Activation of aminocyclopropanes via radical intermediates

Aminocyclopropanes are versatile building blocks for accessing high value-added nitrogen-containing products. To control ring-opening promoted by ring strain, the Lewis acid activation of donor-acceptor substituted systems is now well established. Over the last decade, alternative approaches have emerged proceeding via the formation of radical intermediates, alleviating the need for double activation of the cyclopropanes. This tutorial review summarizes key concepts and recent progress in ring-opening transformations of aminocyclopropanes via radical intermediates, divided into formal cycloadditions and 1,3-difunctionalizations.

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

Transition metal-catalyzed carbon-carbon cross-coupling reactions using sulfonyl derivatives

The goal of this thesis was to find conditions to form C-C double bond and single bond using sulfonyl derivativies, which are arising from the Vogel's oxyallylation cascades. In a second chapter, it is shown that 2-methylprop-2-ene-1-sulfonyl fluorides can be easily prepared via the ene reaction of methallylsilanes and SO2 followed by halogenosis (NCS, then KF). In the presence of a base, aldehydes and 2-methylprop-2-ene-1-sulfonyl fluorides give mixture of (1Z)- and (1E)-1-aryl-3-methylbutadienes. Their (Z)→(E) isomerization by classical means fails or leads to their polymerization. We have discovered that SO2 can isomerize 1-aryl-3-methyl-1,3-dienes at low temperature, without formation of sulfolenes (cheletropic addition/elimination). Preliminary mechanistic studies suggest that SO2 add to the 1,3-dienes forming 1,4-diradical intermediates that are responsible for the (Z)→(E) isomerizations. In the third chapter, we have shown that arenesulfonyl chlorides are versatile electrophilic reagents for C-C cross-coupling reactions. Arene-, arylmethane- and alk-2-ene-1-sulfonyl chlorides undergo desulfitative Stille, carbonylative Stille, Negishi and Suzuki-Miyaura cross-coupling reactions. In these reactions the reactivity order is ArI> ArSO2Cl> ArBr> ArCl. Similarly, desulfitative Sonogashira-Hagihara cross-couplings of arenesulfonyl chlorides with aryl- and alkylacetylenes can be catalyzed by Pd2(dba)3/P(t-Bu)3/CuI. New conditions have been found for the desulfitative Mizoroki-Heck arylation and trifluoromethylation of mono- and disubustituted olefins with arenesulfonyl and trifluoromethanesulfonyl chlorides. This procedure allows one to obtain (E)-1,2-disubstituted alkenes with high stereoselectivity and 1,1,2-disubstituted alkenes with high (E)/(Z) stereoselectivity. If phosphine- and base-free conditions are required, 1 mol% {RhCl(C2H4)2} catalyses the desulfitative cross-coupling reactions. On the contrary to what has been reported for RuCl2(PPh3)2 catalyzed coupling reactions with sulfonyl chlorides, the palladium and rhodium desulfitative Mizoroki-Heck coupling reactions are not inhibited by radical scavenging agents. Moreover, sulfones that are formed from the sulfonylation of alkenes at 60°C can theoretically be envisaged as intermediates in all cross-coupling reactions. However we have shown that they are not desulfitated at higher temperatures in the presence of the Pd or Rh-catalysts. Alk-2-ene-1-sulfonamides can also undergo desulfamylating cross-coupling reaction with Grignard reagents in the presence of a nickel catalyst. In the fouth chapter, we have evaluated the possibility that silyl sulfinates can be used as nucleophilic partners to form C-C bond. Our preliminary results indicate that their hypothesis should be explored further. In a fifth chapter, we have contributed to the development of an efficient one-pot, three component syntheses of sulfonamides and sulfonic esters. We have demonstrated that the ene-reaction of sulfur dioxide with enoxysilanes can be stereoselective under conditions of kinetic control. As others in our laboratory, we have shown that the hetero-Diels-Alder addition of sulfur dioxide to 1-oxy or 1,3-dioxy-1,3-dienes generates zwitterions that add to enoxysilanes or allylsilanes giving silyl sulfinates that can be converted in the same pot into polyfunctional sulfones, sulfonamides or sulfonic esters. Intramolecular S-allylation of intermediate silyl sulfinates has allowed one to prepare new tetrahydro-2H-thiocine derivatives. Our key contribution has been to use enantiomerically enriched amines which has allowed one to obtain enantiomerically enriched polyfunctional sulfonamides.

EPFL2005

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

Transition metal-catalyzed carbon-carbon cross-coupling reactions using sulfonyl derivatives

EPFL2005