Total Synthesis of (−)‐Daphenylline

A concise and highly stereoselective total synthesis of the Daphniphyllum alkaloids (?)‐daphenylline has been accomplished. The synthesis was started from (S)‐carvone and proceeded via a stereoselective Mg(ClO₄)₂‐catalyzed intramolecular amide addition cyclization, an intramolecular Diels–Alder reaction to construct the ABCD tetracyclic core architecture, and a Robinson annulation coupled with an oxidative aromatization sequence. Finally, the DF ring system was installed through an intramolecular Friedel–Crafts cyclization. The total synthesis of (?)‐daphenylline is achieved in 19 steps in the longest reaction sequence and in 7.6 % overall yield.     

Siloxy Alkynes in Annulation Reactions

Siloxy alkynes are a family of versatile species in organic synthesis. This account reviews the annulation reactions of siloxy alkynes for the synthesis of a variety of carbo‐ and heterocyclic products. With various dipolarophiles or dipolarophile‐like reaction partners, siloxy alkynes are capable of forming small (three‐ to six‐membered) rings. Recently, we have expanded the scope to the synthesis of medium‐ and large‐ring lactones, enabled by the design of new amphoteric molecules as well as a new ring‐expansion strategy. These annulation reactions provide not only practically useful syntheses of cyclic molecules, but also important understanding of the fundamental reactivity of siloxy alkynes.     

Total Synthesis of Limonin

Limonoids are highly oxygenated C13α‐triterpenes and common secondary metabolites. Several hundred congeners have been isolated to date. The first total synthesis of (±)‐limonin, the flagship congener of the limonoids, is now reported and features 1) a tandem radical cyclization generating the BCD ring system with the C13α configuration that is essential to the limonoids and a Robinson annulation to construct the limonoid androstane framework, 2) a singlet‐oxygen cycloaddition and a Baeyer–Villiger oxidation to synthesize the highly oxidized D ring, and 3) a Suárez reaction to construct the unique AA′ ring system.     

Total Synthesis of Limonin

Limonoids are highly oxygenated C13α‐triterpenes and common secondary metabolites. Several hundred congeners have been isolated to date. The first total synthesis of (±)‐limonin, the flagship congener of the limonoids, is now reported and features 1) a tandem radical cyclization generating the BCD ring system with the C13α configuration that is essential to the limonoids and a Robinson annulation to construct the limonoid androstane framework, 2) a singlet‐oxygen cycloaddition and a Baeyer–Villiger oxidation to synthesize the highly oxidized D ring, and 3) a Suárez reaction to construct the unique AA′ ring system.     

An Enantiospecific Synthesis of Jiadifenolide

A Robinson annulation, van Leusen homologation, and a desymmetrizing C? H oxidation enabled an enantiospecific synthesis of the neurotrophic natural product jiadifenolide. From a pulegone‐derived building block, a key propellane intermediate was constructed through the use of simple reagents in a highly diastereoselective fashion. A short series of oxidations of this tricylic framework allowed progression to the natural product.     

Samarium(III)‐mediated graft polymerization of ϵ‐caprolactone and L‐lactide on functionalized poly(p‐xylylene)s: model studies and polymerizations

The reductive coupling of aromatic monocarbonyl compounds in the presence of SmI₂ results in the formation of Samarium(III) dialkoxides. These Sm(III) dialkoxides have been utilized as initiators for ring opening polymerization (ROP) of lactones and lactides. The reductive coupling of aromatic dicarbonyl compounds results in the formation of Sm(III) polyalkoxides which have been used as polyinitiator for (ROP) of lactones and lactides. The products of this process are poly(p‐xylylene)s grafted by polylactones or polylactides. Grafting efficiency depends significantly on reaction conditions and is currently limited to 28%. Copyright © 1999 John Wiley & Sons, Ltd.     

Metal‐Free Synthesis of Benzothiophenes by Twofold C−H Functionalization: Direct Access to Materials‐Oriented Heteroaromatics

Due to their ubiquity in nature and frequent use in organic electronic materials, benzothiophenes are highly sought after. Here we set out an unprecedented procedure for the formation of benzothiophenes by the twofold vicinal C?H functionalization of arenes that does not require metal catalysis. This one‐pot annulation proceeds through an interrupted Pummerer reaction/[3,3]‐sigmatropic rearrangement/cyclization sequence to deliver various benzothiophene products. The procedure is particularly effective for the rapid synthesis of benzothiophenes from non‐prefunctionalized polyaromatic hydrocarbons (PAHs).     

Cobalt‐Catalyzed Dual Annulation of o‐Halobenzaldimine with Alkyne: A Powerful Route toward Bioactive Indenoisoquinolinones

A cobalt‐catalyzed dual annulation reaction for the synthesis of variously substituted indenoisoquinolinones from 2‐bromobenzaldehydes, amines, and methyl 2‐(ethynyl)benzoates has been developed. This method could also be applied to the synthesis of an array of highly functionalized bioactive indenoisoquinolinones and their derivatives. A possible mechanism of the cobalt catalysis is proposed, involving imine formation from bromobenzaldehyde and the amine, followed by a series of oxidative addition, alkyne insertion, cyclization reactions, and carbon–carbon double‐bond migration. The regioselective alkyne insertion plays an important role for the success of the second annulation.     

Synthetic and DFT Studies Towards a Unified Approach to Phlegmarine Alkaloids: Aza‐Michael Intramolecular Processes Leading to 5‐Oxodecahydroquinolines

A diastereoselective synthesis of cis‐5‐oxodecahydroquinolines is described in which three stereocenters are generated in a one‐pot reaction. The reaction involves a lithium hydroxide‐promoted Robinson annulation/intramolecular aza‐Michael domino process from an achiral acyclic tosylamine‐tethered β‐keto ester. The development and scope of this reaction was facilitated through the use of DFT‐based mechanistic studies, which enabled the observed diastereodivergent course of the azacyclization to be rationalized. The varying stereochemistry and stability of the resulting decahydroquinolines was found to depend on whether a β‐keto ester or ketone were embedded in the substrates undergoing aminocyclization. This synthetic approach gave access not only to both diastereomeric cis‐decahydroquinolines from the same precursor, but also to the corresponding trans isomers, through an epimerization processes of the corresponding N‐unsubstituted cis‐5‐oxodecahydroquinolines. The described methodology provides advanced building‐blocks with the three relative stereochemistries required for the total synthesis of phlegmarine alkaloids.     

Rhodium‐Catalyzed CH Annulation of Nitrones with Alkynes: A Regiospecific Route to Unsymmetrical 2,3‐Diaryl‐Substituted Indoles

The direct C? H annulation of anilines or related compounds with internal alkynes provides straightforward access to 2,3‐disubstituted indole products. However, this transformation proceeds with poor regioselectivity in the synthesis of unsymmetrically 2,3‐diaryl substituted indoles. Herein, we report the rhodium(III)‐catalyzed C? H annulation of nitrones with symmetrical diaryl alkynes as an alternative method to prepare 2,3‐diaryl‐substituted N‐unprotected indoles with two different aryl groups. One of the aryl substituents is derived from N?C‐aryl ring of the nitrone and the other from the alkyne substrate, thus providing the indole products with exclusive regioselectivity.     

Rhodium‐Catalyzed C?H Annulation of Nitrones with Alkynes: A Regiospecific Route to Unsymmetrical 2,3‐Diaryl‐Substituted Indoles

The direct C H annulation of anilines or related compounds with internal alkynes provides straightforward access to 2,3‐disubstituted indole products. However, this transformation proceeds with poor regioselectivity in the synthesis of unsymmetrically 2,3‐diaryl substituted indoles. Herein, we report the rhodium(III)‐catalyzed C H annulation of nitrones with symmetrical diaryl alkynes as an alternative method to prepare 2,3‐diaryl‐substituted N‐unprotected indoles with two different aryl groups. One of the aryl substituents is derived from NC‐aryl ring of the nitrone and the other from the alkyne substrate, thus providing the indole products with exclusive regioselectivity.     

Substituted 4‐Oxo‐1,2,3,4‐tetrahydroquinoline‐3‐carboxylic Esters by a Tandem Imine Addition‐SNAr Reaction

A tandem imine addition‐S_NAr annulation reaction has been developed as a new approach to the synthesis of 4‐oxo‐1,2,3,4‐tetrahydroquinoline‐3‐carboxylic esters. A series of these structures has been generated by reacting selected imines with tert‐butyl 2‐fluoro‐5‐nitrobenzoylacetate. Structural variations in the final products are accomplished by changing the substituents on the imine and the alkyl group of the ester. The title compounds are isolated as their enols in 55–97% yield without the need for added base or catalysts. The synthesis of the starting materials as well as mechanistic studies and further synthetic conversions of the products are presented.     

A General Entry to Antifeedant Sesterterpenoids: Total Synthesis of (+)‐Norleucosceptroid A, (−)‐Norleucosceptroid B,and (−)‐Leucosceptroid K

The first asymmetric total synthesis of the antifeedant terpenoids (+)‐norleucosceptroid A, (?)‐norleucosceptroid B, and (?)‐leucosceptroid K has been accomplished. This highly concise synthetic route was guided by our efforts to develop a platform for the collective synthesis of a whole family of antifeedant natural products. The synthesis features a Hauser–Kraus‐type annulation followed by an unprecedented, highly efficient intramolecular dilactol aldol‐type condensation reaction to produce the 5,6,5 skeleton. The developed synthetic route proceeds for norleucosceptroid A and B in 16 steps (longest linear sequence) from known compounds.     

A General Entry to Antifeedant Sesterterpenoids: Total Synthesis of (+)‐Norleucosceptroid A, (−)‐Norleucosceptroid B,and (−)‐Leucosceptroid K

The first asymmetric total synthesis of the antifeedant terpenoids (+)‐norleucosceptroid A, (−)‐norleucosceptroid B, and (−)‐leucosceptroid K has been accomplished. This highly concise synthetic route was guided by our efforts to develop a platform for the collective synthesis of a whole family of antifeedant natural products. The synthesis features a Hauser–Kraus‐type annulation followed by an unprecedented, highly efficient intramolecular dilactol aldol‐type condensation reaction to produce the 5,6,5 skeleton. The developed synthetic route proceeds for norleucosceptroid A and B in 16 steps (longest linear sequence) from known compounds.     

Transition Metal-Catalyzed Intermolecular Cascade C−H Activation/Annulation Processes for the Synthesis of Polycycles

Polycycles are abundantly present in numerous advanced chemicals, functional materials, bioactive molecules and natural products. However, the strategies for the synthesis of polycycles are limited to classical reactions and transition metal-catalyzed cross-coupling reactions, requiring pre-functionalized starting materials and lengthy synthetic operations. The emergence of novel approaches shows great promise for the fields of organic/medicinal/materials chemistry. Among them, transition metal-catalyzed C−H activation followed by intermolecular annulation reactions prevail, due to their straightforward manner with high atom- and step-economy, providing rapid, concise and efficient methods for the construction of diverse polycycles. Several strategies have been developed for the synthesis of polycycles, relying on sequential multiple C−H activation/annulation, or combination of C−H activation/annulation and further interaction with a proximal group, or merger of C−H activation with a cycloaddition reaction, or in situ formation of the directing group. These are attractive, efficient, step- and atom-economic methods starting from commercially available materials. This Minireview will provide an introduction to transition metal-catalyzed C−H activation for the synthesis of polycycles, helping researchers to discover indirect connections and reveal hidden opportunities. It will also promote the discovery of novel synthetic strategies relying on C−H activation.     

Phosphine-Catalyzed Annulations between Modified Allylic Derivatives and Polar Dienes and Substituent Effect on the Annulation Mode

in this work, the phosphine-catalyzed annulation reactions between modified allylic derivatives and polar 1,1-dicyano-1,3-dienes have been studied. In the catalysis of PPh3 （20 mol%）, a [4 ＋ 1 ] annulation reaction is realized between a series of l,l-dicyano-2,4-diaryl-1,3-dienes and ethoxycarbonyl-activated allylic acetate, producing polysubstituted cyclopentenes in modest to excellent yields. It is also observed that the substituents of both 1,3-dienes and allylic derivatives have a significant influence on the annulation mode： under the catalysis of PPh3 or PBu3 （20 mol%）, regioselective [3 ＋ 2] annulation products are formed from differently substituted substratcs.     

Revisiting a classic approach to the Aspidosperma alkaloids: an intramolecular Schmidt reaction mediated synthesis of (+)-aspidospermidine

[reaction: see text] A total synthesis of (+)-aspidospermidine (1) is described. The key reactions used in the synthesis of this pentacyclic Aspidosperma alkaloid were a deracemizing imine alkylation/Robinson annulation sequence, a selective "redox ketalization", and an intramolecular Schmidt reaction. A Fischer indolization step carried out on a tricyclic ketone mirrored the sequence reported by Stork and Dolfini in their classic aspidospermine synthesis.     

Formal synthesis of (+/-)-guanacastepene A

A 17 step synthesis of 55, a late intermediate in Danishefsky's guanacastepene A synthesis, has been completed in 4% overall yield. Key features include the use of vinylmagnesium bromide in the Pd-catalyzed coupling with triflate 13 to give triene 16 without the formation of Heck products, a novel extension of the Stork-Jung vinylsilane Robinson annulation that provides tricyclic 2-hydroxymethylcyclohexenone 42 from 23b in four steps and 51% yield, the ability to obtain almost exclusively alpha'-alkylation of 35ba by the proper choice of protecting groups, and the ability to obtain the desired beta-alcohol selectively by reduction of keto alcohol 42 rather than keto ester 53.     

Copper‐Promoted Annulation of Terminal Alkynes with 2‐Aminopyridines to Assemble 2‐Halogenated Imidazo[1,2‐a]pyridines

Copper‐promoted annulation reactions of terminal alkynes with 2‐aminopyridines have been developed for the synthesis of 2‐halogenated imidazo[1,2‐a]pyridines using copper halide as the halogen source. A variety of substrates survived under the reaction conditions and gave the desired products in good yields. This reaction features advantages such as easily available starting materials, broad substrate scope, and mild reaction conditions.     

First total synthesis of (+)-Carainterol A

The first, stereospecific, and elegant synthesis of the natural product (+)-Carainterol A was developed by using the Robinson annulation reaction as a key step to build the eudesmane sketeton.