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.

thiazole - amino acids - heterocycles - antibiotics

References and Notes

1 Rhone-Poulenc SA. inventors; FR  1392453. 

2 Benazet F. Cartier M. Florent J. Godard C. Jung G. Lunel J. Mancy D. Pascal C. Renaut J. Tarridec P. Theilleux J. Tissier R. Dubost M. Ninet L. Experientia  1980,  36 

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7 Mocek U. Knaggs AR. Tsuchiya R. Nguyen T. Beale JM. Floss HG. J. Am. Chem. Soc.  1993,  115:  7557 ; and references therein

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12 Bentley DJ. Fairhurst J. Gallagher PT. Manteuffel AK. Moody CJ. Pinder JL. Org. Biomol. Chem.  2004,  2:  701 

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17 Umemura K. Noda H. Yoshimura J. Konn A. Yonezawa Y. Shin CG. Bull. Chem. Soc. Jpn.  1998,  71:  1391 

18 Moody CJ. Bagley MC. Chem. Commun.  1998,  2049 

19 Bagley MC. Bashford KE. Hesketh CL. Moody CJ. J. Am. Chem. Soc.  2000,  122:  3301 

20 Hughes RA. Thompson SP. Alcaraz L. Moody CJ. Chem. Commun.  2004,  946 

21 Hughes RA. Thompson SP. Alcaraz L. Moody CJ. J. Am. Chem. Soc.  2005,  127:  15644 

22 Adamczyk M. Johnson DD. Reddy RE. Tetrahedron: Asymmetry  1999,  10:  775 

23 Hanessian S. Vanasse B. Can. J. Chem.  1993,  71:  1401 

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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).

26 Singh Y. Stoermer MJ. Lucke AJ. Guthrie T. Fairlie DP. J. Am. Chem. Soc.  2005,  127:  6563 

27 Bredenkamp MW. Holzapfel CW. van Zyl WJ. Synth. Commun.  1990,  20:  2235 

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).

31 Muir JC. Pattenden G. Thomas RM. Synthesis  1998,  613 

32 Bower J. Drysdale M. Hebdon R. Jordan A. Lentzen G. Matassova N. Murchie A. Powles J. Roughley S. Bioorg. Med. Chem. Lett.  2003,  13:  2455 

33 Silberg A. Ursu A. Rev. Roum. Chim.  1965,  10:  897 

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).