Methods for total synthesis of resolvin e1
A scheme and compound technology, applied in the field of total chemical synthesis of dissipativein E1, can solve problems such as inapplicability to commercial production
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[0034] The synthesis method of RvE1 disclosed herein is novel and has fewer steps and better overall yields than those of the prior art. The disclosed methods are also safer because they avoid exothermic steps known in the prior art that can be explosive when scaled up.
[0035] Enantioselectivity of the stereocenter in RvE1 obtained by the method starting from compound 28 or 42, or by the reaction of compounds 43 and 46, obtained by using an appropriate chiral starting material, or by reduction of the keto group with Noyori catalyst to introduce. Enantiomeric excess (ee), a measure for the purity of chiral substances, is measured after preparation of the Mosher esters of the corresponding chiral hydroxyl groups. The cis olefins were prepared by using KHMDS as base and at lower temperature (0-78°C). Thermodynamically stable trans olefins are prepared by standard rt or reflux conditions. They are identified by their (corresponding protons) coupling constants (J values). The...
Embodiment 1
[0041] Embodiment 1. Synthesis of compound 10
[0042] Compound 10 was synthesized as shown in Schemes 5 and 6 according to the following steps.
[0043] Synthesis of Compound 2
[0044] To a solution of imidazole (1 equiv), TBSCl (1 equiv), and DMAP (0.05 equiv) in 40 mL of DCM was added diol 1 (3 g, 33 mmol) at 0-5 °C as shown in Scheme 5. The reaction was stirred and allowed to warm to room temperature overnight. The reaction was quenched with ammonium chloride, the product was extracted with DCM, and the organic layer was washed with sodium bicarbonate and brine, then dried over sodium sulfate and concentrated. Material (6.24g) was carried forward as such. Not UV active, but visible with vanillin (R in 10% ethyl acetate / hexane f = 0.5).
[0045] Synthesis of compound 3
[0046]Compound 2 (6.24 g, 31.5 mmol) was added to a solution of TBDPSCl (1 eq), imidazole (1 eq) and DMAP (0.05 eq) in DCM at 0-5 °C. The reaction was stirred and allowed to warm to room temperature...
Embodiment 2
[0056] Embodiment 2. Synthesis of compound 20c
[0057] Compound 20c was synthesized as shown in Scheme 7 according to the following steps.
[0058] A slurry of aluminum chloride (1.79 g, 1.1 equiv) in 55 mL DCM was cooled in an ice / water bath. A solution of glutaric anhydride (1.39 g) and 2-penten-4-yn-1-ol 18 (1 g, 12.2 mmol) in 25 mL of DCM was added dropwise to the slurry at temperature. After the addition was complete, the reaction was allowed to stir overnight at room temperature. While maintaining the temperature below 10 °C, the reaction mixture was slowly added to 1M HCl solution. The mixture was stirred for about 45 minutes until a clear solution was observed. The phases were separated, the organic layer was washed with brine and dried over sodium sulfate. TLC in 30% ethyl acetate / hexanes. Product spot (R f =0.25) is visible with vanillin and is aqua blue in color. 1H NMR (CDCl 3 ,400MHz): δ6.27(dt,1H,J=16.0,6.0Hz),5.74(d,1H,J=16.0Hz),4.63(d,2H,4Hz),2.44(m,4H...
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