In
this article we describe extensive studies of the catalytic asymmetric
heterodimerization of ketenes to give ketene heterodimer β-lactones.
The optimal catalytic system was determined to be a cinchona alkaloid
derivative (TMS-quinine or Me-quinidine). The desired ketene heterodimer
β-lactones were obtained in good to excellent yields (up to
90%), with excellent levels of enantioselectivity (≥90% ee
for 33 <i>Z</i> and <i>E</i> isomer examples),
good to excellent (<i>Z</i>)-olefin isomer selectivity (≥90:10
for 20 examples), and excellent regioselectivity (only one regioisomer
formed). Full details of catalyst development studies, catalyst loading
investigations, substrate scope exploration, protocol innovations
(including double in situ ketene generation for 7 examples), and an
application to a cinnabaramide A intermediate are described. The addition
of lithium perchlorate (1–2 equiv) as an additive to the alkaloid
catalyst system was found to favor formation of the <i>E</i> isomer of the ketene heterodimer. Ten examples were formed with
moderate to excellent (<i>E</i>)-olefin isomer selectivity
(74:25 to 97:3) and with excellent enantioselectivity (84–98%
ee)
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