Direct enantioselective Michael addition of aldehydes to vinyl ketones catalyzed by chiral amines

Chiral amines such as (S)-2-[bis(3,5-dimethylphenyl)methyl]pyrrolidine and the C(2)-symmetric (2S,5S)-2,5-diphenylpyrrolidine can catalyze the direct enantioselective Michael addition of simple aldehydes to vinyl ketones. The conditions for this organocatalytic reaction have been optimized and it has been found that the chiral amines catalyze the formation of optically active substituted 5-keto aldehydes in good yields and enantioselectivities, using aldehydes and, e.g., methyl vinyl ketone as starting compounds. Taking into account that the chiral amine can activate the aldehyde and/or the enone, the mechanism for the reaction has been investigated. On the basis of intermediate synthesis, nonlinear effect, and theoretical investigations, the mechanism for the catalytic direct enantioselective Michael addition of aldehydes to vinyl ketones is discussed.     

Catalysis of enantioselective [2+1]-cycloaddition reactions of ethyl diazoacetate and terminal acetylenes using mixed-ligand complexes of the series Rh2(RCO2)n(L*4-n). Stereochemical heuristics for ligand exchange and catalyst synthesis

This paper describes the synthesis of mixed Rh(2)(II) complexes containing bridging acetate and R,R-diphenyl-N-triflylimidazolidinone (DPTI) ligands (1, 2, and 9-19), and their function as enantioselective catalysts for the conversion of ethyl diazoacetate and terminal acetylenes to chiral cyclopropenes. Of these catalysts, 1 and 10 functioned with the highest enantioselectivity, in accord with a mechanistic model in which one of the ligand bridges is broken in the intermediate Rh-carbene complex. The synthetic results allow conclusions with regard to kinetically and thermodynamically favored pathways for the synthesis of mixed acetate-DPTI complexes. A new C(2)-symmetric complex having only two anti-DTBTI bridges (23) is shown to be a highly effective chiral catalyst, as expected from the model.     

One-Pot Synthesis of Enantioenriched β-Amino Secondary Amides via an Enantioselective [4+2] Cycloaddition Reaction of Vinyl Azides with N-Acyl Imines Catalyzed by a Chiral Brønsted Acid

A catalytic enantioselective synthesis of β-amino secondary amides was achieved using vinyl azides as the enamine-type nucleophile and chiral N-Tf phosphoramide as the chiral Brønsted acid catalyst through a five-step sequential transformation in one pot. The established sequential transformation involves an enantioselective [4+2] cycloaddition reaction of vinyl azides with N-acyl imines as the key stereo-determining step that is efficiently accelerated by a chiral N-Tf phosphoramide catalyst in a highly enantioselective manner in most cases. Further generation of the iminodiazonium ion intermediate through ring opening of the cycloaddition product and subsequent skeletal rearrangement involving Schmidt-type 1,2-aryl group migration followed by recyclization of the resulting nitrilium ion were also initiated by the same acid catalyst. Final acid hydrolysis of the recyclized products in the same pot gave rise to enantioenriched β-amino amides through C−C bond formation at the α-position of the secondary amides.     

Asymmetric double ring-opening of a C(2h)-symmetric bis-epoxide: improved enantiomeric excess of the product through enantioselective desymmetrisation and 'proof-reading' steps

A new strategy in asymmetric synthesis is described in which the desymmetrisation of a C(2h)-symmetric molecule is followed by a subsequent enantioselective 'proof-reading' step. The double asymmetric ring-opening of the bis-epoxide (1R*,3R*,5S*,7S*)-4,8-dioxa-tricyclo[5.1.0.0(3,5)]octane with azidotrimethylsilane, catalysed by a chiral chromium Salen catalyst, was studied. The reaction involves the initial asymmetric ring-opening of the bis-epoxide to give the intermediate in moderate enantiomeric excess (ca. 50% ee); the second ring-opening step yields the required diazido diol, (1S,3S,4S,6S)-4,6-diazidocyclohexane-1,3-diol, in 72% yield and 70% ee. The origin of proof reading stems from the diversion of the minor enantiomer of the intermediate to a centrosymmetric by-product, a process which improves the enantiomeric excess of the required product. Using alternative conditions, the reaction was optimised to yield the required product in >98% ee.     

A Versatile Enantioselective Catalytic Cyclopropanation-Rearrangement Approach to the Divergent Construction of Chiral Spiroaminals and Fused Bicyclic Acetals

A highly enantioselective synthesis of various chiral heterobicyclic molecules including spiroaminals and fused bicyclic acetals has been developed via a chiral copper catalyzed cyclopropanation-rearrangement (CP-RA) approach under mild reaction conditions. Remarkably, the asymmetric CP-RA for exocyclic vinyl substrates without a pro-stereogenic carbon at the β-position has been realized for the first time and a broad substrate scope with excellent results (33 examples; 34–99 % yields; >95/5 dr and 91–99 % ee) has been achieved. An application of a successive enantioselective CP-RA approach was also described, providing a concise access to complex chiral heteropolycycles.     

Improved Chiral Synthesis of Ravuconazole

A short, elegant, and high yielding synthesis of ravoconazole is presented. The key step of this synthesis is an enantioselective palladium-catalyzed chiral zinc-allene addition reaction. The starting materials are 2-chloro-1-(2,4-difluorophenyl)-ethanone and (R)-4-phenylbutyn-2-ol obtained from enzymatic resolution of its racemate.     

Toward the enantioselective total synthesis of lyngbyatoxin A: on the stereocontrolled introduction of the quaternary stereogenic centre

This paper deals with an approach to the enantioselective total synthesis of Lyngbyatoxin A, with focus on the stereocontrolled introduction of the quaternary stereogenic centre. The key step in the synthesis involves an enantiospecific Lewis-acid mediated rearrangement of chiral vinyl epoxides carrying a 7-substituted indole moiety.     

Asymmetric Addition of Diethylzinc to Aldehydes Using SPINOL Derivatives

Lewis acid catalyzed enantioselective carbon-carbon bond formation is one of the most interesting challenges in catalytic asymmetric synthesis. A convenient route for this synthesis is the addition of organozinc to aldehydes.[1]1,1'-Spirobiindane-7,7'-diol (SPINOL), a new reported C2 symmetrical diol, was recently proven to be an excellent framework for chiral ligands.[2] In this paper, interestingly, we describe the preparation of SPINOL derivatives and application of these ligands to asymmetric addition of diethylzinc to aldehydes as model reaction. Previously, an improved method for the resolution of C2-symmetric spirocyclic SPINOL was presented with crude menthyl chloroformate as resolving reagent.[3] Then (R)-SPINOL with C2-symmetric spirocyclic framework was applied in the asymmetric diethylzinc addition to aromatic aldehydes, which induced high conversions and moderate enantioselectivities for the production of chiral secondary alcohols. Further work of other SPINOL derivative ligands for asymmetric diethylzinc addition to aromatic aldehydes and developing further new SPINOL-based Lewis acid catalyzed asymmetric synthesis are underway.     

Development of a new class of C1-symmetric bisphosphine ligands for rhodium-catalyzed asymmetric hydrogenation

A new class of C₁-symmetric bisphosphine ligands with three hindered quadrants have been obtained through facile synthesis from chiral BINOL derivatives. Their rhodium complexes have exhibited high enantioselectivities (up to 98% ee) in the asymmetric hydrogenation of various unsaturated prochiral olefins, providing an efficient catalytic system for the enantioselective synthesis of chiral amino acids and amines.     

Brønsted-acid and Brønsted-base catalyzed Diels-Alder reactions

The enantioselective Diels-Alder reaction is one of the most important reactions for the synthesis of complex molecules. It provides access to chiral six-membered carbocyclic compounds containing up to four stereogenic centers in a single step. Asymmetric catalysis in the Diels-Alder reaction has mainly been realized using chiral Lewis acids. In this perspective, we describe several cases of chiral Br?nsted-acid and Br?nsted-base catalyzed Diels-Alder reactions, providing an overview of this rapidly growing field.     

三氟甲基磺酸铜(II)手性衍生物:不对称合成中的一类高效催化剂

三氟甲基磺酸铜 [Cu(OTf) 2 ]与各种手性磷氮配体络合催化不对称合成已取得了巨大进展 .详细评述了近五年来该类手性铜催化剂在各种不对称催化反应中的最新应用     

Dynamic kinetic transformation of sulfinyl chlorides: synthesis of enantiomerically pure C(2)-symmetric bis-sulfoxides.

Two modular and highly convergent approaches for the synthesis of both isomers of a large number of optically pure C(2)-symmetric bis-sulfoxides have been developed, and their scope and limitations have been assessed. The first one uses as intermediate diastereomerically pure C(2)-symmetric bis-sulfinate esters 6(S(S),S(S)) and 6(R(S),R(S)), obtained by dynamic kinetic resolution of ethane-1,2-bis-sulfinyl chloride 5. A single inducer of chirality, the glucose-derived DAG (diacetone-D-glucose) 1 is used for the enantioselective synthesis of both diastereomerically pure C(2)-symmetric bis-sulfinate esters, thanks to the opposite stereodirecting effect of pyridine and (i)Pr(2)NEt used to catalyze the reaction. The second approach is based on the copper-catalyzed oxidative coupling of optically pure lithiomethyl sulfoxides. Both isomers of a large number of methyl sulfoxides can be obtained in a convergent manner using (R(S))- and (S(S))-DAG methanesulfinate esters 8R(S) and 8S(S). Methanesulfinates 8R(S) and 8S(S) are also obtained in an enantioselective way by a dynamic kinetic resolution of methane sulfinyl chloride 24. The final bis-sulfoxides are obtained with enhanced enantioselectivities compared to the corresponding monomers, as a result of the Horeau effect which is operating in both approaches. A model based on the formation of pentacoordinated sulfur intermediate is proposed. This model can explain the dynamic kinetic resolution observed via Berry pseudorotations, without the commonly accepted in situ racemization of the starting material. The usefulness of the approaches is demonstrated by the preparation of complexes of Pd(II) and Ru(II) bearing bidentated chiral sulfoxides as ligands.     

Enantioselective Synthesis of Piperidines through the Formation of Chiral Mixed Phosphoric Acid Acetals: Experimental and Theoretical Studies

An enantioselective intramolecular chiral phosphoric acid‐catalyzed cyclization of unsaturated acetals has been utilized for the synthesis of functionalized chiral piperidines. The chiral enol ether products of these cyclizations undergo subsequent in situ enantioenrichment through acetalization of the minor enantiomer. A new computational reaction exploration method was utilized to elucidate the mechanism and stereoselectivity of this transformation. Rather than confirming the originally postulated cyclization proceeding directly through a vinyl oxocarbenium ion, simulations identified an alternative two‐step mechanism involving the formation of a mixed chiral phosphate acetal, which undergoes a concerted, asynchronous S_N2′‐like displacement to yield the product with stereoselectivity in agreement with experimental observations.     

Enantioselective C?C and C?H Bond Formation Mediated or Catalyzed by Chiral ebthi Complexes of Titanium and Zirconium

The development of catalytic processes that effect enantioselective bond formation under mild conditions is an important and challenging task in modern chemical synthesis. In this connection, chiral C₂-symmetric ansa-metallocenes (bridged metallocenes) have found notable applications as catalysts. This article discusses the chemistry of this class of chiral metallocene complexes with regard to their utility in catalytic and enantioselective C? C and C? H bond formation reactions. In addition, where applicable, a brief comparison with other related catalytic enantioselective processes is offered. Many of the reactions effected with high levels of enantioselectivity by catalytic amounts of these complexes are of great significance to the preparation of new materials and in the synthesis of therapeutic agents. For example, zirconocene complexes readily catalyze the enantioselective addition of alkylmagnesium halides to alkenes, and cationic zirconocene complexes may promote the highly stereoregulated copolymerization of terminal alkenes. Furthermore, the related chiral titanocenes are involved in an impressive range of useful asymmetric catalytic reactions, including the enantioselective hydrogenation of olefins and reduction of imines or ketones. This review attempts to bring together the practical aspects of the use of [(ebthi)M] complexes of Group 4 transition metals (catalyst synthesis and resolution), outline the manner in which the C₂-symmetric chiral ligands are believed to initiate stereoselective bond formation, and highlight the aspects of this chemistry that are less well understood and require further research.     

A New Method of Resolution of Racemic 6,6''''-Dihydroxy-5,5''''- biquinoline Using (S)-( + )-Camphorsulfonyl Chloride

The chiral ligand bearing C2-symmetric binaphthyl backbonce (e. g. BINOL, BINAP) is one of the widely used chiral auxiliaries in catalytic asymmetric synthesis. [1] Numerous synthetic approaches to these two compounds have been developed. In contrast, the C2-symmetric ligands containing heterocyclic moiety has been relatively less explored.     

Efficient Synthesis of (−)‐Corynoline by Enantioselective Palladium‐Catalyzed α‐Arylation with Sterically Hindered Substrates

Sterically hindered substrates can be employed in an enantioselective palladium‐catalyzed α‐arylation with the chiral monophosphorus ligand BI‐DIME. This process enabled an efficient synthesis of the antidepressant (S)‐nafenodone, a four‐step enantioselective synthesis of the Sceletium alkaloid (+)‐sceletium A‐4, a concise five‐step enantioselective synthesis of (?)‐corynoline, as well as a three‐step preparation of (?)‐DeN‐corynoline.     

Taming Chiral Quaternary Stereocenters via Remote H-Bonding Stereoinduction in Palladium-Catalyzed (3+2) Cycloadditions

Ring-opening transformations of donor-acceptor (D-A) cyclopropanes enable the rapid assembly of complex molecules. However, the enantioselective formation of chiral quaternary stereocenters using substrates bearing two different acceptors remains a challenge. Herein, we describe the first palladium-catalyzed highly diastereo- and enantioselective (3+2) cycloaddition of vinyl cyclopropanes bearing two different electron-withdrawing groups, a subset of D-A cyclopropanes. The key to the success of this reaction is the remote stereoinduction through hydrogen bond from chiral ligands, which thereby addressed the aforementioned challenge. A variety of chiral five-membered heterocycles were produced in good yields and with high stereoselectivity (up to 99 % yields, 99 : 1 er and >19 : 1 dr). In-depth mechanistic investigations, including control experiments and theoretical calculations, revealed the origin of the stereoselectivity and the importance of H-bonding in stereocontrol.     

Lanthanum-Catalyzed Enantioselective Trifluoromethylation by Using an Electrophilic Hypervalent Iodine Reagent

A highly enantioselective catalytic method for the synthesis of quaternary α-trifluoromethyl derivatives of 3-oxo esters is described. The reaction uses lanthanum(III) triflate and chiral PyBOX-type C₂-symmetric ligands to generate intermediate La^III complexes that incorporate an enolate moiety of the starting 3-oxo ester and the trifluoromethylation transfer reagent. The enantioselectivity of the reaction stems from the efficient blockage of one of the prochiral faces of the La^III enolate by one unit of the C₂-symmetric ligand.     

Chiral N-heterocyclic carbenes as asymmetric acylation catalysts

Chiral N-heterocyclic carbenes are generated from C₂-symmetric 1,3-bis(1-arylethyl)imidazolium salts and potassium tert-butoxide. These C₂-symmetric imidazolidenyl carbenes catalyze enantioselective acylation of racemic secondary alcohols. The asymmetric acylation of 1-(1-naphthyl)ethanol was achieved in up to 68% ee of the acylated product, using (R,R)-1,3-bis[(1-naphthyl)ethyl]imidazolium tetrafluoroborate as a precursor of the chiral N-heterocyclic carbene and vinyl propionate as the acyl donor.     

D2-symmetric dirhodium catalyst derived from a 1,2,2-triarylcyclopropanecarboxylate ligand: design, synthesis and application

Dirhodium tetrakis-(R)-(1-(4-bromophenyl)-2,2-diphenylcyclopropanecarboxylate) (Rh(2)(R-BTPCP)(4)) was found to be an effective chiral catalyst for enantioselective reactions of aryl- and styryldiazoacetates. Highly enantioselective cyclopropanations, tandem cyclopropanation/Cope rearrangements and a combined C-H functionalization/Cope rearrangement were achieved using Rh(2)(R-BTPCP)(4) as catalyst. The advantages of Rh(2)(R-BTPCP)(4) include its ease of synthesis, its tolerance to the size of the ester group in the styryldiazoacetates, and its compatibility with dichloromethane as solvent. Computational studies suggest that the catalyst adopts a D(2)-symmetric arrangement, but when the carbenoid binds to the catalyst, two of the p-bromophenyl groups on the ligands rotate outward to make room for the carbenoid and the approach of the substrate to the carbenoid.