2.40 (m, 1 H), 2.74–2.99 (m, 2 H), 3.04–3.22 (m, 2 H), 3.81–4.01 (m, 2 H), 5.01 (s, 2 H), 6.02 (br, 3 H), 7.10–7.26 (m, 5 H). 13C NMR (100 MHz, CDCl3): δ = 17.2, 19.2, 29.0, 31.2, 39.1, 47.2, 48.2, 59.1, 65.2, 79.2, 127.5, 127.8, 128.2, 141.2, 155.7, 204.2. 77Se NMR (76 MHz, Me2Se–CDCl3): δ = 320.0. HRMS: m/z [M + Na]+ calcd for C22H35N3O4SSe: 540.1411; found: 540.1416. Compound 7h: 1H NMR (300 MHz, CDCl3): δ = 0.95 (t, 3 H, J = 5.5 Hz), 0.99 (d, 3 H, J = 5.6 Hz), 1.10 (s, 9 H), 1.25 (m, 2 H), 1.32 (d, 3 H, J = 5.2 Hz), 2.12–3.32 (m, 5 H), 3.90 (m, 2 H), 4.30 (t, 1 H, J = 4.2 Hz), 4.92 (d, 2 H, J = 5.5 Hz), 5.69 (br, 3 H), 7.21–7.76 (m, 8 H). 13C NMR (100 MHz, CDCl3): δ = 11.0, 14.3, 18.8, 26.5, 28.6, 32.1, 40.2, 48.1, 49.1, 52.3, 57.5, 68.2, 80.4, 126.0, 127.1, 127.8, 128.3, 141.3, 143.7, 155.1, 155.7, 202.3. 77Se NMR (76 MHz, Me2Se–CDCl3): δ = 320.0. HRMS: m/z [M + Na]+ calcd for C30H41N3O4SSe: 642.1881; found: 642.1884. Compound 7i: 1H NMR (300 MHz, CDCl3): δ = 0.98 (d, 6 H, J = 6.5 Hz), 2.40 (m, 1 H), 2.60–3.22 (m, 6 H), 3.87 (m, 1 H), 4.30 (m, 1 H), 4.33 (t, 1 H, J = 4.3 Hz), 4.92 (d, 2 H, J = 6.6 Hz), 5.33 (s, 2 H), 5.99 (br, 3 H), 7.21–7.76 (m, 18 H). 13C NMR (100 MHz, CDCl3): δ = 16.9, 32.8, 34.5, 40.9, 47.5, 49.6, 53.2, 59.9, 64.3, 68.4, 126.3, 126.8, 126.9, 127.0, 127.3, 127.9, 128.1, 128.3, 128.7, 129.0, 139.2, 140.3, 141.3, 143.9, 155.2, 155.9, 201.5. 77Se NMR (76 MHz, Me2Se–CDCl3): δ = 320.0. HRMS: m/z [M + Na]+ calcd for C38H41N3O4SSe: 738.1881; found: 738.1884