New efficient synthetic strategies towards the AB and CD spiroketal fragments of spongistatins and analogues

For thousands of years, nature provided us remedies to treat diseases and its biologically active molecules inspired chemists for the development of new drugs. In 1993, three research groups independently reported the isolation, from sponges, of spongistatin 1. This 42-membered macrolactone, comprises 24 stereogenic centres, a chloro triene side chain, two spiroketals (AB and CD) and two tetrahydropyranyl units (E and F rings). This molecule was found to be among the most potent cancer cells' growth inhibitors tested to date by the U.S. National Cancer Institute. This compound inhibits the microtubule polymerisation with nanomolar to picomolar activities but further biological investigations were precluded by the extremely low quantities that were obtained from the marine organism. This scarce abundance, together with the remarkable structural complexity, prompted many research groups to address this challenge and seven of them reported a total synthesis. Vogel's methodology for the synthesis of 15 carbons polyolic chains was extended to the preparation of highly advanced intermediates of the AB and CD-spiroketals of spongistatin 1. This non-iterative synthesis started with the meso-1,1'-methylenedi[(1R,1'S,5S,5'R)-3-oxo-8-oxabicyclo[3.2.1]oct-6-ene-1-yl] derivative. The diene, obtained after an endo-reduction and the opening of the oxa-bridges, was resolved by mean of Sharpless asymmetric dihydroxylation. After an oxidative cleavage of the first cycle and a 1,3-anti reduction, ozonolysis was used to open the second cycloheptene. Acid catalysed spirocyclisation furnished the rigid core needed for the diastereoselective methylation and the inversion of an hydroxyl group. Finally, the axial/axial configuration of the AB-spiroketal was confirmed by two dimensional NMR analyses. Similar methodology was applied to the synthesis of the CD-fragment. An exo-reduction of the same starting diketone followed by Sharpless asymmetric dihydroxylation and a sequential cleavage of the cycloheptene rings furnished the equatorial/axial spiroketal with all the functionalities of the CD-fragment of spongistatin 1.

Copper-Catalyzed 1,2-Methoxy Methoxycarbonylation of Alkenes with Methyl Formate and Synthetic Studies Towards the Total Synthesis of Koumine, Voacafricine A and Voacafricine B

Balázs Budai

The development of an unusual oxidative alkene difunctionalization using methyl formate and syn-thetic studies towards alkaloid natural products provide the basis of the thesis. The first chapter details the development of a method that forges methoxycarbonyl radical direct-ly from its most accessible precursor: methyl formate. Although the aforementioned transfor-mation was documented in the literature, no synthetically useful method was developed at the time. We were able to identify conditions that transform methyl formate and simple styrene de-rivatives to value added ï¢-methoxy alkanoates and cinnamic acid derivatives under copper cataly-sis. We also demonstrated that by tethering nucleophilic moieties to the styrene substrates, we could access medicinally important heterocycles such as pyrrolidines, tetrahydrofurans and ï§-lactones. Our method proved to be scalable on each classes of substrates. Mechanistic studies re-vealed that methyl formate has an unprecedented double role in the transformation. It acts as a precursor for methoxycarbonyl radical; furthermore, it is the direct source of the ï¢-methoxy func-tion in the synthesis of ï¢-methoxy alkanoates. A ternary ï¢-diketiminato-Cu(I)-styrene complex, fully characterized by NMR spectroscopy and X-ray crystallographic analysis is capable of catalyz-ing the same transformation. We hypothesize that pre-coordination of electron-rich double bond to copper might play an important role in the polarity-mismatched addition between nucleophilic methoxycarbonyl radical and electron rich olefins. Synthetic studies toward the total synthesis of koumine is discussed in the second chapter. Our synthetic strategy features an oxidative ring closing, Fukuyama indole synthesis and an enantiose-lective Diels-Alder cycloaddition for the construction of the core of koumine skeleton. We designed a rapid route to access 1,2-dihydropyridine derivatives and these compounds were examined as dienes in the Diels-Alder cycloaddition reaction. Despite our efforts, we were unable to effect the [4+2] cycloaddition, which eventually lead us to decide to discontinue our campaign. In chapter three, our synthetic efforts toward voacafricine A and voacafricine B is presented. In our pursuit towards the natural products, we devised and followed a divergent and potentially en-antioselective strategy. We successfully developed a synthetic route to reach the key intermediate in five steps. Despite our efforts, we were not able to construct the remaining F ring of the natural product. Our conformational analysis of advanced intermediates suggest that epimerization of the C14 stereocenter potentially unlocks the desired reactivity and enables us to reach the target mol-ecules. Work towards the total synthesis of voacafricine A and voacafricine B is underway and may focus on the conformational manipulation of advanced intermediates to allow the elaboration of the F ring and complete the synthesis.

EPFL2020

Synthetic methodologies for C-C and C-N bond formation involving alkyl radicals

Guido Barzanò

C-C and C-N bonds are some of the most common structures in molecules ranging from drugs to catalysts and to food additives. Many coupling reactions were developed to form these types of bonds with excellent selectivity and good performance. Still, the synthesis of some of those species either depends on traditional methods or requires expensive and rare reagents and catalysts. The use of precious metals in chemistry, and particularly in the industry, can make molecular synthesis expensive and energy-intensive since the extraction of those materials is costly. Moreover, in homogeneous catalysis, the recovery of metal-based catalysts is almost impossible, making these processes unsustainable for the future. Thus, the discovery of chemical reactions that donât involve precious materials is indispensable. This thesis concentrates on the development of two chemical transformations, one performing an sp2-sp3 radical reductive coupling, one performing a photocatalyzed alkyl amination, involving inexpensive reagents and catalysts. The first chapter reviews the existing methodologies which use alkyl radicals to form carbon-carbon and carbon-nitrogen bonds. Alkyl radicals are formed from alkyl halides and pseudo-halides (Acids, esters, tosylates, etc.) via oxidation or reduction performed by metal or photoredox catalyst. The wide variety of available methodologies was illustrated, highlighting the advantages and weaknesses of each reaction. The second chapter of this dissertation is devoted to the development of a new iron-based catalytic method to form stereoselectively Z-alkene boron species from the corresponding boron-alkyne. This novel stereoselective method opens a new way to obtain these types of molecules with cheap reagents, in high yields, with excellent stereoselectivity (Z:E ratio >10:1), and with good tolerance of functional group. The reaction is radical based, avoiding the problem of beta-hydride elimination, which usually occurs in ionic reactions involving metal centers. In order to prove the versatility of this method, the vinyl boron compound formed from this reaction was used for further functionalizations. The formal total synthesis of a 5-HT2c receptor agonist was successfully performed, improving the overall yield of the process, and avoiding the use of expensive and polluting chemicals. The third chapter of this thesis is concentrated on the development of a tandem photoredox/metal base catalyzed functionalization of anilines and imines with alkyl carboxylic esters. In this reaction, no late transition metal is used, and the traditional metal-based photocatalyst is substituted with an inexpensive and more efficient organic dye. The alkylation of amines is a challenging topic in organic chemistry and classical nucleophilic substitution lacks selectivity and scope. Harvesting visible light with a photoredox catalyst opens the possibility to a radical pathway, making this coupling easy and with high tolerance for functional groups. In order to understand the catalytic cycle of the reaction, additional mechanistic studies were conducted, leading to some insight on how this reaction works.

EPFL2020

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

Synthetic methodologies for C-C and C-N bond formation involving alkyl radicals

Guido Barzanò

EPFL2020

Copper-Catalyzed 1,2-Methoxy Methoxycarbonylation of Alkenes with Methyl Formate and Synthetic Studies Towards the Total Synthesis of Koumine, Voacafricine A and Voacafricine B

Balázs Budai

EPFL2020

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

Cotinica Craita

EPFL2006