Synthesis of Analogues of Gingerol and Shogaol, the Active Pungent Principles from the Rhizomes of Zingiber officinale and Evaluation of Their Anti-Platelet Aggregation Effects

Shih, Hung-Cheng; Chern, Ching-Yuh; Kuo, Ping-Chung; Wu, You-Cheng; Chan, Yu-Yi; Liao, Yu-Ren; Teng, Che-Ming; Wu, Tian-Shung

doi:10.3390/ijms15033926

Open AccessArticle

Synthesis of Analogues of Gingerol and Shogaol, the Active Pungent Principles from the Rhizomes of Zingiber officinale and Evaluation of Their Anti-Platelet Aggregation Effects

¹

Department of Chemistry, National Cheng Kung University, Tainan 701, Taiwan

²

Department of Applied Chemistry, National Chiayi University, Chiayi 600, Taiwan

³

Department of Biotechnology, National Formosa University, Yunlin 632, Taiwan

⁴

Department of Biotechnology, Southern Taiwan University, Tainan 710, Taiwan

⁵

College of Medicine, Pharmacological Institute, National Taiwan University, Taipei 100, Taiwan

^*

Author to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

Int. J. Mol. Sci. 2014, 15(3), 3926-3951; https://doi.org/10.3390/ijms15033926

Submission received: 2 January 2014 / Revised: 17 February 2014 / Accepted: 21 February 2014 / Published: 4 March 2014

(This article belongs to the Section Biochemistry)

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Abstract

:

The present study was aimed at discovering novel biologically active compounds based on the skeletons of gingerol and shogaol, the pungent principles from the rhizomes of Zingiber officinale. Therefore, eight groups of analogues were synthesized and examined for their inhibitory activities of platelet aggregation induced by arachidonic acid, collagen, platelet activating factor, and thrombin. Among the tested compounds, [6]-paradol (5b) exhibited the most significant anti-platelet aggregation activity. It was the most potent candidate, which could be used in further investigation to explore new drug leads.

Keywords:

Zingiber officinale; ginger; gingerol; shogaol; anti-platelet aggregation

1. Introduction

Ginger (Chinese name: Shengjiang), derived from the rhizomes of Zingiber officinale Roscoe, is a well-known spice and is most frequently prescribed as a traditional Chinese medicine for its stomachic, antiemetic, antidiarrheal, expectorant, antiasthmatic, hemostatic and cardiologic properties for the treatment of several gastrointestinal and respiratory diseases [1–3]. The most famous traditional medicinal application of Z. officinale is to promote blood circulation for the removal of blood stasis, a mechanism that is related to anti-platelet aggregation activity [4,5]. Numerous chemical investigations of the pungent and bioactive principles of ginger have been carried out [6–19]. The pungent principles reported from the rhizomes of Zingiber officinale include: zingerone, gingerols, gingerdiols, gingerdiones, and shogaols (Figure 1).

In the course of our continuing research program aimed at discovering novel bioactive constituents from natural sources, thrombolytic and vasoactive activity examinations were carried out, and the ether extracts of the rhizomes of Z. officinale were found to exhibit significant anti-platelet aggregation activity and vasorelaxing effects. In our previous article [20], twenty-nine compounds were identified, and [6]-gingerol and [6]-shogaol exhibited potent anti-platelet aggregation bioactivity. These results initiated our interest in searching for more potent antiplatelet aggregation agents from the analogues of gingerol and shogaol. Therefore, in the present study eight groups of compounds (Figure 2) were prepared and subjected to examinations of their anti-platelet aggregation activity.

2. Results and Discussion

2.1. Chemistry

At first, the dehydrozingerone 9 was prepared by vanillin condensation with a good yield (89%), Equation (1). Then the cross aldol condensations of α,β-unsaturated ketone 9 with different aldehydes were investigated using various bases as catalysts. The major products were the dehydrogingerols 3a–f, and the minor products dehydroshogaols 2a–f were obtained in the optimum yield (6%–15%) when lithium bis(trimethylsilyl)amide (LiHMDS) was employed. Therefore, deprotonation of 9 with LiHMDS in tetrahydrofuran at 0 °C and subsequent trapping with aldehydes Equation (2) afforded products 2a–f and 3a–f with moderate yields in a range between 50% and 66% (Table 1).

(1)

(2)

However, similar reaction conditions under air atmosphere furnished low yields of [n]-epoxy-dehydroparadols 7a–f (Equation (3), Table 2), and comparatively, relatively higher yields of dehydroshogaols 2a–f (15%–21%).

(3)

Chlorination and dehydrohalogenation of alcohols 3a–f with HCl and K₂CO₃, respectively, produced quantitative yields of adducts 2a–f Equation (4) and reduced the occurrence of trace amounts of 10. The catalytic hydrogenation of [n]-dehydroshogaols 2a–f over palladium on charcoal afforded [n]-paradols 5 and trace amounts of secondary alcohol 11. It was surprising that [n]-dehydroparadols 6 could be obtained with the same method only reduced the amount of palladium on charcoal from 0.05 to 0.015 eq. The results are shown in Equation (5) and Table 3.

(4)

(5)

(6)

The same hydrogenation procedure was applied in [n]-dehydrogingerols 3, and a high yield of [n]-gingerols 8 was obtained (83%–86%). Dehydration of 8 with HCl/K₂CO₃ gave approximately 85% of [n]-shogaols 4 (Equation (6), Table 4). Although there were many reagents available for the oxidation of secondary alcohols to ketone, unfortunately, most of these oxidizing agents did not show sufficient activity except in the case of Swern oxidation, which yielded a moderate amount of oxidized compound 1 (Equation (7), Table 5).

(7)

2.2. Anti-Platelet Aggregation Evaluation Bioassay

Platelets circulate in the blood of mammals and are involved in hemostasis, leading to the formation of blood clots. Too many platelets form blood clots that may obstruct blood vessels and induce strokes, myocardial infarctions, and pulmonary embolisms. Sometimes this situation also results in the blockage of blood vessels to other parts of the body, including the extremities of the arms or legs [21]. The traditional medicinal use of ginger is to promote the blood circulation necessary for removing blood stasis. Therefore, synthetic derivatives were examined in the anti-platelet aggregation bioassay to test for the presence of activity. The anti-platelet aggregation results are summarized in Tables 6 –13. All the tested compounds displayed significant inhibitory effects on the aggregation of washed rabbit platelets stimulated by arachidonic acid (AA). At a 10 μg/mL concentration, most of the tested compounds with the exception of 3a, 3d, and 7e caused the inhibition percentages of aggregation induced by AA (100 μM) to be higher than 90%. On the other hand, the activities of these synthetic derivatives against platelet activating factor (PAF) and thrombin (Thr) induced aggregation were insignificant.

Among these derivatives, the [n]-paradols (5a–f) series were the most active compounds, and [6]-paradol 5b displayed the most significant inhibition, with an IC₅₀ value of 70 ng/mL (Table 6). [n]-Dehydroparadols (6a–f) were generally less potent than the corresponding [n]-paradols (5a–f) derivatives (Table 7). The most potent compound was [10]-dehydroparadol 6f (n = 8), with an IC₅₀ value of 160 ng/mL, which was a 2.3-fold decrease in activity due to the introduction of an unsaturated C=C bond. The [n]-shogaols (4a–f) series (Table 8) also displayed weaker inhibition of aggregation induced by AA (100 μM) compared to their related [n]-paradol derivatives 5a–f; however, they were more active than the [n]-dehydroparadols (6a–f) series. It was evident that introduction of unsaturated C=C bonds would decrease the inhibitory activity. But the location of unsaturated C=C bonds also influences the inhibitory activity. The [n]-dehydroshogaols (2a–f) (Table 9) which possess one more α,β-unsaturation C=C bond exhibited further decreased inhibitory activity. However, their inhibition aggregation potency induced by collagen (Col) was generally more significant than their [n]-paradol counterparts 5a–f. Among the [n]-shogaols (4a–f) and [n]-dehydroshogaols (2a–f), [10]-shogaols (4f) (n = 8) exhibited the most significant inhibition of aggregation induced by Col (10 μM), with an IC₅₀ value lower than 5 μg/mL. The possible mechanism was one in which the rigid styryl carbonyl ethylene prevented the alkyl tail from turning sideways, where a putative hydrophobic pocket may have been located. Therefore, a free alkyl chain could overcome such an effect.

The addition of a β-hydroxyl group to the α,β-unsaturated ketone to afford [n]-gingerols 8a–f, resulted in a reduction of anti-platelet aggregation activity (Table 10). The introduction of an unsaturated C=C bond to the gingerol skeleton as described above (3a–f) also reduced the inhibition percentages (Table 11). Similarly, a longer side chain produced a more potent derivative. Therefore, both [10]-gingerol 8f and [10]-dehydrogingerol 3f displayed more significant inhibition of aggregation induced by AA (100 μM) as compared to the analogues with shorter side chains.

The [n]-isodehydrogingerdiones 1a–e also showed significant inhibition of platelet aggregation induced by AA (Table 12). [7]-Isodehydrogingerdione 1c was found to be the most effective compound among this series, with an IC₅₀ value of 0.68 μg/mL. Moreover, an epoxide ring next to the α,β-unsaturated ketone produced derivatives 7a–f of lower potency compared with [n]-paradols 5a–f. They were only as potent as the dehydroshogaol series, with IC₅₀ values between 0.96 and 2.38 μg/mL. Apparently, [10]-epoxydehydroparadol 7f exhibited the most significant inhibitory effect among this series with an IC₅₀ value of 0.96 μg/mL (Table 13).

3. Experimental Section

3.1. General

All the chemicals were purchased from Merck KGaA (Darmstadt, Germany), unless specifically indicated. Column chromatography was performed on silica gel (70–230 mesh, 230–400 mesh), and TLC monitoring was executed on Merck precoated Si gel 60 F₂₅₄ plates, using UV light to visualize the spots. The melting points of the purified compounds were determined using a Yanagimoto micromelting point measuring apparatus (Tokyo, Japan) without corrections. The UV spectra were obtained on a Hitachi UV-3210 spectrophotometer (Tokyo, Japan). The IR spectra were obtained as KBr discs on a Jasco Report-100 FT-IR spectrometer (Tokyo, Japan). ¹H and ¹³C NMR spectra were recorded on a Bruker AC-200 NMR spectrometer (Bruker, Billerica, MA, USA). Chemical shifts are shown in δ values (ppm) with tetramethylsilane as an internal standard. The EI mass and high-resolution mass spectra were measured on a VG Analytical Model 70-250S spectrometer (Micromass, Manchester, UK). Elemental analyses were performed on a Perkin-Elmer 240 analyzer (Waltham, MA, USA).

3.2. Synthesis of Derivatives and Spectral Data

3.2.1. Preparation of Dehydrozingerone (9)

10% Sodium hydroxide (7.0 g, 175 mmol) was added dropwise to a solution of vanillin (2.5 g, 16.4 mmol) in acetone (100 mL) at room temperature. The reaction mixture was stirred for 12 h, concentrated under reduced pressure, then neutralized by cold 5% HCl_(aq). The solution was extracted with EtOAc (4 × 50 mL). The organic layers were combined, washed with saturated NaCl_(aq) (brine), dried over MgSO₄, and concentrated under reduced pressure. The product was isolated on silica gel column chromatography (EtOAc/hexanes = 1/4) to afford yellow needles (2.8 g, 89% yield).

Dehydrozingerone (9): mp 126–127 °C (lit. 128–129 °C) [1]; UV (MeOH) λ_max 337, 299 (sh), 249 nm; IR (KBr) ν_max 3312, 2949, 2848, 1670, 1639, 1581, 1515, 1427, 1298, 1218, 1024, 829 cm^{−1; 1}H-NMR (CDCl₃) δ 7.44 (1H, d, J = 16.0 Hz, H-1), 7.09 (1H, dd, J = 8.2, 1.8 Hz, H-6′), 7.05 (1H, d, J = 1.8 Hz, H-2′), 6.92 (1H, d, J = 8.0 Hz, H-5′), 6.58 (1H, d, J = 16.0 Hz, H-2), 6.02 (1H, br s, -OH), 3.93 (3H, s, -OCH₃), 2.36 (3H, s, H-4); ¹³C-NMR (CDCl₃) δ 198.4, 148.2, 146.7, 143.7, 126.8, 124.9, 123.4, 114.7, 109.2, 55.9, 27.2; EIMS m/z (rel. int.) 192 (M⁺, 93), 190 (20), 177 (100), 145 (47), 134 (21), 117 (27), 89 (31), 78 (23), 77 (24), 51 (24).

3.2.2. General Procedure for the Synthesis of [n]-Dehydroshogaols (2a–f) and [n]-Dehydrogingerols (3a–f)

A 1.0 M THF solution of lithium bis(trimethylsilyl)amide (20.8 mL) was added dropwise to a solution of dehydrozingerone (9) (2.0 g, 10.4 mmol) in dry THF (10 mL) at 0 °C under argon. After the mixture had been stirred for 1 h, the appropriate aldehyde (10.5 mmol) was added and stirred for another 15 min. The reaction was then quenched with 5% HCl_(aq) at 0 °C and extracted with EtOAc (4 × 20 mL). The organic layers were combined, washed with brine, dried over MgSO₄, and concentrated under reduced pressure. Products 2 and 3 were isolated using silica gel column chromatography (EtOAc/CH₂Cl₂ = 1/16).

[5]-Dehydroshogaol (2a): yellow syrup (9%); UV (MeOH) λ_max (log ɛ) 356 (4.14), 255 (4.03) nm; IR (neat) ν_max 3325, 2958, 2860, 1652, 1625, 1579, 1514, 1460, 1276, 1126, 1031 cm^{−1; 1}H-NMR (CDCl₃) δ 7.57 (1H, d, J = 15.8 Hz, H-1), 7.13 (1H, dd, J = 8.2, 2.0 Hz, H-6′), 7.06 (1H, d, J = 2.0 Hz, H-2′), 6.99 (1H, dt, J = 15.6, 6.8 Hz, H-5), 6.92 (1H, d, J = 8.2 Hz, H-5′), 6.80 (1H, d, J = 15.8 Hz, H-2), 6.44 (1H, dt, J = 15.6, 1.4 Hz, H-4), 6.04 (1H, br s, -OH), 3.93 (3H, s, -OCH₃), 2.28 (2H, tdd, J = 6.8, 6.8, 1.4 Hz, H-6), 1.57–1.26 (4H, m, H-7, -8), 0.92 (3H, t, J = 7.0 Hz, H-9); ¹³C-NMR (CDCl₃) δ 189.3, 148.2, 148.0, 146.8, 143.3, 129.0, 127.4, 123.3, 122.8, 114.8, 109.7, 56.0, 32.4, 30.3, 22.3, 13.8; EIMS m/z (rel. int.) 260 (M⁺, 66), 259 (26), 217 (56), 177 (80), 168 (45), 152 (65), 151 (100), 137 (40), 123 (21), 111 (35), 97 (35), 91 (23), 71 (44), 69 (55), 57 (94), 55 (85); HREIMS m/z 260.1410 [M]⁺ (Calcd for C₁₆H₂₀O₃, 260.1412).

[5]-Dehydrogingerol (3a): yellow needles (65%), mp 143–144 °C (lit. 144–146 °C) [22]; UV (MeOH) λ_max (log ɛ) 340 (4.46), 271 (sh) (3.62), 244 (4.11) nm; IR (KBr) ν_max 3341, 3150, 2926, 2855, 1626, 1583, 1514, 1284, 1031, 972, 816 cm^{−1; 1}H-NMR (CDCl₃) δ 7.50 (1H, d, J = 16.2 Hz, H-1), 7.11 (1H, dd, J = 8.0, 1.8 Hz, H-6′), 7.05 (1H, d, J = 1.8 Hz, H-2′), 6.93 (1H, d, J = 8.0 Hz, H-5′), 6.58 (1H, d, J = 16.2 Hz, H-2), 6.02 (1H, br s, -OH), 4.13(1H, m, H-5), 3.93 (3H, s, -OCH₃), 2.88 (1H, dd, J = 17.0, 2.8 Hz, H-4), 2.73 (1H, dd, J = 17.0, 8.8 Hz, H-4), 1.58–1.35 (6H, m, H-6~8), 0.92 (3H, t, J = 6.6 Hz, H-9); ¹³C-NMR (CDCl₃) δ 200.9, 148.5, 146.8, 143.8, 126.6, 124.1, 123.7, 114.8, 109.4, 67.9, 56.0, 46.4, 36.2, 27.7, 22.6, 14.0; EIMS m/z (rel. int.) 278 (M⁺, 33), 192 (37), 177 (100), 150 (38), 145 (37), 137 (38), 89 (14); Anal. Calcd for C₁₆H₂₀O₄: C, 69.06%; H, 7.91%; Found: C, 69.09%; H, 7.85%.

[6]-Dehydroshogaol (2b): yellow syrup (15%); UV (MeOH) λ_max (log ɛ) 355 (4.02), 258 (3.93) nm; IR(neat) ν_max 3354, 2956, 2856, 1654, 1625, 1581, 1514, 1267, 1207, 1033 cm^{−1; 1}H-NMR (CDCl₃) δ 7.58 (1H, d, J = 15.8 Hz, H-1), 7.14 (1H, dd, J = 8.2, 1.8 Hz, H-6′), 7.07 (1H, d, J = 1.8 Hz, H-2′), 7.00 (1H, dt, J = 15.6, 7.0 Hz, H-5), 6.94 (1H, d, J = 8.2 Hz, H-5′), 6.81 (1H, d, J = 15.8 Hz, H-2), 6.43 (1H, dt, J = 15.6, 1.4 Hz, H-4), 5.97 (1H, br s, -OH), 3.94 (3H, s, -OCH₃), 2.27 (2H, tdd, J = 7.0, 6.8, 1.4 Hz, H-6), 1.57–1.25 (6H, m, H-7~9), 0.90 (3H, t, J = 6.7 Hz, H-10); ¹³C-NMR (CDCl₃) δ 189.3, 148.1, 148.0, 147.2, 143.3, 129.0, 127.4, 123.3, 122.8, 114.8, 109.7, 56.0, 32.7, 31.4, 27.9, 22.4, 14.0; EIMS m/z (rel. int.) 274 (M⁺, 100), 273 (36), 217 (82), 177 (81), 152 (21), 151 (36), 145 (20), 137 (45), 57 (36), 55 (44); HREIMS m/z 274.1571 [M]⁺ (Calcd for C₁₇H₂₂O₃, 274.1568).

[6]-Dehydrogingerol (3b): yellow needles (59%), mp 123–124 °C (lit. 134–136 °C) [22]; UV (MeOH) λ_max (log ɛ) 341 (4.34), 270 (sh) (3.59), 247 (3.98) nm; IR (KBr) ν_max 3460, 3161, 2962, 2858, 1675, 1589, 1517, 1433, 1281, 1223, 1174, 1076, 872 cm^{−1; 1}H-NMR (CDCl₃) δ 7.50 (1H, d, J = 16.0 Hz, H-1), 7.11 (1H, dd, J = 8.0, 2.0 Hz, H-6′), 7.05 (1H, d, J = 2.0 Hz, H-2′), 6.93 (1H, d, J = 8.2 Hz, H-5′), 6.58 (1H, d, J = 16.0 Hz, H-2), 4.14 (1H, m, H-5), 3.92 (3H, s, -OCH₃), 2.88 (1H, dd, J = 17.2, 3.2 Hz, H-4), 2.72 (1H, dd, J = 17.2, 8.6 Hz, H-4), 1.51–1.25 (8H, m, H-6~9), 0.89 (3H, t, J = 6.4 Hz, H-10); ¹³C-NMR (CDCl₃) δ 200.1, 150.2, 148.7, 143.8, 127.6, 125.1, 124.1, 116.1, 111.4, 68.5, 56.2, 48.4, 38.0, 32.6, 26.0, 23.3, 14.3; EIMS m/z (rel. int.) 292 (M⁺, 51), 192 (20), 177 (100), 150 (47), 137 (40), 89 (10).

[7]-Dehydroshogaol (2c): yellow syrup (13%); UV (MeOH) λ_max (log ɛ) 357 (3.91), 261 (3.95) nm; IR (neat) ν_max 3384, 2954, 2856, 1654, 1625, 1583, 1514, 1274, 1124, 1033 cm^{−1; 1}H-NMR (CDCl₃) δ 7.58 (1H, d, J = 15.8 Hz, H-1), 7.14 (1H, dd, J = 8.1, 1.8 Hz, H-6′), 7.08 (1H, d, J = 1.8 Hz, H-2′), 7.00 (1H, dt, J = 15.6, 6.9 Hz, H-5), 6.93 (1H, d, J = 8.1 Hz, H-5′), 6.81 (1H, d, J = 15.8 Hz, H-2), 6.43 (1H, dt, J = 15.6, 1.4 Hz, H-4), 5.92 (1H, br s, -OH), 3.94 (3H, s, -OCH₃), 2.27 (2H, tdd, J = 6.9, 6.9, 1.4 Hz, H-6), 1.54–1.25 (8H, m, H-7~10), 0.89 (3H, t, J = 6.7 Hz, H-11); ¹³C-NMR (CDCl₃) δ 189.3, 148.2, 148.0, 146.8, 143.4, 129.0, 127.3, 123.3, 122.7, 114.8, 109.7, 55.9, 32.7, 31.6, 28.9, 28.1, 22.5, 14.0; EIMS m/z (rel. int.) 288 (M⁺, 100), 287 (48), 217 (82), 204 (27), 177 (49), 137 (33); HREIMS m/z 288.1725 [M]⁺ (Calcd for C₁₈H₂₄O₃, 288.1725).

[7]-Dehydrogingerol (3c): yellow needles (56%), mp 108–109 °C (lit. 110–112 °C) [22]; UV (MeOH) λ_max (log ɛ) 340 (4.63), 271 (sh) (4.23), 252 (4.39) nm; IR (KBr) ν_max 3447, 3258, 2926, 2855, 1694, 1589, 1512, 1437, 1279, 1221, 1053, 812 cm^{−1; 1}H-NMR (CDCl₃) δ 7.46 (1H, d, J = 16.0 Hz, H-1), 7.04 (1H, dd, J = 8.2, 1.8 Hz, H-6′), 7.00 (1H, d, J = 1.8 Hz, H-2′), 6.88 (1H, d, J = 8.0 Hz, H-5′), 6.53 (1H, d, J = 16.0 Hz, H-2), 4.17–4.06 (1H, m, H-5), 3.87 (3H, s, -OCH₃), 2.85 (1H, dd, J = 17.0, 3.2 Hz, H-4), 2.71 (1H, dd, J = 17.0, 8.6 Hz, H-4), 1.58–1.25 (10H, m, H-6~10), 0.85 (3H, t, J = 6.6 Hz, H-11); ¹³C-NMR (CDCl₃) δ 201.0, 148.6, 147.0, 143.9, 126.7, 124.1, 123.7, 115.0, 109.5, 68.0, 56.0, 46.5, 36.6, 31.8, 29.3, 25.5, 22.6, 14.0; EIMS m/z (rel. int.) 306 (M⁺, 26), 217 (23), 192 (44), 177 (100), 150 (34), 145 (38), 137 (17), 89 (14).

[8]-Dehydroshogaol (2d): yellow syrup (15%); UV (MeOH) λ_max (log ɛ) 357 (4.10), 258 (3.96) nm; IR(neat) ν_max 3395, 2925, 2856, 1660, 1614, 1581, 1514, 1278, 1174, 1033 cm^{−1; 1}H-NMR (CDCl₃) δ 7.58 (1H, d, J = 16.0 Hz, H-1), 7.12 (1H, dd, J = 8.2, 2.0 Hz, H-6′), 7.06 (1H, d, J = 2.0 Hz, H-2′), 6.99 (1H, dt, J = 15.6, 6.9 Hz, H-5), 6.93 (1H, d, J = 8.2 Hz, H-5′), 6.81 (1H, d, J = 16.0 Hz, H-2), 6.43 (1H, dt, J = 15.6, 1.4 Hz, H-4), 6.21 (1H, br s, -OH), 3.91 (3H, s, -OCH₃), 2.26 (2H, tdd, J = 6.9, 6.9, 1.4 Hz, H-6), 1.52–1.27 (10H, m, H-7-11), 0.88 (3H, t, J = 6.8 Hz, H-12); ¹³C-NMR (CDCl₃) δ 189.3, 148.2, 148.0, 146.8, 143.3, 129.0, 127.3, 123.2, 122.7, 114.8, 109.7, 55.9, 32.7, 31.7, 29.1, 29.0, 28.1, 22.6, 14.0; EIMS m/z (rel. int.) 302 (M⁺, 81), 301 (29), 217 (68), 177 (100), 150 (21), 137 (33), 55 (24); HREIMS m/z 302.1879 [M]⁺ (Calcd for C₁₉H₂₆O₃, 302.1881).

[8]-Dehydrogingerol (3d): yellow needles (66%), mp 83–84 °C (lit. 88–90 °C) [22]; UV (MeOH) λ_max (log ɛ) 340 (4.57), 270 (sh) (4.25), 247 (4.38) nm; IR (KBr) ν_max 3451, 3215, 2924, 2855, 1680, 1585, 1510, 1433, 1280, 1116, 854 cm^{−1; 1}H-NMR (CDCl₃) δ 7.51 (1H, d, J = 16.0 Hz, H-1), 7.10 (1H, dd, J = 8.2, 1.8 Hz, H-6′), 7.06 (1H, d, J = 1.8 Hz, H-2′), 6.93 (1H, d, J = 8.2 Hz, H-5′), 6.59 (1H, d, J = 16.0 Hz, H-2), 4.17–4.06 (1H, m, H-5), 3.94 (3H, s, -OCH₃), 2.88 (1H, dd, J = 17.2, 3.1 Hz, H-4), 2.72 (1H, dd, J = 17.2, 8.7 Hz, H-4), 1.56–1.26 (12H, m, H-6~11), 0.88 (3H, t, J = 6.4 Hz, H-12); ¹³C-NMR (CDCl₃) δ 200.2, 150.2, 148.8, 143.9, 127.6, 125.0, 124.2, 116.1, 111.5, 68.6, 56.2, 48.4, 38.1, 32.5, 30.3, 30.0, 26.3, 23.2, 14.3; EIMS m/z (rel. int.) 320 (M⁺, 22), 192 (53), 177 (100), 150 (28), 145 (31), 137 (30), 84 (37), 69 (28), 57 (40), 55(55); Anal. Calcd. for C₁₉H₂₈O₄: C, 71.25%; H, 8.75%; Found: C, 71.26%; H, 8.79%.

[9]-Dehydroshogaol (2e): yellow syrup (13%); UV (MeOH) λ_max (log ɛ) 355 (4.02), 260 (4.03) nm; IR (neat) ν_max 3358, 2925, 2856, 1641, 1587, 1525, 1274, 1120, 1037 cm^{−1; 1}H-NMR (CDCl₃) δ 7.57 (1H, d, J = 15.8 Hz, H-1), 7.11 (1H, dd, J = 8.2, 1.8 Hz, H-6′), 7.06 (1H, d, J = 1.8 Hz, H-2′), 6.99 (1H, dt, J = 15.4, 7.2 Hz, H-5), 6.91 (1H, d, J = 8.2 Hz, H-5′), 6.80 (1H, d, J = 15.8 Hz, H-2), 6.42 (1H, dt, J = 15.4, 1.3 Hz, H-4), 3.90 (3H, s, -OCH₃), 2.25 (2H, tdd, J = 7.2, 6.8, 1.3 Hz, H-6), 1.41–1.26 (12H, m, H-7~12), 0.86 (3H, t, J = 6.6 Hz, H-13); ¹³C-NMR (CDCl₃) δ 189.4, 148.3, 148.1, 146.9, 143.4, 129.0, 127.3, 123.3, 122.7, 114.9, 109.8, 56.0, 32.7, 31.8, 29.3, 29.2, 29.1, 28.2, 22.6, 14.1; EIMS m/z (rel. int.) 316 (M⁺, 100), 315 (36), 217 (83), 204 (23), 177 (86), 137 (44), 55 (21); HREIMS m/z 316.2040 [M]⁺ (Calcd for C₂₀H₂₈O₃, 316.2038).

[9]-Dehydrogingerol (3e): yellow needles (58%), mp 93–94 °C (lit. 93–94 °C) [22]; UV (MeOH) λ_max (log ɛ) 339 (4.50), 270 (sh) (4.10), 250 (4.27) nm; IR (KBr) ν_max 3451, 2926, 2854, 1676, 1583, 1516, 1460, 1280, 1170, 1031, 977, 810 cm^{−1; 1}H-NMR (CDCl₃) δ 7.50 (1H, d, J = 16.0 Hz, H-1), 7.10 (1H, dd, J = 8.2, 1.8 Hz, H-6′), 7.05 (1H, d, J = 1.8 Hz, H-2′), 6.93 (1H, d, J = 8.2 Hz, H-5′), 6.59 (1H, d, J = 16.0 Hz, H-2), 4.17–4.06 (1H, m, H-5), 3.94 (3H, s, -OCH₃), 2.87 (1H, dd, J = 17.1, 3.0 Hz, H-4), 2.72 (1H, dd, J = 17.1, 8.7 Hz, H-4), 1.56–1.28 (14H, m, H-6~12), 0.88 (3H, t, J = 6.4 Hz, H-13); ¹³C-NMR (CDCl₃) δ 200.1, 150.1, 148.7, 143.8, 127.6, 125.0, 124.1, 116.1, 111.4, 68.5, 56.2, 48.4, 38.0, 32.6, 30.4, 30.3, 30.0, 26.3, 23.2, 14.3; EIMS m/z (rel. int.) 334 (M⁺, 33), 316 (27), 217 (22), 192 (50), 177 (100), 150 (30), 145 (27), 137 (46), 57 (20).

[10]-Dehydroshogaol (2f): yellow syrup (6%); UV (MeOH) λ_max (log ɛ) 355 (4.18), 257 (4.04) nm; IR (neat) ν_max 3533, 2925, 2856, 1660, 1614, 1581, 1514, 1278, 1201, 1120, 1031 cm^{−1; 1}H-NMR (CDCl₃) δ 7.58 (1H, d, J = 15.9 Hz, H-1), 7.13 (1H, dd, J = 8.2, 1.8 Hz, H-6′), 7.06 (1H, d, J = 1.8 Hz, H-2′), 6.99 (1H, dt, J = 15.6, 6.8 Hz, H-5), 6.91 (1H, d, J = 8.2 Hz, H-5′), 6.81 (1H, d, J = 15.9 Hz, H-2), 6.42 (1H, dt, J = 15.6, 1.4 Hz, H-4), 6.17 (1H, br s, -OH), 3.92 (3H, s, -OCH₃), 2.25 (2H, tdd, J = 6.8, 6.8, 1.4 Hz, H-6), 1.52–1.26 (14H, m, H-7~13), 0.87 (3H, t, J = 6.7 Hz, H-14); ¹³C-NMR (CDCl₃) δ 189.3, 148.2, 148.0, 146.8, 143.4, 129.0, 127.3, 123.3, 122.7, 114.8, 109.7, 55.9, 32.7, 31.8, 29.5, 29.4, 29.3, 29.2, 28.2, 22.7, 14.1; EIMS m/z (rel. int.) 330 (M⁺, 47), 217 (37), 177 (100), 152 (53), 150 (22), 137 (35), 97 (26), 85 (23), 71 (36), 57 (80), 55 (61); HREIMS m/z 330.2196 [M]⁺ (Calcd for C₂₁H₃₀O₃, 330.2194).

[10]-Dehydrogingerol (3f): yellow needles (50%), mp 74–75 °C (lit. 76–77.5 °C) [22]; UV (MeOH) λ_max (log ɛ) 340 (4.27), 273 (sh) (3.68), 239 (4.06) nm; IR (KBr) ν_max 3414, 2926, 2855, 1656, 1587, 1515, 1460, 1281, 1169, 1031, 979, 810 cm^{−1; 1}H-NMR (CDCl₃) δ 7.51 (1H, d, J = 16.1 Hz, H-1), 7.11 (1H, dd, J = 8.1, 1.8 Hz, H-6′), 7.05 (1H, d, J = 1.8 Hz, H-2′), 6.93 (1H, d, J = 8.1 Hz, H-5′), 6.59 (1H, d, J = 16.1 Hz, H-2), 5.97 (1H, br s, -OH), 4.17–4.06 (1H, m, H-5), 3.93 (3H, s, -OCH₃), 2.88 (1H, dd, J = 17.1, 3.0 Hz, H-4), 2.73 (1H, dd, J = 17.1, 8.7 Hz, H-4), 1.57–1.27 (16H, m, H-6~13), 0.88 (3H, t, J = 6.7 Hz, H-14); ¹³C-NMR (CDCl₃) δ 200.9, 148.4, 146.8, 143.8, 126.7, 124.1, 123.7, 114.8, 109.4, 68.0, 55.9, 46.5, 36.5, 31.8, 29.5 (×2), 29.4, 29.3, 25.5, 22.6, 14.1; EIMS m/z (rel. int.) 348 (M⁺, 24), 232 (21), 192 (17), 177 (52), 150 (76), 145 (12), 137 (29), 97 (29), 91 (45), 57 (100).

3.2.3. General Procedure for the Synthesis of [n]-Epoxydehydroparadol (7a–f)

A 1.0 M THF solution of lithium bis(trimethylsilyl)amide (20.8 mL) was added dropwise to a solution of dehydrozingerone (9) (2.0 g, 10.4 mmol) in dry THF (10 mL) at 0 °C in an air atmosphere. After the mixture had been stirred for 1 h, the appropriate aldehyde (31.4 mmol) was added and stirred for 3 h. The reaction was then quenched with 5% HCl_(aq) at 0 °C and extracted with EtOAc (4 × 20 mL). The organic layers were combined, washed with brine, dried over Na₂SO₄, and concentrated under reduced pressure. Products 2 and 7 were isolated using C-18 gel column chromatography (water/methanol = 1/2).

1-(4-Hydroxy-3-methoxyphenyl)-4,5-expoxynon-1-en-3-one (7a): yellow syrup (8%); UV (MeOH) λ_max (log ɛ) 349 (4.09), 251 (3.75) nm; IR (KBr) ν_max 3451, 2956, 2931, 1693, 1587, 1514, 1465, 1271, 1031 cm^{−1; 1}H-NMR (CDCl₃) δ 7.71 (1H, d, J = 16.0 Hz, H-1), 7.13 (1H, dd, J = 8.2, 1.8 Hz, H-6′), 7.06 (1H, d, J = 1.8 Hz, H-2′), 6.92 (1H, d, J = 8.2 Hz, H-5′), 6.71 (1H, d, J = 16.0 Hz, H-2), 6.01 (1H, br s, -OH), 3.92 (3H, s, -OCH₃), 3.41 (1H, d, J = 2.0 Hz, H-4), 3.11 (1H, td, J = 5.3, 2.0 Hz, H-5), 1.74–1.25 (6H, m, H-6~8), 0.92 (3H, t, J = 6.8 Hz, H-9); ¹³C-NMR (CDCl₃) δ 195.7, 148.7, 146.8, 145.2, 126.8, 124.2, 116.8, 114.8, 109.7, 59.6, 58.4, 56.0, 31.6, 27.9, 22.4, 13.9; EIMS m/z (rel. int.) 276 (M⁺, 38), 177 (100), 145 (20); HREIMS m/z 276.1363 [M]⁺ (Calcd for C₁₆H₂₀O₄, 276.1361).

1-(4-Hydroxy-3-methoxyphenyl)-4,5-expoxydec-1-en-3-one (7b): yellow syrup (10%); UV (MeOH) λ_max (log ɛ) 354 (4.27), 251 (3.93) nm; IR (neat) ν_max 3414, 2954, 2862, 1676, 1585, 1512, 1460, 1272, 1031 cm^{−1; 1}H-NMR (CDCl₃) δ 7.71 (1H, d, J = 15.9 Hz, H-1), 7.13 (1H, dd, J = 8.1, 1.8 Hz, H-6′), 7.06 (1H, d, J = 1.8 Hz, H-2′), 6.91 (1H, d, J = 8.1 Hz, H-5′), 6.71 (1H, d, J = 15.9 Hz, H-2), 3.92 (3H, s, -OCH₃), 3.41 (1H, d, J = 2.0 Hz, H-4), 3.12 (1H, td, J = 5.2, 2.0 Hz, H-5), 1.73–1.24 (8H, m, H-6~9), 0.89 (3H, t, J = 6.8 Hz, H-10); ¹³C-NMR (CDCl₃) δ 195.6, 148.6, 146.7, 145.2, 126.8, 124.2, 116.8, 114.8, 109.7, 59.5, 58.4, 56.0, 31.8, 31.4, 25.4, 22.4, 13.9; EIMS m/z (rel. int.) 290 (M⁺, 39), 178 (21), 177 (100), 145 (22); HREIMS m/z 290.1516 [M]⁺ (Calcd for C₁₇H₂₂O₄, 290.1518).

1-(4-Hydroxy-3-methoxyphenyl)-4,5-expoxyundec-1-en-3-one (7c): yellow syrup (9%); UV (MeOH) λ_max (log ɛ) 352 (4.19), 254 (3.89) nm; IR (neat) ν_max 3408, 2927, 2858, 1672, 1585, 1514, 1434, 1276, 1031 cm^{−1; 1}H-NMR (CDCl₃) δ 7.71 (1H, d, J = 15.8 Hz, H-1), 7.13 (1H, dd, J = 8.4, 2.0 Hz, H-6′), 7.06 (1H, d, J = 2.0 Hz, H-2′), 6.91 (1H, d, J = 8.4 Hz, H-5′), 6.70 (1H, d, J = 15.8 Hz, H-2), 6.05 (1H, br s, -OH), 3.92 (3H, s, -OCH₃), 3.41 (1H, d, J = 2.0 Hz, H-4), 3.13 (1H, td, J = 5.0, 2.0 Hz, H-5), 1.73–1.29 (10H, m, H-6~10), 0.88 (3H, t, J = 6.8 Hz, H-11); ¹³C-NMR (CDCl₃) δ 195.6, 148.6, 146.7, 145.2, 126.8, 124.2, 116.8, 114.8, 109.7, 59.5, 58.4, 56.0, 31.8, 31.6, 28.9, 25.7, 22.4, 13.9 ; EIMS m/z (rel. int.) 304 (M⁺, 46), 178 (26), 177 (100), 145 (26); HREIMS m/z 304.1673 [M]⁺ (Calcd for C₁₈H₂₄O₄, 304.1674).

1-(4-Hydroxy-3-methoxyphenyl)-4,5-expoxydodec-1-en-3-one (7d): yellow syrup (9%); UV (MeOH) λ_max (log ɛ) 351 (4.33), 255 (4.07) nm; IR(neat) ν_max 3395, 2925, 2858, 1672, 1581, 1514, 1434, 1172, 1031 cm^{−1; 1}H-NMR (CDCl₃) δ 7.70 (1H, d, J = 16.0 Hz, H-1), 7.12 (1H, dd, J = 8.2, 2.0 Hz, H-6′), 7.05 (1H, d, J = 2.0 Hz, H-2′), 6.90 (1H, d, J = 8.2 Hz, H-5′), 6.70 (1H, d, J = 16.0 Hz, H-2), 6.16 (1H, br s, -OH), 3.91 (3H, s, -OCH₃), 3.41 (1H, d, J = 2.0 Hz, H-4), 3.12 (1H, td, J = 5.2, 2.0 Hz, H-5), 1.73–1.26 (12H, m, H-6~11), 0.87 (3H, t, J = 6.8 Hz, H-12); ¹³C-NMR (CDCl₃) δ 195.7, 148.7, 146.8, 145.2, 126.8, 124.2, 116.8, 114.8, 109.7, 59.5, 58.4, 56.0, 31.8, 31.7, 29.2, 29.1, 25.8, 22.6, 14.0; EIMS m/z (rel. int.) 318 (M⁺, 37), 178 (22), 177 (100), 145 (19); HREIMS m/z 318.1834 [M]⁺ (Calcd for C₁₉H₂₆O₄, 318.1831).

1-(4-Hydroxy-3-methoxyphenyl)-4,5-expoxytridec-1-en-3-one (7e): yellow syrup (8%); UV (MeOH) λ_max (log ɛ) 353 (4.32), 254 (4.04) nm; IR (neat) ν_max 3404, 2925, 2856, 1672, 1583, 1514, 1434, 1276, 1031 cm^{−1; 1}H-NMR (CDCl₃) δ 7.72 (1H, d, J = 15.8 Hz, H-1), 7.14 (1H, dd, J = 8.2, 1.8 Hz, H-6′), 7.07 (1H, d, J = 1.8 Hz, H-2′), 6.92 (1H, d, J = 8.2 Hz, H-5′), 6.71 (1H, d, J = 15.8 Hz, H-2), 5.95 (1H, br s, -OH), 3.94 (3H, s, -OCH₃), 3.41 (1H, d, J = 2.0 Hz, H-4), 3.13 (1H, td, J = 5.0, 2.0 Hz, H-5), 1.74–1.27 (14H, m, H-6~12), 0.88 (3H, t, J = 6.8 Hz, H-13); ¹³C-NMR (CDCl₃) δ 195.6, 148.7, 146.8, 145.1, 126.9, 124.2, 116.9, 114.8, 109.7, 59.6, 58.4, 56.0, 31.8 (×2), 29.4, 29.3, 29.1, 25.8, 22.6, 14.0; EIMS m/z (rel. int.) 332 (M⁺, 36), 177 (100), 145 (15), 55 (12); HREIMS m/z 332.1990 [M]⁺ (Calcd for C₂₀H₂₈O₄, 332.1987).

1-(4-Hydroxy-3-methoxyphenyl)-4,5-expoxytetradec-1-en-3-one (7f): yellow syrup (8%); UV (MeOH) λ_max (log ɛ) 350 (4.19), 253 (4.17) nm; IR (neat) ν_max 3423, 2925, 2854, 1676, 1585, 1512, 1460, 1274, 1031 cm^{−1; 1}H-NMR (CDCl₃) δ 7.71 (1H, d, J = 15.8 Hz, H-1), 7.14 (1H, dd, J = 8.2, 1.8 Hz, H-6′), 7.07 (1H, d, J = 1.8 Hz, H-2′), 6.92 (1H, d, J = 8.2 Hz, H-5′), 6.72 (1H, d, J = 15.8 Hz, H-2), 5.90 (1H, br s, -OH), 3.94 (3H, s, -OCH₃), 3.41 (1H, d, J = 2.0 Hz, H-4), 3.13 (1H, td, J = 5.4, 2.0 Hz, H-5), 1.74–1.27 (16H, m, H-6~13), 0.88 (3H, t, J = 6.8 Hz, H-14); ¹³C-NMR (CDCl₃) δ 195.7, 148.7, 146.8, 145.2, 126.9, 124.2, 116.8, 114.8, 109.7, 59.6, 58.4, 56.0, 31.9, 31.8, 29.5, 29.4, 29.3, 29.2, 25.8, 22.6, 14.1; EIMS m/z (rel. int.) 346 (M⁺, 33), 177 (100), 151 (23), 150 (55), 55 (20); HREIMS m/z 346.2145 [M]⁺ (Calcd for C₂₁H₃₀O₄, 346.2144).

3.2.4. General Procedure for the Synthesis of [n]-Paradols (5a–f)

A solution of [n]-dehydroshogaols (2a–f) (0.96 mmol) in ethyl acetate (20 mL) containing palladium-charcoal (5%, 0.05 g) was stirred under hydrogen at atmospheric pressure and room temperature for 30 min. The reaction mixture was monitored by TLC until no starting material remained. The catalyst was removed through celite, and the filtrate was concentrated under reduced pressure. The product was isolated using silica gel column chromatography (EtOAc/hexanes = 1/4).

[5]-Paradol (5a): colorless syrup (79%) [23]; UV (MeOH) λ_max (log ɛ) 282 (3.41) nm; IR (neat) ν_max 3439, 2939, 2862, 1707, 1608, 1516, 1452, 1365, 1269, 1031, 806 cm^{−1; 1}H-NMR (CDCl₃) δ 6.79 (1H, d, J = 8.0 Hz, H-5′), 6.67 (1H, d, J = 1.8 Hz, H-2′), 6.63 (1H, dd, J = 8.0, 1.8 Hz, H-6′), 3.82 (3H, s, -OCH₃), 2.84–2.63 (4H, m, H-1, -2), 2.35 (2H, t, J = 7.2 Hz, H-4), 1.58–1.51 (2H, m, H-5), 1.23 (6H, m, H-6~8), 0.87 (3H, t, J = 6.2 Hz, H-9); ¹³C-NMR (CDCl₃) δ 210.8, 146.4, 143.8, 132.9, 120.6, 114.3, 111.1, 55.7, 44.5, 43.0, 31.5, 29.4, 28.8, 23.7, 22.4, 14.0; EIMS m/z (rel. int.) 264 (M⁺, 58), 179 (19), 151 (22), 137 (100); HREIMS m/z 246.1729 [M]⁺ (Calcd for C₁₆H₂₄O₃, 246.1725).

[6]-Paradol (5b): colorless syrup (78%) [23]; UV (MeOH) λ_max (log ɛ) 281 (3.34) nm; IR (neat) ν_max 3451, 2940, 2862, 1713, 1516, 1452, 1367, 1267, 1036, 804 cm^{−1; 1}H-NMR (CDCl₃) δ 6.80 (1H, d, J = 8.0 Hz, H-5′), 6.67 (1H, d, J = 1.8 Hz, H-2′), 6.64 (1H, dd, J = 8.0, 1.8 Hz, H-6′), 3.85 (3H, s, -OCH₃), 2.86–2.63 (4H, m, H-1, -2), 2.36 (2H, t, J = 7.4 Hz, H-4), 1.58–1.51 (2H, m, H-5), 1.24 (8H, m, H-6~9), 0.88 (3H, t, J = 6.2 Hz, H-10); ¹³C-NMR (CDCl₃) δ 210.6, 146.3, 143.8, 133.1, 120.7, 114.3, 111.0, 55.8, 44.6, 43.1, 31.6, 29.5, 29.1, 29.0, 23.8, 22.5, 14.0; EIMS m/z (rel. int.) 278 (M⁺, 67), 179 (21), 151 (23), 137 (100), 117 (19), 99 (23), 55 (21); HREIMS m/z 278.1883 [M]⁺ (Calcd for C₁₇H₂₆O₃, 278.1881).

[7]-Paradol (5c): colorless syrup (81%) [23]; UV (MeOH) λ_max (log ɛ) 282 (3.45) nm; IR (neat) ν_max 3543, 2930, 2858, 1707, 1608, 1516, 1452, 1365, 1269, 1034, 806 cm^{−1; 1}H-NMR (CDCl₃) δ 6.77 (1H, d, J = 8.0 Hz, H-5′), 6.66 (1H, d, J = 1.8 Hz, H-2′), 6.61 (1H, dd, J = 8.0, 1.8 Hz, H-6′), 5.48 (1H, br s, -OH), 3.79 (3H, s, -OCH₃), 2.83–2.61 (4H, m, H-1, -2), 2.33 (2H, t, J = 7.2 Hz, H-4), 1.58–1.51 (2H, m, H-5), 1.22 (10H, m, H-6~10), 0.85 (3H, t, J = 6.8 Hz, H-11); ¹³C-NMR (CDCl₃) δ 210.7, 146.5, 143.9, 132.9, 120.6, 114.4, 111.1, 55.7, 44.4, 42.9, 31.7, 29.4, 29.2, 29.1, 29.0, 23.7, 22.5, 14.0; EIMS m/z (rel. int.) 292 (M⁺, 36), 179 (17), 151 (21), 137 (100), 119 (10), 55 (11).

[8]-Paradol (5d): colorless powder (77%), mp 42–43 °C (lit. 42–43 °C) [23]; UV (MeOH) λ_max (log ɛ) 282 (3.46) nm; IR (KBr) ν_max 3541, 2920, 2856, 1707, 1608, 1514, 1365, 1271, 1030, 806 cm^{−1; 1}H-NMR (CDCl₃) δ 6.82 (1H, d, J = 7.8 Hz, H-5′), 6.68–6.63 (2H, m, H-2′, -6′), 3.86 (3H, s, -OCH₃), 2.87–2.64 (4H, m, H-1, -2), 2.37 (2H, t, J = 7.2 Hz, H-4), 1.58–1.51 (2H, m, H-5), 1.25 (12H, m, H-6~11), 0.88 (3H, t, J = 6.8 Hz, H-12); ¹³C-NMR (CDCl₃) δ 210.6, 146.4, 143.8, 133.1, 120.7, 114.3, 111.0, 55.8, 44.6, 43.1, 31.8, 29.5, 29.3 (×3), 29.2, 23.8, 22.6, 14.1; EIMS m/z (rel. int.) 306 (M⁺, 17), 292 (12), 164 (21), 179 (19), 151 (22), 137 (100), 57 (10); Anal. Calcd. for C₁₉H₃₀O₃: C, 74.50%; H, 9.80%; Found: C, 74.57%; H, 9.84%.

[9]-Paradol (5e): colorless powder (80%), mp 49–50 °C (lit. 48–49 °C) [23]; UV (MeOH) λ_max (log ɛ) 282 (3.41) nm; IR (KBr) ν_max 3516, 2922, 2856, 1712, 1608, 1516, 1361, 1273, 1165, 1028, 856 cm^{−1; 1}H-NMR (CDCl₃) δ 6.81 (1H, d, J = 8.0 Hz, H-5′), 6.68–6.63 (2H, m, H-2′, -6′), 3.86 (3H, s, -OCH₃), 2.86–2.64 (4H, m, H-1, -2), 2.36 (2H, t, J = 7.2 Hz, H-4), 1.58–1.51 (2H, m, H-5), 1.24 (14H, m, H-6~12), 0.87 (3H, t, J = 6.8 Hz, H-13); ¹³C-NMR (CDCl₃) δ 210.6, 146.3, 143.8, 133.1, 120.7, 114.2, 111.0, 56.0, 44.5, 43.1, 31.8, 29.5 (×2), 29.4 29.3, 29.2, 29.1, 23.8, 22.6, 14.1; EIMS m/z (rel. int.) 320 (M⁺, 80), 179 (19), 151 (21), 137 (100), 119 (8); Anal. Calcd. for C₂₀H₃₂O₃: C, 75.00%; H, 10.00%; Found: C, 75.01%; H, 10.01%.

[10]-Paradol (5f): colorless powder (79%), mp 50–51 °C (lit. 50–51 °C) [23]; UV (MeOH) λ_max (log ɛ) 280 (3.44) nm; IR (KBr) ν_max 3486, 2920, 2856, 1707, 1608, 1512, 1361, 1273, 1165, 1028, 856 cm^{−1; 1}H-NMR (CDCl₃) δ 6.81 (1H, d, J = 8.0 Hz, H-5′), 6.68–6.63 (2H, m, H-2′, -6′), 3.85 (3H, s, -OCH₃), 2.86–2.64 (4H, m, H-1, -2), 2.37 (2H, t, J = 7.2 Hz, H-4), 1.58–1.51 (2H, m, H-5), 1.25 (16H, m, H-6~13), 0.88 (3H, t, J = 6.6 Hz, H-14); ¹³C-NMR (CDCl₃) δ 210.6, 146.4, 143.8, 133.0, 120.6, 114.3, 111.0, 55.7, 44.5, 43.0, 31.8, 29.5 (×2), 29.4 29.3 (×2), 29.2, 29.1, 23.7, 22.6, 14.0; Anal. Calcd. for C₂₁H₃₄O₃: C, 75.45%; H, 10.18%; Found: C, 75.49%; H, 10.13%.

3.2.5. General Procedure for the Synthesis of [n]-Dehydroparadols (6a–f)

A solution of [n]-dehydroshogaols (2a–f) (0.96 mmol) in ethyl acetate (20 mL) containing palladium-charcoal (5%, 0.015 g) was stirred under hydrogen at atmospheric pressure and room temperature for 40 min. The reaction mixture was monitored using thin layer chromatography (TLC) until no starting material remained. The catalyst was removed through celite, and the filtrate was concentrated under reduced pressure conditions. The product was isolated using silica gel column chromatography (EtOAc/hexanes = 1/3).

[5]-Dehydroparadol (6a): colorless powder (80%), mp 52–53 °C (lit. 52–53 °C) [23]; UV (MeOH) λ_max (log ɛ) 340 (4.16), 224 (3.79) nm; IR (KBr) ν_max 3400, 2930, 2860, 1666, 1587, 1514, 1460, 1375, 1276, 1033, 979, 812 cm^{−1; 1}H-NMR (CDCl₃) δ 7.48 (1H, d, J = 16.1 Hz, H-1), 7.09 (1H, dd, J = 8.1, 2.0 Hz, H-6′), 7.05 (1H, d, J = 2.0 Hz, H-2′), 6.92 (1H, d, J = 8.1 Hz, H-5′), 6.59 (1H, d, J = 16.1 Hz, H-2), 6.12 (1H, br s, -OH), 3.92 (3H, s, -OCH₃), 2.64 (2H, t, J = 7.1 Hz, H-4), 1.70–1.59 (2H, m, H-5), 1.41–1.22 (6H, m, H-6~8), 0.88 (3H, t, J = 6.5 Hz, H-9); ¹³C-NMR (CDCl₃) δ 200.8, 148.1, 146.8, 142.6, 127.1, 124.1, 123.3, 114.8, 109.4, 55.9, 40.7, 31.6, 29.0, 24.5, 22.5, 14.0; EIMS m/z (rel. int.) 262 (M⁺, 31), 192 (34), 177 (100), 145 (22), 137 (44), 117 (10), 89 (12).

[6]-Dehydroparadol (6b): colorless powder (76%), mp 47–48 °C (lit. 44–45 °C) [23]; UV (MeOH) λ_max (log ɛ) 341 (4.04), 224 (3.85) nm; IR (KBr) ν_max 3400, 2926, 2856, 1666, 1601, 1514, 1460, 1375, 1278, 1031, 979, 810 cm^{−1; 1}H-NMR (CDCl₃) δ 7.47 (1H, d, J = 16.0 Hz, H-1), 7.08 (1H, dd, J = 8.1, 1.8 Hz, H-6′), 7.04 (1H, d, J = 1.8 Hz, H-2′), 6.91 (1H, d, J = 8.1 Hz, H-5′), 6.58 (1H, d, J = 16.0 Hz, H-2), 6.19 (1H, br s, -OH), 3.90 (3H, s, -OCH₃), 2.63 (2H, t, J = 7.2 Hz, H-4), 1.69–1.59 (2H, m, H-5), 1.31–1.27 (8H, m, H-6~9), 0.88 (3H, t, J = 6.6 Hz, H-10); ¹³C-NMR (CDCl₃) δ 200.8, 148.1, 146.8, 142.6, 126.9, 123.9, 123.3, 114.8, 109.4, 55.9, 40.6, 31.6, 29.3, 29.0, 24.5, 22.5, 14.0; EIMS m/z (rel. int.) 276 (M⁺, 31), 192 (40), 177 (100), 145 (19), 137 (71), 117 (10), 89 (11), 55(10); HREIMS m/z 276.1727 [M]⁺ (Calcd for C₁₇H₂₄O₃, 276.1725).

[7]-Dehydroparadol (6c): colorless powder (75%), mp 49–50 °C (lit. 45–46 °C) [23]; UV (MeOH) λ_max (log ɛ) 338 (4.03), 225 (3.80) nm; IR (KBr) ν_max 3401, 2926, 2854, 1676, 1589, 1514, 1460, 1377, 1207, 1033, 979, 810 cm^{−1; 1}H-NMR (CDCl₃) δ 7.46 (1H, d, J = 16.1 Hz, H-1), 7.05 (1H, dd, J = 8.0, 1.8 Hz, H-6′), 7.01 (1H, d, J = 1.8 Hz, H-2′), 6.89 (1H, d, J = 8.0 Hz, H-5′), 6.57 (1H, d, J = 16.1 Hz, H-2), 3.86 (3H, s, -OCH₃), 2.61 (2H, t, J = 7.2 Hz, H-4), 1.67–1.57 (2H, m, H-5), 1.26–1.23 (10H, m, H-6~10), 0.85 (3H, t, J = 6.8 Hz, H-11); ¹³C-NMR (CDCl₃) δ 200.9, 148.3, 146.9, 142.8, 126.8, 123.8, 123.3, 114.9, 109.5, 55.8, 40.5, 31.7, 29.3 (×2), 29.1, 24.5, 22.6, 14.0; EIMS m/z (rel. int.) 290 (M⁺, 15), 205 (12), 192 (28), 177 (63), 137 (100), 91 (11), 55(12); HREIMS m/z 290.1885 [M]⁺ (Calcd for C₁₈H₂₆O₃, 290.1881).

[8]-Dehydroparadol (6d): colorless powder (73%), mp 58–59 °C (lit. 57–58 °C) [23]; UV (MeOH) λ_max (log ɛ) 339 (4.09), 223 (3.96) nm; IR (KBr) ν_max 3401, 2925, 2854, 1675, 1589, 1514, 1460, 1272, 1033, 979, 810 cm^{−1; 1}H-NMR (CDCl₃) δ 7.48 (1H, d, J = 16.0 Hz, H-1), 7.06 (1H, dd, J = 8.0, 1.8 Hz, H-6′), 7.04 (1H, d, J = 1.8 Hz, H-2′), 6.91 (1H, d, J = 8.0 Hz, H-5′), 6.59 (1H, d, J = 16.0 Hz, H-2), 6.19 (1H, br s, -OH), 3.91 (3H, s, -OCH₃), 2.63 (2H, t, J = 7.0 Hz, H-4), 1.67–1.62 (2H, m, H-5), 1.28–1.25 (12H, m, H-6~11), 0.86 (3H, t, J = 6.8 Hz, H-12); ¹³C-NMR (CDCl₃) δ 200.8, 148.1, 146.8, 142.7, 127.0, 123.9, 123.3, 114.8, 109.4, 55.9, 40.6, 31.8, 29.4 (×2), 29.3, 29.2, 24.5, 22.6, 14.0; EIMS m/z (rel. int.) 304 (M⁺, 27), 205 (13), 192 (34), 177 (66), 151 (18), 137 (100), 91 (10), 55(12); Anal. Calcd for C₁₉H₂₈O₃: C, 75.00%; H, 9.21%; Found: C, 74.99%; H, 9.25%.

[9]-Dehydroparadol (6e): colorless powder (74%), mp 56–58 °C (lit. 53–54 °C) [23]; UV (MeOH) λ_max (log ɛ) 337 (3.96), 224 (3.74) nm; IR (KBr) ν_max 3395, 2925, 2854, 1666, 1589, 1516, 1460, 1277, 1033, 979, 812 cm^{−1; 1}H-NMR (CDCl₃) δ 7.47 (1H, d, J = 16.0 Hz, H-1), 7.08 (1H, dd, J = 8.0, 1.8 Hz, H-6′), 7.03 (1H, d, J = 1.8 Hz, H-2′), 6.90 (1H, d, J = 8.0 Hz, H-5′), 6.58 (1H, d, J = 16.0 Hz, H-2), 6.22 (1H, br s, -OH), 3.90 (3H, s, -OCH₃), 2.63 (2H, t, J = 7.2 Hz, H-4), 1.69–1.62 (2H, m, H-5), 1.28–1.24 (14H, m, H-6~12), 0.86 (3H, t, J = 6.6 Hz, H-13); ¹³C-NMR (CDCl₃) δ 200.8, 148.1, 146.8, 142.6, 126.9, 123.9, 123.3, 114.8, 109.4, 55.8, 40.6, 31.8, 29.5, 29.4, 29.3 (×2), 29.2, 24.5, 22.5, 14.0; EIMS m/z (rel. int.) 318 (M⁺, 27), 192 (57), 177 (100), 153 (22), 137 (39), 55(23).

[10]-Dehydroparadol (6f): colorless powder (79%), mp 72–73 °C (lit. 76–77 °C) [23]; UV (MeOH) λ_max (log ɛ) 339 (3.99), 225 (3.78) nm; IR(KBr) ν_max 3412, 2920, 2854, 1666, 1589, 1512, 1460, 1277, 1033 cm^{−1; 1}H-NMR (CDCl₃) δ 7.47 (1H, d, J = 16.0 Hz, H-1), 7.10–7.04 (2H, m, H-2′,6′), 6.89 (1H, d, J = 8.2 Hz, H-5′), 6.58 (1H, d, J = 16.0 Hz, H-2), 6.25 (1H, br s, -OH), 3.90 (3H, s, -OCH₃), 2.63 (2H, t, J = 7.2 Hz, H-4), 1.69–1.59 (2H, m, H-5), 1.28–1.25 (16H, m, H-6~13), 0.86 (3H, t, J = 6.4 Hz, H-14); ¹³C-NMR (CDCl₃) δ 200.8, 148.1, 146.8, 142.6, 126.9, 123.9, 123.3, 114.8, 109.4, 55.8, 40.5, 31.8, 29.5 (×2), 29.4, 29.3 (×2), 29.2, 24.5, 22.6, 14.0.

3.2.6. General Procedure for the Synthesis of [n]-Gingerols (8a–f)

A solution of [n]-dehydrogingerols (3a–f) (1.1 mmol) in ethyl acetate (20 mL) containing palladium-charcoal (5%, 0.04 g) was stirred under hydrogen at atmospheric pressure and room temperature for 40 min. The reaction mixture was monitored using TLC until no starting material remained. The catalyst was removed through celite, and the filtrate was concentrated under reduced pressure. The product was isolated using silica gel column chromatography (EtOAc/hexanes = 1/2).

[5]-Gingerol (8a): colorless powder (85%), mp 44–45 °C (lit. 45–46 °C); UV (MeOH) λ_max (log ɛ) 282 (3.44), 224 (3.85) nm; IR (KBr) ν_max 3460, 2943, 2864, 1704, 1612, 1138, 1371, 1271, 1138, 1034, 806 cm^{−1; 1}H-NMR (CDCl₃) δ 6.78 (1H, d, J = 7.8 Hz, H-5′), 6.64 (1H, d, J = 1.8 Hz, H-2′), 6.61 (1H, dd, J = 7.8, 1.8 Hz, H-6′), 4.34 (1H, br s, -OH), 4.06–3.94 (1H, m, H-5), 3.81 (3H, s, -OCH₃), 2.48–2.65 (4H, m, H-1, -2), 2.52–2.48 (2H, m, H-4), 1.50–1.22 (6H, m, H-6~8), 0.86 (3H, t, J = 7.0 Hz, H-9); ¹³C-NMR (CDCl₃) δ 211.4, 147.0, 144.0, 132.6, 120.7, 114.4, 111.0, 67.6, 55.9, 49.3, 45.4, 36.1, 29.2, 27.6, 22.6, 14.3; EIMS m/z (rel. int.) 280 (M⁺, 31), 205 (9), 150 (50), 137 (100), 91 (10); HREIMS m/z 280.1677 [M]⁺ (Calcd for C₁₆H₂₄O₄, 280.1674).

[6]-Gingerol (8b): colorless syrup (84%); UV (MeOH) λ_max (log ɛ) 282 (3.51) nm; IR (KBr) ν_max 3469, 2937, 2860, 1705, 1608, 1516, 1371, 1140, 1036, 806 cm^{−1; 1}H-NMR (CDCl₃) δ 6.79 (1H, d, J = 7.8 Hz, H-5′), 6.66–6.60 (2H,m, H-2′, -6′), 4.05–3.99 (1H, m, H-5), 3.83 (3H, s, -OCH₃), 2.86–2.66 (4H, m, H-1, -2), 2.53–2.48 (2H, m, H-4), 1.49–1.24 (8H, m, H-6~9), 0.86 (3H, t, J = 6.2 Hz, H-10); ¹³C-NMR (CDCl₃) δ 211.4, 146.4, 143.9, 132.5, 120.6, 114.4, 110.9, 67.6, 55.7, 49.2, 45.3, 36.3, 31.6, 29.1, 25.6, 22.5, 14.0; EIMS m/z (rel. int.) 294 (M⁺, 18), 205 (7), 194 (14), 150 (40), 137 (100), 91 (11); HREIMS m/z 294.1831 [M]⁺ (Calcd for C₁₇H₂₆O₄, 294.1831).

[7]-Gingerol (8c): colorless powder (86%), mp 101–102 °C; UV (MeOH) λ_max (log ɛ) 281 (3.67), 223 (3.95) nm; IR (KBr) ν_max 3524, 2926, 2858, 1705, 1608, 1516, 1369, 1271, 1036, 806 cm^{−1; 1}H-NMR (CDCl₃) δ 6.80 (1H, d, J = 8.0 Hz, H-5′), 6.66–6.60 (2H, m, H-2′, -6′), 4.06–3.95 (1H, m, H-5), 3.84 (3H, s, -OCH₃), 2.86–2.66 (4H, m, H-1, -2), 2.52–2.48 (2H, m, H-4), 1.51–1.25 (10H, m, H-6~10), 0.86 (3H, t, J = 6.6 Hz, H-11); ¹³C-NMR (CDCl₃) δ 211.5, 146.5, 144.0, 132.6, 120.7, 114.5, 111.1, 67.7, 55.8, 49.3, 45.4, 36.5, 31.8, 29.2, 29.1, 25.4, 22.6, 14.1; EIMS m/z (rel. int.) 308 (M⁺, 16), 290 (15), 205 (21), 150 (32), 137 (100), 91 (13), 55 (24); Anal. Calcd. for C₁₈H₂₈O₄: C, 70.12%; H, 9.09%; Found: C, 70.14%; H, 9.04%.

[8]-Gingerol (8d): colorless syrup (83%); UV (MeOH) λ_max (log ɛ) 282 (3.63), 222 (3.93) nm; IR (neat) ν_max 3516, 2928, 2858, 1705, 1608, 1516, 1452, 1271, 1035, 806 cm^{−1; 1}H-NMR (CDCl₃) δ 6.80 (1H, d, J = 7.8 Hz, H-5′), 6.66–6.61 (2H, m, H-2′, -6′), 4.05–3.95 (1H, m, H-5), 3.85 (3H, s, -OCH₃), 2.86–2.67 (4H, m, H-1, -2), 2.53–2.48 (2H, m, H-4), 1.49–1.25 (12H, m, H-6~11), 0.86 (3H, t, J = 6.2 Hz, H-12); ¹³C-NMR (CDCl₃) δ 211.3, 146.4, 143.9, 132.5, 120.6, 114.3, 110.9, 67.6, 55.7, 49.2, 45.3, 36.4, 31.7, 29.4, 29.1, 25.3, 22.5, 14.0; EIMS m/z (rel. int.) 322 (M⁺, 38), 150 (50), 137 (100), 55 (9).

[9]-Gingerol (8e): colorless syrup (84%); UV (MeOH) λ_max (log ɛ) 281 (3.33), 224 (3.71) nm; IR (neat) ν_max 3535, 2924, 2856, 1704, 1608, 1514, 1369, 1271, 1031, 804 cm^{−1; 1}H-NMR (CDCl₃) δ 6.80 (1H, d, J = 7.8 Hz, H-5′), 6.66–6.60 (2H, m, H-2′, -6′), 4.07–3.99 (1H, m, H-5), 3.84 (3H, s, -OCH₃), 2.86–2.66 (4H, m, H-1, -2), 2.53–2.48 (2H, m, H-4), 1.38–1.25 (14H, m, H-6~12), 0.87 (3H, t, J = 6.8 Hz, H-13); ¹³C-NMR (CDCl₃) δ 211.4, 146.5, 143.9, 132.6, 120.7, 114.5, 111.0, 67.7, 55.8, 49.3, 45.4, 36.5, 31.8, 29.5 (×2), 29.2 (×2), 25.4, 22.6, 14.0; EIMS m/z (rel. int.) 336 (M⁺, 32), 318 (14), 205 (17), 150 (36), 137 (100), 55 (9); HREIMS m/z: 336.2300 [M]⁺ (Calcd for C₂₀H₃₂O₄, 336.2300).

[10]-Gingerol (8f): colorless syrup (85%); UV (MeOH) λ_max (log ɛ) 282 (3.43), 224 (3.75) nm; IR (neat) ν_max 3439, 2920, 2854, 1706, 1608, 1514, 1369, 1271, 1031, 804 cm^{−1; 1}H-NMR (CDCl₃) δ 6.78 (1H, d, J = 7.8 Hz, H-5′), 6.65–6.59 (2H, m, H-2′, -6′), 4.05–3.99 (1H, m, H-5), 3.82 (3H, s, -OCH₃), 2.83–2.65 (4H, m, H-1, -2), 2.53–2.49 (2H, m, H-4), 1.38–1.25 (16H, m, H-6~13), 0.87 (3H, t, J = 6.6 Hz, H-14); ¹³C-NMR (CDCl₃) δ 211.3, 146.4, 143.8, 132.4, 120.5, 114.4, 110.9, 67.6, 55.6, 49.2, 45.2, 36.3, 31.7, 29.4 (×3), 29.2, 29.1, 25.3, 22.5, 14.0.

3.2.7. General Procedure for the Synthesis of [n]-Shogaols (4a–f)

Conc. HCl (0.1 mL) was added dropwise to a solution of [n]-gingerols (8a–f) (0.54 mmol) in acetone (10 mL) at room temperature. The reaction mixture was stirred for 15 min and then cooled to 0 °C in an ice bath, neutralized by saturated sodium bicarbonate, and extracted with CH₂Cl₂ (3 × 10 mL). The organic layers were combined, washed with brine, dried over MgSO₄, and concentrated under reduced pressure. The crude product was diluted with acetone (10 mL) and then potassium carbonate (0.81 mmol) was added at room temperature. The reaction mixture was stirred for 6h, then cooled to 0 °C in an ice bath, neutralized by 5% HCl_(aq), and extracted with CH₂Cl₂ (3 × 10 mL). The organic layers were combined, washed with brine, dried over MgSO₄, and concentrated under reduced pressure. The product was isolated using silica gel column chromatography (ethyl acetate/hexanes = 1/3).

[5]-Shogaol (4a): yellow syrup (86%) [24]; UV (MeOH) λ_max (log ɛ) 281 (3.51), 225 (4.31) nm; IR (neat) ν_max 3451, 2932, 2862, 1685, 1629, 1514, 1456, 1271, 1034, 984, 806 cm^{−1; 1}H-NMR (CDCl₃) δ 6.89–6.65 (4H, m, H-2′, -5′, -6′, -5), 6.07 (1H, dt, J = 15.8, 1.6 Hz, H-4), 5.50 (1H, br s, -OH), 3.87 (3H, s, -OCH₃), 2.87–2.79 (4H, m, H-1, -2), 2.25–2.14 (2H, m, H-6), 1.49–1.23 (4H, m, H-7, -8), 0.90 (3H, t, J = 6.8 Hz, H-9); ¹³C-NMR (CDCl₃) δ 199.8, 147.8, 146.3, 143.8, 133.2, 130.3, 120.8, 114.3, 111.1, 55.8, 42.0, 32.1, 30.1, 29.9, 22.2, 13.8; EIMS m/z (rel. int.) 262 (M⁺, 46), 205 (42), 151 (16), 137 (100), 55 (22).

[6]-Shogaol (4b): yellow syrup (85%) [24]; UV (MeOH) λ_max (log ɛ) 282 (3.47), 224 (4.25) nm; IR (neat) ν_max 3424, 2928, 2860, 1662, 1616, 1514, 1456, 1271, 1034, 982, 808 cm^{−1; 1}H-NMR (CDCl₃) δ 6.89–6.65 (4H, m, H-2′, -5′, -6′, -5), 6.08 (1H, dt, J = 16.0, 1.4 Hz, H-4), 5.54 (1H, br s, -OH), 3.86 (3H, s, -OCH₃), 2.89–2.79 (4H, m, H-1, -2), 2.24–2.13 (2H, m, H-6), 1.51–1.26 (6H, m, H-7~9), 0.88 (3H, t, J = 6.5 Hz, H-10); ¹³C-NMR (CDCl₃) δ 199.8, 147.8, 146.3, 143.8, 133.2, 130.2, 120.7, 114.2, 111.0, 55.8, 41.9, 32.4, 31.3, 29.8, 27.1, 22.4, 13.9; EIMS m/z (rel. int.) 276 (M⁺, 43), 205 (52), 151 (16), 137 (100), 119 (10), 55 (18).

[7]-Shogaol (4c): yellow syrup (83%) [24]; UV (MeOH) λ_max (log ɛ) 282 (3.44), 225 (4.18) nm; IR (neat) ν_max 3450, 2927, 2856, 1691, 1626, 1516, 1460, 1367, 1271, 1036, 978, 815 cm^{−1; 1}H-NMR (CDCl₃) δ 6.89–6.65 (4H, m, H-2′, -5′, -6′, -5), 6.08 (1H, dt, J = 16.0, 1.5 Hz, H-4), 3.86 (3H, s, -OCH₃), 2.86–2.82 (4H, m, H-1, -2), 2.24–2.14 (2H, m, H-6), 1.47–1.26 (8H, m, H-7~10), 0.88 (3H, t, J = 6.7 Hz, H-11); ¹³C-NMR (CDCl₃) δ 199.8, 147.9, 146.4, 143.8, 133.2, 130.3, 120.8, 114.3, 111.1, 55.8, 42.0, 32.5, 31.5, 29.8, 28.8, 28.0, 22.5, 14.0; EIMS m/z (rel. int.) 290 (M⁺, 27), 205 (28), 151 (14), 137 (100), 55 (9).

[8]-Shogaol (4d): yellow syrup (79%) [24]; UV (MeOH) λ_max (log ɛ) 282 (3.72), 225 (4.52) nm; IR (neat) ν_max 3433, 2926, 2856, 1675, 1629, 1514, 1456, 1271, 1034, 980, 808 cm^{−1; 1}H-NMR (CDCl₃) δ 6.89–6.65 (4H, m, H-2′, -5′, -6′, -5), 6.08 (1H, dt, J = 15.8, 1.6 Hz, H-4), 3.86 (3H, s, -OCH₃), 2.85–2.82 (4H, m, H-1, -2), 2.24–2.13 (2H, m, H-6), 1.47–1.27 (10H, m, H-7~11), 0.88 (3H, t, J = 6.7 Hz, H-12); ¹³C-NMR (CDCl₃) δ 199.8, 147.9, 146.4, 143.8, 133.2, 130.2, 120.7, 114.3, 111.1, 55.8, 41.9, 32.4, 31.7, 29.8, 29.1, 28.0, 22.6, 14.0; EIMS m/z (rel. int.) 304 (M⁺, 34), 205 (51), 151 (18), 137 (100), 69 (20), 55 (26).

[9]-Shogaol (4e): yellow syrup (85%) [24]; UV (MeOH) λ_max (log ɛ) 282 (3.55), 226 (4.36) nm; IR (neat) ν_max 3432, 2926, 2856, 1685, 1638, 1514, 1471, 1271, 1034, 982, 808 cm^{−1; 1}H-NMR (CDCl₃) δ 6.91–6.66 (4H, m, H-2′, -5′, -6′, -5), 6.08 (1H, dt, J = 15.7, 1.4 Hz, H-4), 3.87 (3H, s, -OCH₃), 2.87–2.80 (4H, m, H-1, -2), 2.25–2.14 (2H, m, H-6), 1.47–1.27 (12H, m, H-7~12), 0.88 (3H, t, J = 6.6 Hz, H-13); ¹³C-NMR (CDCl₃) δ 199.8, 147.9, 146.4, 143.9, 133.2, 130.3, 120.8, 114.3, 111.1, 55.9, 42.0, 32.5, 31.8, 29.9, 29.3, 29.1, 28.1, 22.6, 14.1; EIMS m/z (rel. int.) 318 (M⁺, 35), 205 (58), 151 (16), 137 (100), 55 (15).

[10]-Shogaol (4f): yellow syrup (88%) [24]; UV (MeOH) λ_max (log ɛ) 284 (3.45), 225 (4.16) nm; IR (neat) ν_max 3513, 2924, 2852, 1688, 1638, 1512, 1471, 1271, 1034, 982, 808 cm^{−1; 1}H-NMR (CDCl₃) δ 6.89–6.64 (4H, m, H-2′, -5′, -6′, -5), 6.08 (1H, dt, J = 15.6, 1.4 Hz, H-4), 3.85 (3H, s, -OCH₃), 2.84–2.82 (4H, m, H-1, -2), 2.19–2.13 (2H, m, H-6), 1.43–1.25 (14H, m, H-7~13), 0.87 (3H, t, J = 6.4 Hz, H-14); ¹³C-NMR (CDCl₃) δ 199.9, 147.9, 146.4, 143.9, 133.2, 130.3, 120.7, 114.3, 111.1, 55.8, 41.9, 32.5, 31.8, 29.8, 29.4, 29.3, 29.2, 29.1, 28.1, 22.6, 14.1.

3.2.8. General Procedure for the Synthesis of [n]-Isodehydrogingerdiones (1a–f)

DMSO (0.15 mL, 2.16 mmol) was added dropwise to a solution of oxalyl chloride (0.12 mL, 1.40 mmol) in acetone (10 mL) at −50–60 °C under argon. The reaction mixture was stirred for 3 min, and then a solution of [n]-dehydrogingerols (3a–f) (1.08 mmol) in CH₂Cl₂ (5 mL) was slowly added. The reaction mixture was stirred for another 15 min, Et₃N was added to the mixture; the temperature was changed to 0 °C in an ice bath for 20 min, and the reaction mixture was then neutralized using 5% HCl_(aq) and extracted with CH₂Cl₂ (3 × 10 mL). The organic layers were combined, washed with brine, dried over MgSO₄, and concentrated under reduced pressure. The product [n]-isodehydrogingerdiones (1a–f) and [n]-dehydroshogaols (2a–f) were isolated using silica gel column chromatography (ethyl acetate/hexanes = 1/3).

[5]-Isodehydrogingerdione (1a): yellow syrup (51%); UV (MeOH) λ_max (log ɛ) 369 (4.39), 255 (3.71) nm; IR (KBr) ν_max 3358, 2958, 2866, 1634, 1576, 1512, 1427, 1273, 1030, 966, 837 cm^{−1; 1}H-NMR (CDCl₃) δ 7.51 (1H, d, J = 15.8 Hz, H-1), 7.07 (1H, dd, J = 8.2, 1.8 Hz, H-6′), 7.00 (1H, d, J = 1.8 Hz, H-2′), 6.90 (1H, d, J = 8.2 Hz, H-5′), 6.34 (1H, d, J = 15.8 Hz, H-2), 5.62 (1H, s, H-4), 3.91 (3H, s, -OCH₃), 2.38 (2H, t, J = 7.2 Hz, H-6), 1.70–1.58 (2H, m, H-7), 1.46–1.28 (2H, m, H-8), 0.92 (3H, t, J = 7.2 Hz, H-9); ¹³C-NMR (CDCl₃) δ 200.2, 178.0, 147.6, 146.8, 139.8, 127.6, 122.6, 120.5, 114.8, 109.4, 100.1, 55.9, 39.8, 27.7, 22.4, 13.8.

[6]-Isodehydrogingerdione (1b): yellow syrup (49%); UV (MeOH) λ_max (log ɛ) 369 (4.37), 256 (3.70) nm; IR (KBr) ν_max 3418, 2956, 2864, 1634, 1591, 1512, 1427, 1271, 1032, 970, 816 cm^{−1; 1}H-NMR (CDCl₃) δ 7.51 (1H, d, J = 15.8 Hz, H-1), 7.06 (1H, dd, J = 8.0, 1.8 Hz, H-6′), 7.01 (1H, d, J = 1.8 Hz, H-2′), 6.90 (1H, d, J = 8.0 Hz, H-5′), 6.34 (1H, d, J = 15.8 Hz, H-2), 5.61 (1H, s, H-4), 3.94 (3H, s, -OCH₃), 2.37 (2H, t, J = 7.4 Hz, H-6), 1.69–1.57 (2H, m, H-7), 1.35–1.28 (2H, m, H-8~9), 0.90 (3H, t, J = 6.2 Hz, H-10); ¹³C-NMR (CDCl₃) δ 200.2, 178.0, 147.6, 146.7, 139.8, 127.7, 122.6, 120.5, 114.8, 109.4, 100.1, 55.9, 40.1, 31.4, 25.3, 22.4, 13.9.

[7]-Isodehydrogingerdione (1c): yellow syrup (59%); UV (MeOH) λ_max (log ɛ) 368 (4.17), 257 (3.62) nm; IR (KBr) ν_max 3423, 2928, 2858, 1634, 1582, 1512, 1427, 1273, 1031, 974, 814 cm^{−1; 1}H-NMR (CDCl₃) δ 7.52 (1H, d, J = 15.8 Hz, H-1), 7.08 (1H, dd, J = 8.2, 1.8 Hz, H-6′), 7.02 (1H, d, J = 1.8 Hz, H-2′), 6.91 (1H, d, J = 8.2 Hz, H-5′), 6.33 (1H, d, J = 15.8 Hz, H-2), 5.94 (1H, br s, -OH), 5.62 (1H, s, H-4), 3.93 (3H, s, -OCH₃), 2.37 (2H, t, J = 7.6 Hz, H-6), 1.64–1.61 (2H, m, H-7), 1.30–1.24 (6H, m, H-8~10), 0.89 (3H, t, J = 6.6 Hz, H-11); ¹³C-NMR (CDCl₃) δ 200.2, 178.0, 147.7, 146.8, 139.8, 127.7, 122.6, 120.5, 114.8, 109.5, 100.1, 55.9, 40.1, 31.6, 29.0, 25.6, 22.5, 14.0.

[9]-Isodehydrogingerdione (1e): yellow syrup (48%); UV (MeOH) λ_max (log ɛ) 369 (4.37), 254 (3.72) nm; IR (KBr) ν_max 3423, 2955, 2854, 1634, 1583, 1512, 1427, 1271, 1031, 970, 816 cm^{−1; 1}H-NMR (CDCl₃) δ 7.52 (1H, d, J = 15.6 Hz, H-1), 7.08 (1H, dd, J = 8.2, 1.8 Hz, H-6′), 7.01 (1H, d, J = 1.8 Hz, H-2′), 6.91 (1H, d, J = 8.2 Hz, H-5′), 6.34 (1H, d, J = 15.6 Hz, H-2), 5.91 (1H, br s, -OH), 5.62 (1H, s, H-4), 3.93 (3H, s, -OCH₃), 2.37 (2H, t, J = 7.2 Hz, H-6), 1.67–1.60 (2H, m, H-7), 1.29–1.27 (10H, m, H-8~12), 0.88 (3H, t, J = 6.2 Hz, H-13); ¹³C-NMR (CDCl₃) δ 200.1, 177.9, 147.6, 146.7, 140.0, 127.6, 122.5, 120.5, 114.7, 109.4, 100.1, 55.9, 40.1, 31.8, 29.3, 29.1, 25.6, 22.6, 14.0.

3.3. Antiplatelet Aggregatory Bioassay

An assay of the antiplatelet aggregatory activity of the isolated compound was conducted according to the procedures of Teng and coworkers [25,26]. Washed platelets were prepared from blood withdrawn with a siliconized syringe from the marginal vein of New Zealand rabbits. The platelet suspension was obtained from EDTA-anticoagulated platelet-rich plasma according to the washing procedure described previously. The platelet number was determined using a cell counter (Hema-laser 2, Sebia, France) and adjusted to 3.0 × 10⁸ platelets/mL. The platelet pellets were suspended in Tyrode’s solution containing Ca²⁺ (1 mM) and bovine serum albumin (0.35%). All glassware was siliconized. Platelet aggregation was measured using the turbidimetric method [26]. The aggregations were measured with a Lumi-aggregometer (Model 1020, Payton, Canada) connected to two dual-channel recorders.

4. Conclusions

Eight groups of derivatives based on the skeletons of shogaol and gingerol, the active pungent principles from ginger, were synthesized and evaluated for their antiplatelet bioactivity. Among the compounds synthesized, [6]-paradol 5b displayed the most significant inhibition of platelet aggregation induced by AA. Anti-PAF induced platelet aggregation activity was not found in the present study, suggesting that [6]-paradol 5b is a selective inhibitor. The traditional use of Z. officinale is to promote the blood circulation necessary for removing blood stasis, and the results of this study substantiated the anti-platelet aggregation activity of these synthetic derivatives related to shogaol and gingerol. It is valuable to explore new anti-platelet aggregation drugs based on the skeleton of [n]-paradol or other principles reported from the Zingiber series.

Acknowledgments

The authors wish to express appreciation to the National Science Council, Taiwan, ROC, for financial support of the present research.

Conflicts of Interest

The authors declare no conflicts of interest.

Sample Availability: Samples of all the synthetic compounds are available from the authors.

References

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Figure 1. Chemical structures of the pungent principles from the rhizomes of Zingiber officinale.

Figure 2. Chemical structures of the synthetic analogues of gingerol and shogaol.

Table 1. The yields of products 2 and 3 from cross aldol condensation.

**Table 1.** The yields of products 2 and 3 from cross aldol condensation.
[n]	2 yield%	3 yield%
a: n = 5	9	65
b: n = 6	15	59
c: n = 7	13	56
d: n = 8	15	66
e: n = 9	13	58
f: n = 10	6	50

Table 2. Cross aldol condensation under air atmosphere.

**Table 2.** Cross aldol condensation under air atmosphere.
[n]	2 yield%	7 yield%
a: n = 5	19	8
b: n = 6	21	10
c: n = 7	18	9
d: n = 8	18	9
e: n = 9	16	8
f: n = 10	15	8

Table 3. Hydrogenation of compound 2 to afford product 5 and 6.

**Table 3.** Hydrogenation of compound 2 to afford product 5 and 6.
[n]	5 yield%	6 yield%
a: n = 5	79	80
b: n = 6	78	76
c: n = 7	81	75
d: n = 8	77	73
e: n = 9	80	74
f: n = 10	79	79

Table 4. Hydrogenation and elimination of compound 3 to yield products 8 and 4.

**Table 4.** Hydrogenation and elimination of compound 3 to yield products 8 and 4.
[n]	8 yield%	4 yield%
a: n = 5	85	86
b: n = 6	84	85
c: n = 7	86	83
d: n = 8	83	79
e: n = 9	84	85
f: n = 10	85	88

Table 5. The Swern oxidation of compound 3 to obtain products 2 and 1.

**Table 5.** The Swern oxidation of compound 3 to obtain products 2 and 1.
[n]	2 yield%	1 yield%
a: n = 5	16	51
b: n = 6	15	49
c: n = 7	11	59
e: n = 9	17	48

Table 6. Antiplatelet activity of [n]-paradols 5a–f.

**Table 6.** Antiplatelet activity of [n]-paradols 5a–f.
Inhibition (%)

Inducer	Control	Conc. (μg/mL)	5a	5b	5c	5d	5e	5f
AA (100 μM)	0.0 ± 1.3	10	100.0 ± 1.3 ***	100.0 ± 1.3 ***	100.0 ± 1.3 ***	100.0 ± 1.3 ***	100.0 ± 0.4	100.0 ± 0.4 ***
		5	-	-	100.0 ± 1.3 ***	100.0 ± 1.3 ***	-	100.0 ± 0.4 ***
		2	-	100.0 ± 1.3 ***	94.9 ± 3.4 ***	98.4 ± 0.2 ***	100.0 ± 0.4 ***	87.4 ± 4.8 ***
		1	100.0 ± 1.3 ***	97.0 ± 1.4 ***	93.2 ± 5.0 ***	90.9 ± 4.0 ***	96.9 ± 2.1 ***	75.9 ± 4.7 ***
		0.5	87.1 ± 6.5 ***	92.8 ± 5.4 ***	90.0 ± 7.9 ***	81.6 ± 9.4 ***	89.8 ± 3.8 ***	53.6 ± 2.1 ***
		0.2	63.9 ± 10.6 ***	79.9 ± 8.9 ***	76.0 ± 10.7 ***	76.9 ± 12.1 ***	21.7 ± 3.4 ***	26.4 ± 6.1 ***
		0.1	57.3 ± 12.9 ***	67.6 ± 13.0 ***	68.0 ± 1.7 ***	53.0 ± 13.7 **	-	6.4 ± 2.2 **
		0.05	29.0 ± 13.6	52.6 ± 13.1 ***	17.0 ± 5.0 *	26.7 ± 8.9 *	-	-
		0.02	10.0 ± 3.5 *	14.7 ± 5.6	7.0 ± 3.9	8.1 ± 2.9	-	-
		0.01	−0.9 ± 0.0	5.5 ± 1.4	2.4 ± 1.7	-	-	-
IC₅₀ (μg/mL)	-	-	0.10	0.07	0.12	0.12	0.30	0.49
Col (10 μM)	0.0 ± 0.8	10	61.7 ± 3.8 ***	33.3 ± 4.1 ***	39.7 ± 3.8 ***	52.7 ± 3.5 ***	36.9 ± 5.4 ***	32.9 ± 3.1 ***
PAF (2 ng/mL)	0.0 ± 1.0	10	1.9 ± 0.8 ***	1.9 ± 0.3	0.7 ± 0.1	1.3 ± 0.0	−0.8 ± 0.4	21 ± 1.6
Thr (0.1 U/mL)	0.0 ± 1.0	10	−2.1 ± 0.2 *	0.0 ± 0.6	−2.7 ± 0.1	−1.0 ± 0.2	0.2 ± 0.4	2.5 ± 0.4

^*p < 0.05;

^**p < 0.01;

^***p < 0.001.

Table 7. Antiplatelet activity of [n]-dehydroparadols 6a–f.

**Table 7.** Antiplatelet activity of [n]-dehydroparadols 6a–f.
Inhibition (%)

Inducer	Control	Conc. (μg/mL)	6a	6b	6c	6d	6e	6f
AA (100 μM)	0.0 ± 0.4	10	100.0 ± 0.4 ***	100.0 ± 0.4	100.0 ± 0.4 ***	100.0 ± 0.4 ***	100.0 ± 0.4 ***	100.0 ± 0.4 ***
		5	-	100.0 ± 0.4	97.7 ± 1.6 ***	98.4 ± 0.9 ***	-	-
		2	100.0 ± 0.4 ***	94.9 ± 4.0	96.6 ± 2.5 ***	93.1 ± 5.1 ***	100.0 ± 0.4 ***	100.0 ± 0.4 ***
		1	78.4 ± 8.5 ***	64.9 ± 10.7	86.3 ± 7.4 ***	73.1 ± 1.0 ***	75.2 ± 7.8 ***	97.7 ± 1.6 ***
		0.5	64.2 ± 9.1 ***	50.4 ± 7.2	59.4 ± 7.0 ***	62.3 ± 0.7 ***	55.2 ± 11.6 ***	97.7 ± 1.6 ***
		0.2	38.9 ± 10.8 **	14.5 ± 4.8	40.8 ± 4.0 ***	36.3 ± 0.0 ***	8.7 ± 1.0 ***	79.4 ± 7.7 ***
		0.1	14.4 ± 6.5	6.7 ± 3.2	16.1 ± 1.9 ***	12.2 ± 3.1 *	-	31.4 ± 8.6 *
		0.05	3.4 ± 0.9	-	6.7 ± 1.3 *	-	-	5.4 ± 1.9 *
IC₅₀ (μg/mL)	-	-	0.32	0.56	0.35	0.40	0.52	0.16
Col (10 μM)	0.0 ± 1.0	10	42.8 ± 4.7 ***	39.3 ± 4.6 ***	18.4 ± 1.6 ***	36.1 ± 0.1 *	20.2 ± 2.6 ***	18.9 ± 3.4 ***
PAF (2 ng/mL)	0.0 ± 1.0	10	5.3 ± 3.3	0.4 ± 0.2	0.5 ± 0.5	2.0 ± 2.5	1.1 ± 0.3	−1.0 ± 0.5
Thr (0.1 U/mL)	0.0 ± 0.9	10	4.3 ± 0.1 **	1.8 ± 0.6	3.0 ± 1.6	1.5 ± 0.5	5.0 ± 0.1	0.9 ± 0.5

^*p < 0.05;

^**p < 0.01;

^***p < 0.001.

Table 8. Antiplatelet activity of [n]-shogaols 4a–f.

**Table 8.** Antiplatelet activity of [n]-shogaols 4a–f.
Inhibition (%)

Inducer	Control	Conc. (μg/mL)	4a	4b	4c	4d	4e	4f
AA (100 μM)	0.0 ± 1.2	10	100.0 ± 1.2 ***	100.0 ± 1.2 ***	100.0 ± 1.2 ***	100.0 ± 1.2 ***	100.0 ± 1.2 ***	100.0 ± 1.2 ***
		1	100.0 ± 1.2 ***	100.0 ± 1.2 ***	-	-	-	100.0 ± 1.2 ***
		0.5	70.0 ± 19.6 ***	94.2 ± 3.4 ***	100.0 ± 1.2 ***	100.0 ± 1.2 ***	100.0 ± 1.2 ***	83.1 ± 6.0 ***
		0.2	52.8 ± 22.1 **	78.0 ± 15.2 ***	62.3 ± 18.1 **	74.9 ± 14.3 ***	57.9 ± 1.1 ***	81.2 ± 9.1 ***
		0.1	14.7 ± 8.3	47.3 ± 19.6 *	54.1 ± 21.7 *	14.3 ± 16.0 **	36.0 ± 14.4 *	41.8 ± 17.8 *
		0.05	5.3 ± 2.7	13.7 ± 5.4 *	7.9 ± 2.7	5.2 ± 2.2	7.2 ± 2.7	30.9 ± 21.5
		0.02	-	2.8 ± 1.1	-	-	-	2.8 ± 0.2

IC₅₀ (μg/mL)	-	-	0.23	0.12	0.13	0.15	0.15	0.11

Col (10 μM)	0.0 ± 1.7	10	91.2 ± 6.0 ***	84.5 ± 11.9 ***	78.7 ± 13.2 ***	74.5 ± 14.0 ***	79.3 ± 16.2 ***	91.1 ± 1.9 ***
		5	55.3 ± 7.7 ***	50.1 ± 5.4 ***	41.4 ± 4.3 ***	38.0 ± 7.9 ***	45.5 ± 14.7 **	82.8 ± 7.3 ***
		2	20.0 ± 6.6 *	13.3 ± 2.5 **	9.8 ± 0.6 **	6.0 ± 1.2	27.0 ± 15.6	36.3 ± 14.9 *
		1	1.5 ± 0.7	2.5 ± 2.5	1.7 ± 0.8	-	4.0 ± 2.0	11.3 ± 3.3 *
		0.5	-	-	-	-	-	3.2 ± 0.7

PAF (2 ng/mL)	0.0 ± 1.2	10	9.3 ± 0.1 ***	6.4 ± 0.7 *	6.0 ± 1.3	5.2 ± 1.1	4.5 ± 2.1	6.6 ± 2.2

Thr (0.1 U/mL)	0.0 ± 0.4	10	3.5 ± 0.6 *	1.7 ± 0.2	1.5 ± 0.2	2.2 ± 0.6	1.0 ± 1.0	2.2 ± 3.4

^*p < 0.05;

^**p < 0.01;

^***p < 0.001.

Table 9. Antiplatelet activity of [n]-dehydroshogaols 2a–f.

**Table 9.** Antiplatelet activity of [n]-dehydroshogaols 2a–f.
Inhibition (%)

Inducer	Control	Conc. (μg/mL)	2a	2b	2c	2d	2e	2f
AA (100 μM)	0.0 ± 1.4	10	100.0 ± 1.4 ***	100.0 ± 1.4 ***	100.0 ± 1.4 ***	100.0 ± 1.4 ***	100.0 ± 1.4 ***	100.0 ± 1.4 ***
		5	100.0 ± 1.4 ***	100.0 ± 1.4 ***	100.0 ± 1.4 ***	100.0 ± 1.4 ***	100.0 ± 1.4 ***	96.9 ± 1.1 ***
		2	86.4 ± 7.0 ***	71.1 ± 13.0 ***	84.1 ± 12.4 ***	86.4 ± 9.7 ***	97.7 ± 0.6 ***	95.5 ± 2.3 ***
		1	35.6 ± 12.4 ***	30.7 ± 8.6 **	61.4 ± 18.1 **	54.5 ± 13.4 ***	91.1 ± 6.4 ***	81.4 ± 7.7 ***
		0.5	26.5 ± 18.4	19.7 ± 12.9	19.2 ± 8.1 *	9.2 ± 0.3 ***	31.7 ± 18.3	60.5 ± 19.6 **
		0.2	7.2 ± 3.5	3.3 ± 0.5	5.6 ± 0.9 *	1.5 ± 0.5	8.6 ± 4.2	3.3 ± 1.5
		0.1	-	-	-	-	2.1 ± 0.9	-

IC₅₀ (μg/mL)	-	-	0.96	1.18	0.88	0.99	0.57	0.51

Col (10 μM)	0.0 ± 0.6	10	93.3 ± 5.3 ***	26.9 ± 9.2 *	66.8 ± 14.1 ***	51.6 ± 14.8 **	44.8 ± 7.8 ***	62.1 ± 13.9 ***
		5	29.1 ± 8.0 **	2.1 ± 0.9	7.1 ± 1.5 **	8.3 ± 1.3 ***	-	-
		2	3.5 ± 1.1	-	-	-	-	-
		0.2	92.2 ± 2.2 ***	-	-	-	-	-

PAF (2 ng/mL)	0.0 ± 1.3	10	11.2 ± 1.4 **	5.0 ± 3.1	6.8 ± 0.7 *	5.9 ± 0.7 *	5.9 ± 1.0 *	5.6 ± 0.7 *

Thr (0.1 U/mL)	0.0 ± 0.4	10	5.1 ± 2.1	1.6 ± 1.4	0.9 ± 1.3	1.8 ± 1.6	3.2 ± 1.2	1.0 ± 1.3

^*p < 0.05;

^**p < 0.01;

^***p < 0.001.

Table 10. Antiplatelet activity of [n]-gingerols 8a–f.

**Table 10.** Antiplatelet activity of [n]-gingerols 8a–f.
Inhibition (%)

Inducer	Control	Conc. (μg/mL)	8a	8b	8c	8d	8e	8f
AA (100 μM)	0.0 ± 1.3	10	93.0 ± 2.6 ***	100.0 ± 1.3 ***	93.8 ± 4.2 ***	96.3 ± 1.1 ***	100.0 ± 1.3 ***	100.0 ± 1.3 ***
		5	59.9 ± 13.4 ***	100.0 ± 1.3 ***	79.6 ± 10.5 ***	90.4 ± 4.3 ***	97.0 ± 1.4 ***	99.2 ± 0.5 ***
		2	37.4 ± 15.2 *	75.6 ± 9.7 ***	74.8 ± 12.9 ***	84.1 ± 8.1 ***	77.1 ± 12.4 ***	89.2 ± 5.9 ***
		1	22.7 ± 12.6	38.7 ± 4.7 ***	63.1 ± 16.7 ***	81.7 ± 9.9 ***	72.1 ± 13.4 ***	80.5 ± 9.9 ***
		0.5	6.6 ± 3.5	22.3 ± 3.1 ***	47.3 ± 18.4 *	71.3 ± 14.7 ***	59.4 ± 15.0 **	67.8 ± 10.5 ***
		0.2	-	7.0 ± 0.7 *	27.7 ± 16.7	64.2 ± 15.4 ***	3.8 ± 1.3	20.9 ± 6.8
		0.1	-	-	4.8 ± 3.1	34.3 ± 14.2 *	-	12.8 ± 4.1 *
		0.05	-	-	2.1 ± 2.3	8.0 ± 2.2	-	1.8 ± 0.8
IC₅₀ (μg/mL)	-	-	2.72	1.04	0.72	0.23	0.65	0.45
Col (10 μM)	0.0 ± 0.8	10	20.1 ± 2.1 ***	28.3 ± 6.3 **	41.6 ± 4.7 ***	-	6.6 ± 1.9 *	49.3 ± 6.3 ***
PAF (2 ng/mL)	0.0 ± 1.0	10	−0.6 ± 0.4	0.4 ± 0.0	0.2 ± 0.2	-	−0.4 ± 0.6	−0.3 ± 0.3
Thr (0.1 U/mL)	0.0 ± 1.4	10	−0.5 ± 0.2	−2.7 ± 1.2	−1.2 ± 0.3	0.7 ± 0.1	−1.6 ± 0.5	−4.3 ± 0.1

^*p < 0.05;

^**p < 0.01;

^***p < 0.001.

Table 11. Antiplatelet activity of [n]-dehydrogingerols 3a–f.

**Table 11.** Antiplatelet activity of [n]-dehydrogingerols 3a–f.
Inhibition (%)

Inducer	Control	Conc. (μg/mL)	3a	3b	3c	3d	3e	3f
AA (100 μM)	0.0 ± 0.8	10	78.0 ± 12.7 ***	98.8 ± 0.2 ***	100.0 ± 0.8 ***	84.7 ± 12.4 ***	92.9 ± 5.0 ***	100.0 ± 0.8 ***
		5	63.0 ± 14.3 ***	53.7 ± 11.1 **	76.2 ± 12.0 ***	65.5 ± 16.5 ***	83.2 ± 12.9 ***	100.0 ± 0.8 ***
		2	30.4 ± 19.4	25.7 ± 13.8	15.3 ± 3.9 ***	52.4 ± 21.7 *	19.6 ± 3.9 ***	100.0 ± 0.8 ***
		1	8.5 ± 6.9	16.4 ± 13.5	7.0 ± 3.5	4.4 ± 1.0 *	5.7 ± 0.2 ***	9.8 ± 3.0 **
		0.5	2.8 ± 1.7	6.5 ± 4.8	-	-	-	2.6 ± 0.9
IC₅₀ (μg/mL)	-	-	3.59	4.74	3.19	2.99	3.14	1.20
Col (10 μM)	0.0 ± 0.6	10	7.5 ± 4.2	16.9 ± 8.4	8.7 ± 3.7	10.6 ± 3.3	40.0 ± 7.1 ***	41.3 ± 14.2 *
PAF (2 ng/mL)	0.0 ± 1.3	10	3.1 ± 1.0	4.3 ± 0.8	1.4 ± 0.2	1.5 ± 0.8	3.0 ± 1.8	−0.9 ± 0.6
Thr (0.1 U/mL)	0.0 ± 0.4	10	1.9 ± 0.3	1.7 ± 1.0	0.7 ± 0.6	0.4 ± 0.6	1.0 ± 0.4	1.7 ± 0.1

^*p < 0.05;

^**p < 0.01;

^***p < 0.001.

Table 12. Antiplatelet activity of [n]-isodehydrogingerdiones 1a–c and e.

**Table 12.** Antiplatelet activity of [n]-isodehydrogingerdiones 1a–c and e.
Inhibition (%)

Inducer	Control	Conc. (μg/mL)	1a	1b	1c	1e
AA (100 μM)	0.0 ± 0.4	10	100.0 ± 0.4 ***	100.0 ± 0.4 ***	98.4 ± 0.9 ***	100.0 ± 0.4 ***
		5	100.0 ± 0.4 ***	100.0 ± 0.4 ***	-	100.0 ± 0.4 ***
		2	94.3 ± 4.2 ***	93.1 ± 5.5 ***	100.0 ± 0.4 ***	82.7 ± 6.0 ***
		1	30.8 ± 6.4	59.6 ± 6.0 ***	53.4 ± 4.2 ***	74.7 ± 7.8 ***
		0.5	10.6 ± 2.9 **	7.4 ± 4.1	40.3 ± 9.9 **	26.0 ± 5.4 ***
		0.2	-	-	3.6 ± 1.6	10.2 ± 4.4
IC₅₀ (μg/mL)	-	-	1.28	1.03	0.68	0.75
Col (10 μM)	0.0 ± 1.0	10	53.3 ± 6.3 ***	38.9 ± 10.0 ***	35.2 ± 6.6 ***	36.6 ± 13.8 *
PAF (2 ng/mL)	0.0 ± 1.0	10	0.1 ± 0.4	0.2 ± 0.4	0.2 ± 0.4	2.3 ± 0.3
Thr (0.1 U/mL)	0.0 ± 0.9	10	1.7 ± 0.2	1.7 ± 0.4	0.2 ± 0.1	1.1 ± 0.2

^*p < 0.05;

^**p < 0.01;

^***p < 0.001.

Table 13. Antiplatelet activity of [n]-epoxydehydroparadols 7a–f.

**Table 13.** Antiplatelet activity of [n]-epoxydehydroparadols 7a–f.
Inhibition (%)

Inducer	Control	Conc. (μg/mL)	7a	7b	7c	7d	7e	7f
AA (100 μM)	0.0 ± 0.8	10	96.5 ± 2.3	100.0 ± 0.8	100.0 ± 0.8 ***	100.0 ± 0.8 ***	73.8 ± 13.6 ***	100.0 ± 0.8 ***
		5	87.4 ± 8.5	93.8 ± 4.5	95.7 ± 3.0 ***	67.8 ± 16.5 ***	-	96.5 ± 2.3 ***
		2	46.1 ± 13.7	77.9 ± 10.7	80.1 ± 16.3 ***	51.1 ± 20.2 **	-	83.7 ± 10.7 ***
		1	12.6 ± 3.2	51.1 ± 14.6	41.5 ± 12.1 ***	22.5 ± 14.1 *	-	44.5 ± 18.6 ***
		0.5	-	9.4 ± 2.5	25.1 ± 11.0 **	5.1 ± 0.0 ***	-	37.0 ± 17.6 ***
		0.2	-	-	4.6 ± 0.8 **	-	-	4.1 ± 0.3 ***
IC₅₀ (μg/mL)	-	-	2.38	1.24	1.09	2.24	-	0.96
Col (10 μM)	0.0 ± 1.9	10	45.2 ± 14.0 *	1.8 ± 1.4 **	20.2 ± 7.7	10.7 ± 3.6	3.1 ± 1.0	35.7 ± 0.9 ***
PAF (2 ng/mL)	0.0 ± 0.7	10	4.4 ± 1.7	4.3 ± 0.8 *	2.8 ± 0.8	4.7 ± 0.1 ***	1.3 ± 0.1	1.9 ± 0.3
Thr (0.1 U/mL)	0.0 ± 0.3	10	1.7 ± 1.1	−0.2 ± 0.1	−0.2 ± 0.7	−0.2 ± 0.8	−1.1 ± 1.2	0.0 ± 0.4

^*p < 0.05;

^**p < 0.01;

^***p < 0.001.

© 2014 by the authors; licensee MDPI, Basel, Switzerland This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).

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Shih, H.-C.; Chern, C.-Y.; Kuo, P.-C.; Wu, Y.-C.; Chan, Y.-Y.; Liao, Y.-R.; Teng, C.-M.; Wu, T.-S. Synthesis of Analogues of Gingerol and Shogaol, the Active Pungent Principles from the Rhizomes of Zingiber officinale and Evaluation of Their Anti-Platelet Aggregation Effects. Int. J. Mol. Sci. 2014, 15, 3926-3951. https://doi.org/10.3390/ijms15033926

AMA Style

Shih H-C, Chern C-Y, Kuo P-C, Wu Y-C, Chan Y-Y, Liao Y-R, Teng C-M, Wu T-S. Synthesis of Analogues of Gingerol and Shogaol, the Active Pungent Principles from the Rhizomes of Zingiber officinale and Evaluation of Their Anti-Platelet Aggregation Effects. International Journal of Molecular Sciences. 2014; 15(3):3926-3951. https://doi.org/10.3390/ijms15033926

Chicago/Turabian Style

Shih, Hung-Cheng, Ching-Yuh Chern, Ping-Chung Kuo, You-Cheng Wu, Yu-Yi Chan, Yu-Ren Liao, Che-Ming Teng, and Tian-Shung Wu. 2014. "Synthesis of Analogues of Gingerol and Shogaol, the Active Pungent Principles from the Rhizomes of Zingiber officinale and Evaluation of Their Anti-Platelet Aggregation Effects" International Journal of Molecular Sciences 15, no. 3: 3926-3951. https://doi.org/10.3390/ijms15033926

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Synthesis of Analogues of Gingerol and Shogaol, the Active Pungent Principles from the Rhizomes of Zingiber officinale and Evaluation of Their Anti-Platelet Aggregation Effects

Abstract

1. Introduction

2. Results and Discussion

2.1. Chemistry

2.2. Anti-Platelet Aggregation Evaluation Bioassay

3. Experimental Section

3.1. General

3.2. Synthesis of Derivatives and Spectral Data

3.2.1. Preparation of Dehydrozingerone (9)

3.2.2. General Procedure for the Synthesis of [n]-Dehydroshogaols (2a–f) and [n]-Dehydrogingerols (3a–f)

3.2.3. General Procedure for the Synthesis of [n]-Epoxydehydroparadol (7a–f)

3.2.4. General Procedure for the Synthesis of [n]-Paradols (5a–f)

3.2.5. General Procedure for the Synthesis of [n]-Dehydroparadols (6a–f)

3.2.6. General Procedure for the Synthesis of [n]-Gingerols (8a–f)

3.2.7. General Procedure for the Synthesis of [n]-Shogaols (4a–f)

3.2.8. General Procedure for the Synthesis of [n]-Isodehydrogingerdiones (1a–f)

3.3. Antiplatelet Aggregatory Bioassay

4. Conclusions

Acknowledgments

Conflicts of Interest

References

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