Synthesis of the Anti-Melanogenic Glycerol Fatty Acid Ester Isolated from the Tuber-Barks of Colocasia antiquorum var. esculenta

Abstract

(2′S)-1-O-9-Oxo-(10E,12E)-octadecadienoyl glycerol, a natural anti-melanogenic monoglyceride, is synthesized for the first time. The chiral pool based route employed not only confirms the absolute configuration, but also illustrates the first synthetic entry to the (E,E)-diene keto acid, which is another molecule of biological importance. The confusion caused by the misinterpreted ¹H NMR spectroscopic data for the (E,E)-diene motif in the literature is discussed. The first unequivocal piece of evidence for the assigned (12E) configuration is also presented.

Key words

diols - acylation - glycerolipids - rearrangement - natural products

• References and Notes

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• 15 Here we deliberately stopped the hydrolysis early to ensure that no over-reaction/acyl migrations would occur.
• 16 A solution of acetonide 13 (91 mg, 0.22 mmol) in AcOH–H₂O (4:1 v/v, 2.3 mL) was stirred at 50 °C (oil bath) for 30 min. The heating bath was removed, and sat. aq NaHCO₃ solution (2 mL) was added followed by EtOAc (3 mL). The phases were separated and the aqueous layer was back-extracted with EtOAc (2 × 3 mL). The combined organic layers were washed with brine (3 mL) before being dried over anhydrous Na₂SO₄. Removal of the solvent on a rotary evaporator and column chromatography (PE–EtOAc, 2:1) on silica gel afforded diol 4 (53.9 mg, 66%) as a white solid along with unhydrolyzed starting 13 (31 mg, 0.075 mmol, 34%). Data for 4: Mp 52–54 °C; [α]_D ²⁶ +5.9 (c 0.12, MeOH), [α]_D ²⁶ +6.1 (c 1.00, MeOH), [α]_D ²⁷ +11.7 (c 0.12, DMSO), [α]_D ²⁷ +7.0 (c 0.54, DMSO), [α]_D ²⁷ +7.8 (c 1.00, DMSO) {Lit.³ [α]_D ²⁵ +4.28 (c 0.12, MeOH)}. IR (film of a concd soln in CH₂Cl₂): 3359 (br), 2928, 2852, 1732, 1682, 1634, 1596, 1471, 1406, 1376, 1332, 1310, 1236, 1223, 1182, 1118, 1045, 997 cm^–1. ¹H NMR (500 MHz, CD₃OD): δ = 7.23 (dd, J = 15.6, 9.8 Hz, 1 H), 6.33–6.21 (m, 2 H), 6.12 (d, J = 15.6 Hz, 1 H), 4.15 (dd, J = 11.4, 4.4 Hz, 1 H), 4.06 (dd, J = 11.4, 6.3 Hz, 1 H), 3.85–3.78 (m, 1 H), 3.56 (dd, J = 11.3, 5.4 Hz, 1 H), 3.53 (dd, J = 11.3, 5.7 Hz, 1 H), 2.60 (t, J = 7.4 Hz, 2 H), 2.35 (t, J = 7.4 Hz, 2 H), 2.20 (br q, J = 6.8 Hz, 2 H), 1.62 (quin, J = 6.9 Hz, 2 H), 1.58 (quin, J = 7.2 Hz, 2 H), 1.47 (quin, J = 7.4 Hz, 2 H), 1.39–1.30 (m, 10 H), 0.91 (t, J = 7.0 Hz, 3 H). ¹³C NMR (125 MHz, CD₃OD, with the solvent multiplet set at δ 48.0 as the internal reference): δ = 202.8, 174.4, 146.3, 144.3, 129.2, 127.8, 70.1, 65.5, 63.1, 40.0, 33.9, 33.1, 31.5, 29.15, 29.14, 29.0, 28.5, 24.9, 24.5, 22.5, 13.4. ESI-MS: m/z = 369.5 [M + H]⁺, 391.5 [M + Na]⁺. ESI-HRMS: m/z [M + Na]⁺ calcd for C₂₁H₃₆O₅Na: 391.2455; found: 391.2456.
• 17 The optical rotation for synthetic 4 was measured to be [α]_D ²⁵ +5.9 (c 0.12, MeOH) and [α]_D ²⁵ +6.1 (c 1.00, MeOH); cf. the data reported (see ref. 3) for natural 4: [α]_D ²⁵ +4.28 (c 0.12, MeOH).
• 18 It is worth mentioning that the ¹H and ¹³C NMR spectra of 4 recorded in CDCl₃ (see the Supporting Information) were very similar to those for its functionality regioisomer, (2′S)-1-O-13-oxo-(9E,11E)-octadecadienoyl glycerol,^6a another natural monoglyceride. However, small yet definite differences also exist, representing an interesting piece of evidence for differentiating these two closely related biologically important substances.
• 19 Ma D, Yu Y, Lu X. J. Org. Chem. 1989; 54: 1105
• 20 It appears that all previous investigators working with 6 and related compounds were not aware of the advantage of using benzene-d ₆. Otherwise, the lack of evidence for the (12E) configuration for 6 would not have gone unnoticed until now.
• 21 Since the (12E) configuration for compounds 5 and 4 in this work have now been secured by analysis of the ¹H NMR spectra in benzene-d ₆, the expansion of the ¹H NMR spectrum for the H-12 and H-13 region of acid 5 (and/or 4), recorded in CD₃OD or CDCl₃ (both are much more commonly employed in synthesis than benzene-d ₆), provided in this work may thus be used as a quick reference for confirming the (12E) configuration for closely related compounds. One of the referees pointed out that the use of decoupling techniques could also provide pertinent information about the double-bond configuration.