Serendipitous Synthesis and Configurational Assignment of (–)-Gabosine J

Abstract

2-epi-Gabosine I, unambiguously synthesized from benzyl d-mannopyranoside in nine steps with 34% overall yield, has been shown to be identical to gabosine J by NMR spectral analysis, thereby indicating that the relative stereochemistry of gabosine J was incorrectly determined formerly as a syn-triol. The relative and absolute configurations of (–)-gabosine J are now revised and confirmed as (2S,3S,4R)-trihydroxy-5-hydroxymethylcyclohex-5-en-1-one. Since the specific rotation of the natural product has not been recorded, the absolute configuration of natural gabosine J is either (–)-gabosine J or its enantiomer.

Key words

carbohydrates - Wittig reaction - stereoselective synthesis - natural products - enones

• References

• 1 Tatsuta K, Tsuchiya T, Mikami N, Umezawa S, Umezawa H, Naganawa H. J. Antibiot. 1974; 27: 579
• 2a Bach G, Breiding MS, Grabley S, Hammann P, Hütter K, Thiericke R, Uhr H, Wink J, Zeeck A. Liebigs Ann. Chem. 1993; 3: 241
• 2b Tang YQ, Maul C, Höfs R, Sattler I, Gabley S, Feng X.-Z, Zeeck A, Thiericke R. Eur. J. Org. Chem. 2000; 149
• 3a Takeuchi T, Chimura H, Hamada M, Umezawa H, Yoshka H, Oguchi N, Takahashi Y, Matsuda A. J. Antibiot. 1975; 28: 737
• 3b Chimura H, Nakamura H, Takita T, Takeuchi T, Umezawa M, Kato K, Saito S, Tomisawa T, Iitaka Y. J. Antibiot. 1975; 28: 743
• 4a Aghil O, Bibby MC, Carrington SJ, Double J, Douglas KT, Phillips RM, Shing TK. M. Anti-Cancer Drug Des. 1992; 7: 67
• 4b Oaksmith JM, Ganem B. Tetrahedron Lett. 2009; 50: 3497
• 5a Hamilton DS, Ding Z, Ganem B, Creighton DJ. Org. Lett. 2002; 4: 1209
• 5b Hamilton DS, Zhang X, Ding Z, Hubatsch I, Mannervik B, Houk KN, Ganem B, Creighton DJ. J. Am. Chem. Soc. 2003; 125: 15049
• 5c Joseph E, Eiseman JL, Hamilton DS, Wang H, Tak H, Ding Z, Ganem B, Creighton DJ. J. Med. Chem. 2003; 46: 194
• 6 Kamiya D, Uchihata Y, Ichikawa E, Kato K, Umezawa K. Bioorg. Med. Chem. Lett. 2005; 15: 1111
• 7 Wang C.-H, Wu HT, Cheng HM, Yen T.-J, Lu I.-H, Chang HC, Jao S.-C, Shing TK. M, Li W.-S. J. Med. Chem. 2011; 54: 8574
• 8a Shing TK. M, Tang Y. J. Chem. Soc., Chem. Commun. 1990; 312
• 8b Shing TK. M, Tang Y. Tetrahedron 1990; 46: 6575
• 9a Gabosines G and I: Shing TK. M, Cheng HM. J. Org. Chem. 2007; 72: 6610
• 9b Gabosines A, D, and E: Shing TK. M, Cheng HM. Org. Biomol. Chem. 2009; 7: 5098
• 9c Gabosine K: Shing TK. M, Cheng HM. Synlett 2010; 142
• 9d Gabosines I and K: Shing TK. M, Chen Y, Ng WL. Synlett 2011; 1318
• 9e Gabosines F and O: Shing TK. M, So KH, Kwok WS. Org. Lett. 2009; 11: 5070
• 10 Shing TK. M, Chen Y, Ng WL. Tetrahedron 2011; 67: 6001
• 11 Ley SV, Baeschlin DK, Dixon DJ, Foster AC, Ince SJ, Priepke HW. M, Reynolds DJ. Chem. Rev. 2001; 101: 53
• 12 Zunk M, Kiefel MJ. Tetrahedron Lett. 2011; 52: 1296
• 13 Pmoch C, Pakulski Z. Tetrahedron: Asymmetry 2008; 19: 1494
• 14 Mancuso AJ, Swern D. Synthesis 1981; 165
• 15 Blanchette MA, Choy W, Davis JT, Essenfeld AP, Masamune S, Roush WR, Sakai T. Tetrahedron Lett. 1984; 25: 2183
• 16 Synthesis of Enone 14 To a mixture of 3 Å MS (200 mg), CH₂Cl₂ (3 mL), and DMSO (0.36 ml, 5.00 mmol) was added dropwise TFAA (0.42 mL, 3.00 mmol) at –78 °C under N₂. After 30 min, a solution of the diols 12 (0.265 mg, 0.45 mmol) in CH₂Cl₂ (2 mL) was added dropwise. The reaction mixture was stirred for an additional 5 h at –78 °C, and DIEPA (1.75 mL, 10.00 mmol) was added dropwise. The reaction mixture was stirred at –78 °C for 15 min and then warmed to 25 °C over a period of 2 h. LiCl (38 mg, 0.90 mmol) and Et₃N (0.25 mL, 1.80 mmol) was added to the reaction mixture, and stirring was continued for an additional 1.5 h at the same temperature. The reaction mixture was then filtered, and the filtrate was concentrated under vacuum. Flash chroma-tography (hexane–EtOAc = 8:1) of the crude residue yielded enone 14 (0.144 mg, 70%) as a yellow oil. [α]_D ²⁰ 137.4 (c 1.23, CHCl₃). R_f = 0.6 (n-hexane–EtOAc, 3:1). IR (thin film): 2953, 2886, 2857, 1685, 1630, 1472, 1378, 1257, 1164, 1114, 1034 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 0.05 (3 H, s), 0.06 (3 H, s), 0.88 (9 H, s), 1.17 (3 H, t, J = 7.2 Hz), 1.31 (3 H, s), 1.30 (3 H, s), 3.23 (3 H, s), 3.27 (3 H, s), 3.52–3.63 (2 H, m), 3.94 (1 H, dd, J = 2.7, 13.2 Hz), 4.12 (1 H, dd, J = 1.5, 3.0 Hz), 4.33 (1 H, dt, J = 1.8, 18.3 Hz), 4.58 (1 H, d, J = 18.3 Hz), 4.80 (2 H, s), 4.93 (1 H, dt, J = 1.2, 8.7 Hz), 6.12 (1 H, dd, J = 1.2, 2.1 Hz). ¹³C NMR (75.47 MHz, CDCl₃): δ = –4.9, –4.8, 15.5, 18.2, 18.3, 18.8, 26.4, 26.5, 48.7, 48.7, 61.4, 64.1, 66.0, 71.6, 77.3, 95.1, 100.5, 100.9, 122.2, 162.6, 194.7. ESI-MS: m/z (%) = 483 (100) [M + Na]⁺. ESI-HRMS: m/z calcd for C₂₂H₄₀O₈Si [M + Na]⁺: 483.2385; found: 483.2392
• 17 Synthesis of (–)-Gabosine J (4) To enone 14 (35 mg, 0.08 mmol) was added TFA (2 mL) and H₂O (0.1 mL) at r.t. The resulting solution was stirred for 5 min at r.t. Concentration of the solution followed by flash chromatography (CHCl₃–MeOH = 8:1) yielded (–)-gabosine J (4; 12 mg, 96%) as colorless oil. [α]_D ²⁰ –75.0 (c 0.70, MeOH). R_f = 0.3 (CHCl₃–MeOH = 4:1). IR (thin film): 3311, 2912, 1682, 1438, 1384, 1119, 1087, 1040 cm^–1. ¹H NMR (300 MHz, MeOD): δ = 4.16–4.25 (3 H, m), 4.41 (1 H, dd, J = 17.8, 1.7 Hz), 4.55 (1 H, d, J = 2.5 Hz), 6.10 (1 H, t, J = 1.7 Hz). ¹³C NMR (75.47 MHz, MeOD): δ = 63.2, 69.9, 73.8, 76.5, 122.1, 162.2, 199.9. ESI-MS: m/z (%) = 197 (100) [M + Na]⁺. ESI-HRMS: m/z calcd for C₇H₁₀O₅ [M + Na]⁺: 197.0420; found: 197.0423