UC Santa Barbara

Harnessing the Power of Furfuryl Cations:

The Aza-Piancatelli Rearrangement and Beyond

by

Gesine Kerstin Veits

The ubiquity of amine functional groups in all of nature as well as a large majority of pharmaceutically active molecules makes methodologies capable of quickly constructing carbon-nitrogen bonds invaluable. Reactions capable of constructing these highly desirable bonds in addition to introducing molecular complexity are highly sought-after. Therefore we set out to develop a novel cascade rearrangement of furylcarbinols, a sustainable starting material, to 4-aminocyclopentenones, the aza-Piancatelli rearrangement.

Inspired by Piancatelli's rearrangement of furylcarbinols with water to form 4-hydroxycyclopentenones for the synthesis of prostaglandins, we explored the rearrangement with amine nucleophiles to access valuable 4-aminocyclopentenones. The product-forming cascade is initiated by dysprosium trifluoromethanesulfonate, a relatively underdeveloped Lewis acid catalyst. Activation results in the formation of a furfuryl cation (oxocarbenium ion) that is intercepted by an amine nucleophile and terminates in a 4π conrotatory electrocyclization establishing the observed trans-stereochemistry. The chemistry was initially developed with aniline nucleophiles, and was later extended to substituted hydroxylamines. Mechanistic investigations of the aza-Piancatelli rearrangement have shown that an off-cycle binding of the dysprosium catalyst and the amine nucleophile controls the rate, as observed by a Hammett plot. However, the selectivity of the rearrangement is determined by the ability of a nucleophile to efficiently capture the oxocarbenium ion upon its formation.

The value of the aza-Piancatelli rearrangement has been highlighted by the synthesis of an hNK1 inhibitor and by efforts toward the total synthesis of homoharringtonine, a pharmaceutical drug approved for the treatment of chronic myeloid leukemia. Additionally, a Piancatelli rearrangement of macrocyclic furylcarbinols, to be applied to the total synthesis of coralloidolide F, has been explored.

Finally, chiral phosphoric acids such as (R)-TRIP have been found to be catalysts for the aza-Piancatelli rearrangement capable of inducing enantioselectivity. This is the first example of asymmetric cascade rearrangements of its kind.