Towards the total synthesis of Peperomin D

Abstract

Peperomins A – E are a class of novel and unusual type of secolignans with a common structure except for the different substituents of the aromatic rings. Extracted from different Peperomia type plants found in Taiwan, Venezuela or India, these molecules present a broad range of significant biological activities, from antitumor to anti-HIV, and therefore they are considered as potential chemotherapeutic agents. Thus, it is highly desirable any efficient synthesis of these natural compounds. From all types of peperomins, peperomin D has been described in the literature as the most complicated to synthesize. Therefore, it is an excellent target to challenge new synthetic methods. Keeping in mind this idea, the key step of our approach, and the major improvement compared to other syntheses, involves a catalytic nickel(II) reaction recently developed in our research group.The strength of this reaction is the use of a nickel(II) complex, which is structurally simple, robust, and commercially available. The reaction is highly stereoselective and efficient, as only one of the two possible diastereomers is observed and isolated in excellent yields. After some studies with an N-acyl thioimide containing an ester group, the removal of the chiral auxiliary turned out to be too difficult and, as a consequence, we were forced to modify our synthetic plan. Instead, a new approach based on the reaction of an N-acyl thioimide possessing a terminal olefin was assessed. Preliminary results have been promising. Double bonds are much more resistant to hydride reagents and thus DIBAL-H can be used to reduce the chiral auxiliary. The synthetic approach shown in the former scheme has provided alcohol 19 in an overall yield of 84% over 3 steps. Moreover, it was possible to avoid chromatographic purification of product 6, as well as in the reaction of 18 to give 19. In order to complete the synthesis, further steps involving ozonolysis, cyclization and substrate-controlled α-methylation will be applied. By completing the synthesis with the most complicated peperomin among all of them, the synthetic pathway might also be applied to synthesize all other peperomins. Work is in process.