N-Fluoro Ammonium Salts of Cinchona Alkaloids in Enantioselective Electrophilic Fluorination

From 2000, our two research groups independently and simultaneously designed and developed a novel family of electrophilic fluorinating reagents based on the use of Cinchona alkaloids. The chiral N-fluoro ammonium salts demonstrated the highest efficiency compared to prior art in enantioselective electrophilic fluorination for a wide range of substrates. In this account, we tell our respective stories, how the same idea germinated in our laboratories, the characterization of the chiral reagents, the use in stoichiometric quantity then the development of a catalytic version, the application to the synthesis of chiral fluorinated molecules of pharmaceutical interest, and finally the exploitation of our reagents by other teams and for other applications.     

An efficient catalytic enantioselective fluorination of β-ketophosphonates using chiral palladium complexes

On the basis of our Pd enolate chemistry, we have succeeded in developing an efficient catalytic enantioselective fluorination of β-ketophosphonates. In the presence of chiral Pd complexes 1 (1-10 mol %), various substrates including cyclic and acyclic β-ketophosphonates underwent the reaction with N-fluorobenzenesulfonimide (NFSI) in EtOH to give the corresponding fluorinated products in a highly enantioselective manner (94-98% ee).     

Formation of Chiral Structures in UV-Initiated Formose Reaction

It has been found that the UV-initiated formose reaction in an extremely concentrated aqueous solution of formaldehyde gives sugars and other biologically significant chiral compounds with sp³-hybridized carbon atom. The reaction leads to an optically active condensed phase, which is a result of the spontaneous spatial separation of enantiomers in the racemate into the antipodes, similarly to the separation of enantiomers of different chirality sign in the famous Pasteur experiments. In our opinion, such a scenario is as close as possible to the actually realized de novo scenario of synthesis of chiral prebiotic molecules and matrices.     

Synthesis of Chiral Aminocyclopropanes by Rare‐Earth‐Metal‐Catalyzed Cyclopropene Hydroamination

The search for efficient and selective routes for the synthesis of chiral aminocyclopropane derivatives is of great interest and importance as these structures are important components of biologically active natural products and pharmaceuticals. We herein report the enantioselective intermolecular hydroamination of substituted cyclopropenes with various amines catalyzed by chiral half‐sandwich rare‐earth‐metal complexes. This method constitutes a 100 % atom‐efficient route for the synthesis of a variety of chiral α‐aminocyclopropane derivatives in high yields (up to 96 %) and excellent stereoselectivity (up to >20:1 d.r. and 99 % ee) under mild reaction conditions (25 °C).     

4-Alkyl-6-amino-N 3,N 5-diaryl-2-thioxo-1,2,3,4-tetrahydropyridine-3,5-dicarboxamides: II. Synthesis and selected reactions

New 4-alkyl-6-amino-N ³,N ⁵-diaryl-2-thioxo-1,2,3,4-tetrahydropyridine-3,5-dicarboxamides have been prepared via enantioselective reaction of 3-amino-N-aryl-3-thioxopropanamides with N-aryl-2-cyanoacetamide and aliphatic aldehydes. The prepared products can be regioselectively alkylated at sulfur atom.     

Cu-Catalyzed Asymmetric Kinetic Boron Conjugate Addition of γ-Substituted α,β-Unsaturated γ-Lactams

Chiral α,β-unsaturated γ-lactams bearing simple γ- substituents are found in biologically active molecules and natural products, however, their synthesis still remains difficult. Herein, we report an efficient kinetic resolution (KR) of γ-substituted α,β-unsaturated γ-lactams via a Cu-catalyzed asymmetric boron conjugate addition, which also leads to the efficient synthesis of chiral β-hydroxy-γ-lactams with β,γ-stereogenic carbon centers. The KR proceeded smoothly with a wide range of γ-alkyl or aryl substituted substrates including those bearing aromatic heterocycles and different N-protected substrates in up to 347 of s value. Their highly versatile transformations, synthetic utility in biologically active molecules, and inhibitory activities against cisplatin-sensitive ovarian cancer cell A2780 have also been demonstrated. Differing from the well-known mechanism involving Cu−B species in Cu-catalyzed boron conjugate additions, our mechanistic studies using density functional theory (DFT) calculations and experiments indicate that a Lewis acid Cu^I-catalyzed mechanism is the likely pathway in the catalytic reaction.     

对映选择性亲电氟化反应研究进展

含氟有机化合物, 特别是手性氟化物在医药、农药及功能性材料等相关领域的作用备受注目. 尽管在分子中有立体选择性地引入一个氟原子一直是有机化学家面临的一个挑战性问题, 近年来在化学家们的不断努力下, 对映选择性氟化反应研究取得重要进展. 高光学活性的手性氟化物可通过手性亲电氟化试剂诱导的立体选择性氟化反应, 基于底物的手性氟化反应以及手性催化剂诱导的不对称催化氟化反应等来制备. 特别是, 手性金属配合物和有机催化剂诱导的不对称催化氟化反应被广泛应用于各类手性氟化物的合成, 已成为不对称氟化反应研究的热点. 全面介绍对映选择性亲电氟化反应研究概况和最新进展, 讨论各种不对称氟化反应的特点及应用范围.     

Enantio‐ and Site‐Selective α‐Fluorination of N‐Acyl 3,5‐Dimethylpyrazoles Catalyzed by Chiral π–CuII Complexes

Catalytic enantioselective α‐fluorination reactions of carbonyl compounds are among the most powerful and efficient synthetic methods for constructing optically active α‐fluorinated carbonyl compounds. Nevertheless, α‐fluorination of α‐nonbranched carboxylic acid derivatives is still a big challenge because of relatively high pK_a values of their α‐hydrogen atoms and difficulty of subsequent synthetic transformation without epimerization. Herein we show that chiral copper(II) complexes of 3‐(2‐naphthyl)‐l ‐alanine‐derived amides are highly effective catalysts for the enantio‐ and site‐selective α‐fluorination of N‐(α‐arylacetyl) and N‐(α‐alkylacetyl) 3,5‐dimethylpyrazoles. The substrate scope of the transformation is very broad (25 examples including a quaternary α‐fluorinated α‐amino acid derivative). α‐Fluorinated products were converted into the corresponding esters, secondary amides, tertiary amides, ketones, and alcohols with almost no epimerization in high yield.     

Catalytic enantioselective fluorination of α-cyano acetates catalyzed by chiral palladium complexes

The catalytic enantioselective electrophilic fluorination promoted chiral palladium complexes is described. Treatment of α-cyano acetates with N-fluorobenzenesulfonimide as the fluorine source under mild reaction conditions afforded the corresponding α-cyano α-fluoro acetates in high yields with excellent enantiomeric excesses (85-99% ee).     

推-拉电子体系环丙烷的不对称合成及其对映选择性开环/环化反应研究进展

含有推-拉电子(DA)体系的张力环化合物,例如DA环丙烷,是非常有用的合成砌块,被应用于天然产物全合成以及合成具有生物活性的分子的研究中。 近年来,本课题组利用手性铜、镍等配合物为催化剂,一方面发展了一系列高效合成手性DA环丙烷的新方法;另一方面陆续实现了仲胺、醇、硝酮、氮杂亚胺叶立德、烯醇硅醚、吲哚等多种亲核试剂与DA环丙烷的高对映选择性开环/环化反应。 本文结合我们课题组工作综述了DA环丙烷化合物的不对称合成、开环/环化反应以及动力学拆分方面的主要研究进展并进行了展望。     

Catalytic enantioselective fluorination of oxindoles

We have developed a highly efficient catalytic enantioselective fluorination of oxindole derivatives. In the presence of a catalytic amount of chiral Pd complex 2 (2.5 mol %), various substrates, including aryl- and alkyl-substituted oxindoles, were fluorinated in a highly enantioselective manner (up to 96% ee). In addition, when R was a hydrogen atom, enantioselective fluorination followed by solvolysis gave a monofluorinated ester with up to 93% ee. To our knowledge, this is the first example of catalytic enantioselective fluorination of oxindoles.     

A chiral pool approach for asymmetric syntheses of both antipodes of equol and sativan

For the first time, both antipodes of the isoflavans, equol and sativan were synthesized in >98% ee with good overall yields starting from readily available starting materials. The chiral isoflavan, (?)-equol is produced from soy isoflavones, formonentin and daidzein by the action of intestinal bacteria in certain groups of population and other chiral isoflavans are reported from various phytochemical sources. To produce these chiral isoflavans in gram quantities, Evans' enantioselective aldol condensation was used as a chiral-inducing step to introduce the required chirality at the C-3 position. Addition of chiral boron-enolate to substituted benzaldehyde resulted in functionalized syn-aldol products with >90% yield and excellent diastereoselectivity. Functional group transformations followed by intramolecular Mitsunobu reaction and deprotection steps resulted the target compounds, S-(?)-equol and S-(+)-sativan, with high degree of enantiopurity. By simply switching the chiral auxiliary to (S)-4-benzyloxazolidin-2-one and following the same synthetic sequence the antipodes, R-(+)-equol and R-(?)-sativan were achieved. Both enantiomers are of interest from a clinical and pharmacological perspective and are currently being developed as nutraceutical and pharmacological agents. This flexible synthetic process lends itself quite readily to the enantioselective syntheses of other biologically active C-3 chiral isoflavans.     

Diastereoselective and Enantioselective Synthesis of Multi-Functionalized Isoxazoline-N-Oxides through Asymmetric [4+1] Annulations

A diastereoselective and enantioselective formal [4+1] ylide annulation of chiral sulfonium salts with various substituted Morita-Baylis-Hillman (MBH) adducts leading to optically active isoxazoline N-oxides with three chiral carbon centers has been explored. The salient features of this methodology include a high diastereo- and enantioselective transformation, easily accessible starting materials, and mild reaction conditions. In addition, the isoxazoline N-oxides products can be conveniently transformed into functionalized compounds.     

Synthesis of novel well-defined chain-end-functionalized polystyrenes with dendritic chiral ephedrine moieties and their applications as highly enantioselective diethylzinc addition to N-diphenylphosphinoyl arylimines

A series of novel well-defined chain-end-functionalized polystyrenes having 2, 4, 8, and 16 chiral ephedrine moieties dendritically distributed at their hyperbranched chain-ends were quantitatively synthesized. Their well-defined architectures were fully confirmed by elemental analysis, FTIR, SEC as well as by ¹H and ¹³C NMR spectroscopies. These polymers were precisely controlled in the molecular weight and molecular weight distribution as well as well-defined in chain-end-functionalities. These dendritic chiral polymers serve as highly enantioselective chiral ligands in the enantioselective addition of diethylzinc to a series of N-diphenylphosphinoyl arylimines. Among them, chiral dendrimer having eight ephedrine moieties at the chain-ends afforded the corresponding enantiomerically enriched phosphinoylamides in good to high yields with enantioselectivities up to 93% ee. The obtained enantioselectivities are comparable with those obtained by using N-benzylephedrine and its corresponding copolymer as chiral ligands.     

Chiral Brønsted Acid Catalyzed Enantioconvergent Propargylic Substitution Reaction of Racemic Secondary Propargylic Alcohols with Thiols

Despite the significant progress of the enantioselective reaction using chiral catalysts, the enantioselective nucleophilic substitution reaction at the chiral sp³-hybridized carbon atom of a racemic electrophile has not been largely explored. Herein, we report the enantioconvergent propargylic substitution reaction of racemic propargylic alcohols with thiols using chiral bis-phosphoric acid as the chiral Brønsted acid catalyst. The substitution products were formed in high yields with high enantioselectivities in most cases. The cation-stabilizing effect of the sulfur functional group introduced at the alkynyl terminus is the key to achieving the efficient enantioconvergent process, in which chiral information originating from not only the racemic stereogenic center but also the formed contact ion pair is completely eliminated from the present system.     

Enantioselective hydrogenation of (Z)- and (E)-β-arylenamides catalyzed by rhodium complexes of monodentate chiral spiro phosphorous ligands: a new access to chiral β-arylisopropylamines

A highly enantioselective rhodium-catalyzed hydrogenation of both (Z)- and (E)-β-arylenamides was developed by using monodentate chiral spiro phosphite and phosphine ligands, respectively. The hydrogenation reaction provides an efficient access to optically active β-arylisopropylamines, important building blocks for the synthesis of biologically active compounds.     

Synthesis of Axially Chiral QUINAP Derivatives by Ketone-Catalyzed Enantioselective Oxidation

QUINAPs have emerged as a pivotal class of axially chiral compounds with remarkable features in the stereoinduction of diverse enantioselective transformations. However, the confined substrate range and extravagant price still pose challenges, limiting their broader utilization. Herein, we describe the first atroposelective oxidation of an N atom using a chiral ketone catalyst, allowing the kinetic resolution of QUINAPOs to give both the unreacted substrates and their corresponding N-oxides with excellent enantioselectivity. Importantly, the enantioenriched products can be readily converted into the QUINAP targets without any loss of stereochemical integrity. Mechanistic investigations indicate that a dioxirane, generated through the oxidation of the ketone with oxone, acts as the active catalytic species. Furthermore, we have successfully extended this catalytic system to the kinetic resolution of QUINOLs and the dynamic kinetic transformation of pyridine analogues of QUINAPO possessing a labile stereogenic axis. The practicality of the developed protocol is further demonstrated by the successful application of QUINAPO N-oxide as a Lewis base catalyst in a series of enantioselective transformations.     

Chiral Silver Phosphate Catalyzed Transformation of ortho‐Alkynylaryl Ketones into 1H‐Isochromene Derivatives through an Intramolecular‐Cyclization/Enantioselective‐Reduction Sequence

The transformation of ortho‐alkynylaryl ketones through a cyclization/enantioselective‐reduction sequence in the presence of a chiral silver phosphate catalyst afforded 1H‐isochromene derivatives in high yield with fairly good to high enantioselectivity. An asymmetric synthesis of the 9‐oxabicyclo[3.3.1]nona‐2,6‐diene framework, which has been found in some biologically active molecules, is presented as a demonstration of the synthetic utility of this method.     

Electrolytic partial fluorination of organic compounds. Part 78: Regioselective anodic fluorination of 2-oxazolidinones

Various 2-oxazolidinones were galvanostatically electrooxidized in the presence of various fluoride salts. It was found that a fluorine atom was introduced to the α-position of the nitrogen atom of N-acyl- and N-alkoxycarbonyl-2-oxazolidinones to provide the corresponding α-fluorinated products in moderate to good yields. In the case of N-phenoxycarbonyl derivative, fluorination took place on the phenyl group selectively.     

N-Fluoro-(3,5-di-tert-butyl-4-methoxy)benzenesulfonimide (NFBSI): A sterically demanding electrophilic fluorinating reagent for enantioselective fluorination

We disclose here a novel electrophilic fluorinating reagent, N-fluoro-(3,5-di-tert-butyl-4-methoxy)benzenesulfonimide (NFBSI) as a sterically demanding analogue of popular fluorinating reagent, N-fluorobenzenesulfonmide (NFSI). NFBSI improves the enantioselectivity of the products as much as 18% for the cinchona alkaloid-catalyzed enantioselective fluorination of silylenol ether compared to the use of NFSI.