Stereoselective synthesis of 3-alkylideneoxindoles via palladium-catalyzed domino reactions

We have developed efficient catalytic methods for the stereoselective and diversity synthesis of various (E)-, (Z)-, and disubstituted 3-alkylideneoxindoles and 3-alkylidenebenzofuran-2-ones via palladium-catalyzed Heck/Suzuki-Miyaura, Heck/Heck, and Heck/carbonylation/Suzuki-Miyaura domino reactions.     

Efficient synthesis of the structural core of tetracyclines by a palladium-catalyzed domino Tsuji-Trost-Heck-Mizoroki reaction

The Pd-catalyzed domino Tsuji-Trost-Heck-Mizoroki reactions of compounds 18, 27, and 34, respectively, each containing an allyl acetate and a halogen aryl moiety, lead to the formation of hexahydronaphthacenes 2 and 3 and octahydroanthracene 4 in 62-81 % yield. The octahydroanthracene and hexahydronaphthacene motifs are found in many natural products, for example, the tetracycline antibiotics.     

Synthesis of 2-substituted indoles via a palladium-catalyzed domino Heck reaction and dealkylation

A palladium-catalyzed domino Heck reaction and dealkylation for the preparation of 2-substituted indoles is described. This novel transformation is based on an intramolecular Heck reaction followed by dealkylation.     

Enantioselective palladium-catalyzed total synthesis of vitamin e by employing a domino Wacker-Heck reaction

An enantioselective total synthesis of vitamin E in which a novel palladium-catalyzed domino reaction was employed as the key step is described. This reaction allows the formation of the chiral chroman framework and the concurrent introduction of part of the side chain of vitamin E. The sequence comprises an enantioselective Wacker cyclization and a subsequent Heck reaction. Accordingly, reaction of alkenylphenol 12 with methyl vinyl ketone (13) in the presence of catalytic amounts of Pd(OTFA)(2) (TFA = trifluoroacetate), the enantiopure ligand (S,S)-Bn-BOXAX (8 b; Bn = benzyl, BOXAX = 2,2'-bis(oxazolyl)-1,1'-binaphthyl, and p-benzoquinone (9) as an oxidant gives access to chiral chroman 10 with an enantioselectivity of 97 % ee in 84 % yield. Chroman 10 is then converted into 24 by an aldol condensation reaction with (3R)-3,7-dimethyloctanal (11). Subsequent 1,2-addition of methyllithium, elimination of water, and hydrogenation yields vitamin E.     

An efficient synthesis of 4-substituted coumarin derivatives via a palladium-catalyzed Suzuki cross-coupling reaction

An efficient Pd-catalyzed Suzuki cross-coupling reaction of sterically crowded 4-chlorocoumarin derivatives with air- and moisture-stable potassium organotrifluoroborates is developed. This methodology has been used to generate a series of novel alkyl, aryl, and vinyl substituted coumarin derivatives in good to excellent yields. The twisted conformation of the vinyl groups in the X-ray crystal structures of (2-oxo-4-vinyl-2H-chromen-3-yl)methyl acetate (2) and (2-oxo-4-vinyl-2H-chromen-3-yl)methyl 2,2,2-trichloroacetimidate (3), along with the atropisomerism of 3-(hydroxymethyl)-4-(2-methoxyphenyl)-2H-chromen-2-one (1d), are evidence of the steric crowding in these adducts.     

Studies toward the biomimetic synthesis of tropolone natural products via a hetero Diels-Alder reaction

Analogues of the tropolone natural products pycnidione and epolone B were synthesized via a hetero Diels-Alder reaction of benzotropolone 10 with humulene. The quinone methide benzotropolone 13 was generated in situ by thermalisation of benzotropolone 10. Benzotropolone 10 was derived from phthalic acid via carbonyl ylide 8a followed by an intramolecular 1,3-dipolar cycloaddition and subsequent acid-catalyzed ring opening.     

One-pot approach to chiral chromenes via enantioselective organocatalytic domino oxa-Michael-aldol reaction

A highly enantioselective (S)-diphenylpyrrolinol triethylsilyl ether promoted tandem oxa-Michael-aldol reaction of alpha,beta-unsaturated aldehydes with salicylaldehydes has been developed; the method affords one-pot access to chiral and synthetically useful chromenes in high yields and high enantioselectivities from readily available compounds.     

De novo synthesis of sugar-aza-crown ethers via a domino Staudinger aza-Wittig reaction

A short and highly efficient route to sugar-aza-crown (SAC) ethers has been developed. The key step of the transformation is a one-pot cyclodimerization of C-glycosyl azido aldehydes via a domino Staudinger aza-Wittig reaction. This process allows the preparation of various orthogonally protected SAC ethers, from both alpha- and beta-C-glycosyl azido aldehydes.     

An efficient synthesis of some thiopyranopyrazole-heterocycles via domino reaction in a Brønsted acidic ionic liquid

The thiopyrazole gave many new polycyclic thiopyranopyrazole-heterocycles when it was assembled with a variety of O-alkenylated/alkynylated salicylaldehydes and naphthaldehydes in Brønsted acidic ionic liquid, [Hmim]HSO₄, via domino/Knoevenagel–hetero-Diels–Alder (DKHDA) reaction. The reaction is highly stereoselective and the work-up procedure required no chromatography of products in many cases.     

An efficient synthesis of oseltamivir phosphate (Tamiflu) via a metal-mediated domino reaction and ring-closing metathesis

An efficient synthesis of the influenza neuraminidase inhibitor prodrug oseltamivir phosphate (Tamiflu) from cheap, commercially available d-ribose is described. The main features of this approach comprise a metal (Zn, In)-mediated domino reaction and ring-closing olefin metathesis (RCM) of the resultant functionalized dienes to produce the Tamiflu skeleton. The synthesis described in this Letter represents a new and efficient transformation of a shikimic acid derivative into a 1,2-diamino compound which involved oxidation of an alcohol followed by reductive amination, regioselective ring opening of an amino pentylidene ketal and stereospecific nucleophilic replacement of a triflate with an azide.     

Synthesis of tetrasubstituted alkenes through a palladium-catalyzed domino carbopalladation/C-H-activation reaction

Helical tetrasubstituted alkenes (7) were obtained in a highly efficient way through a palladium-catalyzed domino-carbopalladation/CH-activation reaction of propargylic alcohols 6 in good to excellent yields. Electron-withdrawing- and electron-donating substituents can be introduced onto the upper and lower aromatic rings. The substrates (6) for the domino process were synthesized by addition of the lithiated alkyne (20) to various aldehydes (19); moreover, the substrates were accessible enantioselectively (in 95% ee) by reduction of the corresponding ketone using the Noyori procedure.     

Synthesis of aromatic bisabolene natural products via palladium-catalyzed cross-couplings of organozinc reagents

Aromatic bisabolene derivatives were prepared by two methods involving cross-coupling of organozinc reagents. The first synthesis of (+/-)-glandulone A (10), as well as syntheses of (+/-)-curcuhydroquinone (8) and (+/-)-curcuquinone (9), were accomplished via coupling of a secondary alkyl zinc reagent (1,5-dimethyl-4-hexenylzinc halide, 18) to protected bromohydroquinones using Pd(dppf)Cl(2) as catalyst. Coupling of arylzinc halides with alkenyl triflate 16 using Pd(PPh(3))(4) catalyst provided a number of bisabolene derivatives and led to syntheses of dehydro-alpha-curcumene (2), (+/-)-curcuphenol (3), and (+/-)-elvirol (13). A high-yield synthesis of the (+/-)-heliannuol D precursor 29 is also reported using this method.     

Microwave-promoted synthesis of amino-substituted 2-pyridone derivatives via palladium-catalyzed amination reaction

A rapid and efficient synthesis of amino-substituted 2-pyridones was demonstrated by palladium-catalyzed amination reaction under microwave irradiation. This high-speed synthesis provided a number of amino-substituted 2-pyridones from the corresponding bromo-2-benzyloxypyridines via palladium-catalyzed amination followed by hydrogenolysis of benzyl ether.     

Biomimetic cycloaddition approach to tropolone natural products via a tropolone ortho-quinone methide

[reaction: see text] A study toward a possible biomimetic hetero Diels-Alder reaction is reported between humulene and a novel tropolone ortho-quinone methide. A suitable tropolone ortho-quinone methide precursor has been prepared from 3-methyl-2-furoate. Heating the ortho-quinone methide precursor gave a tropolone ortho-quinone methide, which in the presence of humulene underwent a hetero Diels-Alder reaction to give a deoxy analogue of epolone B.     

Stereocontrolled synthesis of fully functionalized D-glucosamine monosaccharides via a domino nitro-Michael/Henry reaction

A diastereoselective domino nitro-Michael/Henry reaction involving a beta-hydroxyaldehyde and a nitroalkene provides direct access to fully functionalized D-glucosamine monosaccharides.     

A novel synthesis of 2-aryl-2H-indazoles via a palladium-catalyzed intramolecular amination reaction

[reaction: see text] A variety of 2-aryl-2H-indazoles were synthesized by the palladium-catalyzed intramolecular amination of the corresponding N-aryl-N(o-bromobenzyl)hydrazines. Of several sets of reaction conditions surveyed, the combination of Pd(OAc)2/dppf/tBuONa gave the best results. This method applies to a wide scope of substrates containing electron-donating and electron-withdrawing substituents.     

Rapid access to 1,6-anhydro-beta-L-hexopyranose derivatives via domino reaction: synthesis of L-allose and L-glucose

An expeditious and efficient synthesis of 1,6-anhydro-beta-L-hexopyranosyl derivatives 3 as valuable building blocks for the preparation of L-sugars is herein reported. This route relies upon the use of a domino reaction involving five synthetic steps from the 5,6-dihydro-1,4-dithiin 4. As 1,6-anhydro derivatives 3 are obtained, dithioethylene bridge removal and double-bond dihydroxylation give access to protected L-allose and L-glucose in stereoselective fashion and high yields.     

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.