Regioselective and enantiospecific rhodium-catalyzed allylic alkylation reactions using copper(I) enolates: synthesis of (-)-sugiresinol dimethyl ether

The transition metal-catalyzed allylic alkylation represents a fundamentally important cross-coupling reaction for the construction of ternary carbon stereogenic centers. We have developed a regioselective and enantiospecific rhodium-catalyzed allylic alkylation of acyclic unsymmetrical allylic alcohol derivatives using copper(I) enolates to prepare beta-substituted ketones. This protocol represents a convenient asymmetric Claisen rearrangement surrogate in which alpha-substituted enolates permit the introduction of an additional stereogenic center. The synthetic utility of this transformation was highlighted in the construction of a trans-1,2-disubstituted cyclohexene and the total synthesis of (-)-sugiresinol dimethyl ether. Finally, we anticipate that copper(I) enolates may prove useful nucleophiles in related metal-catalyzed reactions.     

Formal (4+1) Cycloaddition and Enantioselective Michael–Henry Cascade Reactions To Synthesize Spiro[4,5]decanes and Spirooxindole Polycycles

Spiro[4,5]decanes and polycyclic compounds bearing spiro[4,5]decane systems are important biofunctional molecules. Described are diastereoselective formal (4+1) cycloaddition reactions to afford oxindole-functionalized spiro[4,5]decanes and organocatalytic enantioselective Michael–Henry cascade reactions of the (4+1) cycloaddition products to generate spirooxindole polycyclic derivatives bearing the spiro[4,5]decane system. Spiro[4,5]decanes bearing oxindoles containing three stereogenic centers and spirooxindole polycycles having seven stereogenic centers, including two all-carbon chiral quaternary centers and one tetrasubstituted chiral carbon center, were obtained with high diastereo- and enantioselectivities.     

Total synthesis of (-)-teucvidin

A concise enantioselective synthesis of (-)-teucvidin has been achieved. Our synthetic strategy involved the diastereoselective Michael/Conia-ene cascade cyclization reaction for rapid establishment of the cis-decalin skeleton with three new stereogenic centers in one pot (72%, single diastereomer), the epoxidation/dealkoxycarbonylation protocol for construction of the fused furanone moiety, and the O-allylation/Claisen rearrangement protocol for construction of the all-carbon quaternary center at C9 of the clerodane skeleton.     

Synthesis of exo- and endocyclic enamino derivatives of 2-(3-arylprop-2-enoyl)cyclohexane-1,3-diones

Condensation of 2-acetylcyclohexane-1,3-diones with aromatic aldehydes in the presence of piperidine, pyrrolidine, hexamethyleneimine, or morpholine gave the corresponding 2-(3-arylprop-2-enoyl)cyclohexane-1,3-diones as the major products and 2-[3-aryl-1-cycloalkylaminoprop-2-en-1-ylidene]cyclohexane-1,3-diones as minor ones. Endocyclic enamino derivatives were synthesized in two steps through enol methyl ethers which reacted with amines. Endocyclic enamino derivatives of 2-(3-arylprop-2-enoyl)cyclohexane-1,3-diones containing an aryl group on the nitrogen atom readily underwent cyclization to 1,2,3,4,5,6,7,8-octahydroquinoline-4,5-dione derivatives.     

Organocatalytic asymmetric one-pot sequential reaction: synthesis of highly substituted spirocyclohexanepyrazolones with six contiguous stereogenic carbons

An atom-economical synthesis of chiral polyfunctionalized spiropyrazolone derivatives based on the development of a new organocatalytic enantioselective one-pot sequential Michael/Michael/Aldol reaction of 1,3-dicarbonyl compounds with unsaturated pyrazolones and α,β-unsaturated aldehydes has been developed. The notable features of this one-pot sequential process include the generation of up to six consecutive stereogenic carbon centers including one quaternary stereocenter and five tertiary stereocenters with high enantioselectivities (up to 95% ee) and excellent diastereoselectivities (>99:1 d.r.).     

Oleylamine-catalyzed Tandem Knoevenagel/Michael Addition of 1,3-Cyclohexanediones with Aromatic Aldehydes

A convenient and efficient method was developed for the synthesis of 2,2'-(arylmethylene)bis(3-hydrox-ycyclohex-2-enone) derivatives via the oleylamine-catalyzed tandem Knoevenagel/Michael addition reactions of aromatic aldehydes and cyclohexane-1,3-diones. This transformation proceeded without any metal catalyst in non-toxic solvent at room temperature with high isolated yields. A plausible mechanism for this process was proposed.     

Highly diastereoselective synthesis of tetrahydrobenzofuran derivatives by palladium-catalyzed reaction of propargylic esters with substituted β-dicarbonyl compounds

Reactions of propargylic esters with 2-substituted cyclohexane-1,3-diones and 2-oxocyclohexanecarboxylic esters in the presence of palladium catalyst are described. Substituted tetrahydrobenzofuran derivatives having a quaternary carbon stereocenter were synthesized in a highly diastereoselective manner.     

Morita-Baylis-Hillman adducts as effective dipolarophiles in copper(I)-catalyzed 1,3-dipolar cycloaddition with azomethine ylides: asymmetric construction of pyrrolidine derivatives containing quaternary stereogenic center

The first catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylides with easily accessible Morita-Baylis-Hillman adducts as the dipolarophiles has been developed successfully and provides the highly substituted pyrrolidines bearing a unique quaternary and two tertiary stereogenic centers in excellent diastereoselectivity and up to 97% ee.     

Reactions of 2-diaminomethylidenecyclohexane-1,3-diones with diethyl malonate

The debenzoylation of 2-[(amino)(benzoylamino)methylidene]cyclohexane-1,3-diones (addition products of cyclohexane-1,3-diones with benzoylcyanamide) affords the corresponding 2-diaminomethylidenecyclohexane-1,3-diones. The latter act as N,N-dinucleophiles in reactions with diethyl malonate in the presence of MeONa to form 6-hydroxy-2-(2,6-dioxocyclohexylidene)-1,2-dihydropyrimidin-4(3H)-ones. This reaction performed at 200 °C in the absence of bases results in the subsequent self-condensation of the dihydropyrimidinones to give 4,5′-bipyrimidine derivatives.     

Construction of three stereocenters via hydrogenative desymmetrization of 2,2,5-trisubstituted cyclohexane-1,3-diones

A Ru-catalyzed hydrogenative desymmetrization of 2,2,5-trisubstituted cyclohexane-1,3-diones was developed for construction of three stereocenters including two coherent and discontiguous chiral centers and a chiral quaternary carbon with excellent enantio-and diastereoselectivities.Stereodivergent synthesis of four stereoisomers could be conducted with high enantioselectivities.The desymmetrization could be achieved at gram scale without loss of reactivity and optical purity,and a formal synthesis of bioactive molecule(-)-isocelorbicol was completed.     

Structural Analysis of the Michael-Michael Ring Closure (MIMIRC) Reaction Products

A representative number of decalin and hydrindane derivatives 2a–l were prepared in 11–91% yield by means of a cascade reaction of cyclohexanone/cyclopentanone enolates and methyl acrylate through a Michael–Michael ring closure (MIMIRC) process. The relative stereochemistry of the four stereogenic centers formed in all products was determined by analyzing the vicinal coupling constants from the ¹H NMR and X-ray crystallography. Such a stereochemical outcome was corroborated by conformational analysis supported by DFT calculations and simulating the ¹H NMR spectra of representative products. All products showed the same relative stereochemistry at C-1 and C-8a, while at C-3 and bridgehead carbon C-4a, configurational changes were observed. The present results provide some insights about the scope and limitations of the triple cascade reaction between cycloalkanone enolates with methyl acrylate. This synthetic protocol is still a simple and very practical alternative to generate decalin and hydrindane derivatives with great structural diversity.     

Synergistic Ir/Cu Catalysis for Asymmetric Allylic Alkylation of Oxindoles: Enantio- and Diastereoselective Construction of Quaternary and Tertiary Stereocenters

3,3-Disubstituted oxindoles bearing quaternary and tertiary stereogenic centers are privileged structural motifs, which widely exist in pharmaceutical and natural products. Herein, a highly regio-, enantio-, and diastereoselective allylic alkylation of 3-alkyl oxindoles through synergistic iridium and copper catalysis is described, which provides a series of 3,3-disubstituted oxindole derivatives containing adjacent quaternary and tertiary stereogenic centers in excellent yields, enantiomeric excess, and diastereomeric ratio (for 30 examples, up to 97 % yield, >99 % ee, and >20 : 1 dr). This method provides exclusive branched selectivity, excellent enantio- and diastereoselectivities, and good functional compatibility. Control experiments suggested that the chiral copper catalyst is required for achieving high reactivities and diastereoselectivities under mild reaction conditions.     

Asymmetric Conjugate Addition of Benzofuran‐2‐ones to Alkyl 2‐Phthalimidoacrylates: Modeling Structure–Stereoselectivity Relationships with Steric and Electronic Parameters

A highly predictive model to correlate the steric and electronic parameters of tertiary amine thiourea catalysts with the stereoselectivity of Michael reactions of 3‐substituted benzofuranones and alkyl 2‐phthalimidoacrylates is described. As predicted, new 3,5‐bis(trifluoromethyl)benzyl‐ and methyl‐substituted tertiary amine thioureas turned out to be highly suitable catalysts for this reaction and enabled the synthesis of enantioenriched α‐amino acid derivatives with 1,3‐nonadjacent stereogenic centers.     

Electrocatalytic cascade approach to the synthesis of dihydro-2'H,3H-spiro[1-benzofuran-2,5'-pyrimidines]

Chemistry of Heterocyclic Compounds - Electrocatalytic cascade assembly of benzylidenebarbiturates and cyclohexane-1,3-diones in methanol in the presence of sodium bromide as mediator in an...     

Stereoinvertive C–C Bond Formation at the Boron-Bound Stereogenic Centers through Copper-Bipyridine-Catalyzed Intramolecular Coupling of α-Aminobenzylboronic Esters

Enantiospecific intramolecular Suzuki–Miyaura-type coupling with α-(2-halobenzoylamino)benzylboronic esters to give 3-substituted isoindolinones is achieved by using copper catalysts with 2,2′-bipyridine-based achiral ligands. Enantioenriched α-aminobenzylboron reactants bearing a hydrogen atom at the boron-bound stereogenic carbons undergo stereoinvertive coupling in the presence of a 6-phenyl-2,2′-bipyridine ligand with high enantiospecificity. α-Aminobenzylboronates bearing fully substituted boron-bound stereogenic centers also gave the 3,3-disubstituted isoindolinones with stereospecific stereochemical inversion in the presence of simple 2,2′-bipyridine as a ligand.     

Iridium‐Catalyzed Stereoselective Allylic Alkylation Reactions with Crotyl Chloride

The development of the first enantio‐, diastereo‐, and regioselective iridium‐catalyzed allylic alkylation reaction of prochiral enolates to form an all‐carbon quaternary stereogenic center with an aliphatic‐substituted allylic electrophile is disclosed. The reaction proceeds with good to excellent selectivity with a range of substituted tetralone‐derived nucleophiles furnishing products bearing a newly formed vicinal tertiary and all‐carbon quaternary stereodyad. The utility of this protocol is further demonstrated via a number of synthetically diverse product transformations.     

Stereoselective Formation of Fully Substituted Ketone Enolates

The application of stereochemically defined acyclic fully substituted enolates of ketones to the enantioselective synthesis of quaternary carbon stereocenters would be highly valuable. Herein, we describe an approach leading to the formation of several new stereogenic centers through a combined metalation–addition of a carbonyl–carbamoyl transfer to reveal in situ stereodefined α,α‐disubstituted enolates of ketone as a single stereoisomer. This approach could produce a series of aldol and Mannich products from enol carbamate with excellent diastereomeric ratios.     

Synthesis of 2-(Tetrazolylacetyl)cyclohexane-1,3-diones

Russian Journal of General Chemistry - 2-(Tetrazolylacetyl)cyclohexane-1,3-diones were synthesized via C-acylation of cyclohexane-1,3-diones with tetrazolylacetic acids in the presence of...     

Fluorinated 2-benzoylcyclohexane-1,3-diones and their vinylogous acyl chlorides in the reactions with primary and secondary amines

The reaction of 5,5-dimethyl-2-[(3-fluoro- and 4-fluoro)benzoyl]cyclohexane-1,3-diones with primary and secondary amines affords their exocyclic enamine derivatives. Under similar conditions 5,5-dimethyl-2-(2-fluorobenzoyl)]cyclohexane-1,3-dione undergoes dehydrofluorination and intramolecular cyclization to give 3,3-dimethyl-2,3,4,9-tetrahydro-1H-xanthene-1,9-dione. The reaction of vinylogous substitution of the enol derivatives of the fluorinated 5,5-dimethyl-2-benzoylcyclohexane-1,3-diones (vinylogous acyl chlorides) with amines results in the formation of the endocyclic enaminoderivatives.     

Water‐Enabled Catalytic Asymmetric Michael Reactions of Unreactive Nitroalkenes: One‐Pot Synthesis of Chiral GABA‐Analogs with All‐Carbon Quaternary Stereogenic Centers

Water enables new catalytic reactions for otherwise unreactive substrate systems. Under the “on water” reaction conditions, extremely unreactive β,β‐disubstituted nitroalkenes smoothly underwent enantioselective Michael addition reactions with dithiomalonates using a chiral squaramide catalyst, affording both enantiomers of highly enantioenriched Michael adducts with all‐carbon‐substituted quaternary centers. The developed “on water” protocol was successfully applied for the scalable one‐pot syntheses of chiral GABA analogs with all‐carbon quaternary stereogenic centers at the β‐position, which might show highly interesting pharmaceutical properties.