Enantioselective Desymmetrization Triggered by Iminium-Enamine Activation: Access to Complex Cyclohepta[b]indoles.

The expeditious construction of complex molecules having multiple stereocentres is highly desirable in organic chemistry. In the present communication, we report the development of an organocatalytic asymmetric desymmetrization of prochiral enal-tethered cyclohexadienones via the C3-selective Friedel-Crafts alkylation of indoles triggered by LUMO-lowering iminium activation/HOMO-raising enamine activation. The reaction provides access to bicyclic enones, which further undergo acid-mediated intramolecular annulation from C2-position to afford highly strained cyclohepta[b]indoles with five contiguous stereocentres and three new C-C bonds in excellent enantioselectivity and diastereoselectivity.

Palladium(0)-Catalyzed Remote Decarboxylative Allylation and Base-Mediated 1,3-Migration.

Herein we have reported the palladium(0)-catalyzed decarboxylative oxa-Michael addition/remote α-allylation/1,3- migration of prochiral allyl carbonate-tethered cyclohexadienones in good yields. This unconventional intramolecular rearrangement is triggered by the base-mediated retro-Michael ring-opening reaction (ß-elimination) and subsequent syn-selective oxa-Michael addition on the less substituted enone functionality. The generality of tandem decarboxylative allylation was examined with various substrates and in the gram-scale reaction.

Metal-free oxidative formal C(sp2)-H arylation of cyclopentene-1,3-diones with ß-naphthols.

An efficient, mild, and transition-metal free formal C(sp2)-H arylation of prochiral 2,2-disubstituted cyclopentene-1,3-diones is reported. This oxidative arylation with ß-naphthols proceeds via base-mediated C-Michael addition followed by aerial oxygen insertion and a subsequent α-hydroperoxy elimination sequence. This operationally simple and environmentally benign transformation is highly scalable and does not require any pre-functionalization. Moreover, this reaction affords excellent yields of α-substituted ß-naphthols bearing all-carbon quaternary centers.

Transition-Metal Catalyzed Stereoselective Desymmetrization of Prochiral Cyclohexadienones.

The development of transition-metal catalyzed enantioselective and diastereoselective transformations has contributed many advances in the field of synthetic organic chemistry. Particularly, stereoselective desymmetrization of prochiral cyclohexadienones represents a powerful strategy for accessing highly functionalized and stereochemically enriched scaffolds, which are often found in biologically active compounds and natural products. In recent years, several research groups including our group have made a significant progress on transition-metal catalyzed stereoselective desymmetrizations of 2,5-cyclohexadienones. In this account, we will provide an overview of the recent developments in this area employing Pd, Cu, Rh, Au, Ag, Ni, Co, and Mn-catalysts.

Enantioselective Desymmetrization of Prochiral Cyclopentene-1,3-diones Triggered by Remote C(sp2)-N Bond Formation.

The enantioselective desymmetrization via remote C(sp2)-H amidation of the prochiral 2,2-disubstituted cyclopentene-1,3-dione with N-methoxybenzamide has been developed. The overall process was catalyzed by a chiral bifunctional thiourea catalyst through a sequential conjugate-addition-elimination-tautomerization. This strategy provides rapid access to highly functionalized five-membered carbocycles, bearing an all-carbon quaternary stereogenic center through remote stereocontrol in high yields with moderate to excellent enantioselectivities.

Rh-Catalyzed diastereoselective desymmetrization of enone tethered-cyclohexadienones via tandem arylative cyclization.

The rhodium-catalyzed arylative cyclization of enone tethered-cyclohexadienones has been developed with high efficiency, thus providing cis-fused bicyclic enones in good yields and with excellent diastereoselectivities. Furthermore, this mild transformation has a broad range of substrate scope and excellent functional group tolerance. In addition, bicyclic products have an enone functionality, which can be a synthetically valuable handle for further transformations.

Syntheses of 2-Aroyl Benzofurans through Cascade Annulation on Arynes.

The highly efficient and expedient route for the syntheses of 2-aroyl benzofurans has been developed via the cascade [2+2] followed by a [4+1] annulation on arynes. The overall transformation proceeded through the formation of ortho-quinone methide by the insertion of transient aryne into N, N-dimethylformamide and subsequent trapping with sulfur ylide. Moreover, this transformation has a broad range of substrate scope with a high functional-group tolerance. This new reaction was successfully utilized in the synthesis of the potent CYP19 aromatase inhibitor and late-stage functionalization on the bioactive complex estrone.

Synthetic Strategy toward the Pentacyclic Core of Melodinus Alkaloids.

The three-component Povarov reaction is efficiently utilized for construction of the pentacyclic framework of complex Melodinus alkaloids, which is amenable to expansion to other complex natural products. The key steps were Povarov reaction, one-pot reductive cyclization, and ring-closing metathesis (RCM) reaction.

Tunable Diastereoselective Desymmetrization of Cyclohexadienones Triggered by Copper-Catalyzed Three-Component Coupling Reaction.

Catalytic tandem diastereoselective desymmetrization of cyclohexadienone-containing 1,6-enynes has been achieved through copper-catalyzed [3 + 2]-cycloaddition followed by ketenimine formation and subsequent intramolecular conjugate addition. The cascade reaction provides cis-hydrobenzofurans in good yields with excellent diastereoselectivity. The exo- or endo-selectivity of bicyclic scaffolds depends on the selection of the base in the reaction. In addition, N-tethered bicyclic products further transformed into tricyclic compounds via intramolecular Michael addition.

Insertion of N-Tosylacetimidates/Acetimidamides onto Arynes via [2 + 2] Cycloaddition.

A novel insertion reaction of N-tosylacetimidates and N-tosylacetimidamides onto arynes via a benzocyclobutene intermediate followed by ring cleavage is developed to afford o-benzylbenzoic acid derivatives in good yields. Interestingly, the use of cyclic 2-sulfonyliminoindolines provided two distinct products such as azepanimines via [2 + 2] cycloaddition and indolamines via protonation based on solvent medium.

Palladium-catalyzed regioselective domino cyclization of cyclohexadienones.

A mild and efficient Pd-catalyzed arylative domino carbocyclization of cyclohexadienone-containing 1,6-enynes is described. The reaction tolerates a variety of functionalized boronic acids to afford a cis-fused bicyclic framework containing an α,ß-unsaturated ketone with excellent regio- and diastereoselectivity in good yields. The tandem process proceeds with ß-arylation of propargylic ether followed by conjugate addition of a vinyl palladium intermediate and subsequent protonolysis of a palladium enolate.

Phosphate Tether-Mediated Ring-Closing Metathesis for the Generation of Medium to Large, P-Stereogenic Bicyclo[n.3.1]phosphates.

A phosphate tether-mediated ring-closing metathesis study towards the synthesis of P-stereogenic bicyclo[6.3.1]-, bicyclo[7.3.1]-, and bicyclo[8.3.1]phosphates is reported. This study demonstrates expanded utility of phosphate tether-mediated desymmetrization of C2-symmetric, 1,3-anti-diol dienes in generating complex medium to large, P-stereogenic bicyclo[n.3.1]phosphates..

Synthetic Studies to Lyngbouilloside: A Phosphate Tether-Mediated Synthesis of the Macrolactone Core.

A concise synthetic pathway to the originally assigned structure of lyngbouilloside macrolactone (3) is reported. The core macrocycle 3 was synthesized via a phosphate tether-mediated, one-pot, sequential RCM/CM/chemoselective hydrogenation reaction, Roskamp homologation, and a high yielding Boeckman acylketene cyclization.

A modular phosphate tether-mediated divergent strategy to complex polyols.

An efficient and divergent synthesis of polyol subunits utilizing a phosphate tether-mediated, one-pot, sequential RCM/CM/reduction process is reported. A modular, 3-component coupling strategy has been developed, in which, simple "order of addition" of a pair of olefinic-alcohol components to a pseudo-C 2-symmetric phosphoryl chloride, coupled with the RCM/CM/reduction protocol, yields five polyol fragments. Each of the product polyols bears a central 1,3-anti-diol subunit with differential olefinic geometries at the periphery.

Cascade Oxypalladation/1,3-Palladium Shift to Access Cyclopentene-Fused Isocoumarins.

Fused isocoumarins are frequently found in several natural products and pharmaceuticals. Herein, a cascade annulation of 2-alkynylbenzoate-tethered cyclic 1,3-diones via sequential trans-oxypalladation, carbonyl insertion, 1,3-Pd shift, and ß-hydride elimination is reported. This method provides efficient access to highly diastereoselective tetracyclic cyclopentene-fused isocoumarins containing two contiguous quaternary stereocenters. A plausible reaction mechanism is proposed on the basis of mechanistic studies, including deuterium labeling experiments. Studies toward enantioselective synthesis using a chiral Bpy ligand gave encouraging initial results.

Organocatalytic enantioselective desymmetrization of enal-tethered cyclohexane-1,3-diones.

Organocatalytic asymmetric desymmetrization of prochiral cyclohexane-1,3-diones has been demonstrated through the merging of iminium and enamine activation. The tandem annulation reaction proceeds through a sequential oxa-Michael addition/intramolecular aldol reaction/[1,3]-amino oxetane rearrangement pathway. Mechanistic study using an 18O-water experiment suggests oxetane rearrangement instead of direct dehydration. The formation of other competing Rauhut-Currier products via alkoxy-elimination was not observed.

Strategic enzymatic enantioselective desymmetrization of prochiral cyclohexa-2,5-dienones.

Asymmetric desymmetrization through the selective reduction of one double bond of prochiral 2,5-cyclohexadienones is highly challenging. A novel method has been developed for synthesizing chiral cyclohexenones by employing an ene-reductase (Bacillus subtilis YqjM) enzyme that belongs to the OYE family. Our strategy demonstrates high substrate scope and enantioselectivity towards substrates containing all-carbon as well as heteroatom (O, N)-containing quaternary centers. The mechanistic studies (kH/D = ∼1.8) indicate that hydride transfer is probably the rate-limiting step. Mutation of several active site residues did not affect the stereochemical outcomes. This work provides a convenient way of synthesizing various enantioselective γ,γ-disubstituted cyclohexanones using enzymes.

Phosphate-tether-mediated ring-closing metathesis for the preparation of complex 1,3-anti-diol-containing subunits.

An array of examples of diastereoselective, phosphate-tether-mediated ring-closing metathesis reactions, which highlight the importance of product ring size and substrate stereochemical compatibility, as well as complexity, is reported. Studies focus primarily on the formation of bicyclo[n.3.1]phosphates, involving the coupling of C2-symmetric dienediol subunits with a variety of simple, as well as complex, alcohol partners.

Combined Lewis Acid Catalyzed Diastereoselective Halogenative Cascade Annulation of Enone-Tethered Cyclohexadienones.

The cascade difunctionalization of α,ß-unsaturated carbonyls by nucleophilic halogenation followed by enolate trapping with other electrophiles is highly challenging in synthetic organic chemistry. Herein, we report a chemo- and diastereoselective cascade annulation of enone-tethered cyclohexadienones by using an unconventional combined Lewis acid catalyzed halogenation reaction in the presence of an In(III)-catalyst and trimethylsilyl halide. The reaction provides highly functionalized bicyclic enones with four contiguous stereocenters.

Solvent-Mediated Enantioselective Rauhut-Currier Cyclization via Iminium and Enamine Activation.

In this work, we have developed an unconventional and highly enantioselective solvent-promoted Rauhut-Currier cyclization of enal-tethered cyclohexadienone by exploiting the reactivity of a simple Jørgensen-Hayashi catalyst through the merging of iminium and enamine activation. This asymmetric desymmetrization reaction has broad substrate scope in good yields with high to excellent enantioselectivity. DFT calculations suggest that the elimination of the alkoxy group is the rate-limiting step and that it proceeds through proton abstraction by solvent instead of a direct 1,3-proton shift.