(-)-DIOP synthesis

Yield:32305-98-9 60.7%

Reaction Conditions:

in tetrahydrofuran;Carnea E-22 at 40 - 50;Product distribution / selectivity;Inert atmosphere;

Steps:

4.A.i
A 250 mL 3 neck round bottom glass reactor equipped with a Teflon coated stir bar, a thermometer and its adapter, a reflux condenser with a gas inlet on top, and a Claisen adapter to which is attached a 60 mL addition funnel and a Teflon stopcock sample port is heated with a heat gun while purging with a rapid flow of N₂ to degas. The reactor is then charged with 16.0 grams of (-)-1,4-di-O-tosyl-2,3-O-isopropylidene-L-threitol (CASNo. 37002-45-2, 36.1 mmol), aka bis(tosylate) and flushed with N₂ purge for an additional 30 minutes. The bis(tosylate) is then dissolved in 100 mL of degassed, anhydrous THF. The sodium diarylphosphide solution prepared in Step 2). A). above is then transferred via cannula to the 60 mL addition funnel in parts and added dropwise to the rapidly stirring bis(tosylate) at rate so as to maintain a reactor temperature below 40° C. Upon addition to the electrophile, the reddish-orange color of the diarylphosphide salt rapidly disappears to give a final suspension with a beige color. After all of the phosphide is added, an oil bath is placed beneath the reactor and the contents heated to 50° C. for 45 minutes to complete phosphide coupling step. The Claisen adapter assembly is then replaced by a short path distillation head and roughly 50% of the THF is removed. Then 100 mL of degassed heptane and water, each, are added to effect a phase split. The biphasic solution is then passed through an inerted glass fritted funnel to remove the carbon black and the lower aqueous phase removed via cannula. The upper organic phase is rinsed with an additional 50 mL of degassed water, again removed via cannula. The organic heptane phase is then extracted with 100 mL of anhydrous, degassed acetonitrile, the lower acetonitrile phase removed via cannula, and again the organic heptane phase is extracted with 50 mL of degassed acetonitrile. The acetonitrile phases are combined and transferred to a 1 neck round bottom flask with a Teflon stopcock on top with a 24/40 standard tapered ground glass joint on top. The volatiles are removed on a rotary evaporator to yield a viscous orange-brown glassy solid that is further dried under vacuum. In a dry box, the Teflon stopcock is replaced with a Claisen adapter to which is attached a reflux condenser with a gas inlet on top and a Teflon stopcock sample port. The glassy solid is then dissolved in crystallized in 100 mL of degassed methanol introduced by cannula or syringe followed by heating to reflux to completely dissolve the ligand. The heat is removed and the DIOP ligand suspension in the flask is immersed in an ice batch and cooled to -10° C. to yield a white to off-white/beige colored solid. The solid DIOP ligand is collected on a glass fritted Schlenck filter, rinsed with chilled methanol, and then dried overnight on the frit under vacuum. A total of 11.7 grams (23.5 mmol, 498.34 g/moll) of the (-)-DIOP ligand was isolated. The ligand is fully characterized by ¹H(CDCl₃: δ=7.58-7.29 ppm, cm, 20H, aromatic; δ=4.0-3.8 ppm, dd, 2H, -CH-; 6-2.50-2.25 ppm, ddd, 4H, -CH₂-; δ1.35 ppm, s, 6H, -CH₃) ¹³C (not reported here, but consistent with desired product), and ³¹P NMR (CDCl₃: δ=-22.87 ppm, singlet, and a mol % P purity>99%) and by ICP for a total phosphorus content of 12.2 wt % P (theory=12.4 wt % P) representing a chemical purity of approximately 98.4% for molecular formula=C₃₁H₃₂P₂O₂ and molecular weight=498.34 g/mol.

References:

Arkema Inc. US2010/234642, 2010, A1 Location in patent:Page/Page column 13

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