First total synthesis of Artekeiskeanol B and D

Synthesis of natural products, Artekeiskeanol B and D are described. The important protocols involved in the synthesis are oxidative C-C bond cleavage, Still-Gennari olefination, debenzylation and Mitsunobu etherification. The synthesis was started from commercially available Geraniol and 2,4-dihydroxy benzaldehyde.


Introduction
Coumarins and their derivatives are abundantly available as natural products, particularly from plant plethora. [1][2][3][4][5][6] Coumarins, were first isolated by Vogel and Guibourt, independently in 1820, from tonka beans and melilot flowers respectively and the first synthesis was reported by Perkin in 1868. The coumarin derivatives have occupied a huge space in pharmaceuticals and also in other areas like cosmetics. [7][8][9] Artekeiskeanol A-D ( Figure 1) are coumarin derivatives, isolated from Artemisia keiskeana, a traditional medicinal plant. [10][11][12] The biological importance and their structural fascination attracted us to carry out their synthesis. As part of our regular research program, in the synthesis of biologically active natural products, [13][14][15][16][17][18][19] we have already reported the total synthesis of Artekeiskeanol A and C. 20 Whereas, in this report, presenting the total synthesis of Artekeiskeanol B and D. In this work, we have followed, our previous protocol (Scheme 1) 20 for the synthesis of 7-hydroxy coumarin's entitled as isofraxidin and scopoletin, which are the main intermediates for Artekeiskeanol A -D. (Figure 1).

Results and Discussion
Herein, we report the synthesis of Artekeiskeanol B and D, respectively as shown in the scheme-2, as a prolongation to our previous work reported earlier. 20 The key steps in our convergent strategy involve Still-Gennari olefination and Mitsunobu reaction. The Key precursor (11) could be synthesized from commercially available geraniol.

Conclusions
In summary, we report the first total synthesis of Artekeiskeanol B and D in 9 steps with an overall yield, 13.6% each. The key reactions involved in this synthesis are oxidative cleavage of olefin, selective debenzylation, Still-Gennari olefination for the synthesis of aliphatic side chain 11 with desired cis and trans configuration respectively at C-6/C-2 and Mitsunobu etherification for coupling of sidechain with scopoletin (3) and isofroxadin (4) to acheive the targets Artekeiskeanol B and D.

Experimental Section
General. All the air and moisture sensitive reactions were carried out under inert atmosphere (nitrogen or argon). Oven-dried glass apparatus were used to perform all the reactions. Freshly distilled anhydrous solvents were used for air and moisture sensitive reactions. Commercially available reagents were used as such.
Purification of compounds was carried out via column chromatography by using silica gel (60-120 mesh) packed in glass columns. 1 H NMR and 13 C NMR were recorded in CDCl3 on 100 MHz and 400 MHz spectrometer, using TMS as an internal standard. IR spectra were recorded on a Perkin-Elmer FT-RT 240-c Spectrophotometer using Thin Film optics. Mass spectra were recorded on a Finnigan MAT 1020 mass spectrometer operating at 70eV. High resolution mass spectra (HRMS) [ESI+] were obtained using TOF spectrometer.
The solvent was distilled off in vacuum to give crude compound, which was then purified by column chromatography using silica gel (60-120 mesh) by eluting with EtOAc-Hexane (1:1) mixture to afford, epoxide 6 (4.1g, 77%) as a yellow oil.

Methyl-(2Z,6E)-8-(benzyloxy)-2,6-dimethylocta-2,6-dienoate (8).
To a stirred solution of epoxide 6 (3g, 1.11 mmol) in dry THF (16 mL) was added a solution of H5IO6 (3.9g, 17.3 m mol), which was dissolved in water (8 mL) at 0 o C and the resulting mixture was stirred for 30 min. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with sat. NaHCO3 and stirred for 30 min. The aqueous layer was extracted with EtOAc (2x30 mL) and the combined organic layer was washed with brine, dried over Na2SO4, concentrated under reduced pressure. The obtained aldehyde 7 (95%), which was used as such for further reaction without purification.
To a stirred solution of 18-crown-6-ether (5.6g, 21.10 mmol) and methyl 2-(bis(2,2,2-trifluoro ethoxy)phosphoryl)propanoate (4.2g, 12.66 mmol) in dry THF (15 mL) at -78 o C was added a solution of KHMDS (2.52g, 12.66 mmol) and stirred for 20 min, then crude aldehyde 7, in dry THF was added and stirred for another 30 min at the same temperature. After completion of the reaction (confirmed by TLC), the reaction mixture was quenched with sat. ammonium chloride. The aqueous layer was extracted with hexane (2x30 mL) and the combined organic layers were washed with brine, dried over Na2SO4. The solvent was evaporated under reduced pressure to give crude compound, which was then purified by column chromatography using silica gel (60-120 mesh) by eluting with EtOAc-Hexane (1:9) mixture to afford, compound 8 (2.77g, 88%) as a yellow oil over two steps.   (11). To a stirred solution of naphthalene (4.9g, 38.5 mmol) in dry THF (50 mL) was added lithium (0.17g, 24.06 mmol) at room temperature and stirred for 2 h. Then, added compound 10 (1.8g, 4.81 mmol), which was dissolved in dry THF (10 mL) at -45 o C and stirred for 1h at the same temperature. After completion of the reaction (confirmed by TLC), the reaction mixture was quenched with sat.NH4Cl and the aqueous layer was extracted with EtOAc