Convergent synthesis | EPFL Graph Search

In chemistry a convergent synthesis is a strategy that aims to improve the efficiency of multistep synthesis, most often in organic synthesis. In this type of synthesis several individual pieces of a complex molecule are synthesized in stage one, and then in stage two these pieces are combined to form the final product. In linear synthesis the overall yield quickly drops with each reaction step: :A → B → C → D Suppose the yield is 50% for each reaction; the overall yield of D is only 12.5% from A. In a convergent synthesis :A → B (50%) :C → D (50%) :B + D → E (25%) the overall yield of E (25%) looks much better. Convergent synthesis is applied in the synthesis of complex molecules and involves fragment coupling and independent synthesis. This technique is more useful if the compound is large and symmetric, where at least two aspects of the molecule can be formed separately and still come together. Examples:

Convergent synthesis is encountered in dendrimer synthesis where br

Convergent synthesis is encountered in dendrimer synthesis where br

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

Divergent Reactivity of Thioalkynes in Lewis Acid Catalyzed Annulations with Donor-Acceptor Cyclopropanes

Bence Márton Hegedüs, Sophie Lucie Racine, Rosario Scopelliti, Jérôme Waser

Efficient methods for the convergent synthesis of (poly) cyclic scaffolds are urgently needed in synthetic and medicinal chemistry. Herein, we describe new annulation reactions of thioalkynes with phthalimide-substituted donor-acceptor cyclopropanes, which gave access to highly substituted cyclopentenes and polycyclic ring systems. With silyl-thioalkynes, the Lewis acid catalyzed[3+2] annulation reaction with donor-acceptor cyclopropanes took place to afford 1-thio-cyclopenten-3-amines. On the other hand, an unprecedented polycyclic compound was formed with alkyl-thioalkynes through a reaction pathway directly involving the phthalimide group. The two transformations proceeded in good yields and tolerated a large variety of functional groups.

Wiley-Blackwell2016

New Strategies for the Functionalization of Alkenes Exploiting Tethering Chemistry and Ring Strain

Bastian Antoine Rodolphe Claude Muriel

Amino alcohols, cyclopropanes and nitriles are privileged structural motifs found in the scaffold of natural products and bioactive compounds. In addition, they are versatile building blocks in organic chemistry. The development of new and increasingly efficient synthetic methods to access these chemical motifs from readily available feedstocks is therefore highly desirable. In this context, alkenes have been substrates of choice to rapidly access complex molecules, as two new functionalities can be installed across their double bond. To achieve such transformations, palladium catalysis and radical chemistry stand as two of the most efficient strategies. In this thesis, a new palladium-catalyzed carboamination of allylic alcohols using a trifluoroacetaldehyde-based tether was first investigated. The tether could be easily installed on diverse allylic alcohol substrates, the formed hemiaminals underwent in high yield and diastereoselectivities the desired transformation under optimized conditions. Both alkynyl- and aryl-bromides could be used as electrophilic partners in the reaction. For the latter, in order to supress a competitive Heck-pathway, a new phosphine-based ligand âFuXPhosâ had to be developped and was key to reach high yields for the aminoarylation in combination with CsOTf as additive. The tether in the obtained products could be cleaved under acidic conditions delivering valuable amino alcohol derivatives. This difunctionalization strategy mediated by palladium was then applied to the strained alkene of cyclopropenes. While preliminary results for the intramolecular carbo-amination and carbo-etherification of cyclopropenes could be obtained, the difficulty to access the starting materials for these transformations led to consider a more convergent approach to access functionalized cyclopropanes. Using radical chemistry, a novel synthesis of bicyclo[3.1.0]hexanes could be developed, by a (3+2) annulation of cyclopropylanilines with cyclopropenes mediated by photoredox. The scope of the transformation was broad for both reaction partners, but the products were obtained with low diastereoselectivities. It was found that by combining difluorocyclopropenes with a bulky aromatic N-substituent on the cyclopropylamine, the corresponding fluorinated bicyclo[3.1.0]hexanes could be accessed in good yields and diastereoselectivities under slightly re-optimized conditions. Finally, the possibility to achieve an amination reaction of cyclopropenes using N-centered radicals was investigated. It was discovered that the addition of azidyl radicals to the double bond of cyclopropenes under photoredox conditions led to the formation of two new products coming from an unexpected ring cleavage: an alkenyl nitrile and a quinoline. While the formation of the quinoline product could not be optimized above 47% yield, conditions could be found for the selective formation of the alkenyl nitrile in high yields using cheap and commercial reagents. Through the scope investigations it was discovered that an aryl-substituent on the double bond of the cyclopropene substrates was necessary for the transformation to proceed. Despite this limitation various substrates could be engaged in the transformation and delivered the corresponding alkenyl nitriles in high yields. With 1,2-diaryl substituted cyclopropenes a synthesis of valuable polycyclic aromatic compounds could be developed, through a one pot radical amination / oxidative cyclization.

EPFL2021