Palladium-catalyzed tandem reaction to construct benzo[c]phenanthridine: application to the total synthesis of benzo[c]phenanthridine alkaloids

A concise and efficient synthesis of benzo[c]phenanthridines was accomplished by the palladium-catalyzed ring-opening coupling of azabicyclic alkene with o-iodobenzoates, followed by tandem cyclization. The strategy was successfully applied in the total synthesis of benzo[c]phenanthridine alkaloids such as sanguinarine, chelerythrine, nitidine and avicine.     

A Divergent Synthetic Route to the Vallesamidine and Schizozygine Alkaloids: Total Synthesis of (+)‐Vallesamidine and (+)‐14,15‐Dehydrostrempeliopine

The total synthesis of representative members of the schizozygine alkaloids, (+)‐vallesamidine and (+)‐14,15‐dehydrostrempeliopine, were completed from a late‐stage divergent intermediate. The synthesis took advantage of efficient nitro‐group reactions with the A/B/C ring skeleton constructed concisely on a gram scale through an asymmetric Michael addition, nitro‐Mannich/lactamisation, Tsuji–Trost allylation, and intramolecular C?N coupling reaction. Other key features of the synthesis are a novel [1,4] hydride transfer/Mannich‐type cyclisation to build ring E and a diastereoselective ring‐closing metathesis reaction to construct ring D. This approach gave access to a late‐stage C14,C15 alkene divergent intermediate that could be simply transformed into (+)‐vallesamidine, (+)‐14,15‐dehydrostrempeliopine, and potentially other schizozygine alkaloids and unnatural derivatives.     

Total syntheses of (-)-haemanthidine, (+)-pretazettine, and (+)-tazettine

[structures: see text] The total syntheses of the amaryllidaceae alkaloids haemanthidine, pretazettine, and tazettine as optically pure enantiomers are reported. Using D-mannose as the starting material, the critical relative stereochemical relationships are established with an intramolecular nitrone-alkene cycloaddition reaction. The synthetic route leads successively to (-)-haemanthidine and then to (+)-pretazettine and (+)-tazettine, taking advantage of the well-established complex relationships among these three alkaloids.     

General approach for the synthesis of sarpagine indole alkaloids. Enantiospecific total synthesis of (+)-vellosimine, (+)-normacusine B, (-)-alkaloid Q3, (-)-panarine, (+)-Na-methylvellosimine, and (+)-Na-methyl-16-epipericyclivine

The first total synthesis of (+)-Na-methyl-16-epipericyclivine (9) was completed [from d-(+)-tryptophan methyl ester] in an overall yield of 42% (eight reaction vessels). The optical rotation [[alpha]D +22.8 (c 0.50, CHCl3)] obtained on this material confirmed that the reported optical rotation [[alpha]D 0 (c 0.50, CHCl3)]47 was biogenetically unreasonable. The total syntheses of (+)-vellosimine, (+)-normacusine B, (-)-alkaloid Q3, (-)-panarine, and (+)-Na-methylvellosimine are also described. Moreover, a mixed sample (1:1) of synthetic (-)-panarine and natural (-)-panarine yielded only one set of signals in the 13C NMR; this indicated that the two compounds are identical and further confirmed the correct configuration of (+)-vellosimine, (+)-normacusine B, and (-)-alkaloid Q3. In this approach, the key templates, (-)-Na-H,Nb-benzyltetracyclic ketone 15a and (-)-Na-methyl,Nb-benzyltetracyclic ketone 43 were synthesized on multihundred gram scale by the asymmetric Pictet-Spengler reaction and a stereocontrolled Dieckmann cyclization via improved sequences. An intramolecular palladium (enolate-mediated) coupling reaction was employed to introduce the C(19)-C(20) E-ethylidene function in the sarpagine alkaloids for the first time in stereospecific fashion.     

Formal synthesis of nitidine and NK109 via palladium-catalyzed domino direct arylation/N-arylation of aryl triflates

The use of aryl triflates as reaction partners in a palladium-catalyzed domino direct arylation/N-arylation provides a great advantage due to the availability of starting materials. Furthermore, it allows expedient access to biologically interesting benzo[c]phenanthridine alkaloids.     

A general strategy for the synthesis of vincamajine-related indole alkaloids: stereocontrolled total synthesis of (+)-dehydrovoachalotine, (-)-vincamajinine, and (-)-11-methoxy-17-epivincamajine as well as the related quebrachidine diol, vincamajine diol, and vincarinol

[structures: see text] The highly convergent stereocontrolled total synthesis of (-)-vincamajinine (7), (-)-11-methoxy-17-epivincamajine (9), and the oxygen-bridged (+)-dehydrovoachalotine (22) are described. Key steps in the synthesis of 7 and 9 involved the stereospecific enolate-driven palladium-catalyzed cross-coupling reaction, a Tollens reaction, an acid-assisted intramolecular cyclization to form the C(7)-C(17) quaternary center, and two stereospecific reductions. The efficiency of this strategy is illustrated by the completion of the synthesis of 7 and 9 in 16 [from d-(+)-tryptophan methyl ester 17] and 17 (from the Sch?llkopf chiral auxiliary 27) reaction vessels, respectively. This constitutes the first total synthesis of these indole alkaloids and provides the first regiospecific route to 11-methoxy-substituted ajmaline/vincamajine-related alkaloids. The synthesis of 22 required a novel DDQ-mediated cyclization to furnish the C(6)-O(17) bond, executed in stereospecific fashion. Completion of these syntheses illustrates a concise and versatile strategy for the synthesis of vincamajine-related alkaloids, which has also been employed to prepare the related compounds quebrachidine diol (53), vincamajine diol (56), and vincarinol (59).     

Total synthesis of oxyfagaronine, phenolic benzo[c]phenanthridine and general synthetic way of 2,3,7,8- and 2,3,8,9-tetrasubstituted benzo[c]phenanthridine alkaloids

Benzo[c]phenanthridine alkaloids such as oxynitidine, oxysanguinarine, oxyavicine and phenolic oxyfagaronine were synthesized from easily available starting benzonitriles 5 and toluamides 6 using a lithiated toluamide-benzonitrile cycloaddition reaction. The coupling reaction provided 3-arylisoquinolinones that were transformed to the benzo[c]phenanthridones. This method is highly efficient and could be useful for preparing diverse substituted aromatic benzo[c]phenanthridine compounds on a multi gram scale.     

A versatile total synthesis of benzo[c]phenanthridine and protoberberine alkaloids using lithiated toluamide-benzonitrile cycloaddition

A new versatile synthesis of benzo[c]phenanthridine and protoberberine alkaloids using lithiated toluamide-benzonitrile cycloaddition was carried out. The coupling reaction between benzonitrile 6 with o-toluamides (8a-c) afforded 3-arylisoquinolines (9a-c) that were transformed to the protoberberines (11a-c) or benzo[c]phenanthridines (14a-c). These compounds were synthesized by ring closure of the two-carbon chain on either position 2 or 4 of the 3-arylisoquinolinone (9a-c). Several kinds of substituted benzo[c]phenanthridine alkaloids such as oxysanguinarine, oxyavicine, and oxynitidine as well as protoberberines such as 8-oxocoptisine, 8-oxopseudoberberine, and 8-oxopseudocoptisine were synthesized.     

An asymmetric synthesis of (+)-grandisol, a constituent of the aggregation pheromone of the cotton boll weevil, via a kinetic resolution

A novel approach to the asymmetric synthesis of (+)-grandisol, (1R, 2S)-isopropenyl-1-methylcyclobutaneethanol, involves the use of catalytic kinetic resolution of a primary allylic alcohol, [(1RS, 5SR)-5-methylbicyclo[3.2.0]hept-2-en-2-yl] methanol. The allylic alcohol is prepared in four steps from simple achiral materials involving the use of a modified Shapiro reaction. The resolved alcohol (95% ee) is then reduced in two steps to the corresponding methyl alkene, (1S,5R)-2,5-dimethylbicyclo[3.2.0]hept-2-ene. This alkene is converted to (+)-grandisol (95% ee), in three steps, by modified literature procedures.     

Enantioselective Syntheses of Strychnos and Chelidonium Alkaloids through Regio- and Stereocontrolled Cooperative Catalysis

We describe enantioselective syntheses of strychnos and chelidonium alkaloids. In the first case, indole acetic acid esters were established as excellent partner nucleophiles for enantioselective cooperative isothiourea/Pd catalyzed α-alkylation. This provides products containing indole-bearing stereocenters in high yield and with excellent levels of enantioinduction in a manner that is notably independent of the N-substituent. This led to concise syntheses of (−)-akuammicine and (−)-strychnine. In the second case, the poor performance of ortho-substituted cinnamyl electrophiles in the enantioselective cooperative isothiourea/Ir catalyzed α-alkylation was overcome by appropriate substituent choice, leading to enantioselective syntheses of (+)-chelidonine, (+)-norchelidonine, and (+)-chelamine.     

Decarboxylative Conjunctive Cross-coupling of Vinyl Boronic Esters using Metallaphotoredox Catalysis

The synthesis of complex alkyl boronic esters through conjunctive cross-coupling of vinyl boronic esters with carboxylic acids and aryl iodides is described. The reaction proceeds under mild metallaphotoredox conditions and involves an unprecedented decarboxylative radical addition/cross-coupling cascade of vinyl boronic esters. Excellent functional-group tolerance is displayed, and application of a range of carboxylic acids, including secondary α-amino acids, and aryl iodides provides efficient access to highly functionalized alkyl boronic esters. The decarboxylative conjunctive cross-coupling was also applied to the synthesis of sedum alkaloids.     

Total synthesis of (+)-hyacinthacine A2 based on SmI2-induced nitrone umpolung

[reaction: see text] A concise total synthesis of (+)-hyacinthacine A(2), a polyhydroxylated pyrrolizidine alkaloid, is described using our recently discovered inversion of the C-N bond polarity in nitrones. In the key step, the diastereoselective reductive coupling of a L-xylose-derived cyclic nitrone with ethyl acrylate allowed the assembly of the bicyclic core of the target molecule, by way of a tandem formation of the C-C and C-N bonds. The method opens a novel, short, and general route for the synthesis of other pyrrolizidine alkaloids.     

Decarboxylative Conjunctive Cross‐coupling of Vinyl Boronic Esters using Metallaphotoredox Catalysis

The synthesis of complex alkyl boronic esters through conjunctive cross‐coupling of vinyl boronic esters with carboxylic acids and aryl iodides is described. The reaction proceeds under mild metallaphotoredox conditions and involves an unprecedented decarboxylative radical addition/cross‐coupling cascade of vinyl boronic esters. Excellent functional‐group tolerance is displayed, and application of a range of carboxylic acids, including secondary α‐amino acids, and aryl iodides provides efficient access to highly functionalized alkyl boronic esters. The decarboxylative conjunctive cross‐coupling was also applied to the synthesis of sedum alkaloids.     

Highly Stereoselective Total Syntheses of (±)-Chelidonine and of (±)-Norchelidonine by an Intramolecular o-Quinodimethane/Nitrostyrene-Cycloaddition

Conversion of 2-bromomethylstyrene 22 and benzocyclobutenyl carbamate 28 to the benzophenanthridine alkaloids (±)-chelidonine ( 1 , five steps, 25% from 28 ) and to (±)-norchelidonine ( 2 , six steps, 24% from 28 ) are described. The key step 29 → 31 involves a highly regio- and stereocontrolled intramolecular Diels-Alder reaction of the (E)-quinodimethane 30 .     

Stereoselective total syntheses of three Lycopodium alkaloids, (-)-magellanine, (+)-magellaninone, and (+)-paniculatine, based on two Pauson-Khand reactions

The total syntheses of (-)-magellanine, (+)-magellaninone, and (+)-paniculatine were completed from diethyl l-tartrate via the common intermediate in a stereoselective manner. The crucial steps in these syntheses involved two intramolecular Pauson-Khand reactions of enynes: the first Pauson-Khand reaction constructed the bicyclo[4.3.0] carbon framework, the corresponding A and B rings of these alkaloids in a highly stereoselective manner, whereas the second Pauson-Khand reaction stereoselectively produced the bicyclo[3.3.0]skeleton, which could be converted into the C and D rings of the target natural products.     

A mild,nonbasic synthesis of thioethers. The copper-catalyzed coupling of boronic acids with N-thio(alkyl,aryl, heteroaryl)imides

[reaction: see text] A new synthesis of thioethers is described. The reaction of boronic acids with aryl, heteroaryl, and alkyl N-thioimides in the presence of catalytic quantities of a Cu(I) carboxylate affords good to excellent yields of thioethers. This reaction takes place in the absence of a base under mild conditions (THF, 45-50 degrees C, 2.5-12 h) and represents an interesting complement to known methods for thioether synthesis.     

The total synthesis of (+)-dragmacidin F

The first total synthesis of (+)-dragmacidin F has been accomplished, establishing the absolute configuration of this biologically important, antiviral marine alkaloid. The convergent route described features a palladium-mediated oxidative pyrrole carbocylization reaction to construct the [3.3.1] bicycle, as well as a highly selective Suzuki coupling to build the carbon skeleton of the natural product. A late-stage Neber rearrangement allows for the facile installation of the aminoimidazole moiety to provide (+)-dragmacidin F.     

Total synthesis and stereochemical reassignment of (+)-dolastatin 19

[reaction: see text] A revised configurational assignment for the cytotoxic marine macrolide dolastatin 19 is proposed and validated by total synthesis. Key features of the route include an asymmetric vinylogous aldol reaction to install the isolated C13 stereocenter and (E)-trisubstituted alkene, two sequential 1,4-syn boron-mediated aldol reactions, and a Mukaiyama glycosylation to append the l-rhamnose-derived pyranoside.     

Angucyclinone antibiotics: total syntheses of YM-181741, (+)-ochromycinone, (+)-rubiginone B2, (-)-tetrangomycin, and MM-47755

A concise and highly enantioselective route has been developed for the synthesis of angucyclinone-type natural products. Utilizing this strategy, total syntheses of five natural products YM-181741, (+)-ochromycinone, (+)-rubiginone B2, (-)-tetrangomycin, and MM-47755 have been accomplished in 22%, 23%, 19%, 18%, and 12% overall yields, respectively. Our approach for the synthesis of these natural products having the benz[a]anthraquinone skeleton is based on a sequential intramolecular enyne metathesis, intermolecular Diels-Alder reaction (DAR), and aromatization. The intramolecular enyne metathesis reaction was employed for the synthesis of enantiopure 1,3-dienes in excellent yields. Furthermore, the synthesis of YM-181741 as well as structurally similar angucyclinones such as (+)-ochromycinone and (+)-rubiginone B2 was achieved via asymmetric enolate alkylation of an oxazolidinone in excellent de. The related angucyclinones (-)-tetrangomycin and MM-47755, bearing a labile tertiary alcohol, were synthesized via Sharpless asymmetric epoxidation of a known allylic alcohol followed by opening the epoxide with Red-Al. The introduction of oxygen functionality at C-1 in all these natural products was accomplished by photooxygenation under a positive pressure of oxygen.     

Oxidative Coupling Approach to Sarpagine Alkaloids: Total Synthesis of (−)-Trinervine,Vellosimine, (+)-Normacusine B,and (−)-Alstomutinine C

Sarpagine alkaloids are bioactive indole natural products that contain a highly rigid indole-fused 1-azabicyclo[2.2.2]octane, more than 100 members of which have been identified. Herein, a detailed examination of the intramolecular oxidative coupling between a ketone and a Weinreb amide for assembling the complex 1-azabicyclo[2.2.2]octane core structure of sarpagine family alkaloids is described. Precise late-stage manipulations of the ketone and Weinreb amide enable the divergent syntheses of (−)-trinervine, (+)-vellosimine, (+)-normacusine B, and (−)-alstomutinine C. Other notable transformations of the synthesis featured an aza-Achmatowicz/indole cyclization cascade to generate the azabicyclo[3.3.1]nonane structure, a regioselective elimination reaction to form the ethylidene motif embedded in the (+)-vellosimine and (+)-normacusine B structures, and a diastereoselective indole oxidative rearrangement to form the spirooxindole structure in (−)-alstomutinine C.