An approach toward the alkaloid (±)-mersicarpine using a rhodium(II) carbenoid cyclization-cycloaddition cascade of an α-diazo dihydroindolinone

A tandem carbonyl ylide/1,3-dipolar cycloaddition cascade of α-diazo indole-2,3-dione with several different dipolarophiles was investigated. The intermolecular Rh(II)-catalyzed reaction occurs efficiently and affords dipolar cycloadducts in high yields. The analogous intramolecular reaction also takes place and gives an azapolycyclic product derived from trapping of the carbonyl ylide dipole with a tethered alkene. The power of the intramolecular cascade sequence is that it rapidly assembles polycyclic ring systems containing both multiple stereocenters and adjacent quaternary carbon centers in a single step in high yield. This cascade reaction was successfully utilized in a model study directed toward the total synthesis of mersicarpine.     

Ligand Effects on the Chemoselectivity of Transition Metal Catalyzed Reactions of α-Diazo Carbonyl Compounds

The transition metal catalyzed reaction of α-diazo carbonyl compounds has found numerous applications in organic synthesis, and its use in either heterocyclic or carbocyclic ring formation is well precedented. Early work in this area made use of insoluble copper catalysts. Although these catalysts are still employed today, their use has decreased significantly with the advent of homogeneous copper catalysts and catalysts based on other metals. The discovery that Rh^II carboxylates facilitate nitrogen loss from diazo compounds rekindled significant interest in the field of diazo/carbenoid chemistry. Since the realization that Rh^II carboxylates are superior catalysts for the generation of transient electrophilic metal carbenoids from α-diazo carbonyl compounds, intramolecular carbenoid addition and insertion reactions have assumed strategic importance in C? C bond-forming reactions in organic synthesis. In contrast to other catalysts that are suitable for carbenoid reactions of diazo compounds, those constructed with the dirhodium(II ) framework are most amenable to ligand modifications that, in turn, can influence reaction selectivity. This article will emphasize the chemical behavior of transition metal carbenoid complexes that are greatly affected by the nature of the ligand groups attached to the metal center. Much of the discussion will center on the ability of the dirhodium(II ) ligands to determine reaction preference toward different functional groups on the same molecule.     

Rhodium(I)-catalyzed nucleophilic ring-opening reactions of oxabicyclo adducts derived from the [4 + 2]-cycloaddition of 2-imido-substituted furans

A series of 2-imido-substituted furans containing tethered unsaturation were prepared by the addition of the lithium carbamate of furan-2-ylcarbamic 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-1H-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 pi-bond followed by a nitrogen-assisted cleavage of the carbon-oxygen bond occurs to furnish a pi-allyl rhodium(III) species. Addition of the nucleophile then occurs from the least hindered terminus of the resulting pi-allyl rhodium(III) complex. Proton exchange followed by rhodium(I) decomplexation ultimately leads to the cis-diastereomer.     

Application of the aza-Achmatowicz oxidative rearrangement for the stereoselective synthesis of the Cassia and Prosopis alkaloid family

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 and 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 provide a formal chiral synthesis of these alkaloids.     

Synthesis of the tetracyclic framework of the erythrina alkaloids using a [4 + 2]-cycloaddition/Rh(I)-catalyzed cascade of 2-imidofurans

Several 2-imido substituted furans were found to undergo a rapid intramolecular [4 + 2]-cycloaddition to deliver oxabicyclo adducts in good to excellent yields. By using a Rh(I)-catalyzed ring opening of the resulting oxabicyclic adduct, it was possible to prepare several highly functionalized tetrahydro-1H-indol-2(3H)-one derivatives which were then used to prepare several erythrina alkaloids. By taking advantage of the Rh(I)-catalyzed reaction, it was possible to convert tert-butyl 3-oxo-5-carbomethoxy-10-oxa-2-azatricyclo[5.2.1.0(1,5)]dec-8-ene-2-carboxylate into the ring opened boronate by reaction with phenylboronic acid. Treatment of the boronate with pinacol/acetic acid afforded the corresponding diol which was used in a successful synthesis of racemic 3-demethoxyerythratidinone. During the course of these studies, several novel rearrangement reactions were encountered while attempting to induce an acid-initiated Pictet Spengler cyclization of a key lactam intermediate. The IMDAF/Rh(I)-catalyzed ring opening cascade sequence was also applied to the total synthesis of (+/-)-erysotramidine as well as the lycorine type alkaloid (+/-)-epi-zephyranthine.     

An efficient synthesis of (+/-)-Lycoricidine featuring a Stille-IMDAF cycloaddition cascade

[reaction: see text] 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.     

Rhodium(II)-catalyzed cyclization of amido diazo carbonyl compounds

A series of acyclic diazo ketoamides were prepared from N-benzoyl-N-alkylaminopropanoic acids and were treated with a catalytic amount of rhodium(II) acetate. The resultant carbenoids underwent facile cyclization onto the neighboring amide carbonyl oxygen atom to generate seven-membered carbonyl ylide dipoles. Subsequent collapse of the dipoles with charge dissipation produce bicyclic epoxides which undergo further reorganization to give substituted 5-hydroxydihydropyridones in good yield. Depending on the nature of the substituent groups, it was possible to trap some of the initially formed carbonyl ylide dipoles with a reactive dipolarophile such as DMAD. In other cases, cyclization of the dipole to the epoxide is much faster than bimolecular trapping. A related cyclization/rearrangement sequence occurred when diazo ketoamides derived from the cyclic pyrrolidone and piperidone ring systems were subjected to catalytic quantities of Rh(II) acetate. With these systems, exclusive O-cyclization of the amido group onto the carbenoid center occurs to generate a seven-ring carbonyl ylide dipole. Starting materials are easily prepared, and the cascade sequence proceeds in good yield and does not require special precautions. The overall procedure represents an efficient one-pot approach toward the synthesis of various indolizidine and quinolizidine ring systems.     

The reaction of cyclic carbinol amides with triflic anhydride as a method to prepare alpha-trifluoromethyl-sulfonamido furans

[reaction: see text] A novel synthesis of alpha-trifluoromethyl-sulfonamido furans via the reaction of cyclic carbinol amides with triflic anhydride has been developed. The reaction proceeds under very mild conditions with a wide set of representative lactams to provide the alpha-trifluoromethyl-sulfonamido-substituted furan in high yield. Rapid access to a 5-substituted indoline can be achieved by thermolysis of the N-but-3-enyl-substituted sulfonamido furan.     

Regiochemical aspects associated with the cycloaddition of diazopyrazolinones to electron deficient acetylenes

The regiospecificity with which members of the 4-diazopyrazolin-5-one system undergo intermolecular cycloaddition to propiolate ester has been found to be markedly dependent upon the substituent groups present.