Combined Theoretical and Experimental Study on High Diastereoselective Chirality Transfer Based on [2.2]Paracyclophane Derivative Chiral Reagent

We report a paracyclophane N–Me thioamide chiral
reagent
for the asymmetric thio-Claisen rearrangement with high diasteroselectivity.
Comparisons between candidate chiral reagent N-phenyl-N-([2.2]­paracyclophan-4-yl)­amide,
N-methyl amide, N-phenyl thioamide, and N-methyl thioamide are made
both by experiment and theoretical calculations to clarify the principle
behind the high diasteroselectivity. Dynamic 1H NMR phenomenon
tested by varying temperature (VT) experiments has proved that N–Ph
amides have triple splitting peaks, while N–Ph
thioamide would reduce the number to two, further substituting the
Ph to Me made dynamic phenomenon disappear. So the side chain is thought
to be the most rigid in N–Me thioamide, which accounts for
a structure prerequisite favoring high efficient chirality transfer.
This is confirmed by theoretical calculation: remarkable energy difference
exists between the Re and Si faces
of the chiral molecule. To further clarify the possible pathways for
thio-Claisen rearrangement, theoretical prediction is adopted. The
result implies that the cisoid pathways will dominate the process.
Further experiment confirmed this: with N–Me thioamide, the
asymmetrical reaction affords γ-unsaturated thioamides in good
yields and high diastereoselectivities up to 98%. After removing the
thioamide auxiliaries under hydrolysis conditions, product β,γ-substituted
chiral alcohols reached high enantiopurity of 98% ee.