An Easy Route to Enantiomerically Enriched 7- and 8-Hydroxy­stearic Acids by Olefin-Metathesis-Based Approach

Abstract

The synthesis of enantiomerically enriched 7- and 8-hydroxy­stearic acids (7- and 8-HSA) has been successfully accomplished starting from chiral nonracemic 1-pentadecen-4-ol and 1-tetradecen-4-ol, respectively. Their Yamaguchi’s esterification with 4-pentenoic and 5-hexenoic acids, respectively, afforded the suitable dienic esters which were submitted to ring-closing metathesis reaction. After hydrogenation and basic hydrolysis of the complex reaction mixture, chiral nonracemic 7- and 8-HSA were obtained in about 40% total yield.

Key words

hydroxystearic acid - ring closing metathesis - cross metathesis - homoallylic alcohols - lipase B from Candida antarctica - kinetic enzymatic resolution

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• 33 For derivatization with (R)-(–)-O-acetylmandelic acid and related ¹H NMR signals, see ref. 13. The diastereomeric ratio was calculated on the crude for (R)-7- and (R)-8-HSA derivatives and on the product purified by preparative TLC for (S)-7- and (S)-8-HSA derivatives.
• 34 General Procedure for Derivatization with Mosher Acid (R)-(+)-α-Methoxy-α-trifluoromethylphenylacetic acid [(+)-MTPA, for derivatization of 7-HSA methyl esters] (0.012 g), or (S)-(–)-α-methoxy-α-trifluorophenylacetic acid [(–)-MTPA, for 8-HSA methyl esters], and DMAP (0.003 g) were dissolved, under nitrogen atmosphere, in anhydrous CH₂Cl₂ (300 μL) and stirred at 0 °C (ice-bath). To this solution of methyl hydroxystearate (0.008 g) and DCC (0.010 g) dissolved in anhydrous CH₂Cl₂ (500 μL) was added dropwise. After a few minutes, a white solid precipitated. The reaction was monitored by TLC (eluent: n-hexane–EtOAc, 3:1) until completion (sometimes addition of a further amount of DCC and DMAP was necessary to reach completion). The solvent was removed, and the crude was dissolved in CDCl₃ and analyzed by ¹H NMR and ¹⁹F NMR. The diastereomeric ratio was calculated by integration of the ¹⁹F NMR ­signals; hexafluorobenzene (δ = –163.0 ppm) was used as internal standard. (R)-Methyl 7-{[(R)-3,3,3-Trifluoro-2-methoxy-2-phenylpropanoyl]oxy}octadecanoate [(7R,2′R)-14a] ¹H NMR (400 MHz, CDCl₃): δ = 7.58–7.50 (m, 2 H, Ph), 7.42–7.37 (m, 3 H, Ph), 5.07 (quint, 1 H, J = 6.4 Hz, CHOH), 3.66 (s, 3 H, COOCH₃), 3.55 (br s, 3 H, OCH₃), 2.28 (t, 2 H, J = 7.3 Hz, CH₂CO), 1.80–1.40 (m, 6 H, CH₂), 1.40–1.10 (m, 22 H, CH₂), 0.88 (t, 3 H, J = 6.2 Hz, CH₃) ppm. ¹⁹F NMR (376 MHz, CDCl₃): δ = –72.360 ppm. (S)-Methyl 7-{[(R)-3,3,3-Trifluoro-2-methoxy-2-phenylpropanoyl]oxy}octadecanoate [(7S,2′R)-14a] ¹H NMR signals undiscernible from those of the 7R,2′R diastereomer. ¹⁹F NMR (376 MHz, CDCl₃): δ = –72.323 ppm. (R)-Methyl 8-{[(S)-3,3,3-Trifluoro-2-methoxy-2-phenylpropanoyl]oxy}octadecanoate [(8R,2′S)-14b] ¹H NMR (400 MHz, CDCl₃): δ = 7.59–7.50 (m, 2 H, Ph), 7.45–7.36 (m, 3 H, Ph), 5.07 (quint, 1 H, J = 6.5 Hz, CHOH), 3.67 (s, 3 H, COOCH₃), 3.55 (br s, 3 H, OCH₃), 2.27 (t, 2 H, J = 7.5 Hz, CH₂CO), 1.82–1.40 (m, 6 H, CH₂), 1.40–1.10 (m, 22 H, CH₂), 0.87 (t, 3 H, J = 7.0 Hz, CH₃) ppm. ¹⁹F NMR (376 MHz, CDCl₃): δ = –72.369 ppm. (S)-Methyl 8-{[(S)-3,3,3-Trifluoro-2-methoxy-2-phenylpropanoyl]oxy}octadecanoate [(8S,2′S)-14b] ¹H NMR signals are undiscernible from those of the 8R,2′S dia­stereomer. ¹⁹F NMR (376 MHz, CDCl₃): δ = –72.405 ppm.