Umpolung with Sulfur Dioxide: Carbon-Carbon Cross-Coupling of Electron-Rich 1,3-Dienes and Alkenes; Application to the Enantioselective Synthesis of Long-Chain Polyketide Fragments

Claudia Jana Exner, Maris Turks, Pierre Vogel
2009
Journal paper

Abstract

At low temperature and in the presence of an acid catalyst, sulfur dioxide undergoes hetero-Diels-Alder additions with 1-oxy-1,3-dienes, giving unstable sultines, which are ionized into zwitterionic species and react as 1-oxyallylic cation intermediates (Umpolung with SO2) with electron-rich alkenes such as allylsilanes or enoxysilanes. The (beta,gamma-unsaturated silyl sulfinates so-obtained can be desulfinylated in situ to generate polyketide fragments containing up to three contiguous stereogenic centers in one-pot operations. This reaction cascade can be applied in two-directional chain elongation approaches for the asymmetric synthesis of long chain polyketide fragments using 1-[(S)- or (R)-1-phenylethoxy]1,3-dienes.

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New access to long-chain polyketides and spiroketals by umpolung of electron rich dienes with sulfur dioxide

Freddy Fonquerne

Natural polyketides show important biological activity. The inherent stereochemical complexity present in this class of molecules has captured the imagination of organic chemists. Their stereocontrolled, asymmetric total synthesis is a permanent and stimulating area of research. Previous efforts in our group demonstrated that the Umpolung of electron rich 1,3-dienes with SO2 could represent an efficient synthetic strategy to polyketides. 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 a Lewis or protic acid. The resulting zwitterionic intermediates can be trapped with enoxysilanes (oxyallylation) to generate the corresponding substituted alkenylsulfinates. Desilylation of the latter under acidic conditions leads to allylsulfinic acid intermediates, which, after retro-ene desulfitation, produce 4-alkoxyhepta-6-en-2-one core, a valuable fragment in polyketide natural product synthesis. This new SO2 cascade reaction, hetero-Diels-Alder addition/oxyallylation/retro-ene desulfitation (Vogel's cascade) has been extended to 1-alkoxy-3-acyloxy-1,3-pentadienes. Their use in this cascade reaction allowed the generation of 1,3-polyols array containing keto and enol ester functions, suitable for further chain elongation. In addition, this work highlights the extension of this methodology to other types of p-nucleophiles. The use of carefully elaborated allylsilanes allowed the preparation in a single operation (one pot double oxyallylation reaction) of long chain polyketides of 13 carbons units. Finally, a new route to the spiroketals A/B and C/D and of Spongistatins is presented in order to demonstrate the utility and the versatility of this approach.

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

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

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Laure Bouchez

EPFL2004