Synlett 2019; 30(03): 338-342
DOI: 10.1055/s-0037-1611976
letter
© Georg Thieme Verlag Stuttgart · New York

Synthesis of 8-HEPE and 10-HDoHE in both (R)- and (S)-Forms via Wittig Reactions with COOH-Ylides

Yuta Suganuma
,
Shun Saito
,
Yuichi Kobayashi*
This work was supported by JSPS KAKENHI Grant Number JP15H05904.
Further Information

Publication History

Received: 18 November 2018

Accepted after revision: 12 December 2018

Publication Date:
10 January 2019 (online)


Abstract

Wittig reactions using carboxy (CO2H) ylides derived from a carboxylic phosphonium salt and NaN(TMS)2 (NaHMDS) in a 1:1 ratio were applied to the synthesis of 8-HEPE and 10-HDoHE, which are metabolites of eicosapentaenoic acid and docosahexaenoic acid, respectively. The attempted Wittig reaction of 3-(TBS-oxy)pentadeca-4E,6Z,9Z,12Z-tetraenal with the carboxy ylide (2 equiv) derived from Br Ph3P+(CH2)4CO2H and NaHMDS (1:1) competed with the elimination of the TBS-oxy group at C3 to give a mixture of the Wittig product and the elimination product in 45–50% and 30–40% yields, respectively. The elimination was suppressed completely by using three equiv of the carboxy ylides in THF/HMPA (7–8:1), and the subsequent desilylation gave 8-HEPE in (R)- and (S)-forms. Similarly, both enantiomers of 10-HDoHE were synthesized.

Supporting Information

 
  • References and Notes

  • 3 Shing TK. M, Gibson KH, Wiley JR, Watt CI. F. Tetrahedron Lett. 1994; 35: 1067
  • 4 Butovich IA, Hamberg M, Rådmark O. Lipids 2005; 40: 249
  • 5 Signal-to-noise (S/N) ratios of 1H NMR and 13C NMR spectra are ca. 95% and ca. 97%, respectively.
  • 6 Matsumura K, Hashiguchi S, Ikariya T, Noyori R. J. Am. Chem. Soc. 1997; 119: 8738
  • 7 Ogawa N, Kobayashi Y. Tetrahedron Lett. 2009; 50: 6079
  • 8 de la Torre A, Lee YY, Mazzoni A, Guy A, Bultel-Poncé V, Durand T, Oger C, Lee JC.-Y, Galano J.-M. Chem. Eur. J. 2015; 21: 2442
  • 9 Since the observed specific rotation of (R)-1 ([α]D 21 +6 (c 1.58, CHCl3)) was inconsistent with the reported data for 86% ee11 ([α]D 24 +33.4 (c 2.1, CHCl3)), the reported 1H NMR analysis of the MTPA ester derived from the methyl ester of (R)-1 was applied to our sample to determine ca. 96.6% ee of (R)-1 (δ = 6.50–6.62 (m) and 6.60–6.69 (dd) ppm). Since accurate calculation was prevented by the slight overlap of the signals, the methyl ester was subjected to chiral HPLC analysis to establish 96.9% ee. In addition, the Δδ values between the (S)- and (R)-MTPA esters of the methyl ester indicated the (R)-chirality. The results are presented in the ESI.
  • 12 To an ice-cold suspension of 4a (374 mg, 0.844 mmol, 3 equiv) in THF (2.4 mL) and HMPA (0.5 mL) was added NaHMDS (1.0 M in THF, 0.843 mL, 0.843 mmol, 3 equiv). The resulting reddish-orange mixture was stirred at 0 °C for 1 h and cooled to –90 °C. A solution of aldehyde (R)-3 (98 mg, 0.281 mmol, 1 equiv) in THF (0.7 mL) and HMPA (0.1 mL) was added to the mixture dropwise. After 1 h, the mixture was warmed to 0 °C over 2 h before addition of saturated NH4Cl. The resulting mixture was extracted with EtOAc three times. The combined extracts were dried over MgSO4 and concentrated to afford a residue, which was purified by chromatography on silica gel to give olefin (R)-27 (102 mg, 84%) as the sole product: liquid; Rf = 0.21 (hexane/EtOAc, 4:1); [α]D 20 –21 (c 0.86, CHCl3). IR (neat): 1710, 1255, 836, 776 cm–1. 1H NMR (300 MHz, CDCl3): δ = 0.04 (s, 3 H), 0.05 (s, 3 H), 0.90 (s, 9 H), 0.97 (t, J = 7.5 Hz, 3 H), 1.69 (quint., J = 7.5 Hz, 2 H), 2.08 (quint., J = 7.5 Hz, 2 H), 2.09 (q, J = 7.5 Hz, 2 H), 2.25 (t, J = 6.0 Hz, 1 H), 2.22–2.31 (m, 2 H), 2.81 (t, J = 6.0 Hz, 2 H), 2.95 (t, J = 6.0 Hz, 2 H), 4.20 (q, J = 6.0 Hz, 1 H), 5.25–5.51 (m, 7 H), 5.66 (dd, J = 15.0, 6.0 Hz, 1 H), 5.98 (t, J = 11.1 Hz, 1 H), 6.48 (dd, J = 15.0, 11.1 Hz, 1 H), 10.2–11.2 (br s, 1 H) ppm. 13C-APT NMR (75 MHz, CDCl3): δ = –4.7 (+), –4.4 (+), 14.3 (+), 18.3 (–), 20.6 (–), 24.5 (–), 25.6 (–), 25.9 (+), 26.1 (–), 26.7 (–), 33.5 (–), 36.4 (–), 73.0 (+), 124.4 (+), 126.8 (+), 127.0 (+), 127.6 (+), 128.2 (+), 128.9 (+), 129.5 (+), 130.2 (+), 132.1 (+), 136.7 (+), 180.3 (+) ppm. HRMS (FAB+): m/z calcd for C26H43O3Si [(M – H)+]: 431.2981; found: 431.2990.