Retrosynthetic analysis | EPFL Graph Search

Retrosynthetic analysis is a technique for solving problems in the planning of organic syntheses. This is achieved by transforming a target molecule into simpler precursor structures regardless of any potential reactivity/interaction with reagents. Each precursor material is examined using the same method. This procedure is repeated until simple or commercially available structures are reached. These simpler/commercially available compounds can be used to form a synthesis of the target molecule. E.J. Corey formalized this concept in his book The Logic of Chemical Synthesis. The power of retrosynthetic analysis becomes evident in the design of a synthesis. The goal of retrosynthetic analysis is a structural simplification. Often, a synthesis will have more than one possible synthetic route. Retrosynthesis is well suited for discovering different synthetic routes and comparing them in a logical and straightforward fashion. A database may be consulted at each stage of the analysis, to de

Synthetic Studies toward Amanita Phalloides Toxins

Philipp Georg Werner Seeberger

Amatoxins are ribosomally synthesized and post-translationally modified bicyclic octapeptides biosynthesized by the deadly basidiomycete fungus Amanita phalloides. Amongst this group, alpha-amanitin is the most widely known toxin and is currently under investigation as part of an antibody-drug conjugate to treat pancreatic cancer. As a consequence, an efficient, modular synthetic route to the molecule is highly desirable. This thesis describes our efforts toward the development of a novel synthesis of alpha-amanitin. An unprecedented tryptathionine formation was envisioned as the key step, which would generate the characteristic cross-linker between cysteine and tryptophan and allow for late stage diversification of the molecule. The transformation would be realized in analogy to a report by Fagnou and co-workers, describing a Rh(III)-catalyzed oxidative annulation of aniline derivatives with internal alkynes to form 2,3-disubstituted indoles. In this effort, several methods for the regioselective formation of 2-substituted indoles were identified in studies with a model thioalkyne. 3,4-Dimethoxybenzyl was chosen as an orthogonal protecting group for the indole nitrogen, and the regioselectivity with respect to substitution on the ring was controlled by exploiting the sterics of the substituent. A method for the selective preparation of 3 sulfenyl indoles was also identified. For several decades, the total synthesis of amanitin had been prevented due to the lack of an efficient method to prepare the characteristic unnatural amino acid dihydroxyisoleucine (DhIle). The present thesis describes a novel, efficient and modular synthesis of this challenging scaffold. The crucial anti-diastereselectivity in the generation of its characteristic stereocenters was obtained in an organocatalyzed asymmetric Mannich reaction/olefination protocol. To avoid lactonization, an alternative synthetic route to a DhIle-containing dipeptide 234 was developed, allowing for the efficient preparation of the valuable diol on a larger scale. Subsequently, preliminary results demonstrated the feasibility of a proposed Pd(II)-catalyzed thioalkynylation by the synthesis of a model dipeptide, and its applicability on a model macrocyclic peptide scaffold was shown. This was later used as a proof of concept for the key Cp*Rh(III)-catalyzed tryptathionine formation. Unfortunately, the isolation of this bicyclic octapeptide was so far unsuccessful, as was the preparation of the target amanitin scaffold. As a consequence, an alternative synthetic strategy to this peptide scaffold was developed. Future works would include its preparation on a larger scale to evaluate the key transformation and access the target alpha-amanitin. The envisioned strategy for the synthesis of alpha-amanitin was also probed for the potential preparation of phalloidin, another potent compound produced by the Death Cap mushroom, with interesting applications as a biological tool. In this effort, a novel synthetic route to a dipeptide containing the characteristic dihydroxyleucine moiety was developed. A route to the cyclic phalloidin scaffold was explored, as well as a potential alternative route to the linear scaffold to allow for efficient scaling of the synthesis.

EPFL2020

Catalytic Enantioselective Transformations Involving C-H Bond Cleavage by Transition-Metal Complexes

Caio Costa Oliveira, Nicolai Cramer, Christopher Gordon Newton, Shouguo Wang

The development of new methods for the direct functionalization of unactivated C-H bonds is ushering in a paradigm shift in the field of retrosynthetic analysis. In particular, the catalytic enantioselective functionalization of C-H bonds represents a highly atom- and step-economic approach toward the generation of structural complexity. However, as a result of their ubiquity and low reactivity, controlling both the chemo- and stereoselectivity of such processes constitutes a significant challenge. Herein we comprehensively review all asymmetric transition-metal-catalyzed methodologies that are believed to proceed via an inner-sphere-type mechanism, with an emphasis on the nature of stereochemistry generation. Our analysis serves to document the considerable and rapid progress within in the field, while also highlighting limitations of current methods.

2017

Total Synthesis of Alstilobanine C, Undulifoline and Alstilobanine B

Nicolas David Gaeng

The total synthesis of pentacyclic monoterpene indole alkaloids is the focus of this thesis. Total syntheses of (±)-alstilobanine C, (±)-undulifoline and (±)-alstilobanine B, three natural products from the Ulean family of alkaloids, were accomplished. The characteristic features of our synthesis included: a) a domino sequence involving a highly diastereoselective Michael addition followed by chemoselective C-acylation of the resulting enolate by Mander¿s ester; b) an unprecedented Lewis acid mediated intramolecular addition of enolate to oxonium, generated in situ from MOM protective group; c) a sequence of chemoselective reduction/indolization/intramolecular aza-Michael addition. This domino process afforded directly the (±)-alstilobanine C, a pentacyclic monoterpene indole alkaloid in 87% yield. Reductive N-methylation of (±)-alstilobanine C provided (±)-undulifoline which, upon N-oxidation, was further converted to (±)-alstilobanine B. Enantioselective total synthesis of the same natural products through a different synthetic route is presented. After exploring different unsuccessful strategies, an enzymatic desymmetrization of a meso compound was adopted for the synthesis of enantioenriched cyclopentenone intermediate. Applying the two domino sequence developed previously, namely, Michael addition/C-acylation and oxepane formation, an efficient synthesis of the oxobicyclo[4.2.1]nonane was realized. A palladium-catalyzed decarboxylative cross-coupling, a methodology developed in our group, afforded an advanced bicyclic intermediate with all the carbon and functional groups needed to accomplish the total synthesis. However, conversion of the vinyl group to alkylazide or its synthetic equivalent proved to be difficult in spite of the efforts dedicated to this seemingly trivial transformation.

EPFL2018

Synthetic Studies toward Amanita Phalloides Toxins

Philipp Georg Werner Seeberger

EPFL2020