Quinine total synthesis | EPFL Graph Search

The total synthesis of quinine, a naturally-occurring antimalarial drug, was developed over a 150-year period. The development of synthetic quinine is considered a milestone in organic chemistry although it has never been produced industrially as a substitute for natural occurring quinine. The subject has also been attended with some controversy: Gilbert Stork published the first stereoselective total synthesis of quinine in 2001, meanwhile shedding doubt on the earlier claim by Robert Burns Woodward and William Doering in 1944, claiming that the final steps required to convert their last synthetic intermediate, quinotoxine, into quinine would not have worked had Woodward and Doering attempted to perform the experiment. A 2001 editorial published in Chemical & Engineering News sided with Stork, but the controversy was eventually laid to rest once and for all when Williams and coworkers successfully repeated Woodward's proposed conversion of quinotoxine to quinine in 2007. Chemica

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

Total Synthesis of Alstolactine A & Synthetic Studies Towards Members of Akuammiline Alkaloids

Raphaël Beltran

The work presented in this thesis focuses on the synthesis of monoterpene indole alkaloids. The first part describes the development of a general methodology to provide an enantioenriched platform, useful for the convergent synthesis of Akuammiline alkaloids. Despite a series of attempts using chiral phosphoric acids, the enantioselective desymmetrization of meso-1,3-diones turned out to be complex and was unfortunately unsuccessful. The second part details our first approach toward the total synthesis of (±)-alstolactine A, (±)-alstolactine B and (±)-alstolactine C. A robust eighteen-step sequence was developed, however, the numerous issues we encountered while attempting to complete the synthesis led us to re-evaluate our strategy. The third part of this thesis details the 22 steps synthesis of (±)-alstolactine A from commercially available starting materials. Our approach involves: a) creation of a quaternary stereocenter C7 at an early stage; b) rapid build-up of the first lactone; c) diastereoselective azidolactonization; d) [Ni(cod)2]-mediated intramolecular cyclization to construct the azabicyclo[3.3.1]nonane bridged system and e) formation of the last lactone via epoxide opening. Finally, the fourth and fifth parts describe the synthetic studies toward various members of the Akuammiline family: (±)-alstolactine B and (±)-alstolactine C and the possibilities to reach (±)-scholarisine K, (±)-scholarisine L and (±)-scholarisine M starting from an advanced intermediate from our strategy.

EPFL2019

Synthetic Studies toward Amanita Phalloides Toxins

Philipp Georg Werner Seeberger

EPFL2020