A new strategy for the synthesis of complex natural products

October 09, 2019

Chemists from the University of Basel have succeeded in synthesizing two complex natural products from the group of dithiodiketopiperazines (DTPs). For this, they employed a new strategy based on "C-H bond activation," resulting in a short and high yielding route. In the most recent edition of the Journal of the American Chemical Society, the researchers describe their new concept for the total synthesis of Epicoccin G and Rostratin A.

Certain microorganisms, such as fungi, are a rich source of secondary metabolites, which have great potential in medicinal applications. Of particular interest among these secondary metabolites are the dithiodiketopiperazines (DTPs), as they possess a variety of interesting biological activities that could be used in the development of new drugs for malaria or cancer. However, despite extensive efforts over the past decade, relatively few total syntheses of these molecules have been completed and obtaining the necessary quantities for further investigation remains a challenging target.

Professor Olivier Baudoin and first author Pierre Thesmar from the Department of Chemistry at the University of Basel have now succeeded in the development of an efficient and scalable synthesis of two of these structurally challenging natural products.

C-H bond activation as a new synthetic strategy

The synthesis route used by the Basel team employed a new strategy for the ring system construction involving a method known as "C-H bond activation," which in recent years has become a valuable synthetic tool. In this key step, two rings are simultaneously formed by a twofold reaction in which a carbon-hydrogen bond (C-H bond) is cleaved and a carbon-carbon bond (C-C bond) formed. This route allows efficient access to a common intermediate on multigram quantities from inexpensive, commercially available starting materials.

This intermediate was then converted to the first natural DTP, Epicoccin G, in seven additional steps. Compared with the previous single total synthesis of the same molecule, the current synthesis displays 14 steps instead of 17, and a much higher overall yield of 19.6% rather than 1.5%.

Next challenge: Rostratin A

Following the successful synthesis of Epicoccin G, the research team ventured to synthesize Rostratin A, a related natural DTP, for the first time and on a larger scale. This molecule displays a number of daunting structural elements that necessitated a significant adaptation of the synthesis end-game. After much experimentation, optimization of each step and validation on multigram quantities, Rostratin A was synthesized on a 500 mg scale. Overall, this total synthesis was completed in 17 steps and with a high overall yield of 12.7%.

The new strategy reveals the high potential of the C-H bond activation method in the field of natural product synthesis. In a next step, the researchers aim to synthesize other natural DTPs and their analogues in order to conduct more advanced studies and further evaluate the medicinal potential.
-end-
Further information

Prof. Dr. Olivier Baudoin, University of Basel, Department of Chemistry, phone +41 61 207 1198, email: olivier.baudoin@unibas.ch

University of Basel

Related Natural Products Articles from Brightsurf:

New nitrogen products are in the air
A nifty move with nitrogen has brought the world one step closer to creating a range of useful products -- from dyes to pharmaceuticals -- out of thin air.

How do bacteria build up natural products?
The active agents of many drugs are natural products, so called because often only microorganisms are able to produce the complex structures.

Live Biotherapeutic products -- a new regulatory approach for the safety assessment of a specific category of biological medicinal products
These exist complex challenges when developing Live Biotherapeutic Products (LBPs).

Even natural products can be harmful for the unborn child
Plant products ingested by pregnant women through their diet are broken down by the intestinal microbiota into chemical substances, some of which can cross the placental barrier and reach the fetus.

Determining the atomic structure of natural products more rapidly and accurately
Many drugs are derived from natural products. But before natural products can be exploited, chemists must first determine their structure and stereochemistry.

A new strategy for the synthesis of complex natural products
Chemists from the University of Basel have succeeded in synthesizing two complex natural products from the group of dithiodiketopiperazines (DTPs).

Fighting drug resistance with fast, artificial enhancement of natural products
Japanese researchers have identified multiple promising new drug candidates to treat antibiotic-resistant infections, including superbugs.

Hydrogen-natural gas hydrates harvested by natural gas
A recent study has suggested a new strategy for stably storing hydrogen, using natural gas as a stabilizer.

An unnatural way to make natural products
Researchers have developed an innovative new process for synthesizing isoprenoids, which are chemical compounds used in countless pharmaceutical and consumer products.

En route to custom-designed natural products
Microorganisms often assemble natural products similar to industrial assembly lines.

Read More: Natural Products News and Natural Products Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.