Sulfur dioxide mediated one-pot, three- and four-component syntheses of polyfunctional sulfonamides and sulfonic esters: Study of the stereoselectivity of the ene reaction of sulfur dioxide

The ene reaction of sulfur dioxide with enoxysilanes or with allylsilanes generates silyl sulfinates that can be brominated (Br-2 or NBS) or chlorinated (NCS or Cl-2) to produce the corresponding sulfonyl halides. They react with primary and secondary amines or alcohols to give the corresponding sulfonamides and sulfonic esters, respectively. 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 situ into polyfunctional sulfonamides or sulfonic esters. This realizes quick access to libraries of complicated sulfonamides and sulfonic esters applying one-pot, three- and four-component methods.

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

Sulfur dioxide mediated syntheses of polyene containing natural products

Laure Bouchez

The goal of this thesis was to open a new route to the synthesis of conjugated trienes using a new SO2-based C-C bond forming reactions developed in Lausanne. In addition, the potential of SO2 for applications in synthetic organic chemistry has been exploited. Firstly, we discovered that under suitable conditions sulfur dioxide is able to undergo ene reaction with different building blocks such as enoxysilanes and allylsilanes to form the corresponding sulfinates. The latter can be used as key intermediates for the preparation of β-ketones, β-keto-sulfonamides and β-keto-sulfonic esters. This approach allows preparing β-keto-sulfonamides in one-pot operations. Up to now, the same type of compounds would require multi-steps syntheses. Considering the importance of sulfonamides and sulfonic esters in medicinal chemistry we prepared representative examples of such compounds. Secondly, our studies demonstrate, for the first time, that sulfones containing (E)-alkene units can be obtained through the reaction of (E,E)-1-silyloxy-2-methylpenta-1,3-diene with substituted enoxysilanes and an excess of sulfur dioxide, followed by subsequent quenching with electrophiles. Importantly, this four-component reaction yields (E)-alkenes only in the presence of a protic acid promoter and only with 1-silyloxypentadienes. In all cases mixtures of α,β-syn and α,β-anti ketones are obtained. The α,β-diastereoselectivity of the oxyallylation (face selectivity of the enoxysilane addition) does not surpass 6:1 (3R,4S vs.3S,4S). Interestingly only β,ε-like substituted ε-sulfonylketones are formed, in contrast with the (Z)-isomers which present unlike β,ε-relative configuration. Thirdly, sulfur dioxide-based chemistry was applied for the asymmetric synthesis of the conjugated (E,E,E)-triene moiety of apoptolidinone, a highly potent apoptosis inducing agent with a daunting molecular architecture. Two main synthetic routes towards the synthesis of the trienic fragment of apoptolidinone were developed, one leading to the racemic fragment and a second route leading to the enantiomerically enriched C(1)-C(9) fragment. The latter was transformed further into the fragment already synthesized by Nicolaou and co-workers, demonstrating that this second route is significantly shorter than the route previously reported in the literature. The same methodology yields also facile access to the trienic part C(5)-C(14) fragment of restricticin. This underlines further the general applicability and the high flexibilities of our method toward the synthesis of trienes.

EPFL2004

Umpolung of 1-alkoxy-3-acyloxy-1,3-dienes with sulfur dioxide and its application in polypropionate synthesis

Maris Turks

Under appropriate conditions sulfur dioxide reacts with 1,3-dienes in the hetero-Diels-Alder fashion. In the case of 1-alkoxy-1,3-dienes the 6-alkoxy-3,6-dihydro-1,2-oxatiin-2-oxides (sultines) so-obtained can be ionized in the presence of Lewis or protic acid, thus realizing Umpolung of these electron-rich systems. The zwitterionic intermediates can be trapped as electrophiles with enoxysilanes (oxyallylation) to generate substituted silyl alkenylsulfinates. Desilylation of the latter under acidic conditions 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. This new SO2 reaction cascade, hetero-Diels-Alder addition/oxyallylation/retro-ene desulfitation (Vogel's cascade), was expanded to 1,3-dioxy-1,3-dienes. It was demonstrated that 1-alkoxy-3-(trialkylsilyl)oxy-1,3-dienes (Danishefsky's dienes) undergo ene reaction with sulfur dioxide due to migratory properties of trialkylsilyl substituent. The use of 1-alkoxy-3-acyloxy-2-methyl-1,3-pentadienes and enoxysilanes in Vogel's cascades resulted in an efficient synthesis of stereotriads containing keto and enol ester functions, suitable for further chain elongation. Good anti,syn and anti,anti selectivities were achieved using of (Z)- and (E)-enoxysilanes, respectively. The synthetic potential of the method was demonstrated by the short synthesis of 3,5-dihydroxycyclohexanone subunit of baconipyrones A and B as well as that of the hydroxydiketone subunit of baconipyrones C and D ((-)-(4S,6S)-4,6-dimethyl-5-hydroxynonan-3,7-dione). Further applications were shown by expeditious formal asymmetric total synthesis of rifamycin S and initiation of synthesis of C(27)-C(37) fragment of brasilinolides A and C. The method was extended to other π-nucleophiles, such as allylsilanes. A small library of differently substituted homoallylic ethers was synthesized to demonstrate utility of this new approach. Iterative Vogel's cascade employing newly obtained fragments provided long-chain polypropionate fragments such as (-)-(1Z,2S,3S,7S,8R,9R)-1-ethylidene-9-hydroxy-2,8-dimethyl-3,7-bis((1S,1'S)-phenylethoxy)-5-methylene-undec-1-yl benzoate in a very short and efficient way. Further generalization of π-nucleophiles led to the discovery of new ene reactions of SO2 with allylgermanes and allylboronates. A number of new chiral auxiliaries were prepared and tested in order to improve chemo- and diastereoselectivity in diene reactions with sulfur dioxide. The results demonstrated the superiority of inexpensive and readily available 1-arylethanols (and particularly 1-phenylethanol) over other types of chiral auxiliaries.

EPFL2004

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

EPFL2005

Sulfur dioxide mediated syntheses of polyene containing natural products

Laure Bouchez

EPFL2004

Umpolung of 1-alkoxy-3-acyloxy-1,3-dienes with sulfur dioxide and its application in polypropionate synthesis

Maris Turks

EPFL2004