Catalytic Asymmetric Synthesis of 3,3′‐Diaryloxindoles as Triarylmethanes with a Chiral All‐Carbon Quaternary Center: Phase‐Transfer‐Catalyzed SNAr Reaction

Catalytic asymmetric synthesis of unsymmetrical triarylmethanes with a chiral all‐carbon quaternary center was achieved by using a chiral bifunctional quaternary phosphonium bromide catalyst in the S_NAr reaction of 3‐aryloxindoles under phase‐transfer conditions. The presence of a urea moiety in the chiral phase‐transfer catalyst was important for obtaining high enantioselectivity in this reaction.     

Versatile In Situ Generated N‐Boc‐Imines: Application to Phase‐Transfer‐Catalyzed Asymmetric Mannich‐Type Reactions

The efficient construction of nitrogen‐containing organic compounds is a major challenge in chemical synthesis. Imines are one of the most important classes of electrophiles for this transformation. However, both the available imines and applicable nucleophiles for them are quite limited given the existing preparative methods. Described herein are imine precursors which generate reactive imines with a wide variety of substituents under mild basic conditions. This approach enables the construction of various nitrogen‐containing molecules which cannot be accessed by the traditional approach. The utility of the novel imine precursor was demonstrated in the asymmetric Mannich‐type reaction under phase‐transfer conditions.     

Phase‐Transfer‐Catalyzed Asymmetric Synthesis of Axially Chiral Anilides

Catalytic asymmetric synthesis of axially chiral o‐iodoanilides and o‐tert‐butylanilides as useful chiral building blocks was achieved by means of binaphthyl‐modified chiral quaternary ammonium‐salt‐catalyzed N‐alkylations under phase‐transfer conditions. The synthetic utility of axially chiral products was demonstrated in various transformations. For example, axially chiral N‐allyl‐o‐iodoanilide was transformed to 3‐methylindoline by means of radical cyclization with high chirality transfer from axial chirality to C‐centered chirality. Furthermore, stereochemical information on axial chirality in o‐tert‐butylanilides could be used as a template to control the stereochemistry of subsequent transformations. The transition‐state structure of the present phase‐transfer reaction was discussed on the basis of the X‐ray crystal structure of ammonium anilide, which was prepared from binaphthyl‐modified chiral ammonium bromide and o‐iodoanilide. The chiral tetraalkylammonium bromide as a phase‐transfer catalyst recognized the steric difference between the ortho substituents on anilide to obtain high enantioselectivity. The size and structural effects of the ortho substituents on anilide were investigated, and a wide variety of axially chiral anilides that possess various functional groups could be synthesized with high enantioselectivities. This method is the only general way to access a variety of axially chiral anilides in a highly enantioselective fashion reported to date.     

Diphenylprolinol Silyl Ether as a Catalyst in an Enantioselective,Catalytic Michael Reaction for the Formation of α,α‐Disubstituted α‐Amino Acid Derivatives

Direct and enantioselective : Diphenylprolinol silyl ether was found to catalyze the direct, asymmetric Michael reaction of 4‐substituted 2‐aryl‐2‐oxazoline‐5‐one and α,β‐unsaturated aldehydes, affording the chiral α,α‐disubstituted α‐amino acid derivatives with excellent enantioselectivity.

     

Preparation of Chiral Amino Esters by Asymmetric Phase‐Transfer Catalyzed Alkylations of Schiff Bases in a Ball Mill

The asymmetric alkylation of Schiff bases under basic conditions in a ball mill was performed. The starting Schiff bases of glycine were prepared beforehand by milling protected glycine hydrochloride and benzophenone imine, in the absence of solvent. The Schiff base was then reacted with a halogenated derivative in a ball mill in the presence of KOH. By adding a chiral ammonium salt derived from cinchonidine, the reaction proceeded asymmetrically under phase‐transfer catalysis conditions, giving excellent yields and enantiomeric excesses up to 75 %. Because an equimolar amount of starting material was used, purification was greatly simplified.     

Pseudoephedrine‐Directed Asymmetric α‐Arylation of α‐Amino Acid Derivatives

Available α‐amino acids undergo arylation at their α position in an enantioselective manner on treatment with base of N′‐aryl urea derivatives ligated to pseudoephedrine as a chiral auxiliary. In situ silylation and enolization induces diastereoselective migration of the N′‐aryl group to the α position of the amino acid, followed by ring closure to a hydantoin with concomitant explulsion of the recyclable auxiliary. The hydrolysis of the hydantoin products provides derivatives of quaternary amino acids. The arylation avoids the use of heavy‐metal additives, and is successful with a range of amino acids and with aryl rings of varying electronic character.     

Efficient Synthesis of β‐Hydroxy‐α‐Amino Acid Derivatives via Direct Catalytic Asymmetric Aldol Reaction of α‐Isothiocyanato Imide with Aldehydes

An easily available and efficient chiral N,N′‐dioxide–nickel(II) complex catalyst has been developed for the direct catalytic asymmetric aldol reaction of α‐isothiocyanato imide with aldehydes which produces the products in morderate to high yields (up to 98 %) with excellent diastereo‐ (up to >99:1 d.r.) and enantioselectivities (up to >99 % ee). A variety of aromatic, heteroaromatic, α,β‐unsaturated, and aliphatic aldehydes were found to be suitable substrates in the presence of 2.5 mol % L ‐proline‐derived N,N′‐dioxide L5 –nickel(II) complex. This process was air‐tolerant and easily manipulated with available reagents. Based on experimental investigations, a possible transition state has been proposed to explain the origin of reactivity and asymmetric inductivity.     

Catalytic Enantioselective Synthesis of N,Cα,Cα‐Trisubstituted α‐Amino Acid Derivatives Using 1H‐Imidazol‐4(5H)‐ones as Key Templates

1H‐Imidazol‐4(5H)‐ones are introduced as novel nucleophilic α‐amino acid equivalents in asymmetric synthesis. These compounds not only allow highly efficient construction of tetrasubstituted stereogenic centers, but unlike hitherto known templates, provide direct access to N‐substituted (alkyl, allyl, aryl) α‐amino acid derivatives.     

A Base‐Free Neutral Phase‐Transfer Reaction System

Although phase‐transfer reactions catalyzed by using quaternary ammonium salts are generally believed to require base additives, we discovered that, even without any base additives, conjugate additions of 3‐substituted oxindoles to nitroolefins proceeded smoothly in the presence of lipophilic quaternary ammonium bromide under water–organic biphasic conditions. The mechanism of this novel base‐free neutral phase‐transfer reaction system is investigated and the assumed catalytic cycle is presented together with interesting effects of water and lipophilicity of the phase‐transfer catalyst. The base‐free neutral phase‐transfer reaction system can be applied to highly enantioselective conjugate addition and aldol reactions under the influence of chiral bifunctional ammonium bromides as key catalysts. The structure of the chiral ammonium enolate intermediate is discussed based on the single‐crystal X‐ray structures of relevant ammonium salts and the importance of bifunctional design of catalyst is clearly explained in the model of intermediate.     

Recent Developments in Asymmetric Phase‐Transfer Reactions

Phase‐transfer catalysis has been recognized as a powerful method for establishing practical protocols for organic synthesis, because it offers several advantages, such as operational simplicity, mild reaction conditions, suitability for large‐scale synthesis, and the environmentally benign nature of the reaction system. Since the pioneering studies on highly enantioselective alkylations promoted by chiral phase‐transfer catalysts, this research field has served as an attractive area for the pursuit of “green” sustainable chemistry. A wide variety of asymmetric transformations catalyzed by chiral onium salts and crown ethers have been developed for the synthesis of valuable organic compounds in the past several decades, especially in recent years.     

Catalytic Asymmetric Phase‐Transfer Michael Reaction and Mannich‐Type Reaction of Glycine Schiff Bases with Tartrate‐Derived Diammonium Salts

Catalytic asymmetric Michael and Mannich‐type reactions of glycine Schiff bases with chiral two‐center organocatalysts, tartrate‐derived diammonium salts (TaDiASs), are described. On the basis of conformational studies, optimized TaDiASs with a 2,6‐disubstituted cyclohexane spiroacetal were newly designed. These TaDiASs catalyzed the asymmetric Michael and Mannich‐type reactions of glycine Schiff bases with higher enantioselectivity than previous catalysts. In the Mannich‐type reaction, aromatic N‐Boc‐protected imines (Boc=tert‐butoxycarbonyl) as well as enolizable alkyl imines were applicable. As a synthetic application of the catalytic asymmetric Mannich‐type reaction with the optimized TaDiASs, we developed a catalytic asymmetric total synthesis of (+)‐nemonapride, which is an antipsychotic agent.     

Bifunctional Guanidine via an Amino Amide Skeleton for Asymmetric Michael Reactions of β‐Ketoesters with Nitroolefins: A Concise Synthesis of Bicyclic β‐Amino Acids

Two activations are better than one : The chiral bifunctional guanidine 1 , which features an amino amide backbone, catalyzes the asymmetric Michael addition of a range of substrates and gives products with excellent stereoselectivities. The method also allows the efficient synthesis of optically pure β‐amino acid esters. Both the guanidine group and the NH proton of the amide were important for the dual activation.

     

Asymmetric Fluorinative Dearomatization of Tryptophol Derivatives by Chiral Anion Phase‐Transfer Catalysis

An asymmetric fluorinative dearomatization reaction of tryptophol derivatives was developed via chiral anion phase‐transfer catalysis. Various fluorinated furoindolines were obtained in moderate to excellent yields and enantioselectivity in the presence of Selectfluor. The preliminary mechanistic studies suggested the existence of an in situ formed tryptophol boronic ester plays a critical role in determining the enantioselectivity. This method features the facile introduction of a fluorine atom in a highly enantioselective manner and construction of two contiguous quaternary stereogenic centers.     

Catalytic Asymmetric 1,2‐Addition of α‐Isothiocyanato Phosphonates: Synthesis of Chiral β‐Hydroxy‐ or β‐Amino‐Substituted α‐Amino Phosphonic Acid Derivatives

α‐Amino phosphonic acid derivatives are considered to be the most important structural analogues of α‐amino acids and have a very wide range of applications. However, approaches for the catalytic asymmetric synthesis of such useful compounds are very limited. In this work, simple, efficient, and versatile organocatalytic asymmetric 1,2‐addition reactions of α‐isothiocyanato phosphonate were developed. Through these processes, derivatives of β‐hydroxy‐α‐amino phosphonic acid and α,β‐diamino phosphonic acid, as well as highly functionalized phosphonate‐substituted spirooxindole, can be efficiently constructed (up to 99 % yield, d.r. >20:1, and >99 % ee). This novel method provides a new route for the enantioselective functionalization of α‐phosphonic acid derivatives.