Stereoselective Synthesis of Euscapholide and Tetraketide via Prins Cyclisation and Ring-Closing Metathesis

A concise and diastereoselective total synthesis of tetra- ketide and euscapholide is described in ten steps in 10.6% overall yield from acetaldehyde and ( S )-pent-4-ene-1,2-diol


Mild conditions Simple operation
High diastereoselectivity Exclusive products in the ratio 65: 35 10.6% overall yield in ten steps Natural products from terrestrial plant sources have been a source of discovery for numerous biologically active compounds. 1 Along this line, tetraketide (1) and euscapholide (2) are a dioxabicyclo[3.3.1]nonan-3-one derivative and a ,-unsaturated -lactone that were obtained from the leaves of Euscaphis japonica. 2 Natural products containing ,-unsaturated -lactone and bicyclic lactone/pyrone structural motifs have attracted attention because of their unusual structural architecture, electrophilic nature as Michael acceptors, and range of biological properties including analgesic, antibacterial, antifungal, anti-inflammatory, antiparasitic, antidiabetic, and cytotoxic activities ( Figure 1). 3,4 In addition, some of them have been used in traditional medicine for treating arthritis, headache, and hepatitis infections, 4h headaches, morning sickness, cancer, pulmonary diseases, and a variety of other bacterial and fungal infections. 4d Owing to their interesting chemical framework and promising biological profiles, these compounds have attracted much attention from the chemical synthesis community over the past decade. 5 Recently O'Doherty et al. reported the total synthesis of euscapholide (2) 6 and Mohapatra et al. reported the total synthesis of tetraketide (1). 7 The absolute structures of 1 and 2 were assigned based on NMR spectroscopic and circular dichroism analyses. Compound 2 shows anti-inflammatory activity; whereas its analogue, 3,7-dihydroxy-5-octenolide, which lacks the Michael acceptor, does not show any antiinflammatory activity and the biological activity of 1 remains to be assessed. 4j,k However, further biological evaluation of compounds 1 and 2 is hindered due to their limited availability from natural sources. Hence, a concise, unified, and efficient approach has been developed toward the total synthesis of 1 and 2, which can provide sufficient amounts of the target compounds for further biological evaluation.

Figure 1
Bioactive natural products bearing the ,-unsaturated -lactone motif 5a,b The retrosynthetic analysis of 1 and 2 is illustrated in Scheme 1. An assessment of the structures of tetraketide (1) and euscapholide (2) showed that bicyclic lactone 1 could be derived from an intramolecular oxa-Michael addition reaction of 2, which could be accessed from acrylated compound 3 through ring-closing metathesis (RCM). Precursor 3 could be obtained from iodopyran 4, which could, in turn, be accessed from acetaldehyde 5 and homoallylic alcohol 6

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via Prins cyclization. Finally, homoallylic alcohol 6 could be obtained from epichlorohydrin 7 using Jacobsen hydrolytic kinetic resolution.
In conclusion, a concise, enantio-and diastereoselective total synthesis of tetraketide (1) and euscapholide (2) has been accomplished in ten steps with an overall yield of over 10%. Jacobsen hydrolytic kinetic resolution, ring-closing metathesis, Prins cyclisation reaction and oxa-Michael addition reaction are the key steps. The operational expediency, synthetic efficiency, and high diastereoselectivity make the synthetic process practicable. We believe the current strategy provides a reliable route for the synthesis of structural analogues of ,-unsaturated -lactones and -pyrones for structure-activity studies.

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Commercial reagents were used without further purification and all solvents were purified by standard techniques. Infrared spectra were recorded with a Perkin-Elmer 683 spectrometer. Specific rotations were obtained with a Jasco Dip 360 digital polarimeter. NMR spectra were recorded in CDCl 3 with Varian Unity 400 and 500 MHz NMR spectrometers. Chemical shifts () are quoted in parts per million and are referenced to tetramethylsilane (TMS) as an internal standard. Coupling constants (J) are quoted in Hertz and the resonance multiplicity abbreviations used are: s, singlet; d, doublet; t, triplet; q, quartet; q quintet; dt, doublet of triplets; dd, doublet of doublets; ddd, doublet of doublet of doublets; dddd, double double doublet of doublets; m, multiplet. Column chromatographic separations were carried out on silica gel (60-120 mesh) and flash chromatographic separations were carried out using 230-400 mesh, silica gel. Mass spectra were recorded with Micromass VG-7070H for EI and VG Autospec M FABMS spectrometers.

2-[(Benzyloxy)methyl]oxirane (8)
To a stirred suspension of NaH (8 g, 333 mmol) in anhydrous THF (400 mL) at 0 °C, was added dropwise benzyl alcohol (24 g, 222 mmol) dissolved in anhydrous THF (100 mL). After 30 minutes, epichlorohydrin 7 (20.5 g, 222 mmol) was added and the reaction mixture was allowed to rise to r.t. and stirred for 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was quenched at 0 °C with saturated aqueous ammonium chloride (100 mL), diluted with EtOAc (100 mL) and extracted with EtOAc (2 × 100 mL). The combined organic extracts were washed with brine (100 mL) and dried over Na 2 SO 4 . After filtration and removal of solvent under reduced pressure, the crude oxirane was purified by column chromatography eluting with 5% EtOAc/hexane to give pure product 8 (34.4 g, 94% yield) as a colourless liquid.

(S)-Pent-4-ene-1,2-diol (6)
To a stirred suspension of lithium (16 g, 250 mmol) in liquid NH 3 (160 mL) was added 11 (16 g, 83.3 mmol) dissolved in anhydrous THF (100 mL). The mixture was stirred for 20 minutes and quenched with solid NH 4 Cl (15 g). The ammonia was allowed to evaporate at r.t., ether (100 mL) was added to the residue and the mixture was filtered through Celite ® . The filtrate was dried over Na 2 SO 4 , filtered, and the solvent was removed under reduced pressure. The residue was purified by column chromatography eluting with 70% EtOAc/hexane to afford diol 6 (7.6 g, 90% yield) as a colourless liquid.

(2S,4R,6S)-Tetrahydro-2-(hydroxymethyl)-6-methyl-2H-pyran-4ol (12)
TFA (21.5 mL) was added slowly to a solution of homoallylic alcohol 6 (2.5 g, 24.5 mmol) and acetaldehyde 5 (3.24 g, 73.5 mmol) in anhydrous CH 2 Cl 2 (50 mL) at 25 °C and the reaction mixture was stirred for 6 h at r.t. After completion of reaction, as monitored by TLC, the reaction was quenched with saturated aqueous NaHCO 3 (60 mL) and the pH was adjusted to >7 by addition of triethylamine. The two layers were separated, the aqueous layer was extracted with CH 2 Cl 2 (4 × 50 mL) and the combined organic layers were concentrated under reduced pressure. The crude residue was dissolved in MeOH (40 mL), potassium carbonate (10.16 g, 73.52 mmol) was added, and the mixture was stirred for 0.5 h. The MeOH was removed under reduced pressure and water (25 mL) was added. The mixture was extracted with CH 2 Cl 2 (3 × 50 mL), dried over anhydrous Na 2 SO 4 , filtered, and the solvent was removed under reduced pressure. Purification of the crude material by column chromatography eluting with 60% EtOAc/ hexane afforded pure 12 (1.86 g, 52%) as a pale-yellow solid.

-2-(Iodomethyl)-6-methyltetrahydro-2Hpyran-4-yl)oxy) Dimethylsilane (4)
To a stirred solution of 14 (3.8 g, 9.2 mmol) in acetone (40 mL) was added NaI (20.7 g, 137.7 mmol) and the mixture was heated to reflux for 24 hours. After completion of reaction as monitored by TLC, the acetone was removed under reduced pressure. To the resulting residue was added water and CH 2 Cl 2 , and the organic layer was extracted, dried over Na 2 SO 4 , filtered, concentrated under reduced pressure, and purified by silica gel chromatography eluting with 7% EtOAc/hexane to afford 15 (3.1 g, 91%) as a colourless liquid.

(R)-6-((S)-2-(Benzyloxy)propyl)-5,6-dihydro-2H-pyran-2-one (19)
A solution of compound 18 (0.70 g, 2.5 mmol) in anhydrous CH 2 Cl 2 (500 mL) was degassed and Grubbs' second generation catalyst (0.05 mg, 0.06 mmol) was added at r.t. under nitrogen atmosphere and the resulting pale-purple solution was heated to reflux for 12 hours. After completion of reaction (monitored by TLC), the majority of the solvent was distilled off and the concentrated solution was stirred at r.t. for 2 hours under air bubbling in order to decompose the catalyst. Evaporation to dryness under reduced pressure gave a brown residue that was purified by column chromatography on silica gel eluting with 40% EtOAc/hexane to afford cyclic lactone 19 (0.43 g, 70%) as a colourless oil.