Coupling of alkenes and alkynes: synthesis of the C1-C11 And C18-C28 fragments of miyakolide

A transition metal-mediated, atom-economical approach toward the crucial A and D rings of miyakolide is described. A Pd-catalyzed alkyne-alkyne coupling/6- endo- dig cyclization is employed to assemble the A ring fragment. The key D ring pyran is constructed utilizing an Ru-catalyzed alkene-alkyne coupling followed by a Pd-catalyzed allylic alkylation to establish the all-cis stereochemistry.     

Synthesis of tricyclic and tetracyclic sultones by Pd-catalyzed intramolecular cyclization

A new efficient synthesis of aromatic six-membered ring sultones by the implementation of ligand-free Pd-catalyzed intramolecular cyclization of aromatic sulfonates derived from various bromo phenols and naphthols is described.     

Total synthesis of (+)-lysergic acid

A stereocontrolled total synthesis of (+)-lysergic acid (1) is achieved using three metal-catalyzed methodologies for the construction of three key rings. Highlights of the synthesis include Pd-catalyzed indole synthesis to form the B ring, a RCM reaction to form the D ring, and an intramolecular Heck reaction to form the C ring.     

Pd-mediated synthesis of substituted benzenes fused with carbocycle/heterocycle

A new Pd-catalyzed one-pot multicomponent coupling reaction for the construction of benzene ring fused with carbocycle or heterocycle under a Cu-free condition is described.     

A concise asymmetric synthesis of cis-2,6-disubstituted N-aryl piperazines via Pd-catalyzed carboamination reactions

A concise, modular, asymmetric synthesis of cis-2,6-disubstituted piperazines from readily available amino acid precursors is described. The key step in the synthesis is a Pd-catalyzed carboamination of a N1-aryl-N2-allyl-1,2-diamine with an aryl bromide. The products are obtained in 14-20:1 dr, with >97% ee, and the key cyclizations are the first examples of six-membered ring formation via Pd-catalyzed carboamination reactions of unsaturated amines with aryl halides.     

Synthesis of the ABC ring system of Jiadifenin via Pd-catalyzed cyclizations

An efficient route toward the central ABC system of jiadifenin has been developed using two key Pd-catalyzed cyclizations. A protic solvent-activated Mizoroki-Heck reaction was used to construct the C(9) quaternary carbon and the A ring. A cascading Tsuji-Trost cyclization/lactonization sequence was employed to establish the BC ring system and the C(5,6) stereochemistry.     

Total syntheses of furaquinocin A, B, and E

A modular approach to the total synthesis of furaquinocins culminated in the total syntheses of furaquinocin A, B, and E. A Pd-catalyzed dynamic kinetic asymmetric transformation (DYKAT) on carbonates derived from Baylis-Hillman adducts, followed by a reductive Heck cyclization allows the enantio- and diastereoselective construction of dihydrobenzofuran 32. Introduction of a double unsatured side chain via Horner-Wadsworth-Emmons reaction and assembly of the naphthoquinone with squaric acid based methodology leads to furaquinocin E. The use of differentially substituted squaric acid derivatives allows the synthesis of three analogues of furaquinocin E. The additional stereocenters in furaquinocin A and B can be introduced with a diastereoselective Sakurai allylation. The stereoselective elongation of the side chain is possible using cross metathesis or ring closing metathesis. The obtained late-stage intermediates were successfully transformed to furaquinocin A and B.     

N,N-Disubstituted propargylamines as tools in the sequential 1,3-dipolar cycloaddition/arylation processes to the formation of polyheterocyclic systems

Starting from N,N-disubstituted propargylamines, through a one-pot sequential 1,3-dipolar cycloaddition/Pd-catalyzed arylation, polyheterocyclic systems were obtained in only one step. The outcome of the cycloadditions, performed with 1,3-dipoles nitriloxide and azide, was totally regioselective. The subsequent Pd-catalyzed arylation achieved using ligand-free conditions involved the unsubstituted carbon of the heterocyclic ring.     

Synthetic studies on azadirachtin: stereoselective construction of the ABCE ring system

A new method for constructing the ABCE ring system of azadirachtin in a stereoselective manner was developed. The synthesis of the model compound features (1) stereoselective construction of the highly hindered C8 quaternary center by an intermolecular addition reaction of an allylborane with an aldehyde and (2) construction of the E ring moiety by the Pd-catalyzed Nazarov cyclization.     

Tartaric acid-derived chiral phosphite-type P,N-ligands: behavioural features in Pd-catalyzed asymmetric transformations

A practical synthesis of new phosphoramidite, phosphite and diamidophosphite P,N-ligands derived from (R,R)-tartaric acid was carried out. A study of these chiral inducers showed them to provide up to 93% ee in the Pd-catalyzed asymmetric allylations of (E)-1,3-diphenylallyl acetate, up to 84% ee in the Pd-catalyzed asymmetric alkylation of cinnamyl acetate with ethyl 2-oxocyclohexane-1-carboxylate and up to 63% ee in the Pd-catalyzed desymmetrization of N,N′-ditosyl-meso-cyclopent-4-ene-1,3-diol biscarbamate. The effects of the structural modules, such as the nature of the phosphorus-containing ring or exocyclic substituent as well as of the nature of palladium source on the catalytic activity and enantioselectivity were investigated.     

Total synthesis of bryostatins: the development of methodology for the atom-economic and stereoselective synthesis of the ring C subunit

Bryostatins, a family of structurally complicated macrolides, exhibit an exceptional range of biological activities. The limited availability and structural complexity of these molecules makes development of an efficient total synthesis particularly important. This article describes our initial efforts towards the total synthesis of bryostatins, in which chemoselective and atom-economical methods for the stereoselective assembly of the ring C subunit were developed. A Pd-catalyzed tandem alkyne-alkyne coupling/6-endo-dig cyclization sequence was explored and successfully pursued in the synthesis of a dihydropyran ring system. Elaboration of this methodology ultimately led to a concise synthesis of the ring C subunit of bryostatins.     

Pd(II)-catalyzed cascade reaction with 1,3-chirality transfer; stereoselective synthesis of chiral nonracemic 2,2'-THF-THF ring units

A Pd(II)-catalyzed cascade reaction of chiral nonracemic allylic alcohols possessing an internal mono- or diepoxide and a terminal alcohol provided a contiguous THF-THF ring unit stereospecifically. The cyclization takes place in a 5-exo-tet-5-exo-trig fashion with high chirality transfer through a syn-S(N)2' like process for the formation of the internal THF ring. Chiral bis- and tris-THF-THF ring units were effectively prepared from acyclic precursors by the Pd-catalyzed reaction.     

Intramolecular Heck cyclization to the galanthamine-type alkaloids: total synthesis of (±)-lycoramine

A novel approach towards the construction of the galanthamine skeleton was demonstrated by the total synthesis of (±)-lycoramine. The key steps include a Pd-catalyzed intramolecular cyclization to form the seven-membered azepane ring and a spontaneous intramolecular Michael addition to afford the five-membered furan ring. This synthetic route has also been demonstrated to be useful for the preparation of novel derivatives with simplified galanthamine skeletons.     

Derivatization of a tris-oxazole using Pd-catalyzed coupling reactions of a 5-bromooxazole moiety

Modification at the C5 position of an oxazole ring contained in a 2,4-concatenated tris-oxazole by Pd-catalyzed coupling reactions was performed. Novel Pd-catalyzed amination and alkoxylation of a 5-bromooxazole derivative as well as Suzuki-Miyaura coupling and Migita-Stille coupling have been demonstrated. A wide variety of functional groups, including aryl, heteroaryl, primary and secondary amines, and phenol, were introduced in the 5-bromooxazole moiety in moderate to excellent yields using Pd(OAc)₂/S-PHOS or Pd(OAc)₂/X-PHOS as a catalyst.     

In situ generation of vinyl allenes and its applications to one-pot assembly of cyclohexene, cyclooctadiene, 3,7-nonadienone, and bicyclo[6.4.0]dodecene derivatives with palladium-catalyzed multicomponent reactions

A novel tandem Pd-catalyzed cross-coupling and [4 + 4] cycloaddition sequence allows the rapid synthesis of eight-membered carbocycles starting from alpha-bromovinyl arenes and propargyl bromides in one reaction vessel. It is noteworthy that four components are assembled into one molecule via this procedure. In contrast to alpha-bromovinyl arenes, alpha-bromovinyl alkanes afforded tandem cross-coupling and homo [4 + 2] cycloaddition products. Subjecting an equimolar mixture of alpha-bromostyrene and 2-bromo-1-octene to propargyl bromides furnished the tandem Pd-catalyzed cross-coupling and hetero [4 + 2] cycloaddition product. Exposure of equimolar mixtures of alpha-bromovinyl arenes to allenylindium resulted in tandem a Pd-catalyzed cross-coupling and hetero [4 + 4] cycloaddition products. Synthesis of vinylallene from the reaction of vinyl triflate with allenylindium followed by Pd-catalyzed carbon monoxide insertion reaction gave the corresponding 3,7-nonadienone product via tandem Pd-catalyzed cross-coupling and [4 + 4 + 1] annulation. Tandem Pd-catalyzed cross-coupling, [4 + 4] cycloaddition, and [4 + 2] cycloaddition provided the rapid synthesis of bicyclo[6.4.0]dodecene derivatives starting from alpha-bromovinyl arenes, propargyl bromides, and dienophiles in one operation, in which five components were integrated into one molecule.     

Ligand-accelerated Pd-catalyzed ketone γ-arylation via C-C cleavage with aryl chlorides

A highly efficient Pd-catalyzed arylative ring expansion of cyclobutanols via C-C bond cleavage is presented. The method allows the coupling of aryl chlorides at low catalyst loadings with a wide range of functional groups and substitution patterns, thus constituting a straightforward alternative for preparing rather elusive γ-arylated ketones.     

Hydrogen-bond directed palladium-catalyzed allylic substitution of cyclic substrates

The regioselectivity of the Pd-catalyzed allylic substitution of cyclic substrates possessing an adjacent amide functional group was investigated. With imide-like nucleophiles, six-membered ring substrates were found to proceed with a high level of regiodirection whereas hydrogen-bond directed addition was not a significant factor in the five-membered ring substrates.     

Development of a catalytic enantioselective synthesis of the guanacastepene and heptemerone tricyclic core

For nearly two decades, synthetic chemists have been fascinated by the structural complexity and synthetic challenges afforded by the guanacastepene and heptemerone diterpenoids. Numerous synthetic approaches to these compounds have been reported, but to date the application of enantioselective catalysis to this problem has not been realized. Herein we report an enantioselective synthesis of an advanced intermediate corresponding to the tricyclic core common to the guanacastepenes and heptemerones. Highlights of this work include sequential Pd-catalyzed decarboxylative allylic alkylation reactions to generate the two all carbon quaternary stereocenters, the use of ring-closing metathesis to close the A ring in the presence of a distal allyl sidechain, and a regio- and diastereoselective oxidation of a trienol ether to introduce oxygenation on the A ring.     

A highly efficient enantioselective synthesis of 2-methyl chromans via four sequential palladium-catalyzed reactions

An enantioselective synthesis of substituted 2-methyl chromans was accomplished in four steps using four sequential Pd-catalyzed reactions. A study of the key palladium-catalyzed regioselective aryl ether ring formation of two different substrates was also carried out to better understand the factors which affect the selectivity of the reaction.     

Enantioselective synthesis of (-)-codeine and (-)-morphine

A new synthetic strategy for the synthesis of the opiate and amaryllidaceae alkaloids emerges employing a Pd-catalyzed asymmetric allylic alkylation to set the stereochemistry. The pivotal tricyclic intermediate is available in six steps from 2-bromovanillin and the monoester of methyl 6-hydroxycyclohexene-1-carboxylate, the latter available from glutaraldehyde and the Emmons-Wadsworth-Horner phosphate reagent. This intermediate requires only two steps to convert to (-)-galanthamine. Using a Heck vinylation, we found that the fourth ring of codeine/morphine is formed. The final ring formation involves a novel visible light-promoted hydroamination. Thus, six steps are required to convert the pivotal tricyclic intermediate into codeine, which has been demethylated in high yield to morphine.