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Synlett 2010(5): 715-720  
DOI: 10.1055/s-0029-1219393
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of Thioureido-Linked Peptidomimetics, Glycosylated Amino Acids, and Neoglycoconjugates Using Bis(benzotriazolyl)methanethione as Thioacylating Agent

Vommina V. Sureshbabu*, Gundala Chennakrishnareddy, Hosahalli P. Hemantha
Peptide Research Laboratory, Department of Studies in Chemistry, Central College Campus, Dr. B. R. Ambedkar Veedhi, Bangalore University, Bangalore 560001, India
e-Mail: sureshbabuvommina@rediffmail.com; e-Mail: hariccb@hotmail.com; e-Mail: hariccb@gmail.com;
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Publication History

Received 15 June 2009
Publication Date:
18 February 2010 (online)

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Abstract

A practical synthesis of thiourea-linked peptidomimetics, glycosylated amino acids, and neoglycoconjugates is described employing bis(benzotriazolyl)methanethione as thiocarbonylating reagent. The entire protocol is mild, efficient, high-yielding, and free from hazardous reagents. All the intermediates and products have been isolated and fully characterized by ¹H NMR, ¹³C NMR, and mass spectrometry.

Key words

peptidomimetics - isothiocyanates - thioureidopeptides - pseudoglycoconjugates

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The absence of racemization during the course of the reaction was verified through ¹H NMR analysis of the unsymmetrical thioureas prepared by the reaction of N β -Fmoc-Phe-ψ[NHCSNH] with optically pure (R)- and
(S)-1-phenylethylamine. The methyl protons of the phenylethylamine moiety in N β-Fmoc-Phe-ψ[NHCSNH]-(R)-(+)-1-phenylethylamine and N β-Fmoc-Phe-ψ[NHCSNH]-(S)-(-)-1-phenylethylamine were observed as distinct doublets at δ = 1.30, 1.32 ppm and δ = 1.29, 1.31 ppm, respectively. For N β-Fmoc-Phe-ψ[NHCSNH]-(R,S)-(±)-1-phenylethylamine, the corresponding methyl resonances were observed as two doublets at δ = 1.32, 1.30 ppm and δ = 1.31, 1.29 ppm. This clearly showed that there was no formation of an epimeric mixture (absence of two CH3 doublets when optically pure phenylethylamine was coupled) during the reaction.

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General Procedure for the Preparation of 3, 5, or 8
To a solution N β-Fmoc/Boc/Z-amino alkyl amine 2 (1.0 mmol), amino acid ester 4, and O-protected β-glycosyl amine 7 (1.0 mmol) in CH2Cl2 (10 mL), Bt-CS-Bt 1 (1.0 mmol) was added at r.t., and the reaction mixture was stirred overnight. After the completion of reaction (as monitored by TLC), it was diluted with CH2Cl2, the organic layer was washed with 10% NaHCO3 (to remove benzotriazole byproduct), brine, and dried over anhyd Na2SO4. The solvent was removed under reduced pressure to afford 3, 5, or 8 which were recrystallized from CH2Cl2-n-hexane.
General Procedure for the Preparation of 6a-i, 10a-c, and 11a-d To a stirring solution of 3, 5, or 8 (1.0 mmol) in CH2Cl2 (10 mL) was added amino-free amino acid ester (1.0 mmol), or O-protected β-glycosyl amine (1.0 mmol), or N α-Cbz-β-amino-l-alanine methyl ester (1.0 mmol) followed by the addition of DIPEA (1.0 mmol) at r.t. The mixtrue was stirred for about 5-6 h until completion (TLC analysis). The solvent was removed in vacuo, and the residue was taken into EtOAc. The organic layer was washed with 10% citric acid solution, NaHCO3 (10%) solution, brine, and dried over anhyd Na2SO4. The solvent was removed under reduced pressure and the residue recrystallized from CH2Cl2-
n-hexane to afford the title compounds.
Fmoc-β-Ile-ψ[NH-CS-NH]-β-Ala-OMe (6a)
¹H NMR (400 MHz, CDCl3): δ = 0.83-0.96 (m, 6 H), 1.25 (m, 2 H), 2.00 (m, 2 H), 2.35 (t, J = 8.0 Hz, 2 H), 3.37 (t, J = 8.0 Hz, 2 H), 3.56 (s, 3 H), 3.67 (m, 2 H), 3.81 (m, 1 H), 4.18 (m, 1 H), 4.37 (m, 2 H), 5.35 (br, 1 H), 6.84 (br, 1 H), 7.31-7.76 (m, 8 H). ¹³C NMR (100 MHz, CDCl3): δ = 12.1, 15.9, 25.8, 30.9, 33.9, 37.8, 40.1, 47.6, 52.3, 56.4, 67.5, 125.6, 125.7, 127.6, 128.2, 141.7, 144.2, 158.0, 173.5, 183.1 HRMS: m/z calcd for C26H33N3O4S: 506.2089 [M + Na]; found: 506.2079 [M + Na].
Z -β-Cys(Bz I)-ψ[NH-CS-NH]- β -Leu-OMe (6e)
¹H NMR (400 MHz, CDCl3): δ = 0.98 (d, J = 6.8 Hz, 6 H), 1.23 (m, 2 H), 1.76 (m, 1 H), 2.40 (m, 2 H), 2.53-2.67 (m, 2 H), 3.35 (m, 1 H), 3.47 (m, 1 H), 3.77 (m, 3 H), 3.89-3.99 (m, 4 H), 5.04 (s, 2 H), 5.04 (s, 2 H), 5.30 (br, 1 H), 7.23-7.33 (m, 10 H). ¹³C NMR (100 MHz, CDCl3): δ = 21.9, 22.6, 23.0, 25.2, 34.1, 36.9, 44.5, 44.6, 49.6, 55.4, 55.6, 67.3, 127.7, 128.4, 128.6, 128.9, 129.6, 136.9, 137.1, 138.1, 156.7, 175.1, 183.8: HRMS: m/z calcd for C27H37N3O4S2Na: 554.2123 [M + Na]; found: 554.2119 [M + Na]
OMe-Phe-[NH-CS-NH]-Val-OMe (6g)
¹H NMR (400 MHz, CDCl3): δ = 0.95 (d, J = 7.6 Hz, 6 H), 2.23 (m, 1 H), 3.12 (m, 2 H), 3.34 (m, 1 H), 3.67 (s, 3 H), 3.76 (s, 3 H), 3.83 (m, 1 H), 6.80 (br, 1 H), 7.10-7.32 (m, 5 H). ¹³C NMR (100 MHz, CDCl3): δ = 18.4, 18.5, 30.5, 37.1, 52.2, 52.6, 60.1, 64.2, 126.8, 127.5, 129.4, 136.3, 168.8, 173.1, 183.4. HRMS: m/z calcd for C17H24N2O4S: 375.1354 [M + Na]; found: 375.1351 [M + Na].
Compound (11b)
¹H NMR (300 MHz, CDCl3): δ = 2.05 (br, 1 H), 3.64 (s, 3 H), 3.93 (m, 1 H), 4.18 (m, 1 H), 4.41 (m, 2 H), 4.51 (m, 2 H), 5.06 (m, 3 H), 5.64 (s, 2 H), 5.96 (br, 1 H), 7.14-8.01 (m, 25 H). ¹³C NMR (100 MHz, CDCl3): δ = 53.6, 53.8, 62.7, 68.0, 69.7, 69.9, 71.9, 72.3, 77.8, 83.3, 128.2, 128.8, 128.9, 129.0, 129.2, 129.4, 130.4, 130.5, 131.1, 133.6, 133.9, 134.2, 134.4, 136.1, 157.2, 165.9, 166.5, 168.2, 168.9. 171.2, 183.2. HRMS: m/z calcd for C47H43N3O13S: 912.2414 [M + Na]; found: 912.2409 [M + Na].
Compound (11d)
¹H NMR (300 MHz, CDCl3): δ = 2.06 (br, 1 H), 3.64 (s, 3 H), 3.87 (m, 1 H), 4.42-4.49 (m, 3 H), 4.62-4.66 (m, 5 H), 4.82 (m, 1 H), 5.00-5.04 (m, 3 H), 5.17 (m, 1 H), 5.41 (m, 3 H), 5.61 (m, 1 H), 5.70 (m, 1 H), 5.93-5.98 (m, 2 H), 7.20-8.08 (m, 40 H). ¹³C NMR (100 MHz, CDCl3): δ = 50.1, 53.5, 56.1, 63.2, 67.8, 68.5, 69.9, 70.5, 71.5, 71.9, 72.1, 73.0, 73.1, 75.2, 82.6, 102.1, 119.0, 119.1, 119.6, 120.1, 120.4, 120.7, 121.1, 121.4, 127.7, 127.8, 127.9, 128.2, 128.3, 128.4, 128.8, 129.1, 129.5, 130.3, 130.4, 130.5, 131.1, 131.3, 132.0, 132.3, 133.9, 134.4, 136.5, 137.1, 137.2: 157.6, 170.1, 170.2, 170.4, 170.9, 171.0, 171.3, 171.7, 171.9, 183.1. HRMS: m/z calcd for C74H65N3O21S: 1386.3729 [M + Na]; found: 1386.3719 [M + Na].