Expeditious asymmetric synthesis of a stereoheptad corresponding to the C(19)-C(27)-ansa chain of rifamycins: Formal total synthesis of Rifamycin S

In the presence of sulfur dioxide and an acid promoter, (-)-(1E,3Z)-2-methyl-1-((1S)-1-phenyleth- oxy)penta-1,3-dien-3-yl isobutyrate reacts with (Z)-3-(trimethylsilyloxy)-pent-2-ene giving a silyl sulfinate intermediate that undergoes, in the presence of palladium catalyst, a desilylation and retro-ene elimination of SO2 with formation of (-)-(1Z,2S,3R,4S)-1-ethylidene-2,4-dimethyl-5-oxo-3-((1S)-1-phenylethoxy )-heptyl isobutyrate as major product. This ethyl ketone undergoes cross-aldol reaction with (2S)2-methyl-3-[(tert-butyldimethylsilyl)- oxy]propanal giving an aldol that is reduced into a stereoheptad corresponding to the C(19)-C(27)-segment of Rifamycins with high diastereoselectivity and enantiomeric excess.

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

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

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

Cotinica Craita

EPFL2006

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

Maris Turks

EPFL2004

Sulfur dioxide mediated syntheses of polyene containing natural products

Laure Bouchez

EPFL2004