Organocatalytic asymmetric chlorinative dearomatization of naphthols

An organocatalytic asymmetric chlorinative dearomatization of naphthols was realized for the first time, providing chiral naphthalenones with a Cl-containing all-substituted stereocenter in excellent yields and enantioselectivity (up to 97% yield and 96% ee). The reaction features mild reaction conditions, good tolerance of diverse functional groups and simple reaction operation.     

Asymmetric Henry reactions catalyzed by copper(II) complexes of chiral 1,2,4-triazine-oxazoline ligands: the impact of substitution in the oxazoline ring on ligand activity

An enantiomerically pure 1,2,4-triazine-oxazoline ligand with an indanol-derived substituent in the oxazoline ring has been synthesized using Buchwald–Hartwig amination of 3-bromo-1,2,4-triazine. The catalytic efficiency of the ligand was estimated in the asymmetric nitroaldol (Henry) reaction of nitromethane with several aromatic and aliphatic aldehydes. The appropriate nitroaldol products were formed in good yields (up to 91%) and with up to 92% ee. In order to investigate the influence of the conformational rigidity and the additional stereocenter in the oxazoline ring on the catalytic activity of the ligand, a 1,2,4-triazine-oxazoline ligand with two phenyl substituents in the oxazoline ring was synthesized and tested in the asymmetric nitroaldol reaction.     

Catalytic asymmetric intermolecular Stetter reaction of glyoxamides with alkylidenemalonates

An asymmetric intermolecular Stetter reaction of glyoxamide and alkylidenemalonates has been developed. Catalyzed by a novel N-heterocyclic carbene, the Stetter adducts are formed in good yield and excellent enantioselectivity. The presence of a sensitive epimerizable stereocenter is tolerated under these mildly basic reaction conditions if a bulky amine base is used. The products may be further elaborated to provide synthetically useful intermediates.     

Enantioselective total synthesis of macrolide antitumor agent (-)-lasonolide A

[structure: see text] An enantioselective total synthesis of (-)-lasonolide A is described. The upper tetrahydropyran ring was constructed stereoselectively by an intramolecular 1,3-dipolar cycloaddition reaction. The bicyclic isooxazoline led to the tetrahydropyran ring as well as the quaternary stereocenter present in the molecule. The lower tetrahydropyran ring was assembled by a catalytic asymmetric hetero-Diels-Alder reaction as the key step. Three stereocenters were enantioselectively installed in this single step reaction.     

A highly enantio- and diastereoselective molybdenum-catalyzed asymmetric allylic alkylation of cyanoesters

An efficient molybdenum-catalyzed asymmetric allylic alkylation (Mo-AAA) of cyanoester nucleophiles is reported. A number of highly functionalized branched cyanoesters containing a quaternary carbon stereocenter with a vicinal tertiary stereocenter are obtained. This method generates a number of functionalized cyanoesters in excellent yield and chemoselectivity in good to excellent diastereoselectivity and enantioselectivity.     

Asymmetric synthesis of tetrahydroquinolines with quaternary stereocenters through the Povarov reaction

The asymmetric Povarov reaction with α-alkyl styrenes as dienophiles was catalyzed by an N,N'-dioxide L4-Sc(OTf)(3) complex. Enantiopure tetrahydroquinoline derivatives with a quaternary stereocenter at the C4 position were synthesized for the first time. A wide variety of α-alkyl styrenes and N-aryl aldimines were tolerated in the reaction, to give excellent diastereo- (up to 99:1 d.r.) and enantioselectivities (92 to >99% ee). In addition, the reaction could be performed on the gram scale without any loss of yield, diastereoselectivity, or enantioselectivity. An intermolecular hydrogen-shift reaction was found to be a side reaction, which offered a method to synthesize the corresponding quinoline derivatives with chiral quaternary sterocenters.     

Copper(I)‐Catalyzed Asymmetric Dearomatization of Indole Acetamides with 3‐Indolylphenyliodonium Salts

The rapid and direct asymmetric synthesis of 3‐(3a‐indolyl)hexahydropyrroloindoline motifs is an extremely important part of the total synthesis of several alkaloid structures. Herein, an intermolecular, asymmetric cascade dearomatization reaction of indole acetamides with 3‐indolylphenyliodonium salts has been developed. This protocol provides a straightforward access to 3‐(3a‐indolyl)hexahydropyrroloindolines bearing an all‐carbon quaternary stereocenter at the C3 position of the indoline ring with high enantioselectivities. The utility of the protocol has been demonstrated by the formal asymmetric synthesis of folicanthine.     

Enantioselective total synthesis of (-)-dactylolide

[reaction: see text] The enantioselective total synthesis of (-)-dactylolide is reported. The absolute stereochemistry of the tetrahydropyran was established by catalytic asymmetric Jacobsen hetero-Diels-Alder reaction. The remote C19 stereocenter was introduced by a sequence of chelation-controlled Grignard addition and Ireland-Claisen rearrangement.     

A concise,selective synthesis of the polyketide spacer domain of a potent bryostatin analogue

[reaction: see text] A concise, asymmetric synthesis of the polyketide spacer domain portion (C1-C13) of a highly potent bryostatin analogue was developed. The route utilizes asymmetric hydrogenation methodology to install the C3, C5, and C11 stereocenters, while a substrate directed syn reduction sets the C9 stereocenter. The spacer domain 1 is obtained in 10 steps with a 25% overall yield and is readily incorporated into the synthesis of 2.     

Chemo‐, Diastereo‐, and Enantioselective Iridium‐Catalyzed Allylic Intramolecular Dearomatization Reaction of Naphthol Derivatives

An iridium‐catalyzed intramolecular asymmetric allylic dearomatization reaction of naphthol derivatives is described. Challenges confronted in this reaction include chemoselectivity between carbon and oxygen atoms as nucleophilic centers, diastereoselectivity when contiguous chiral centers are generated, and enantioselective control for constructing an all‐carbon quaternary stereocenter. In the presence of an iridium catalyst generated from [{Ir(dbcot)Cl}₂] (dbcot=dibenzocyclooctatetraene) and a new THQphos (tetrahydroquinolinedinaphthophosphoramidite) ligand, various spironaphthalenones were obtained with up to greater than 95:5 C/O selectivity, greater than 95:5 d.r., and 99 % ee, thus providing a general method for the dearomatization of naphthols.     

A catalytic asymmetric ring-expansion reaction of isatins and α-alkyl-α-diazoesters: highly efficient synthesis of functionalized 2-quinolone derivatives

Asymmetric expansion: A catalytic asymmetric ring-expansion reaction of the title compounds occurs in the presence of a Sc(OTf)(3) catalyst bearing an N,N'-dioxide-based ligand. Highly functionalized 2-quinolone derivatives containing a chiral C4-quaternary stereocenter were obtained in high yields and high levels of selectivity under mild reaction conditions (see scheme; Tf=trifluoromethanesulfonyl).     

Enantioselective [4 + 2]-annulation of chiral crotylsilanes: application to the synthesis of a C1-C22 fragment of leucascandrolide A

[reaction: see text] The asymmetric synthesis of a C1-C22 fragment (2) of leucascandrolide A is described. Synthetic highlights include the construction of the C9-C22 pyran fragment using a formal [4 + 2]-annulation of a chiral organosilane. A diastereoselctive Mukaiyama aldol was used to introduce the C9 stereocenter and complete the assembly of the macrocycle's carbon skeleton.     

Direct Catalytic Enantio‐ and Diastereoselective Ketone Aldol Reactions of Isocyanoacetates

A catalytic asymmetric aldol addition/cyclization reaction of unactivated ketones with isocyanoacetate pronucleophiles has been developed. A quinine‐derived aminophosphine precatalyst and silver oxide were found to be an effective binary catalyst system and promoted the reaction to afford chiral oxazolines possessing a fully substituted stereocenter with good diastereoselectivities and excellent enantioselectivities.     

Enantioselective total synthesis of (+)-gigantecin: exploiting the asymmetric glycolate aldol reaction

The enantioselective synthesis of the potent, selective, cytotoxic, annonaceous acetogenin, (+)-gigantecin, has been completed. An asymmetric glycolate aldol serves to establish the stereocenters at C13,14 and at C21,22. A Carreira asymmetric acetylide addition is used to establish the C17 stereocenter.     

Enantioselective synthesis of the AB-ring system of the antitumor antibiotic tetrazomine

The synthesis of the 1,2,3,4-tetrahydroisoquinoline moiety of tetrazomine was accomplished in 18 steps and in 3% overall yield from commercially available o-anisaldehyde. The reaction sequence utilizes a Sharpless asymmetric dihydroxylation to install the stereocenter and an intramolecular Friedel--Crafts hydroxyalkylation with an N-protected 2-oxo-acetamide to close the heterocyclic ring.     

Enantio- and Diastereoselective Synthesis of Chiral Tetrasubstituted α-Amino Allenoates Bearing a Vicinal All-Carbon Quaternary Stereocenter with Dual-Copper-Catalysis

The skeletons of chiral tetrasubstituted allenes bearing a vicinal all-carbon quaternary stereocenter are of importance but still challenging to synthesize. Herein, we report enantio- and diastereoselective γ-additions of 1-alkynyl ketimines with dual-copper-catalysis under mild conditions, affording chiral tetrasubstituted α-amino allenoates bearing a vicinal all-carbon quaternary stereocenter in high yields (up to 99 % yield) with excellent enantioselectivities (up to 99 % ee) and diastereoselectivities (up to >20 : 1 dr). Importantly, the stereodivergent synthesis of the products was realized by the asymmetric γ-addition reaction and the Grignard reagent promoted epimerization. Moreover, the dual-copper-catalyzed γ-addition reactions were smoothly applied to a gram-scale reaction and adopted to introduce chiral tetrasubstituted allenyl moieties into bioactive molecules. Mechanistic experiments and density functional theory (DFT) calculations demonstrated that the asymmetric γ-addition reactions were catalyzed by double chiral copper catalysts.     

Asymmetric Total Synthesis of (−)‐Stenine and 9a‐epi‐Stenine

A route for the asymmetric synthesis of (?)‐stenine, a member of the Stemona alkaloid family used as folk medicine in Asian countries, is described. The key features of the sequence employed include stereoselective transformations on a cyclohexane ring controlled by a chiral auxiliary unit and an intramolecular Mitsunobu reaction to construct the perhydroindole ring system. By using an intermediate in the route to (?)‐stenine, an asymmetric synthesis of 9a‐epi‐stenine was also executed. The C(9a) stereocenter in 9a‐epi‐stenine was installed by using a Staudinger/aza‐Wittig reaction of a keto–azide precursor followed by reduction of the resulting imine. The results of this effort demonstrate the applicability of the chiral auxiliary based strategy to the preparation of naturally occurring alkaloids that contain highly functionalized cyclohexane cores.     

Toward the second generation synthesis of aplyronine A: stereocontrolled assembly of the C1-C19 segment by using an asymmetric Nozaki-Hiyama-Kishi coupling

An efficient synthesis of the C1-C19 segment of aplyronine A is described. Stereoselective construction of the C14-C15 (E)-trisubstituted double bond and the C13 stereocenter was achieved by using an asymmetric Nozaki-Hiyama-Kishi coupling.     

An Asymmetric Hydrogenation/N-Alkylation Sequence for a Step-Economical Route to Indolizidines and Quinolizidines

The direct catalytic asymmetric hydrogenation of pyridines for the synthesis of piperidines remains a challenge. Herein, we report a one-pot asymmetric hydrogenation of pyridines with subsequent N-alkylation using a traceless Brønsted acid activation strategy. Catalyzed by an iridium-BINAP complex, the substrates undergo ketone reduction, cyclization and pyridine hydrogenation in sequence to form indolizidines and quinolizidines. The absolute configuration of the stereocenter of the alcohol is retained and influences the formation of the second stereocenter. Experimental and theoretical mechanistic studies reveal that the chloride anion and certain noncovalent interactions govern the stereoselectivity of the cascade reaction throughout the catalytic process.