Enantioselective synthesis

Enantioselective synthesis, also called asymmetric synthesis, is a form of chemical synthesis. It is defined by IUPAC as "a chemical reaction (or reaction sequence) in which one or more new elements of chirality are formed in a substrate molecule and which produces the stereoisomeric (enantiomeric or diastereomeric) products in unequal amounts." Put more simply: it is the synthesis of a compound by a method that favors the formation of a specific enantiomer or diastereomer. Enantiomers are stereoisomers that have opposite configurations at every chiral center. Diastereomers are stereoisomers that differ at one or more chiral centers. Enantioselective synthesis is a key process in modern chemistry and is particularly important in the field of pharmaceuticals, as the different enantiomers or diastereomers of a molecule often have different biological activity. Overview Many of the building blocks of biological systems such as sugars and amino acids are produced exclusivel

Catalytic enantioselective Pictet-Spengler reaction of carbonyl compounds: Development and application to the asymmetric total synthesis of indole alkaloids

Rémi Julien Sylvain Andres

This thesis consists in an extensive study about the enantioselective Pictet-Spengler reaction (EPSR) and its application to the total synthesis of monoterpene indole alkaloids (MIAs). The general introduction presents the literature background about this powerful yet still unsolved synthetic transformation. The use of ketone derivatives up to date is mainly underlined.The first chapter describes the enantioselective total synthesis of arborisidine for which an unprecedented EPSR with an Î±-diketone was developed. An oxidative cyclization allowed to build a strained bridged system which was rearranged following a one-pot aza-Cope/Mannich â oxidation â epimerization sequence to reach the natural product. We discovered an interesting epimerization phenomenon between arborisidine and its epimer which, after being conscienciously studied, raised the question of which isomer is the natural product.The development of a new class of single H-bond donor organocatalysts identified in the previous structure-enantioselectivity relationship process is then detailed. These prolinamides present the advantages to be cheap, easier to prepare and to purify than other known catalysts, and provide a new molecular scaffold for enantioselective H-bonding catalysis. They allow a general access to quaternary-center containing tetrahydro-Î²-carbolines derived from Î±-diketones, bulky Î±-ketoesters and Î±-ketoamides, the latter being extensively explored. They also compete with known methods with aldehydes as substrates. The products can all be obtained in good yields and enantioselectivities. The scope is large and shows excellent functional group tolerance to the exception of acidic protons close to the ketone center and sterically hindered ketone derivatives. In line with Jacobsenâs recent discovery, rearomatization is the rate- and enantioselectivity-determining step. The transformation of Î±-diketones is investigated by Vincent, Morgane and Julia, and that of Î±-ketoesters by Fenggang. Of interest, Fenggang showed that the use of two H-bond donor squaramide-organocatalysts was mandatory in order to make the reaction general with Î±-ketoesters.The power of this method was then further demonstrated. The stereocontrolled divergent total synthesis of voacafricines A and B thanks to an asymmetric PSR is the object of the third chapter. Its application allowed to install all the carbons contained in the natural products in a controlled manner, and a complexity-generating oxidative cleavage â cascade cyclization â selective reduction allowed to reach a key hemiacetal intermediate. On one hand this moiety was activated to generate the desired ammonium which provided voacafricine A after in situ hydrolysis. It could on the other hand be used to functionalize the adjacent carbon atom and the same synthetic sequence was applied to get voacafricine B.The enantioselective total synthesis of alstratine A is finally reported. Believing that the aminal could be made at the last step of the synthesis, we identified a precursor whose structure analysis suggested a possible application of an intramolecular inverse electron demand Diels-Alder reaction. The synthesis began with an EPSR of an Î±-ketoester. Funtional group manipulations followed by IMDA successfully built most of the contiguous stereocenters in a controlled fashion. The acid-mediated cyclization then took place without any issues. Alstratine A specific rotation reported in the isolation paper is corrected herein.

EPFL2022

Total asymmetric synthesis of advanced polyketide fragments of apoptolidinone and rectricticin using new organic chemistry of sulfur dioxide

Cotinica Craita

Under appropriate conditions sulfur dioxide reacts with 1,3-dienes in a hetero-Diels-Alder fashion. In the case of 1-alkoxy-1,3-dienes the 6-alkoxy-3,6-dihydro-1,2-oxathiin-2-oxides (sultines) so-obtained can be ionized in the presence of Lewis or protic acids. The zwitterionic intermediates can be trapped as electrophiles with enoxysilanes (oxyallylation) to generate substituted silyl alkenylsulfinates. The latter can then be reacted with TBAF and an electrophile to generate polyfunctional sulfones (one pot, four component syntheses). Alternatively, desilylation through silicon/palladium transmetallation, in the presence of a catalytic amount of Pd(OAc)2, leads to intermediate allylsulfinic acids, which, after retro-ene desulfitation, produce 4-alkoxyhept-6-en-2-one core, a valuable fragment in polyketide natural product synthesis. The first part of this work described the application of an asymmetric version of this new SO2 reaction cascade, hetero-Diels-Alder addition/oxyallylation/retro-ene desulfitation (Vogel's cascade), using enantiomerically enriched dienes. The synthesis of a variety of β-alkoxy ketones was realized with good α,β-syn selectivity, starting from different enoxysilanes, illustrating the versatility of the method. An iterative Vogel's cascade employing newly obtained fragments provided long-chain polypropionate fragments such as (-)-(4R,5R,6S,9S,10R,2E,11E)-4,6,10-trimethyl-5,9-bis-((1S)-1-phenylethoxy)-trideca-2,11-dien-7-one in a very short and efficient way. The synthetic potential of Vogel's cascade reaction was demonstrated by the short and elegant synthesis of the enantiomerically enriched polypropionate fragment (C16-C28) of apoptolidinone, aglycon of apoptolidin, a highly potent apoptosis inducing agent. In the second part of thesis the one pot polyfunctional sulfone synthesis, developed in our group was successfully combined with the aldol methodology of Paterson to reach an advanced polyketide fragment, a potential intermediate in the total synthesis of Restricticin. Finally, in the last part of this study, we have demonstrated that methallyl silylsulfinates, known as new reagents for alcohol silylation are very precious and efficient reagents for the silylation of phenols and carboxylic acids. Additionally, the chemoselectivity of these reagents on substrates containing different hydroxyl groups was demonstrated.

EPFL2006

Catalytic enantioselective Pictet-Spengler reaction of carbonyl compounds: Development and application to the asymmetric total synthesis of indole alkaloids

Rémi Julien Sylvain Andres

EPFL2022

Total asymmetric synthesis of advanced polyketide fragments of apoptolidinone and rectricticin using new organic chemistry of sulfur dioxide

Cotinica Craita

EPFL2006

Non-iterative asymmetric synthesis of potential precursors of the spiroacetals of spongistatins

Catalytic enantioselective Pictet-Spengler reaction of carbonyl compounds: Development and application to the asymmetric total synthesis of indole alkaloids

Total asymmetric synthesis of advanced polyketide fragments of apoptolidinone and rectricticin using new organic chemistry of sulfur dioxide

Catalytic enantioselective Pictet-Spengler reaction of carbonyl compounds: Development and application to the asymmetric total synthesis of indole alkaloids

Total asymmetric synthesis of advanced polyketide fragments of apoptolidinone and rectricticin using new organic chemistry of sulfur dioxide

Non-iterative asymmetric synthesis of potential precursors of the spiroacetals of spongistatins