A highly efficient total synthesis of (±)-Lycoricidine is described. The synthesis features the ready preparation of the lycoricidine skeleton by a Stille-IMDAF cycloaddition cascade. The resulting cycloadduct is then used for the stereocontrolled installation of the other functionality present in the C-ring of the target molecule.
An approach to the hexacyclic framework of the kopsifoline alkaloids has been developed and is based on a Rh(II)-catalyzed cyclization-cycloaddition cascade. The resulting [3+2]-cycloadduct was readily converted into the TBS enol ether 23. Oxidation of the primary alcohol present in 23 followed by reaction with CsF afforded compound 24 that contains the complete hexacyclic skeleton of the kopsifolines.
A new strategy for the synthesis of (±)-aspidophytine has been developed and is based on a Rh(ll)-catalyzed cyclization/dipolar-cycloaddition sequence. The resulting [3+2]-cycloadduct undergoes an efficient Lewis acid mediated cascade that rapidly provides the complete skeleton of aspidophytine. The synthesis also features a mild decarbomethoxylation reaction.
A series of 2-imido substituted furans containing tethered unsaturation were prepared by the addition of the lithium carbamate of furan-2-yl carbamic acid tert-butyl ester to a solution of the mixed anhydride of an appropriately substituted 3-butenoic acid. The initially formed imido furans undergo a rapid intramolecular [4+2]-cycloaddition at room temperature to deliver the Diels-Alder cycloadducts in good to excellent yield. Isolation of the highly labile oxabicyclic adduct is believed to be a consequence of the lower reaction temperatures employed as well as the presence of the extra carbonyl group, which diminishes the basicity of the nitrogen atom thereby retarding the ring cleavage/rearrangement reaction generally encountered with related systems. By using a Rh(I)-catalyzed ring opening of the oxabicyclic adduct with various nucleophilic reagents, it was possible to prepare highly functionalized hexahydro-1 H-indol-2(3H)-one derivatives in good yield. The major stereoisomer obtained possesses a cis-relationship between the nucleophile and hydroxyl group in the ring-opened product. The stereochemistry was unequivocally established by X-ray crystallographic analysis. Coordination of Rh(I) to the alkenyl π-bond followed by a nitrogen-assisted cleavage of the carbon-oxygen bond occurs to furnish a π-allyl rhodium(III) species. Addition of the nucleophile then occurs from the least hindered terminus of the resulting π-allyl rhodium(III) complex. Proton exchange followed by rhodium(I) decomplexation ultimately leads to the cis-diastereomer.
cis-2-Methyl-6-substituted piperidin-3-ol alkaloids of the Cassia and Prosopis species are readily prepared by a combination of an aza-Achmatowicz oxidative rearrangement, dihydropyridone reduction followed by a Stereoselective allylsilane addition to a N-sulfonyliminium ion. The stereochemical outcome of the reduction reaction can be attributed to steric hindrance between the pseudoaxially oriented 2,6-substituents and the equatorially approaching hydride reagent which explains the exclusive formation of the cis-alcohol by axial approach of the hydride. The unsaturation present in the (E)-methyl-pent-3-enoate side chain was removed by catalytic reduction and the remaining ester group was converted to the corresponding Weinreb’s amide. This key intermediate was utilized for the synthesis of azimic acid, deoxocassine, cassine and spicigerine. The facile preparation of (S)-N-tosylamidofuran 16 and its conversion to the chiral Achmatowicz oxidation product 18 provides a formal chiral synthesis of these alkaloids.
The Rh(II)-catalyzed reaction of the E-isomer of 2-diazo-3,6-dioxo-6-phenyl-hex-enoic acid methyl ester was carried out in the presence of various carbonyl compounds and was found to give 1,3-dioxoles in moderate to good yield. In an attempt to prepare the starting -diazo substrate, an unexpected pseudo-dimerization reaction was encountered when 5-phenyl-furan-2,3-dione was heated in the presence of sodium methoxide.
The decarbomethoxylation reaction of a substituted α-hydroxy-α-carbomethoxy pentacyclic substituted ketone, used as an advanced intermediate in the synthesis of the alkaloid aspidophytine, can be elected by heating with MgI2 in CH3CN. The reaction was shown to proceed by a novel α-hydroxy β-dicarbonyl to α-ketol ester rearrangement. It was possible to isolate a carbonate intermediate in 75% yield, thereby providing support for the proposed pathway.
Using a rhodium(II)-catalyzed cyclization/cycloaddition sequence as the key reaction step, the icetexane core of komaroviquinone was constructed by an intramolecular dipolar-cycloaddition of a carbonyl ylide dipole across a tethered π-bond. The ylide was arrived at by cyclization of a rhodium carbenoid intermediate onto a proximal ester group. Efforts towards the preparation of the required precursor for elaboration to the natural product are discussed.
Tandem carbonyl ylide formation-1,3-dipolar cycloaddition of α-diazo N-acetyl-tetrahydro-β-carbolin-1-one derivatives occur efficiently in the presence of a dirhodium catalyst to afford bimolecular cycloadducts in high yield. The Rh(II)-catalyzed reaction also takes place intramolecularly to give products derived from trapping of the carbonyl ylide dipole with a tethered alkene. The power of the intramolecular cascade sequence is that it rapidly assembles a pentacyclic ring system containing three new stereocenters and two adjacent quaternary centers stereospecifically in a single step and in high yield.
Sequential transformations enable the facile synthesis of complex target molecules from simple building blocks in a single preparative step. Their value is amplified if they also create multiple stereogenic centers. In the ongoing search for new domino processes, emphasis is usually placed on sequential reactions which occur cleanly and without forming by-products. As a prerequisite for an ideally proceeding one-pot sequential transformation, the reactivity pattern of all participating components has to be such that each building block gets involved in a reaction only when it is supposed to do so. The development of sequences that combine transformations of fundamentally different mechanisms broadens the scope of such procedures in synthetic chemistry. This mini review contains a representative sampling from the last 15 years on the kinds of reactions that have been sequenced into cascades to produce heterocyclic molecules.