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.