Use of sultines in the asymmetric synthesis of polypropionate antibiotics

Abstract

At low temperature and in the presence of an acid catalyst, SO 2 adds to 1,3-dienes equilibrating with the corresponding 3,6-dihydro-1,2-oxathiin-2-oxides (sultines). These compounds are unstable above -60°C and equilibrate with the more stable 2,5-dihydrothiophene 1,1-dioxides (sulfolenes). The hetero-Diels-Alder additions of SO 2 are suprafacial and follow the Alder endo rule. The sultines derived from 1-oxy-substituted and 1,3-dioxydisubstituted 1,3-dienes cannot be observed at -100°C but are believed to be formed faster than the corresponding sulfolenes. In the presence of acid catalysts, the 6-oxy-substituted sultines equilibrate with zwitterionic species that react with electron-rich alkenes such as enoxysilanes and allylsilanes, generating β,γ-unsaturated silyl sulfinates that can be desilylated and desulfinylated to generate polypropionate fragments containing up to three contiguous stereogenic centers and an (E)-alkene unit. Alternatively, the silyl sulfinates can be reacted with electrophiles to generate polyfunctional sulfones (one-pot, four-component synthesis of sulfones), or oxidized into sulfonyl chlorides and reacted with amines, then realizing a one-pot, four-component synthesis of polyfunctional sulfonamides. Using enantiomerically enriched dienes such as 1-[(R)-or 1-(S)-phenylethyloxy]-2-methyl-(E,E)-penta-1,3-dien-3-yl isobutyrate, derived from inexpensive (R)-or (S)-1-phenylethanol, enantiomerically enriched stereotriads are obtained in one-pot operations. The latter are ready for further chain elongation. This has permitted the development of expeditious total asymmetric syntheses of important natural products of biological interest such as the baconipyrones, rifamycin S, and apoptolidin A.

Concise Synthesis of Complicated Polypropionates through One‐Pot Dissymmetrical Two‐Directional Chain Elongation

“…[c] The opposite enantiomer than the one shown was obtained. [d] This result has been previously published, see Vogel et al [7] Scheme 4. Possible reaction pathways for a SO 2 -induced one-pot, two-directional oxyallylation cascade.…”

“…[4] We have reported the one-pot synthesis of stereotriads 7 using an oxyallylation reaction cascade that combines electron-rich dienes 1 and carbon nucleophiles 4, such as enoxysilanes, through SO 2 -umpolung (Scheme 1). [5,6,7] Dienes 1, containing a 1-arylethyl chiral auxiliary, [8] undergo heteroDiels-Alder (HDA) addition with SO 2 to generate six-membered sultine 2, which is subsequently broken down to the zwitterionic species 3 by Lewis acid assisted heterolysis. NuAbstract: Herein, a major breakthrough in a sulfur dioxide-mediated oxyallylation cascade reaction is reported that allows the preparation of complex long-chain polyketide fragments with more than ten stereogenic centers through a carefully designed desymmetrization process.…”

“…Sulfinic acid 6 then undergoes a highly stereoselective retro-ene reaction with concomitant desulfinylation into stereotriad 7. Using our method, we have developed access to 4,5-anti-5,6-syn [7] and 4,5-anti-5,6-anti-stereotriads. [11] Stereotriads 7 contain two structural motifs for further chain elongation in both directions: 1) the ketone moiety on one side can be used directly in aldol condensations, and 2) the enol ester on the other side can be transformed into an enolate for use in stereoselective aldol reactions.…”

Efficient Asymmetric Synthesis of Long‐Chain Polyketides Containing up to Ten Contiguous Stereogenic Centres by Double Chain Elongation

“…[5] We have reported one-pot syntheses of the stereotriads 7 through oxyallylation reaction cascades in which the electron-rich dienes 1 and the enoxysilanes 4 are coupled through SO 2 umpolung (Scheme 1). [6][7][8] The dienes 1, each containing a 1-arylethyl chiral auxiliary, [9] undergo hetero-(Z)-enol isobutyrate units remained intact were obtained. After suitable protection, these were converted into their corresponding lithium (Z)-enolates, which could react with isopropylidene D-glyceraldehyde [(+)-9] to give aldol products that were reduced to various stereodecads (polyketides with ten contiguous stereogenic centres).…”

The Catalyzed Desulfinylative Allylation of Carbonyl Compounds with Alk‐2‐enesulfonyl Chlorides and Silyl Alk‐2‐enesulfinates

“…[29,30] As these compounds can also be obtained by the H-ene reaction of alkenes with SO 2 /BCl 3 , followed by neutralization with NH 3 and reaction with silyl chlorides [10] (Scheme 5), we wondered whether these systems could be employed as nucleophilic allylating agents.…”