B01 Synthesis of DBFOX/Ph Ligands

Synthesis of DBFOX Ligands:
Synthesis of (R,R)-4,6-dibenzofurandiyl-2,2'-bis(4-phenyloxazoline) (R,R-DBFOX/Ph) starts with the known bislithiation at 4,6-positions of the commercially available dibenzofuran. The lithiated intermediate is dicarboxylated with dry ice to give 4,6-dibenzofurandicarboxylic acid (44% based on dibenzofuran) which is sparingly soluble in most organic solvents. Conversion of the diacid to the corresponding acid chloride was very difficult under normal conditions of acid chloride preparation because of its low solubility. Indeed, treatment the diacid with either thionyl chloride in chloroform under reflux or refluxing with thionyl chloride without solvent was ineffective, and the starting diacid was quantitatively recovered unchanged. However, we found in the process of surveying reaction solvents that the diacid is soluble in trifluoroacetic acid with a color change to deep violet. Accordingly, the diacid was treated under reflux with thionyl chloride in the presence of trifluoroacetic acid. Removal of the excess thionyl chloride was followed by treatment with (R)-2-phenyl-2-aminoethanol to give the corresponding amide. The usual cyclization procedure including a sequence of chlorination of the hydroxyl group to chloroethyl moiety and cyclization by the aid of sodium hydroxide gave R,R-DBFOX/Ph in 63% yield for the total steps starting from diacid. Other ligands having isopropyl (DBFOX/i-Pr) and benzyl (DBFOX/Bn) shielding substituents at 4-position of the oxazoline ring can be prepared by similar routes.

Purity and Structure of DBFOX/Ph Ligand:
The DBFOX/Ph ligand thus prepared was found to be an enantiomeric purity of 98.3% ee by HPLC using a chiral column (Daicel chiralcel OD-H with hexane - i-PrOH = 9:1 v/v, 1 ml/min, t(R) = 23.7 min, t(S) = 27.4 min). The ligand R,R-DBFOX/Ph with this enantiomeric purity is suitable in the following asymmetric reactions. Although attempted purification by crystallization forms a film on the wall of flask, crystallization from ethyl acetate - hexane gives small crystals. X-Ray diffraction analysis shows that two chiral 4-phenyloxazoline rings of DBFOX/Ph are attached to the 4 and 6 positions of dibenzofuran skeleton so that the minimum distance between these two nitrogens can be 4.1 A.

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