A Total Synthesis of (+)-Bacillamide B

Abstract

A total synthesis of the halophile-derived natural product (+)-bacillamide B is described. The route relies upon a Hantzsch synthesis of ethyl (S)-2-acetoxyethylthiazole-4-carboxylate followed by a dipyridyl disulfide-mediated coupling between the corresponding carboxylic acid and tryptamine. This synthesis has unambiguously demonstrated that in contrast to the previous tentative stereochemical assignments the stereochemistry of the alcohol at C15 of the title compound has S-configuration.

Key words

extremophile - total synthesis - natural product - heterocycle - thiazole

References and Notes

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• 6a Jeong SY. Ishida K. Ito Y. Okada S. Murakami M. Tetrahedron Lett.  2003,  44:  8005 
• 6b For a synthesis of bacillamide A(1), see: Figueira VBC. Prabhahar S. Lobo AM. Arkivoc  2005,  (xiv):  14 
• 7 Konda Y. Suzuki Y. Omura S. Masayuki O. Chem. Pharm. Bull.  1976,  24:  92 
• 8 Smith HE. Records R. Tetrahedron  1966,  22:  813 
• 10 Pettit GR. Melson PS. Holzapfel CW. J. Org. Chem.  1985,  50:  2654 
• 11 Schmidt U. Gleich P. Griesser H. Utz R. Synthesis  1986,  992 
• 13a Mukaiyama T. Matsueda R. Maruyama H. Bull. Chem. Soc. Jpn.  1970,  43:  1271 
• 13b Schmidt and co-workers have demonstrated the use of this reagent for coupling of thiazole carboxylic acids bearing unprotected secondary alcohols without loss of stereointegrity, see: Schmidt U. Gleich P. Angew. Chem. Int. Ed. Engl.  1985,  24:  569 
• 15 Yu LL. Li ZY. Peng CS. Li ZY. Guo YW. Helv. Chim. Acta  2009,  92:  607 

9

The ambiguity regarding the stereochemistry, coupled with the lack of commercially available R-enantiomer, led us to commence the synthesis from the S-antipode.

12

(S)-2-Hydroxyethylthiazole-4-carboxylic acid (9): Ethyl (S)-2-acetoxyethylthiazole-4-carboxylate^¹¹ (8; 121 mg, 0.50 mmol) was stirred in a solution of 2 M LiOH (1 mL), MeOH (1 mL) and THF (1 mL) at 20 ˚C for 18 h. After this time the mixture was diluted with water (5 mL) and shaken with acidified IR-120 ion-exchange resin (3 mL) for 2 min. The ion-exchange resin was filtered and the filtrate was evaporated to give ethyl (S)-2-hydroxyethylthiazole-4-carboxylic acid (9; 69 mg, 88%) as a yellow oil. IR (film): 3301, 1703, 1495, 1195 cm^-¹; ^¹H NMR (270 MHz, acetone-d ₆): δ = 1.55 (d, J = 6.7 Hz, 3 H, CH₃), 5.09 (q, J = 6.7 Hz, 3 H, CHOH), 8.30 (s, 1 H, SCH); ^¹³C NMR (67.5 MHz, acetone-d ₆): δ = 24.8 (CH₃), 68.9 (CHOH), 128.9 (C5), 148.3 (C4), 162.8 (CO₂H), 179.8 (C2).

14

(+)-Bacillamide B (2): A solution of tryptamine (6.4 mg, 0.04 mmol) and Ph₃P (10.5 mg, 0.04 mmol) in CH₂Cl₂ (2 mL) was added dropwise over 5 min to a solution of (S)-2-hydroxyethylthiazole-4-carboxylic acid (9; 6.9 mg, 0.04 mmol) and dipyridyl disulfide (8.8 mg, 0.04 mmol) in CH₂Cl₂ (2 mL) at 20 ˚C. After 24 h, the supernatant solvent was removed and evaporated in vacuo. The residue was purified by flash column chromatography (SiO₂; 2% MeOH-CHCl₃) to give bacillamide B (2; 6.8 mg, 54%) as a light-yellow amorphous solid. [α]_D ^²0 +10.1 (c 0.10, MeOH) [Lit.⁵ +7.4 (c 0.095, MeOH)]; IR (film): 3411bw, 3293bw, 2923w, 1642s, 1546s, 1492m, 1456m, 1250w, 1187w, 1103m, 1009w cm^-¹; ^¹H NMR (400 MHz, DMSO-d ₆): δ = 10.81 (s, 1 H), 8.35 (t, J = 6.0 Hz, 1 H), 8.13 (s, 1 H), 7.60 (d, J = 7.8 Hz, 1 H), 7.33 (d, J = 8.0 Hz, 1 H), 7.18 (d, J = 1.7 Hz, 1 H), 7.06 (t, J = 7.5 Hz, 1 H), 6.97 (t, J = 7.4 Hz, 1 H), 6.24 (d, J = 5.0 Hz, 1 H), 4.94 (dq, J = 6.5, 5.2 Hz, 1 H), 3.54 (dd, J = 7.0, 6.5 Hz, 2 H), 2.93 (t, J = 7.5 Hz, 2 H), 1.47 (d, J = 6.5 Hz, 3 H); ^¹³C NMR (100 MHz, DMSO-d ₆): δ = 178.6, 160.5, 149.9, 136.2, 127.2, 123.0, 122.5, 120.9, 118.40, 118.20, 111.7, 111.3, 66.6, 25.3, 24.1; MS: m/z [M + H]⁺ calcd for C₁₆H₁₈N₃O₂S: 316.1120; found: 316.1128.