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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Tetrahedron Lett. Author manuscript; available in PMC 2010 June 10.
Published in final edited form as:
Tetrahedron Lett. 2009 June 10; 50(23): 2713.
doi:  10.1016/j.tetlet.2009.03.145
PMCID: PMC2817976

Synthesis of (+/-)-Oleocanthal via a Tandem Intramolecular Michael Cyclization-HWE Olefination


A synthesis of racemic oleocanthal has been accomplished in eleven steps from 1,3 propanediol by a key tandem intramolecular Michael cyclization-Horner Wadsworth Emmons olefination.

The secoiridoids are a class of plant-derived monoterpenes containing the substituted pyran core of secologanin (1). This class of natural products arises in biological systems from the oxidative cleavage of the loganin skeleton (2) by the cytochrome P450 enzyme secologanin synthase.1 Secologanin then undergoes various modifications to produce a wide array of structures displaying diverse biological activity including analgesic2, anti-inflammatory3, anti-arthritic4, anti-allergenic5, antibacterial6, and antiviral7 activities. Coupling of the simple secoiridoids with tryptamine gives rise to a large class (>250 examples) of indole and oxindole alkaloids including geissoschizine, strychnine, reserpene, ajmaline, and the Vinca alkaloids with highly varied carbon frameworks and biological profiles.

We reasoned that, given the structural similarities of the secologanin-derived natural products, synthetic access to the more complex secoiridoid and secologanin tryptamine alkaloids could be obtained through a single strategically functionalized intermediate. As a test case for our strategy, our attention focused on the secoiridoid oleocanthal (3) both for its relative structural simplicity which retains the compact arrangement of functionality of the secoiridoids as well as its demonstrated potency as an inhibitor of the COX-1 and COX-2 enzymes3,8, making it an ideal entry point into the synthesis of this class of natural products.

Important to our retrosynthetic analysis was proceeding through an intermediate with functionalities that could be independently manipulated allowing for future adaptation of this synthesis to produce a diverse selection of natural product targets. Lactone 5 appeared ideal for this purpose as it contains the requisite carbon backbone as well as properly situated synthetic handles with orthogonal reactivities.

We envisioned the dialdehyde moiety of 3 arising from the reduction and oxidation of lactone 5 whose carbon framework could be assembled through a key tandem Michael cyclization and Horner-Wadsworth-Emmons (HWE) olefination9 of phosphonoacetic ester 6. This allows for the simultaneous assembly of the desired lactone core, the addition of the two-carbon olefin sidechain, and the introduction of a stereogenic center. Studies to control the absolute configuration of this new stereogenic center through the introduction of chiral auxiliaries are currently underway.

Assembly of lactone 5 began with the synthesis of aldehyde 7 from 1,3-propanediol utilizing the method reported by Schaus and coworkers.10 Reaction of 7 with commercially available trimethyl acetophosphonate under Masamune-Roush conditions produced the unsaturated ester 8 as a single isomer and in good yield (Scheme 2). Deprotection and subsequent esterification gave the desired substrate 6, which upon treatment with Cs2CO3 and acetaldehyde in warm acetonitrile underwent sequential intramolecular Michael cyclization and HWE olefination to yield lactone 5 as an inconsequential 1.6 : 1 mixture of E/Z isomers.

Scheme 2
Synthesis of lactone 5.

Selective hydrolysis of the methyl ester of 5 yielded acid 9 that was esterified with protected tyrosol 10 affording lactone 11, which upon reduction and Dess-Martin oxidation gave the dialdehyde precursor to oleocanthal as a single isomer (Scheme 3). This sensitive dialdehyde rapidly decomposed when treated with standard deprotection conditions (HF, HF-pyr, TBAF) but underwent clean deprotection to furnish (+/-)-oleocanthal when the neutral conditions described in the literature by Smith, et al. were employed (HF, TBAF aqueous THF at pH = 7).2

Scheme 3
Synthesis of (+/-)-oleocanthal.

We have demonstrated a short and scalable synthesis of (+/-)-oleocanthal, which can be readily adapted to allow access to a diverse selection of secoiridoid natural products. Current efforts are underway to both control the absolute stereochemistry of the key intramolecular Michael cyclization step of this approach and to then employ this method to synthesize several secoiridoids and secologanin tryptamine alkaloids.

Synthesis of Ester 8

To a flame dried 2 L round-bottomed flask (RBF) charged with 20.98 mL (121.3 mmol, 1.1 equiv.) methyl 2-(dimethoxyphosphoryl)acetate dissolved in 1000 mL dry MeCN was added 6.170g (145.5 mmol, 1.2 equiv.) LiCl and then 21.12 mL (121.3 mmol, 1.2 equiv.) iPr2NEt. The reaction was stirred at ambient temperature for 15min and then 22.84 g (121.3 mmol, 1 equiv.) aldehyde 7 dissolved in a minimum of MeCN was added. After stirring for 4 h the reaction was concentrated to approximately 50% volume, added to brine, and extracted 3 times with EtOAc. Combined organic layers were dried over Na2SO4, concentrated, and purified by silica gel chromatography eluting with 4:1 hex./EtOAc to yield 28.56 g (96%) of the title compound as a colorless oil. 1HNMR (300 MHz, CDCl3): [delta] 6.96 (dt, J = 15.6, 7.2Hz, 1H), 5.87 (dt, J = 15.9, 1.5Hz, 1H), 3.71 (s, 3H), 3.70 (m, 2H), 2.40 (qd, J = 6.6, 1.8Hz, 2H), 0.87 (s, 9H), 0.04 (s, 6H); 13CNMR (75MHz, CDCl3): [delta] 167.1, 146.4, 122.7, 61.7, 51.6, 35.9, 26.0, 18.5, -5.2; IR (NaCl, film): 1729, 1660 cm-1; HRMS (+TOF): [M+H]+ 245.1568 calcd for C12H25O3Si, found: 245.1571; Rf = 0.40 (9:1 hex./EtOAc).

Synthesis of Phosphonate 6

To a 1 L HDPE bottle was added 24.85 g (101.7 mmol, 1 equiv.) (E)-methyl 5-(tert-butyldimethylsilyloxy)pent-2-enoate (8) dissolved in 500 mL dry THF followed by 53 mL HF as a 48% solution in H2O. The reaction was stirred for 6 h at ambient temperature, then slowly added to NaHCO3(sat.), and extracted twice with EtOAc. Combined organic layers were dried over Na2SO4 and concentrated. The resulting residue was dissolved in 1:1 hex./EtOAc and filtered through a short silica gel plug. Concentration yielded 11.90 g (90%) of the desired alcohol as a pale yellow oil.

An oven-dried 100 mL RBF was charged with 2.940 g (22.58 mmol, 1 equiv.) of the above alcohol, 4.560 g (27.11 mmol, 1.2 equiv.) 2-(dimethoxyphosphoryl)acetic acid, and 45 mL dry CH2Cl2. To this was added 5.590 g (27.11 mmol, 1.2 equiv.) DCC dissolved in a minimum volume of CH2Cl2. The reaction was stirred for 45 min at ambient temperature before being filtered through a Celite pad and concentrated. Purification by flash chromatography eluting with EtOAc yielded 6.310 g (>99%) of 6 as a colorless solid. 1HNMR (300 MHz, CDCl3): δ 6.84 (dt, J = 15.6, 6.9Hz, 1H), 5.83 (dt, J = 15.9, 1.5 Hz, 1H), 4.18 (t, J = 6.3 Hz, 2H), 3.74 (s, 3H), 3.70 (s, 3H), 3.65 (s, 3H), 2.91 (d, JHP = 21.6 Hz, 2H), 2.49 (qd, J = 6.6, 1.5 Hz, 2H); 13CNMR (75MHz, CDCl3) δ 166.6, 165.7, 144.1, 123.5, 63.6, 53.4, 51.7, 34.3, 32.5, 31.4; IR (NaCl, film): 1724, 1660; HRMS (+TOF) calcd for C10H18O7P [M+H]+ 281.0785, found= 281.0788; Rf = 0.18 (EtOAc).

Synthesis of Lactone 5

To 179 mg (0.639 mmol, 1 equiv.) (E)-methyl 5-(2-(diethoxyphosphoryl)acetoxy)pent-2-enoate (6) dissolved in 3 mL dry MeCN in an oven-dried 25 mL RBF was added 416 mg (1.28 mmol, 2 equiv.) Cs2CO3. The reaction was heated to reflux for 1.5 h, cooled to 0°C, and 107 μL (1.92 mmol, 3 equiv.) freshly distilled acetaldehyde was added in a single portion. The reaction was vigorously stirred for 16 h at ambient temperature and was then acidified with 1N HCl. This mixture was extracted 3 times with EtOAc. Combined organic layers were dried over Na2SO4, concentrated, and purified by silica gel flash chromatography eluting with 2:1 to 1:1 hex./EtOAc to yield 53.0 mg (42%) of 5 (1.6 : 1 E/Z) as a yellow oil.

Synthesis of Lactone 11

To 69.0 mg (0.345 mmol, 1 equiv.) crude lactone 5 dissolved in 2 mL 3:1 THF:H2O in a 10 mL RBF was added 25.0 mg (1.03 mmol, 3 equiv.) LiOH. The reaction was stirred at ambient temperature for 2 h and then acidified with 1N HCl. This mixture was extracted 3 times with EtOAc, dried over Na2SO4, and concentrated. The resulting residue was purified by silica gel flash chromatography eluting with 1:1:0.01 to 0:1:0 hex./EtOAc/HOAc to yield 44.0 mg (70%) of the desired acid as an inseparable mixture (1.6 : 1 E/Z) of E/Z isomers as a pale yellow oil.

To 36.0 mg (0.193 mmol, 1 equiv.) of the above acid dissolved in 2 mL dry CH2Cl2 in an oven-dried 10 mL RBF and cooled to 0 °C was added 85.0 mg (0.290 mmol, 1.5 equiv.) 2-(4-(triisopropylsilyloxy)phenyl)ethanol (10) followed by 60.0 mg (0.290 mmol, 1.5 equiv.) DCC and a spatula tip of DMAP. The reaction was stirred 16 h at ambient temperature, filtered through celite, concentrated, and purified by silica gel flash chromatography eluting with 2:1 hex./EtOAc to yield 89.0 mg (>99%) of the title compound as a colorless oil. 1HNMR (300 MHz, CDCl3): Z-isomer δ 7.05 (m, 2H), 6.82 (m, 2H), 6.19 (qd, J = 7.2, 1.5 Hz, 1H), 4.26 (t, J = 6.9 Hz, 2H), 4.11 (td, J = 9.0, 3.6 Hz, 1H), 3.81 (m, 1H), 3.09 (m, 1H), 2.84 (dt, J = 17.1, 6.9 Hz, 3H), 2.44 (ddd, J = 15.6, 8.9, 6.3 Hz, 2H), 2.04 (dd, J = 7.2, 1.2 Hz, 3H), 1.24 (m, 3H), 1.10 (s, 18H), E-isomer δ7.01-7.09 (m, 3H), 6.79 (m, 2H), 4.24-4.38 (m, 3H), 4.16 (m, 1H) 3.32 (m, 1H), 2.85 (t, J = 7.2 Hz, 2H), 2.41 (m, 2H), 1.83 (d, J = 7.5 Hz, 3H), 1.70 (m, 2H), 1.22 (m, 3H), 1.07 (m, 18H); 13CNMR (75 MHz, CDCl3) mixture of isomers δ 172.4, 171.4, 166.5, 154.9, 142.1, 139.6, 133.8, 130.2, 129.9, 129.8, 120.1, 120.1, 68.2, 65.5, 38.0, 34.4, 34.1, 29.6, 27.4, 27.0, 25.8, 25.2, 18.3, 14.4, 12.8; IR (NaCl, film) 1732, 1511 cm-1; HRMS (+TOF) calcd for C26H41O5Si [M+H]+ 461.2728, found 461.2722; Rf = 0.24 (2:1 hex./EtOAc).

Synthesis of Oleocanthal (3)

To 47.0 mg (0.102 mmol, 1equiv.) (S)-4-(triisopropylsilyloxy)phenethyl 2-(3-ethylidene-2-oxotetrahydro-2H-pyran-4-yl)acetate (11) dissolved in 1 mL dry THF in a 10 mL flame-dried RBF at -78°C was slowly added 102 μL of a 1M solution of DIBAL in toluene. After stirring the reaction for 1 h at -78°C 100 μL dry MeOH was added, the reaction was allowed to warm to ambient temperature, and 5 mL saturated Rochelle's salt solution was added. After stirring for 30 min this mixture was extracted 3 times with EtOAc, dried over Na2SO4, concentrated, and purified by silica gel flash chromatography eluting with 4:1 hex./EtOAc to yield 48 mg of the desired alcohol as a colorless oil.

This residue was dissolved in 1 mL dry CH2Cl2, charged to a 10 mL oven-dried RBF, and cooled to 0°C. To this solution was added 65.0 mg (0.153 mmol, 1.5 equiv.) Dess-Martin periodinane and the reaction was stirred for 3 h at ambient temperature before the addition of 5 mL 5:1 Na2S2O3(sat.):NaHCO3(sat.) solution. This mixture was stirred for 15 min before being extracted 3 times with CH2Cl2. Combined organic layers were dried over Na2SO4 and concentrated. Flash chromatography eluting with 4:1 hex./EtOAc yielded 26.0 mg (55%) of the desired dialdehyde as a colorless oil.

To 7.0 mg of the above dialdehyde dissolved in 250 μL dry THF at 0°C was added 50 μL of a solution prepared by the addition of 40% HF (aq.) to a 1M THF solution of TBAF until the pH of the resulting solution reached 7 as evidenced by pH paper. The reaction was stirred for 2 h at 0 °C, added to brine, and extracted 3 times with EtOAc. Combined organic layers were dried over Na2SO4, concentrated, and taken up in 1:2 hex./EtOAc. This solution was filtered through a short plug of silica gel and concentrated to yield 3.7 mg (80%) of (+/-)-oleocanthal as a colorless film. All spectral properties matched data reported in the literature.8

Figure 1
Structures of several secologanin derivatives.
Scheme 1
Retrosynthetic analysis.


We gratefully acknowledge financial support from the National Institutes of Health (Grant GM068011). Mass spectra were obtained on instruments supported by the National Institutes of Health Shared Instrumentation Grant No. GM49631. We also gratefully acknowledge an Eli Lilly Graduate Fellowship to BJE from Eli Lilly.


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