Synthesis of the ‘Northern-Hemisphere’ Fragments of the Thiopeptide Antibiotic Nosiheptide

Abstract

The northern-hemisphere fragments 4 and 5 of the thiopeptide antibiotic nosiheptide have been synthesized from Boc-Glu-OBn 7 and Boc-Thr 12 in 21.8% and 16.8% overall yields, respectively.

Key words

thiazole - amino acids - heterocycles - antibiotics

References and Notes

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25

Analytical Data of ( S , S )-1-Benzyl-5-methyl 2- tert -butoxycarbonylamino-4- tert -butyldimethylsiloxy Pentanedioate ( 9).
¹H NMR (300 MHz, CDCl₃): δ = 7.40-7.26 (5 H, br s, ArH), 5.30 (1 H, d, J = 8.3 Hz, NH), 5.22 (1 H, d, J = 12.4 Hz, CHHPh), 5.11 (1 H, d, J = 12.4 Hz, CHHPh), 4.47 (1 H, m, CHNH), 4.28 (1 H, m, CHOSi), 3.70 (3 H, s, OMe), 2.28-2.09 (2 H, m, 3-CH₂), 1.42 (9 H, s, CMe₃), 0.91 (9 H, s, CMe₃), 0.04 (3 H, s, Me), 0.03 (3 H, s, Me). ¹³C NMR (75 MHz, CDCl₃): δ = 173.8 (C), 172.5 (C), 155.9 (C), 135.9 (C), 129.3 (CH), 128.8 (CH), 128.6 (CH), 80.2 (C), 69.9 (CH), 67.5 (CH₂), 52.5 (Me), 51.5 (CH), 36.7 (CH₂), 28.7 (Me), 26.1 (Me), 18.6 (C), -3.18 (Me).

28

It is established that Boc-groups can be deprotected in the presence of tert-butyl esters (for an example, see ref. 21) and of tert-butyldimethylsilyl ethers (cf. deprotection of compound 19).

29

Synthesis of ( S , S )- tert -Butyl 2-[(1- tert -butoxycarbonyl-amino-3- tert -butyldimethylsiloxy-3-methoxy-carbonyl)propyl]thiazole-4-carboxylate ( 4).
To a solution of (S,S)-2-tert-butoxycarbonylamino-4-tert-butyldimethylsiloxy-4-methoxycarbonyl-thiobutanamide (11, 1.20 g, 2.95 mmol) and tert-butyl bromopyruvate (2.30 g, 10.33 mmol) in 1,2-dimethoxyethane (42 mL) at -30 °C was added KHCO₃ (1.18 g, 11.80 mmol). The mixture was stirred at -10 °C for 6 h. The colorless solid was filtered off and washed with 1,2-dimethoxyethane. The filtrate was concentrated in vacuo. The mixture was diluted in 1,2-dimethoxyethane (42 mL) and cooled at -30 °C before addition of TFAA (1.24 mL, 8.85 mmol) and 2,6-lutidine (2.06 mL, 17.70 mmol). The mixture was stirred overnight at -20 °C. The mixture was partitioned between EtOAc and brine, the organic layer separated and concentrated in vacuo. The crude product was purified by flash chromatography (EtOAc-light PE, 1:5) to give the title compound (1.33 g, 85%) as a colorless sticky solid. ¹H NMR (300 MHz, CDCl₃): δ = 7.93 (1 H, s, H-4), 5.77 (1 H, d, J = 8.1 Hz, NHBoc), 5.15 (1 H, m, CHOSi), 4.42 (1 H, m, CHNH), 3.70 (3 H, s, OMe), 2.51-2.40 (2 H, m, CH₂), 1.57 (9 H, s, CMe₃), 1.42 (9 H, s, CMe₃), 0.91 (9 H, s, CMe₃), 0.05 (3 H, s, Me), 0.01 (3 H, s, Me). ¹³C NMR (75 MHz, CDCl₃): δ = 173.8 (2 × C), 160.8 (C), 155.6 (C), 149.0 (C), 126.9 (CH), 82.3 (C), 80.5 (C), 69.9 (CH), 52.5 (CH), 50.5 (Me), 39.1 (CH₂), 28.7 (Me), 28.6 (Me), 26.1 (Me), 18.5 (C), -4.6 (Me), -5.1 (Me). MS (FI): m/z = 531 (14) [MH⁺], 473 (100), 418 (8), 417 (32), 132 (38), 57 (84).

30

Synthesis of Methyl 2-[( S )-1-( tert -Butoxycarbonyl-amino)-( R )-2-(4-methoxybenzyloxy)propyl]thiazole-4-carboxylate ( 16).
To a solution of N-tert-butoxycarbonyl-O-(4-methoxy-benzyl)thiothreoninamide (15, 1.60 g, 4.51 mmol) in 1,2-dimethoxyethane (31 mL) was added at 0 °C methyl bromopyruvate (1.68 mL, 15.80 mmol) and KHCO₃ (1.80 g, 18.04 mmol). The mixture was stirred 1 h at 0 °C before addition of TFAA (1.89 mL, 13.53 mmol) and 2,6-lutidine (3.15 mL, 27.06 mmol) at the same temperature. The mixture was stirred 2 h at 0 °C. The mixture was diluted in EtOAc and washed with brine. The organic layer was dried over Na₂SO₄ and concentrated in vacuo. The crude product was purified by flash chromatography (light PE-EtOAc, 2:1 to 1:2) to give the title compound (1.46 g, 74%) as a yellow-brown oil. ¹H NMR (300 MHz, CDCl₃): δ = 8.09 (1 H, s, H-4), 6.95 (2 H, d, J = 8.6 Hz, ArH), 6.75 (2 H, d, J = 8.6 Hz, ArH), 5.70 (1 H, d, J = 8.7 Hz, NHBoc), 5.00 (1 H, d, J = 8.5 Hz, CHNH), 4.39 (1 H, d, J = 11.3 Hz, CHHPh), 4.31 (1 H, m, CHHMe), 4.14 (1 H, d, J = 11.1 Hz, CHPh), 3.93 (3 H, s, OMe), 3.76 (3 H, s, OMe), 1.46 (9 H, s, CMe₃), 1.27 (3 H, d, J = 6.2 Hz, Me). ¹³C NMR (75 MHz, CDCl₃): δ = 175.0 (C), 162.3 (C), 159.6 (C), 156.1 (C), 147.3 (C), 130.1 (C), 129.8 (CH), 127.8 (CH), 114.0 (CH), 80.8 (C), 76.0 (CH), 71.5 (CH₂), 58.1 (CH), 55.6 (Me), 52.8 (Me), 28.7 (Me), 16.9 (Me).

34

Synthesis of Methyl 2-{( S )-1-[2-(2-Bromothiazole-4-carbonylamino)-( R )-3-( tert -butyldimethyl-siloxy)butanoylamino]-( Z )-propenyl}thiazole-4-carboxylate ( 5).
To a stirred solution of methyl 2-{(S)-1-[(S)-2-tert-butoxy-carbonylamino-(R)-3-(tert-butyldimethylsiloxy)butanoyl-amino]-(Z)-propenyl}thiazole-4-carboxylate (19, 482 mg, 0.94 mmol) in CH₂Cl₂ (13 mL) was added TFA (1.74 mL, 23.46 mmol). The mixture was stirred 30 min at 20 °C. The solvent was removed in vacuo and the residue was azeotroped with toluene. To the crude thiazole amine trifluoroacetate and 2-bromo-4-thiazolecarboxylic acid (254 mg, 1.22 mmol) in CH₂Cl₂ (12 mL) at 0 °C was added PyBOP (587 mg, 1.13 mmol) and N,N-diisopropylethyl-amine (0.80 mL, 4.70 mmol). The mixture was stirred 15 min at 0 °C and then overnight at r.t. The solvent was removed in vacuo. The mixture was partitioned between EtOAc and sat. solution of NaHCO₃. The organic layer was washed with brine, dried over Na₂SO₄ and concentrated. The crude product was purified by flash chromatography (light PE-EtOAc, 1:1 to 1:2) to give the title compound (496 mg, 87%) as a colorless solid, mp 69-73 °C; [α]_D ²⁵ +24.0 (c 0.5, CHCl₃). HRMS: m/z calcd for C₂₂H₃₁BrN₄O₅S₂Si + H: 603.0767; found: 603.0768. IR (CH₂Cl₂): ν_max = 3387, 3294, 2954, 2930, 2856, 1727, 1670, 1536, 1473, 1432, 1244, 1215, 1094, 1014, 838, 779 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 8.41 (1 H, br s, NH), 8.22 (1 H, d, J = 6.4 Hz, NH), 8.07 (2 H, s, 2 × H-4), 6.66 (1 H, q, J = 7.1 Hz, =C=CH), 4.71 (1 H, dd, J = 6.4, 3.8 Hz, CHNH), 4.57 (1 H, m, CHOSi), 3.92 (3 H, s, OMe), 1.85 (3 H, d, J = 7.1 Hz, =CMe), 1.31 (3 H, d, J = 6.4 Hz, CHMe), 0.92 (9 H, s, CMe₃), 0.22 (3 H, s, Me), 0.18 (3 H, s, Me). ¹³C NMR (75 MHz, CDCl₃): δ = 168.3 (C), 167.8 (C), 162.0 (C), 160.5 (C), 149.6 (C), 147.2 (C), 136.6 (C), 128.1 (CH), 127.7 (CH), 127.4 (CH), 68.1 (CH), 58.8 (CH), 52.8 (Me), 26.2 (Me), 19.1 (Me), 18.3 (C), 14.7 (Me), -4.3 (Me), -4.6 (Me); one quaternary C unobserved. MS (CI): m/z = 605/603 (95) [MH⁺], 587 (15), 525 (13), 199 (33), 133 (21), 115 (14).