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.     

Synthesis of (+/-)-3H-epivincamine via a Rh(II)-triggered cyclization/cycloaddition cascade

A synthesis of (+/-)-3H-epivincamine is reported. Important steps include (1) a Rh(II)-catalyzed intramolecular [3+2]-cycloaddition of an alpha-diazo indolo amide, (2) a reductive ring opening of the cycloadduct, (3) a decarboethoxylation reaction, and (4) a base-induced keto-amide ring contraction.     

Application of the Rh(II) cyclization/cycloaddition cascade for the total synthesis of (+/-)-aspidophytine

[Structure: see text] A new strategy for the synthesis of (+/-)-aspidophytine has been developed and is based on a Rh(II)-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.     

Rh(I)-catalyzed ring opening of an IMDAF-derived oxabicyclo cycloadduct as the key step in the synthesis of (+/-)-epi-zephyranthine.

[reaction: see text] A new strategy for epi-zephyranthine has been developed that is based in part on an extraordinarily facile intramolecular Diels-Alder reaction of a 2-imido-substituted furan. By using a Rh(I)-catalyzed ring opening of the resulting oxabicyclic adduct, the cis-diol stereochemistry of epi-zephyranthine was established.     

Tandem Rh(i)-catalyzed [(5+2)+1] cycloaddition/aldol reaction for the construction of linear triquinane skeleton: total syntheses of (+/-)-hirsutene and (+/-)-1-desoxyhypnophilin

A tandem reaction involving a Rh(I)-catalyzed two-component [(5+2)+1] cycloaddition and an aldol condensation has been developed to construct the tricyclo[6.3.0.02,6]undecane skeleton and its heteroatom-imbedded analogues. Meanwhile, this method has been successfully applied to natural product synthesis for the first time. The present strategy enables a straightforward approach to the natural linear triquinane skeleton, as demonstrated by concise and step economical syntheses of hirsutene and 1-desoxy-hypnophilin, whereby the linear triquinane core is diastereoselectively established in one manipulation with correct placement of all stereocenters, including two quarternary centers. This first application of the Rh(I)-catalyzed [(5+2)+1] cycloaddition in natural product synthesis highlights the efficiency of this methodology for constructing complex fused ring systems.     

A general synthetic route to differentially functionalized angularly and linearly fused [6-7-5] ring systems: a Rh(I)-catalyzed cyclocarbonylation reaction

Investigations of a Rh(I)-catalyzed cyclocarbonylation reaction reveal its general synthetic utility for accessing highly functionalized tricyclic [6-7-5] linear and angular ring systems from allene-ynes. Three types of allene-ynes were prepared and subjected to Rh(I)-catalyzed cyclocarbonylation conditions. For three series of allene-ynes, the [6-7-5] ring systems were afforded in varying yields depending on the substrate structure. One series of allene-ynes afforded the [6-6-5] ring system possessing an alpha-alkylidene cyclopentenone as a result of a selective reaction with the proximal double bond of the allene.     

An approach toward isoindolobenzazepines using the ammonium ylide/Stevens

Ammonium ylides derived from the Cu(II)-catalyzed decomposition of alpha-diazo carbonyls tethered to tertiary amines underwent a benzylic Stevens [1,2]-rearrangement to give tetrahydroisoquinolines or benzazepines containing fused five-membered rings, a feature found in the cephalotaxus alkaloids. Model studies were also carried out toward the synthesis of lennoxamine, a member of the isoindolobenzazepine family of alkaloids. The approach utilized is based on the Rh(II)-catalyzed reaction of an alpha-diazo carbonyl compound containing an amido group in the gamma-position. Treatment of several N,N-dialkyl-substituted amido diazo-esters with Rh2(OAc)4 in benzene at 80 degrees C in the presence of several dienophiles gave [4 + 2]-cycloadducts derived from the Diels-Alder reaction of a transient alpha-amino isobenzofuran intermediate. In the absence of an external trapping agent, no rearranged product derived from an ammonium ylide intermediate could be detected in the crude reaction mixture. In contrast to this result, reaction of the related diazo dihydroisoquinoline amide 46 with Rh2(OAc)4 afforded the isoindolobenzazepine ring system in high yield. Formation of the 5,7-fused skeleton was rationalized in terms of a spirocyclic ammonium ylide that underwent a preferential Stevens [1,2]-shift of the benzylic carbon atom. While we were ultimately thwarted in using the ammonium ylide/rearrangement cascade for a lennoxamine synthesis by an uncooperative diazo transfer reaction, the cascade sequence was shown to be useful for the preparation of various isoindolobenzazepines.     

Features and applications of [Rh(CO)(2)Cl](2)-catalyzed alkylations of unsymmetrical allylic substrates

A novel regio- and stereoselective [Rh(CO)2Cl]2-catalyzed allylic alkylation of unsymmetrical allylic carbonates was discovered. The regioselectivity of the reaction favors product ratios in which substitution occurs at the carbon bearing the leaving group. When an enantiomerically enriched carbonate (> or = 99% ee) was examined, the Rh(I)-catalyzed allylic alkylation proceeded stereoselectively to provide the alkylation product with retention of absolute stereochemistry (98% ee). To establish the scope of the [Rh(CO)2Cl]2-catalyzed allylic alkylation, a variety of carbon and heteroatom nucleophiles were examined and the results described. As an application of the Rh(I)-catalyzed allylic alkylation, a series of novel domino reactions have been developed that couple the unique regio- and stereoselective [Rh(CO)2Cl]2-catalyzed alkylation of allylic trifluoroacetates with an intramolecular Pauson-Khand annulation, a cycloisomerization, or a [5+2] cycloaddition. A unique aspect of the method described is the use of a single catalyst to effect sequential transformations in which the catalytic activity is moderated simply by controlling the reaction temperature. Implementation of such processes provides a rapid and efficient entry to a variety of bicyclic carbon skeletons from simple precursors.     

Synthesis, resolution, and applications of 2, 2'-bis(diphenylphosphino)-3,3'- binaphtho[2,1-b]furan

[structure: see text] A short five-step synthesis of (+/-)-2,2'-bis(diphenylphosphino)-3, 3'-binaphtho[2,1-b]furan (BINAPFu, 1) starting from 2-naphthoxyacetic acid is reported. The resolution of BINAPFu 1 was possible using our newly developed resolution procedure for phosphines wherein (1S)-camphorsulfonyl azide was used to prepare the bisphosphinimine of BINAPFu via the Staundinger reaction. BINAPFu consistently outperformed BINAP in an asymmetric Heck reaction between 2,3-dihydrofuran and phenyl triflate.     

Consecutive Rh(I)-catalyzed Alder-ene/Diels-Alder/Diels-Alder reaction sequence affording rapid entry to polycyclic compounds

Conversion of acyclic allenynes to polycyclic compounds using consecutive transition metal catalyzed carbon-carbon bond forming reactions in a single chemical operation is described. Reaction of an allenyne with a Rh(I) catalyst affords a cross-conjugated triene via a formal Alder-ene reaction. The triene then participates in a Rh(I)-catalyzed intramolecular [4+2] cycloaddition reaction to generate a new conjugated diene. An external dienophile is added to this diene which then undergoes a second [4+2] cycloaddition reaction to afford a complex polycyclic ring system. This reaction sequence demonstrates the synthetic potential of allenynes and cross conjugated trienes and highlights the rapid increases in molecular complexity that are possible by one-pot sequential transition metal catalyzed carbon-carbon bond forming reactions.     

Application of Rh(I)-catalyzed C-H bond activation to the ring opening of 2-cycloalkenones in the presence of amines

[reaction: see text]. Herein described is the application of the Rh(I)-catalyzed C-H bond activation to the ring-opening of 2-cycloalkenones in the presence of cyclohexylamine. This reaction includes the C-C double bond cleavage of 2-cycloalkenones through the conjugate addition of cyclohexylamine followed by the retro-Mannich-type fragmentation. The resulting ring-opened intermediates subsequently underwent either chelation-assisted hydroacylation to afford a ring-opened dicarbonyl compound or beta-alkylation via a ring contraction.     

Formal total synthesis of (±)-hirsutic acid C using the tandem Rh(I)-catalyzed [(5+2)+1] cycloaddition/aldol reaction

A concise formal total synthesis of the linear triquinane natural product (±)-hirsutic acid C has been achieved. This synthesis features a tandem Rh(I)-catalyzed [(5+2)+1] cycloaddition/aldol reaction as the key step to build the triquinane skeleton.     

Facile construction of novel polycyclic ring systems using a metallocarbenoid-induced cyclization of acetylenic diazo carbonyl compounds

The Rh(II)-catalyzed reaction of diazo 2-propynyl maolonamic acid ester derivatives produce furo[3,4-c]furans in excellent yield. The methodology was applied to the synthesis of several polyheterocyclic systems by first generating a 2-alkoxy-substituted furan and then allowing it to undergo a subsequent intramolecular Diels-Alder cycloaddition. Ring opening of the resulting cycloadduct is followed by deprotonation to furnish a rearranged keto lactone.     

Total synthesis of (+)-achalensolide based on the rh(i)-catalyzed allenic Pauson-Khand-type reaction

The first total synthesis of (+)-achalensolide was achieved from a commercially available d-(-)-isoascorbic acid. The known epoxide, derived from d-(-)-isoascorbic acid, was converted into the allenyne, the Rh(I)-catalyzed Pauson-Khand-type reaction of which directly provided the bicyclo[5.3.0]decane system, a core framework of the title natural product. The construction of the gamma-lactone moiety and some chemical modifications resulted in the completion of the total synthesis of (+)-achalensolide.     

General access to the vinca and tacaman alkaloids using a Rh(II)-catalyzed cyclization/cycloaddition cascade

The total synthesis of several members of the vinca and tacaman classes of indole alkaloids has been accomplished. The central step in the synthesis consists of an intramolecular [3+2]-cycloaddition reaction of an alpha-diazo indoloamide which delivers the pentacyclic skeleton of the natural product in excellent yield. The acid lability of the oxabicyclic structure was exploited to establish the trans-D/E ring fusion of (+/-)-3H-epivincamine (3). Finally, a base induced keto-amide ring contraction was utilized to generate the E-ring of the natural product. A variation of the cascade sequence of reactions used to synthesize (+/-)-3H-epivincamine was also employed for the synthesis of the tacaman alkaloids (+/-)-tacamonine and (+/-)-apotacamine.     

Transition metal-catalyzed intermolecular [5+2] and [5+2+1] cycloadditions of allenes and vinylcyclopropanes

Initial examples of the intermolecular Rh(I)-catalyzed [5+2] cycloaddition reaction of bifunctional allenes and vinylcyclopropanes are described. The reactions proceed with facility and in yields of up to 99% with a variety of alkyne-, ester-, styrene-, or cyano-substituents on the allene to afford the corresponding cycloadducts. In the presence of CO, the reaction proceeds to an eight-membered ring cycloadduct and its transannularly closed product, providing the first example of a three-component [5+2+1] cycloaddition with allenes.     

Cycloaddition chemistry of 2-vinyl-substituted indoles and related heteroaromatic systems

[reaction: see text] The intramolecular Diels-Alder cycloaddition reaction (IMDAF) of several N-phenylsulfonylindolyl-substituted furanyl carbamates containing a tethered pi-bond on the indole ring were examined as an approach to the iboga alkaloid catharanthine. Only in the case where the tethered pi-bond contained two carbomethoxy groups did the [4 + 2]-cycloaddition occur. Push-pull dipoles generated from the Rh(II)-catalyzed reaction of diazo imides, on the other hand, undergo successful intramolecular 1,3-dipolar cycloaddition across both alkenyl and heteroaromatic pi-bonds to provide novel pentacyclic compounds in good yield and in a stereocontrolled fashion. The facility of the cycloaddition was found to be critically dependent on conformational factors in the transition state. Ligand substitution in the rhodium(II) catalyst markedly altered the product ratio between [3 + 2]-cycloaddition and intramolecular C-H insertion. The variation in reactivity reflects the difference in electrophilicity between the various rhodium carbenoid intermediates. Intramolecular C-H insertion is enhanced with the more electrophilic carbene generated using Rh(II) perfluorobutyrate.     

Rh(I)-catalyzed direct ortho-alkenylation of aromatic ketimines with alkynes and its application to the synthesis of isoquinoline derivatives

[reaction: see text] Novel synthetic methods of both ortho-alkenylated aromatic ketones and isoquinoline derivatives have been developed through the Rh(I)-catalyzed direct ortho-alkenylation of common aromatic ketimines with alkynes. Furthermore, a highly efficient one-pot synthesis of isoquinoline derivatives was achieved by simply mixing aromatic ketone, benzylamine, and alkyne under a Rh(I) catalyst.     

Enantioselective synthesis of (-)-roccellaric acid

[reaction in text] A new strategy for the synthesis of anti-4,5-disubstituted gamma-butyrolactones starting from inexpensive furan-2-carboxylic methyl ester was developed. By applying this methodology, the enantioselective synthesis of (-)-roccellaric acid ((-)-17) was accomplished using a copper(I)-catalyzed asymmetric cyclopropanation, a tin(IV)-catalyzed retroaldol/lactonization sequence of cyclopropanols, and a ruthenium-catalyzed intermolecular metathesis reaction as key steps.     

Mo(CO)6- and [Rh(CO)2Cl]2-catalyzed allenic cyclocarbonylation reactions of alkynones: efficient access to bicyclic dienediones

Allenyl alkynones are efficiently transformed into fused bicyclic dienediones via cyclocarbonylation reaction conditions. Mo(CO)6/DMSO reaction conditions result in the formation of a bicyclo[3.3.0]octenone ring system, and the [Rh(CO)2Cl]2-catalyzed reaction affords bicyclo[4.3.0]nonenone and bicyclo[5.3.0]decenone scaffolds.