Highly enantioselective reaction of alpha-selenoorganolithium compounds with chiral bis(oxazoline)s and preparation of enantioenriched benzylidencyclohexanes

The enantioselective reaction of alpha-seleno carbanions derived from bis(phenylseleno)acetal and bis(2-pyridylseleno)acetal in the presence of bis(oxazoline)s with various electrophiles gave products with high enantioselectivity. The enantioselective reaction of alpha-lithio benzyl 2-pyridyl selenide gave the products with stereochemistry reverse to that obtained in the reaction of alpha-lithio benzyl phenyl selenide. Mechanistic investigation suggests the enantiodetermination of these reactions at -78 degrees C depends on dynamic thermodynamic resolution. The enantioselective reaction was applied to the preparation of enantioenriched olefins and epoxide.     

Enantioselective organocatalytic three-component Petasis reaction among salicylaldehydes, amines, and organoboronic acids

The catalytic enantioselective three-component Petasis reaction among salicylaldehydes, amines, and organoboronic acids with a newly designed thiourea-binol catalyst is presented. A broad range of alkylaminophenols can be obtained in good yield (up to 92%) and good to high enantioselectivity (up to 95% ee). A possible reaction pathway for this catalytic enantioselective Petasis reaction is tentatively proposed.     

Acid-base catalysis of chiral Pd complexes: development of novel catalytic asymmetric reactions and their application to synthesis of drug candidates

Using the unique character of the chiral Pd complexes 1 and 2, highly efficient catalytic asymmetric reactions have been developed. In contrast to conventional Pd(0)-catalyzed reactions, these complexes function as an acid-base catalyst. Thus active methine and methylene compounds were activated to form chiral palladium enolates, which underwent enantioselective carbon-carbon bond-forming reactions such as Michael reaction and Mannich-type reaction with up to 99% ee. Interestingly, these palladium enolates acted cooperatively with a strong protic acid, formed concomitantly during the formation of the enolates to activate electrophiles, thereby promoting the C-C bond-forming reaction. This palladium enolate chemistry was also applicable to electrophilic enantioselective fluorination reactions, and various carbonyl compounds including beta-ketoesters, beta-ketophosphonates, tert-butoxycarbonyl lactone/lactams, cyanoesters, and oxindole derivatives could be fluorinated in a highly enantioselective manner (up to 99% ee). Using this method, the catalytic enantioselective synthesis of BMS-204352, a promising anti-stroke agent, was achieved. In addition, the direct enantioselective conjugate addition of aromatic and aliphatic amines to alpha,beta-unsaturated carbonyl compound was successfully demonstrated. In this reaction, combined use of the Pd complex 2 having basic character and the amine salt was the key to success, allowing controlled generation of the nucleophilic free amine. This aza-Michael reaction was successfully applied to asymmetric synthesis of the CETP inhibitor torcetrapib.     

Enantioselective and Regiodivergent Functionalization of N‐Allylcarbamates by Mechanistically Divergent Multicatalysis

A pair of mechanistically divergent multicatalytic reaction sequences has been developed consisting of nickel‐catalyzed isomerization of N‐allylcarbamates and subsequent phosphoric‐acid‐catalyzed enantioselective functionalization of the resulting intermediates. By appropriate selection of reaction partners, in situ generated imines and ene‐carbamates are mechanistically partitioned to yield opposing functionalized products. Formal α‐functionalization to give protected α‐arylamines is achieved upon enantioselective Friedel–Crafts reaction with arene nucleophiles, whereas formal β‐functionalization is achieved upon reaction with diarylimine electrophiles in an enantioselective Povarov‐[4+2] cycloaddition.     

One‐Pot Organocatalytic Asymmetric Synthesis of 3‐Nitro‐1,2‐dihydroquinolines by a Dual‐Activation Protocol

Generally, amine‐catalyzed enantioselective transformations rely on chiral enamine or unsaturated iminium intermediates. Herein, we report a protocol involving dual activation by an aromatic iminium and hydrogen‐bonding. An enantioselective aza‐Michael–Henry domino reaction of 2‐aminobenzaldehydes with nitroolefins has been developed through this protocol using primary amine thiourea catalysts to provide a variety of 3‐nitro‐1,2‐dihydroquinolines in moderate yields and with up to 90 % ee. The mechanism for the catalytic enantioselective reaction was confirmed by ESI mass spectrometric detection of the reaction intermediates. The products formed are substructures found in skeletons of important biological and pharmaceutical molecules.     

Direct enantioselective aldol-Tishchenko reaction catalyzed by chiral lithium diphenylbinaphtholate

Chiral lithium diphenylbinaphtholate is an effective catalyst for the enantioselective aldol-Tishchenko reaction, affording 1,3-diol derivatives with three contiguous chiral centers and high stereoselectivities. Successive aldol-aldol-Tishchenko reactions gave a triol derivative with five consecutive chiral centers. The present reaction was applicable to highly enantioselective Evans-Tishchenko reduction.     

Enantioselective hydrolysis of N-acylated alpha-amino esters at a biphasic interface: tandem reaction kinetic resolution using a chiral complexing agent

[reaction: see text] Highly enantioselective hydrolytic kinetic resolutions of esters derived from N-acylated alpha-amino acids proceed rapidly at hydrocarbon/water interfaces in the presence of a proline-derived chiral selector. When performed in tandem with an enantioselective biphasic esterification reaction, esters of 100% enantiomeric excess are obtained     

An effective enantioselective approach to the securinega alkaloids: total synthesis of (-)-norsecurinine

[reaction: see text] A highly versatile approach to the enantioselective synthesis of securinega alkaloids is presented. Crucial steps are a palladium-catalyzed enantioselective imide alkylation, a vinylogous Mannich reaction, and a ring-closing metathesis process. Through this strategy, the synthesis of (-)-norsecurinine has been accomplished in nine steps and 11% overall yield.     

Asymmetric Morita-Baylis-Hillman reactions catalyzed by chiral Brønsted acids

Chiral BINOL-derived Br?nsted acids catalyze the enantioselective asymmetric Morita-Baylis-Hillman (MBH) reaction of cyclohexenone with aldehydes. The asymmetric MBH reaction requires 2-20 mol % of the chiral Br?nsted acid 2e or 2f and triethylphosphine as the nucleophilic promoter. The reaction products are obtained in good yields (39-88%) and high enantioselectivities (67-96% ee). The Br?nsted-acid-catalyzed reaction is the first example of a highly enantioselective asymmetric MBH reaction of cyclohexenone with aldehydes.     

Copper-catalyzed enantioselective Henry reactions of alpha-keto esters: an easy entry to optically active beta-nitro-alpha-hydroxy esters and beta-amino-alpha-hydroxy esters

The catalytic enantioselective Henry reaction of alpha-keto esters with nitromethane has been developed. The reaction conditions have been optimized by the screening of different chiral Lewis acids, solvents, and bases, and it was found that the copper(II)-tert-butyl bisoxazoline complex in combination with triethylamine catalyzed a highly enantioselective reaction giving optically active beta-nitro-alpha-hydroxy esters in high yields and with excellent enantiomeric excesses. The scope of the reaction is demonstrated by the reaction of a variety of different alpha-keto esters. The catalytic enantioselective Henry reaction of beta,gamma-unsaturated-alpha-keto esters proceeds as a 1,2-addition reaction exclusively, in contrast to the uncatalyzed reaction where both the 1,2- and 1,4-addition products are formed. It is demonstrated that the beta-nitro-alpha-hydroxy esters can be converted into, e.g., Boc-protected beta-amino-alpha-hydroxy esters in high yields and without loss of optical purity. The mechanism for the reaction is discussed, and it is postulated that both the alpha-keto ester and nitromethane/nitronate is coordinated to the metal center during the reaction course.     

Enantioselective organocatalytic intramolecular Diels-Alder reactions. The asymmetric synthesis of solanapyrone D

The first direct enantioselective organocatalytic intramolecular Diels-Alder reaction has been accomplished. The use of iminium catalysis has provided a new catalytic strategy for the enantioselective [4 + 2] cycloisomerization of a wide variety of tethered diene-enal systems. The use of imidazolidinones 1 and 2 as the asymmetric catalysts has been found to mediate the enantioselective construction of [4.4.0] and [4.3.0] ring systems. Application of this methodology to the highly efficient asymmetric synthesis of the marine metabolite solanpyrone D has also been accomplished. A diverse spectrum of aldehyde substrates can also be accommodated in this new organocatalytic transformation. Importantly, this technology has been utilized to execute the first enantioselective, catalytic Type II IMDA reaction.     

Enantioselective formal synthesis of (−)-aurantioclavine using Pd-catalyzed cascade cyclization and organocatalytic asymmetric aziridination

The enantioselective formal synthesis of (?)-aurantioclavine is described. The core tricyclic skeleton was synthesized using a Pd-catalyzed Heck insertion–allylic amination cascade. The stereocenter was constructed by a highly enantioselective organocatalytic asymmetric aziridination reaction.     

Chiral N,N Ligands Enabling Palladium‐Catalyzed Enantioselective Intramolecular Heck–Matsuda Carbonylation Reactions by Sequential Migratory and CO Insertions

Unprecedented enantioselective intramolecular Heck carbonylation reactions of arenediazonium salts were enabled by a chiral N,N ligand. This reaction constitutes the first enantioselective Heck carbonylation that proceeds through migratory insertion followed by CO insertion. The enantioenriched functionalized dihydrobenzofurans were obtained in good to high yields and enantiomeric ratios of up to 98:2 under mild and operationally simple reaction conditions.     

Exploiting C3-symmetry in the dynamic coordination of a chiral trisoxazoline to copper(II): improved enantioselectivity, and catalyst stability in asymmetric lewis acid catalysis

Chiral C3-symmetric trisoxazolines are highly efficient stereodirecting ligands in enantioselective Cu(II) Lewis acid catalysis which is based on the concept of a stereoelectronic hemilability of the divalent copper; in direct comparison with the analogous bisoxazoline systems they are more efficient in the enantioselective alpha-amination as well as the enantioselective Mannich reaction of prochiral beta-ketoesters.     

Enantioselective Synthesis of Chiral Amides by a Phosphoric Acid Catalyzed Asymmetric Wolff Rearrangement**

The enantioselective addition of potent nucleophiles to ketenes poses challenges due to competing background reactions and poor stereocontrol. Herein, we present a method for enantioselective phosphoric acid catalyzed amination of ketenes generated from α-aryl-α-diazoketones. Upon exposure to visible light, the diazoketones undergo Wolff rearrangement to generate ketenes. The phosphoric acid not only accelerates ketene capture by amines to form a single configuration of aminoenol intermediates but also promotes an enantioselective proton-transfer reaction of the intermediates to yield the products. Mechanistic studies elucidated the reaction pathway and explained how the catalyst expedited the transformation and controlled the enantioselectivity.     

Catalytic Enantioselective Synthesis of C1‐ and C2‐Symmetric Spirobiindanones through Counterion‐Directed Enolate C‐Acylation

A catalytic enantioselective route to C₁‐ and C₂‐symmetric 2,2′‐spirobiindanones has been realized through an intramolecular enolate C‐acylation. This reaction employs a chiral ammonium counterion to direct the acylation of an in situ generated ketone enolate with a pentafluorophenyl ester. This reaction constitutes the first example of a direct catalytic enantioselective C‐acylation of a ketone and provides an efficient and highly enantioselective route to axially chiral spirobiindanediones. These products can be diastereoselectively derivatized, offering access to a range of functionalized spirocyclic architectures.     

Synthetic studies on cyathins: enantioselective total synthesis of (+)-allocyathin B2

[reaction: see text] The enantioselective total synthesis of (+)-allocyathin B(2) has been achieved. Our approach features a convergent enantioselective construction of the 5-6-7 tricyclic core system using the originally developed chiral building blocks via asymmetric catalysis, the intramolecular aldol reaction in high yield, successful samarium diiodide-mediated ring expansion, and a newly developed double-bond installation method.     

Catalytic asymmetric cyanosilylation of ketones with chiral Lewis base

The development of broadly applicable and practical catalytic approaches for the enantioselective creation of quaternary stereocenters remains a highly desirable yet challenging goal. In this Communication, we describe a highly enantioselective cyanosilylation of acetal ketones (alpha,alpha-dialkoxy ketones) catalyzed by modified cinchona alkaloids. This reaction is the first highly enantioselective cyanosilylation of ketones catalyzed by an organic chiral Lewis base and is found to be highly efficient with acetal ketones bearing a broad range of alkyl, aryl, alkenyl, and alkynyl substituents. This new catalytic asymmetric reaction, coupled with the versatility of the acetal functionality, provides a broadly useful synthetic method for chiral building blocks bearing quaternary stereocenters. Acetal ketones, readily accessible but previously unexplored in asymmetric synthesis, demonstrate unusual reactivity and selectivity toward the nucleophilic cyanosilylation, thereby suggesting that they may be interesting substrates for other catalytic enantioselective reactions.     

Asymmetric Mannich reactions with in situ generation of carbamate-protected imines by an organic catalyst

The instability of carbamate-protected alkyl imines has greatly hampered the development of catalytic asymmetric Mannich reactions suitable for the synthesis of optically active carbamate-protected chiral alkyl amines. A highly enantioselective Mannich reaction with in situ generation of carbamate-protected imines from stable alpha-amido sulfones catalyzed by an organic catalyst was developed. This reaction provides a concise and highly enantioselective route converting aromatic and aliphatic aldehydes into optically active aryl and alkyl beta-amino acids. [reaction: see text].     

Mechanistic aspects of alkene oxidation using chiral hypervalent iodine reagents

Recent progress in the area of hypervalent iodine-induced enantioselective oxidation is reviewed with emphasis from a mechanistic point of view. Chiral lactate and lactamide sidechains in hypervalent iodine reagents induce herical chirality around the iodine reaction site, which provides a chiral environment suitable for enantioselective transformations. The stereochemical outcomes of alkene oxidation are also compiled and used for systematically understanding the reaction mechanism of oxidative double bond difunctionalization.