Synthesis of γ-lactams and γ-lactones via intramolecular Pd-catalyzed allylic alkylations.

Abstract

CONSPECTUS: Lactones and lactams are a well-known class of natural products and can be used as building blocks in organic synthesis. In addition, they can be found in many natural sources and synthetic drugs and have a broad range of biological or odorant properties. Chemists can create these useful compounds through palladium catalysis, which is a highly efficient tool for organic synthesis and is conveniently functional group tolerant. In this Account, we describe our work over the past 15 years in intramolecular Pd-catalyzed allylations where we have tethered the nucleophile and the electrophile by either an amide or an ester moiety, to produce γ-lactams and γ-lactones. We discuss in detail how the nature of the heteroatom tether influences the regioselectivity of the reaction. For example, a ketone [-C(O)CH2-] tether leads to mixtures of 5-exo and 7-endo cyclization products, while ester or amide [-C(O)X-] tethers afford sole 5-exo products. However, in the case of X = O, we were required to overcome two issues in the synthesis of γ-lactones. First of all, the tethering ester function can compete with the allylic leaving group in the oxidative addition to the Pd(0) center. Second, in this case, the proportion of the conformers that have a suitable geometry for cyclization is very low. When we insert a juxtaposed silyl group on the allyl fragment, the molecule can undergo oxidative addition and functionalization of the lactone via Hiyama cross-coupling. We also performed DFT calculations on these systems, which allowed us to better understand the behavior of [-C(O)X-] and [-C(O)CH2-] tethers. Computations also let us rationalize the different reactivities that we observed as a function of the geometry (Z or E) of the starting substrates. In addition, we were able to synthesize natural products or analogs (α-kainic acid, isoretronecanol, and picropodophyllin). We could turn these allylation reactions into asymmetric transformations and incorporate them into domino sequences. Thus, an allylation/Mizoroki-Heck sequence allowed us to straightforwardly access an aza-analog of picropodophyllin, as well as reach the lysergic acid backbone. Finally, we found that through carbopalladation of allenes, we could efficiently synthesize the key η(3)-allylpalladium intermediates that were then ready for allylation reactions.