Synthesis of Each Enantiomer of Rocaglamide by Means of a Palladium(0)‐Catalyzed Nazarov‐Type Cyclization

Abstract

A recently reported Pd 0 -catalyzed asymmetric Nazarov-type cyclization has been successfully applied in the key step of the first catalytic asymmetric total synthesis of (À)-rocaglamide (natural) and (+)-rocaglamide. The stereochemistry at the C3 position that controls the stereochemistry of all other stereocenters is determined in the cyclization step. This versatile and modular synthesis proceeds from simple reagents.Rocaglamide was isolated in 1982 by King and co-workers from Aglaia elliptifolia, a tree native to south-east Asia, the extracts from which are used in traditional medicine.[1] More than 100 related compounds have been isolated from related Aglaia species.[2] Pharmacological interest in this class of compounds derives from their potent cytostatic and antiinflammatory activities, [3][4][5] which are the result of rocaglamide impairing multiple targets. Rocaglamide targets protein translation initiation by targeting the eukaryotic initiation factor eIF4A and thereby inactivates heat shock factor 1 (HSF1), which is a transcriptional regulator that controls the heat shock response and processes essential for anabolic metabolism. As such these compounds can deprive cancer cells of energy and impair the proliferation of malignant and premalignant cells.[6] Rocaglamide has also been reported to impair transcription factor NFkB signaling (which contributes to its anti-inflammatory activity) and the kinase pathway cRAF-MEK-ERK. [7,8] Significant progress toward clinical development has only taken place during approximately the last three years, in large part because of problems with supply of materials. There are barriers in scaling up the isolation of rocaglamide from the natural source because it occurs as a mixture with structurally related compounds which are difficult to separate. Trost et al. published the first chiral-pool total synthesis of rocaglamide in 1990.[9] Since then several syntheses of racemic rocaglamide have been described.[10] The biogenetically inspired enantioselective synthesis by Porco and co-workers provides the ponapensin-thapsakon family of compounds as well as rocaglamide and is the current state-ofthe-art procedure.[10a] We describe an efficient and scalable synthesis [11] of both enantiomeric forms of rocaglamide that makes use of a Nazarov-type cyclization that we have recently described in the key step. [12] The core of rocaglamide is a fully substituted cyclopentane ring containing adjacent quaternary centers at the C3a and C8b positions. Stereochemical control, especially at the C3 position, has been a challenge for many of the previously published syntheses. Embedded within the rocaglamide we perceived a structure that we could access enantioselectively through a Pd 0 -catalyzed Nazarov-type cyclization that we have recently developed.[12] Although Frontier and co-workers [10o] and Magnus et al. [10p] have prepared racemic rocaglamide by means of Nazarov cyclizations, our strategy disconnects the molecule differently. The first steps of our synthesis are summ...