Diastereoselective Indole-Dearomative Cope Rearrangements by Compounding Minor Driving Forces.

Reported herein is the discovery of a diastereoselective indole-dearomative Cope rearrangement. A suite of minor driving forces promote dearomatization: (i) steric congestion in the starting material, (ii) alkylidene malononitrile and stilbene conjugation events in the product, and (iii) an unexpected intramolecular π-π* stack on the product side of the equilibrium. The key substrates are rapidly assembled from simple starting materials, resulting in many successful examples. The products are structurally complex and bear vicinal stereocenters generated by the dearomative Cope rearrangement. They also contain a variety of functional groups for interconversion to complex architectures.

Room Temperature Cu-Catalyzed N-Arylation of Oxazolidinones and Amides with (Hetero)Aryl Iodides.

N,N'-Bis(pyridin-2-ylmethyl)oxalamide (BPMO) was found to be an apposite promoter for the Cu-catalyzed N-arylation of oxazolidinones and primary and secondary amides with (hetero)aryl iodides at room temperature. Excellent chemoselectivity reached between aryl iodides and aryl bromides, and a wide range of functional groups tolerated the reaction conditions, which led to the formation of greatly diverse N-arylation products.

Oxidative cyanation of 2-oxindoles: formal total synthesis of (±)-gliocladin C.

Efficient oxidative direct cyanations of 3-alkyl/aryl 2-oxindoles using Cyano-1,2-BenziodoXol-3(1H)-one (CBX) (2a) have been reported under 'transition metal-free' conditions to synthesize a wide variety of 3-cyano 3-alkyl/aryl 2-oxindoles sharing an all-carbon quaternary center under additive-free conditions. The application of this process is shown by the formal total synthesis of (±)-gliocladin C (11c) in a few steps.

An expeditious route to the synthesis of the enantioenriched tetracyclic core of ergot alkaloids via an organocatalytic aldol reaction.

The synthesis of the tetracyclic skeleton of ergot alkaloids has been developed via a key organocatalytic enantioselective aldol reaction using paraformaldehyde as the C1-unit in the presence of thiourea catalyst followed by a key Pd-catalyzed directed coupling accelerated by the DavePhos ligand. Utilizing the aforementioned strategy, we have synthesized a key tetracyclic intermediate in up to 95% ee with high yield.

Copper-Catalyzed Coupling Reaction of (Hetero)Aryl Chlorides and Amides.

Cu2O/N,N'-bis(thiophen-2-ylmethyl)oxalamide is established to be an effective catalyst system for Goldberg amidation with inferior reactive (hetero)aryl chlorides, which have not been efficiently documented by Cu-catalysis to date. The reaction is well liberalized toward a variety of functionalized (hetero)aryl chlorides and a wide range of aromatic and aliphatic primary amides in good to excellent yields. Furthermore, the arylation of lactams and oxazolidinones is achieved. The present catalytic system also accomplished an intramolecular cross-coupling product.

Synthesis of 2-Oxindoles Sharing Vicinal All-Carbon Quaternary Stereocenters via Organocatalytic Aldol Reaction.

An organocatalytic enantioselective aldol reaction using paraformaldehyde as C1-unit has been developed for the synthesis of 2-oxindoles sharing vicinal all-carbon quaternary stereocenters. The methodology is eventually employed in the formal total synthesis of (+)-folicanthine (1b).

Unified Approach to the Spiro(pyrrolidinyl-oxindole) and Hexahydropyrrolo[2,3-b]indole Alkaloids: Total Syntheses of Pseudophrynamines 270 and 272A.

The first enantioselective total syntheses of architecturally interesting prenylated pyrroloindole alkaloids, (-)-pseudophrynamines 272A (3d) and 270 (3b), have been achieved starting from enantioenriched 2-oxindoles having all-carbon quaternary stereocenters. A common strategy involving a thio-urea catalyzed aldol reaction is employed for the total synthesis of both spiro(pyrrolidinyl-oxindole) and hexahydropyrrolo[2,3-b]indole alkaloids.

Concise total syntheses of (±)-mesembrane and (±)-crinane.

A straightforward and unified strategy to access Amaryllidaceae alkaloids comprising a cis-3a-aryloctahydroindole scaffold has been developed. The strategy features Eschenmoser-Claisen rearrangement of allylalcohol as a key step for the installation of all-carbon quaternary stereocenters present in these alkaloids. The consequent iodolactonization-reduction-oxidation sequence beautifully assembles the advanced intermediate keto-aldehyde 10a, b in synthetically viable yields. The methodology has been successfully applied in the efficient syntheses of (±)-mesembrane (1a) and (±)-crinane (2a).

Enantioselective construction of vicinal all-carbon quaternary centers via catalytic double asymmetric decarboxylative allylation.

We report a catalytic stereoconvergent construction of vicinal all-carbon quaternary centers via double stereoablative enantioselective alkylation of a mixture having racemic and meso diastereomers of esters to afford exceptional levels of diastereo- (up to 17 : 1) and enantioselectivity (up to >99% ee). The strategy offers an efficient and general approach to dimeric cyclotryptamine alkaloids sharing a labile C(3a)-C(3a') σ-bond in the hexahydropyrroloindoline core.

Acid-catalyzed reactions of 3-hydroxy-2-oxindoles with electron-rich substrates: synthesis of 2-oxindoles with all-carbon quaternary center.

A Lewis acid catalyzed reaction of in situ generated 2H-indol-2-one () with various 2π and other electron-rich substrates has been developed. A variety of electron-rich substrates such as allyl/methallyltrimethylsilane, phenylacetylene, styrenes, acetophenone, and indoles have been used. The methodology provides a straightforward approach for the synthesis of 2-oxindoles with an all-carbon quaternary center at the pseudobenzylic position.

Expeditious approach to pyrrolophenanthridones, phenanthridines, and benzo[c]phenanthridines via organocatalytic direct biaryl-coupling promoted by potassium tert-butoxide.

A methodology involving a "transition metal-free" intramolecular biaryl-coupling of o-halo-N-arylbenzylamines has been developed in the presence of potassium tert-butoxide and an organic molecule as catalyst. The reaction appears to proceed through KO(t)Bu-promoted intramolecular homolytic aromatic substitution (HAS). Interestingly, this biaryl coupling also works in the presence of potassium tert-butoxide as sole promoter. On extending our approach further, we found that N-acyl 2-bromo-N-arylbenzylamines undergo a one-pot N-deprotection/biaryl coupling followed by oxidation, thus offering an expeditious route to the phenanthridine and benzo[c]phenanthridine skeletons. The strategy has been applied to a concise synthesis of Amaryllidaceae alkaloids viz. oxoassoanine (1b), anhydrolycorinone (1d), 5,6-dihydrobicolorine (2d), trispheridine (2b), and benzo[c]phenanthridines alkaloids dihydronitidine (3b), dihydrochelerythidine (3d), dihydroavicine (3f), nornitidine (3h), and norchelerythrine (3j).

Intramolecular dehydrogenative coupling of sp2 C-H and sp3 C-H bonds: an expeditious route to 2-oxindoles.

An intramolecular-dehydrogenative-coupling (IDC) using "transition-metal-free" oxidation conditions has been achieved to synthesize a variety of 2-oxindoles bearing an all-carbon quaternary stereogenic center at the benzylic position. The methodology involves a one-pot C-alkylation of ß-N-arylamido esters (3, 6) with alkyl halides using potassium tert-butoxide concomitant with a dehydrogenative coupling. A radical-mediated pathway has been tentatively proposed for the oxidative process.

Intramolecular direct dehydrohalide coupling promoted by KO(t)Bu: total synthesis of Amaryllidaceae alkaloids anhydrolycorinone and oxoassoanine.

A transition-metal-free intramolecular dehydrohalide coupling via intramolecular homolytic aromatic substitution (HAS) with aryl radicals has been developed in the presence of potassium tert-butoxide and an organic molecule as the catalyst. The methodology has been applied to a concise synthesis of Amaryllidaceae alkaloids viz. oxoassoanine (1b), anhydrolycorinone (1d), and other related structures. Interestingly, the method also works only in the presence of potassium tert-butoxide.