Construction of the Pentacyclic Core and Formal Total Synthesis of (rac)‐Renieramycin T

Abstract

Invited for this month's cover picture is the group of Professor Naoki Saito at the Graduate School of Pharmaceutical Sciences, Meiji Pharmaceutical University (Japan). They achieved the first total synthesis of renieramycin T in 2016, and they have been following an alternative route to supply a large amount of it in order to promote research of the next stage, such as structure–activity relationship studies. This paper reports a formal total synthesis in 21 steps from a known piperazine‐2,5‐dione derivative. The key step of this synthesis is the modified Pictet–Spengler cyclization of a primary amine with an oxomalonic acid ester derivative followed by decarboxylation, and stereo‐controlled protonation at C‐1 position of the enol intermediate from the less‐hindered face. Read the full text of their Full Paper at https://doi.org/10.1002/open.201800112.

Did serendipity play a part in this work?

It is very important to find unpredictable experimental results under the international collaborative research. Renieramycin T has an amino nitrile group, which is very important and has strong antitumor activity. Before starting our collaboration, our co‐workers already isolated renieramycins possessing the acetone residue instead of nitrile at the C‐21 position, and the bioactivities were dramatically reduced. We considered that this acetone residue was derived from the marine organisms being treated with KCN prior to extraction. As a result, we succeeded in isolating chemically stabilized renieramycins with highly potent antitumor activity. Thus, our collaborative research was started about 20 years ago.

What future opportunities do you see?

We believe that a lot of new medicines might be produced with many exciting scientific results from a variety of marine organisms found in the Asian sea. The characteristic methodology presented in this paper should add the new choice to synthetic strategies of these natural products and accelerate medicinal chemistry research based on such natural products. We would like to continue the development of antitumor drugs and provide important information for drug discovery through the synthetic supply of natural products and biological evaluation of various derivatives.

What was the biggest challenge on the way to the results presented in this paper?

Slight differences in chemical structure (benzene ring having a 1,3‐dioxole ring and a 1,2‐dimethoxy group) resulted in failure in the key step of the Pictet–Spengler reaction, and we needed to change the synthetic route into an alternative strategy. To resolve this problem, we developed a methodology for the stereoselective construction of the characteristic framework of biologically active renieramycin T by combining the Pictet–Spengler and decarboxylation reactions, inspired by the three‐dimensional structure of bistetrahydroisoquinoline natural products. This synthetic strategy could be applied to a series of other natural products.

S. Kimura, N. Saito, ChemistryOpen 2018, 7, 753.