Formal synthesis of (+/-)-dendrobine: use of the amidofuran cycloaddition/rearrangement sequence

The formal synthesis of the alkaloid (+/-)-dendrobine (4) was accomplished using the IMDAF cycloaddition/rearrangement sequence of a furanyl carbamate. Conversion of the rearranged cycloadduct to Kende's advanced intermediate in eight steps completed the formal synthesis of (+/-)-dendrobine.     

Synthesis of some members of the hydroxylated phenanthridone subclass of the Amaryllidaceae alkaloid family

The total synthesis of several members of the hydroxylated phenanthridone subclass of the Amaryllidaceae alkaloid family has been carried out. (+/-)-Lycoricidine and (+/-)-7-deoxypancratistatin were assembled through a one-pot Stille/intramolecular Diels-Alder cycloaddition cascade to construct the core skeleton. The initially formed [4+2]-cycloadduct undergoes nitrogen-assisted ring opening followed by a deprotonation/reprotonation of the resulting zwitterion to give a rearranged hexahydroindolinone on further heating at 160 degrees C. The stereochemical outcome of the IMDAF cycloaddition has the side arm of the tethered vinyl group oriented exo with respect to the oxygen bridge. The resulting cycloadduct was used for the stereocontrolled installation of the remaining functionality present in the C-ring of the target molecules. Key features of the synthetic strategy include (1) a lithium hydroxide induced tandem hydrolysis/decarboxylation/elimination sequence to introduce the required pi-bond in the C-ring of (+/-)-lycoricidine, and (2) conversion of the initially formed Diels-Alder adduct into an aldehyde intermediate which then undergoes a stereospecific decarbonylation reaction mediated by Wilkinson's catalyst to set the trans-B-C ring junction of (+/-)-7-deoxypancratistatin.     

Formal total synthesis of (+/-)-gamma-lycorane and (+/-)-1-deoxylycorine using the [4+2]-cycloaddition/rearrangement cascade of furanyl carbamates

The total syntheses of gamma-lycorane and (+/-)-1-deoxylycorine were accomplished using an intramolecular Diels-Alder cycloaddition of a furanyl carbamate as the key step. The initially formed [4+2]-cycloadduct undergoes nitrogen-assisted ring opening followed by deprotonation/reprotonation of the resulting zwitterion to give a rearranged hexahydroindolinone. The stereochemical outcome of the IMDAF cycloaddition has the side arm of the tethered alkenyl group oriented syn with respect to the oxygen bridge. The key intermediate used in both syntheses corresponds to hexahydroindolinone 20. Removal of the t-Boc group in 20 followed by reaction with 6-iodobenzo[1,3]dioxole-5-carbonyl chloride afforded enamide 22. Treatment of this compound with Pd(OAc)(2) employing the Jeffrey modification of the Heck reaction provided the galanthan tetracycle 24 in good yield. Compound 24 was subsequently converted into (+/-)-gamma-lycorane using a four-step procedure to establish the cis-B,C-ring junction. A radical-based cyclization of the related enamide 33 was used for the synthesis of 1-deoxylycorine. Heating a benzene solution of 33 with AIBN and n-Bu(3)SnH at reflux gave the tetracyclic compound 38 possessing the requisite trans fusion between rings B and C in good yield. After hydrolysis and oxidation of 38 to 40, an oxidative decarboxylation reaction was used to provide the C(2)(-)C(3)(-)C(12) allylic alcohol unit characteristic of the lycorine alkaloids. The resulting enone was eventually transformed into (+/-)-1-deoxylycorine via known synthetic intermediates.     

A Cycloaddition Approach toward the Synthesis of Substituted Indolines and Tetrahydroquinolines

The intramolecular Diels-Alder reaction of 2-substituted aminofurans (IMDAF) results in the formation of various indolines and tetrahydroquinolines. The isolation of these ring systems from the IMDAF reaction can be rationalized in terms of an initial [4 + 2]-cycloaddition that first produces an oxa-bridged cycloadduct, which was not detected since it readily underwent nitrogen-assisted ring opening. Proton exchange followed by an eventual dehydration provides the aromatic product. In certain cases, the intermediate cyclohexadienol can be isolated and independently converted to the final product in high yield. The starting 2-aminofurans were readily prepared from furanyl acyl azide by a Curtius rearrangement in the presence of an alcohol. Alkylation of the resulting N-alkyl carbamate with an alkenyl bromide allows for the synthesis of a wide variety of cycloaddition precursors. The scope of the IMDAF reaction was evaluated by using mono- and disubstituted alkenes, electron rich and electron deficient olefins, and acetylenic tethers. Cyclic 2-amidofurans were also synthesized using a related intramolecular Diels-Alder reaction of 2-amido-substituted oxazoles which contain a tethered alkyne. This transformation represents a new route to this rare heterocyclic ring system. The sequential cycloaddition method was used for a formal synthesis of the pyrrolophenanthridone alkaloid hippadine.     

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.     

An IMDAF cycloaddition approach toward the synthesis of the lycopodium alkaloid (±)-fawcettidine

Using an intramolecular [4 + 2] cycloaddition/rearrangement cascade of 3-(1,4-dioxaspiro[4.4]non-7-en-7-yl)-N-furan-2-ylpropionamide (23) as the key step, the BCD core of the lycopodium alkaloid fawcettidine was constructed. Heating the initially formed Diels-Alder cycloadduct at 180 °C results in a nitrogen-assisted ring opening followed by a deprotonation/reprotonation of the ensuing zwitterion to give a rearranged hexahydroindolinone. Our attempts to induce a related intramolecular furan Diels-Alder reaction (IMDAF) from the corresponding ketone of 23 failed to give any cycloaddition product. Instead, the only product obtained corresponded to a cyclopentenone derivative derived by isomerization of the double bond into the thermodynamically more stable α,β-position. Efforts toward construction of the final skeleton of fawcettidine by ring A closure of the rearranged cycloadduct derived from furanyl amide 23 are discussed.     

Using the Pummerer cyclization-deprotonation-cycloaddition cascade of imidosulfoxides for alkaloid synthesis

The Pummerer reaction of imidosulfoxides bearing tethered alkenyl groups has been employed for the synthesis of several alkaloids. The required imidosulfoxides necessary for the cascade sequence were easily obtained by heating the appropriate amide with (ethylsulfeny)acetyl chloride followed by sodium periodate oxidation. The initially formed thionium ion, obtained by treating the imidosulfoxide with acetic anhydride and p-toluenesulfonic acid, reacts with the neighboring imido group, and the resulting oxonium ion undergoes subsequent deprotonation to produce an isomünchnone dipole. This mesoionic betaine intermediate undergoes ready intramolecular dipolar cycloaddition across the neighboring pi-bond. Exposure of the resulting cycloadducts to additional acetic anhydride leads to ring opening and formation of a 5-acetoxy-substituted 2(1H)-pyridone. This six-ring heterocyclic system constitutes a valuable building block for the synthesis of a variety of pyridine, quinolizidine, and clavine alkaloids. The cyclization-deprotonation-cycloaddition cascade has been successfully applied to the synthesis of the naturally occurring alkaloids onychnine, dielsiquinone, (+/-)-lupinine, (+/-)-anagyrine, (+/-)-pumiliotoxin C, and (+/-)-costaclavine.     

A short total synthesis of aureothin and N-acetylaureothamine

The total synthesis of the nitrophenyl pyrones, (+/-)-aureothin and (+/-)-N-acetylaureothamine, starting from known 2-ethyl-6-methoxy-3,5-dimethyl-4H-pyran-4-one are described. The key steps involved in the synthesis are the construction of the tetrahydrofuran motif using a palladium-catalyzed cycloaddition and the ruthenium-catalyzed cross-metathesis reaction of an alkenyl boronic ester. [reaction: see text]     

Intramolecular formal aza-[3 + 3] cycloaddition approach to indoloquinolizidine alkaloids. A stereoselective total synthesis of (+/-)-tangutorine

[reaction: see text] A 19-step stereoselective total synthesis of (+/-)-tangutorine is described here. The total synthesis features an intramolecular aza-[3 + 3] formal cycloaddition strategy and also a Heck coupling for constructing the C2-C3 bond. This work provides a novel approach toward the indoloquinolizidine family of 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.     

A Catalytic Diastereoselective Formal [5+2] Cycloaddition Approach to Azepino[1,2‐a]indoles: Putative Donor–Acceptor Cyclobutanes as Reactive Intermediates

A catalytic formal [5+2] cycloaddition approach to the diastereoselective synthesis of azepino[1,2‐a]indoles is reported. The reaction presumably proceeds through a Lewis acid catalyzed formal [2+2] cycloaddition of an alkene with an N‐indolyl alkylidene β‐amide ester to form a donor–acceptor cyclobutane intermediate, which subsequently undergoes an intramolecular ring‐opening cyclization. Azepine products are formed in up to 92 % yield with high degrees of diastereoselectivity (up to 34:1 d.r.).     

Synthesis of redox-active, intramolecular charge-transfer chromophores by the [2+2] cycloaddition of ethynylated 2H-cyclohepta[b]furan-2-ones with tetracyanoethylene

Ethynylated 2H-cyclohepta[b]furan-2-ones 5-15 have been prepared by Pd-catalyzed alkynylation of 3-iodo-5-isopropyl-2H-cyclohepta[b]furan-2-one (2) with the corresponding ethynylarenes or the reaction of 2-iodothiophene with 3-ethynyl-5-isopropyl-2H-cyclohepta[b]furan-2-one (4) under Sonogashira-Hagihara conditions. Compounds 5-15 reacted with tetracyanoethylene in a formal [2+2] cycloaddition reaction, followed by ring opening of the initially formed [2+2] cycloadducts, cyclobutenes, to afford the corresponding 1,1,4,4-tetracyanobutadienyl (TCBD) chromophores 16-26 in excellent yields. The intramolecular charge-transfer interactions between the 2H-cyclohepta[b]furan-2-one ring and TCBD acceptor moiety were investigated by UV/Vis spectroscopy and theoretical calculations. The redox behavior of the novel TCBD derivatives 16-26 was examined by cyclic voltammetry and differential pulse voltammetry, which revealed multistep electrochemical reduction properties, depending on the number of TCBD units in the molecule. Moreover, a significant color change was observed by UV/Vis spectroscopy under electrochemical reduction conditions.     

Highly stereoselective formal

[formula: see text] Highly stereoselective formal [3 + 3] cycloaddition reactions of chiral vinylogous amides with alpha, beta-unsaturated iminiums are described. A mechanistic model is proposed to rationalize the observed stereoselectivity. The 6 pi-electron electrocyclic ring closure appears to be reversible, and a preferred rotation of the alkenyl group, one of the three 2 pi-components, during the ring closure step provides the thermodynamically favored diastereomer as the major product.     

A two-directional synthesis of (+/-)-perhydrohistrionicotoxin

An entirely two-directional synthesis of (+/-)-perhydrohistrionicotoxin is presented, utilizing a tandem oxime formation/Michael addition/[3 + 2] cycloaddition as the key step. This approach also constitutes formal syntheses of (+/-)-histrionicotoxin and (+/-)-histrionicotoxin 235A.     

Sequential cycloaddition approach to the tricyclic core of vibsanin E. Total synthesis of (+/-)-5-epi-10-epi-vibsanin E

[chemical reaction: see text]. A direct access to (+/-)-5-epi-10-epi-vibsanin E is described, based on three key cycloaddition steps, a rhodium-catalyzed [4 + 3] cycloaddition, a heteronuclear [4 + 2] cycloaddition, and a photochemically induced [4 + 2] cycloaddition.     

A one-pot bicycloannulation method for the synthesis of tetrahydroisoquinoline systems

A highly effective method for the synthesis of the core indolo[2,3-alpha]quinolizidine skeleton found in yohimbine is described. The reaction of N-monosubstituted thioamides with bromoalkenoyl chlorides furnishes thioisomünchnones as transient 1,3-dipoles that undergo ready intramolecular cycloaddition across the tethered pi-bond to give thio-bicycloannulated products in a one-pot operation. The stereochemical outcome of the intramolecular reaction is the consequence of an endo cycloaddition of the neighboring pi-bond across the transient thioisomünchnone dipole. A major limitation of the method is that when a hydrogen is present in the alpha-position of the thioamide the initially formed thio-N-acyliminium ion undergoes proton loss to produce a S,N-ketene acetal at a faster rate than dipole formation. Treatment of tetrahydro-beta-carboline-1-thione with 2-bromooct-7-enoyl chloride followed by reductive removal of sulfur from the cycloadduct resulted in the formation of (+/-)-alloyohimbanone. Attempts to cycloadd the thioisomünchnone dipole across several nucleophilic pi-bonds failed, and instead, products derived from cyclization of the pi-bond onto the initially formed thio-N-acyliminium ion were formed. The resulting N,S-ketals were further converted into several tetrahydroisoquinoline alkaloids in good yield.     

On the [2+2] cycloaddition of 2-aminothiazoles and dimethyl acetylenedicarboxylate. Experimental and computational evidence of a thermal disrotatory ring opening of fused cyclobutenes

The reaction of 2-(phenylamino)- and 2-(dimethylamino)thiazoles with dimethyl acetylenedicarboxylate led unexpectedly to dimethyl 6-(phenylamino)- and 6-(dimethylamino)-3,4-pyridinedicarboxylates. Those compounds reasonably result from a sequence of reactions initiated by a [2 + 2] cycloaddition of the alkyne to the formal C=C of the thiazole ring. These pyridines were obtained in nearly all the cases assayed as the exclusive reaction products under rather mild conditions and in fair to good yields. In contrast, the regioisomeric 2-amino-3,4-pyridinedicarboxylates, which would result from a [4 + 2] cycloaddition followed by sulfur extrusion, were only obtained in one particular case. The two reaction paths leading alternatively to both regioisomers were investigated computationally. The respective [2 + 2] and [4 + 2] cycloadducts were found to be formed stepwise from a common dipolar intermediate. Notably, the step following the [2 + 2] cycloaddition (i.e., the ring opening of the fused cyclobutene intermediate to give an all-cis 1,3-thiazepine) was found to take place in a disrotatory mode. Although geometric constraints and electronic factors may reduce the energy for the disrotation, the implication of the fused five-membered ring in the electronic reorganization leading to the 1,3-thiazepine is determinant. In this sense, this step could be regarded also as a thermally allowed six-electron five-center disrotatory electrocyclic ring opening. The proposed mechanism was experimentally supported by the isolation of several intermediates and other experimental facts.     

Rhodium-catalyzed [2 + 2 + 2] cycloaddition of alkenyl isocyanates and alkynes

A rhodium(I)-catalyzed [2 + 2 + 2] cycloaddition between alkenyl isocyanates and alkynes has been developed. Heating a mixture of an alkenyl isocyanate and a symmetrical internal alkyne in the presence of [Rh(ethylene)2Cl]2/P(4-OMe-C6H4)3 in toluene delivers substituted indolizinones and quinolizinones. Depending on the substrates, a rare fragmentation of the isocyanate unit can be involved within the cycloaddition process to furnish a vinylogous amide embedded in the indolizinone.     

Studies on the synthesis of (+/-)-stenine: a combined intramolecular [4 + 2]-cycloaddition/rearrangement cascade

Several cyclic 2-(methylthio)-5-amidofurans containing tethered unsaturation were prepared via the reaction of dimethyl(methylthio)sulfonium tetrafluoroborate (DMSTF) with beta-alkoxy-gamma-dithiane lactams. Thermolysis of these furans resulted in an intramolecular Diels-Alder reaction (IMDAF). The resulting oxa-bridge cycloadducts underwent a subsequent 1,2-methylthio shift to form tricyclic lactams in high yield. Furan 9, annealed to an azepine ring, underwent the IMDAF reaction at or below room temperature. Conformational effects imposed by the placement of a carbonyl group within the tether, combined with a rotational bias about the C(2)-N bond, enhances the rate of the IMDAF reaction of the seven-ring system so that it occurs readily at 25 degrees C. The feasibility of using the cascade sequence in the context of a total synthesis of the Stemona alkaloid (+/-)-stenine was explored. The eventual synthesis of (+/-)-stenine was carried out by an intramolecular Diels-Alder reaction of a 2-amido-5-methylthio-substituted furan containing a trans-pent-3-enoic acid methyl ester side chain in order to create the desired azepinoindole skeleton. This was followed by a series of reductions to set the syn-anti stereochemical relationship at the incipient ring fusion sites present in stenine. All six stereocenters at the azepinoindole core were derived in high stereoselectivity from the functionality present in the rearranged cycloadduct 10. Compound 10 was converted to stenine in 11 additional steps via a sequence that features a Crabtree's-catalyst directed hydrogenation, iodolactonization, and a Keck allylation.     

Applications of intramolecular diels-alder reactions of heterodienes. Facile syntheses of the heteroyohimbine alkaloids tetrahydroalstonine and akuammigine.

A facile, formal synthesis of the heteroyohimbine alkaloids tetrahydroalstonine (1) and akuammigine (2) has been completed in which the D/E ring system is constructed by the novel cyclization of the triene 10, a process which involves the intramolecular [4+2] cycloaddition of a heterodiene with an α,β-unsaturated amide.