Catalytic Asymmetric Synthesis of Axially Chiral Methylenecyclopropanes.

Stereoisomers arising from the rotational restriction about a CN single bond, namely CN atropisomers, have recently attracted considerable attention in the field of synthetic organic chemistry. Diverse CN atropisomeric compounds have been prepared with high optical purity through catalytic enantioselective reactions, and they have been used in various asymmetric reactions as chiral building blocks and chiral ligands. CN atropisomers are attractive compounds from the viewpoint of not only synthetic organic chemistry but also medicinal chemistry. Recently, various CN atropisomeric bioactive compounds have been found, and their biological activity, the target selectivity, and the pharmacokinetics have been revealed to differ significantly between atropisomers. On the other hand, we feel that the chemistry community is still not fully aware of the fascinating biological properties of CN atropisomers. This review article comprehensively describes CN atropisomeric compounds exhibiting diverse biological activities as well as the synthesis or separation of atropisomers and their rotational stability.

Chemo- and stereoselective transformations of polyborylalkanes are powerful and efficient methods to access optically active molecules with greater complexity and diversity through programmed synthetic design. Among the various polyborylalkanes, gem-diborylalkanes have attracted much attention in organic chemistry as versatile synthetic handles. The notable advantage of gem-diborylalkanes lies in their ability to generate two key intermediates, α-borylalkyl anions and (gem-diborylalkyl) anions. These two different intermediates can be applied to various enantioselective reactions to rapidly access a diverse set of enantioenriched organoboron compounds, which can be further manipulated to generate various chiral molecule libraries via stereospecific C(sp3)-B bond transformations.In this Account, we summarize our recent contributions to the development of catalytic chemo- and stereoselective reactions using gem-diborylalkanes as versatile nucleophiles, which can be categorized as follows: (1) copper-catalyzed enantioselective coupling of gem-diborylalkanes with electrophiles and (2) the design and synthesis of (diborylmethyl)metallic species and their applications to enantioselective reactions. Since Shibata and Endo reported the Pd-catalyzed chemoselective Suzuki-Miyaura cross-coupling of gem-diborylalkanes with organohalides in 2014, Morken and Hall subsequently developed the first enantioselective analogous reactions using TADDOL-derived chiral phosphoramidite as the supporting ligand of a palladium catalyst. This discovery sparked interest in the catalytic enantioselective coupling of gem-diborylalkanes with electrophiles. Our initial studies focused on generating chiral (α-borylmethyl)copper species by enantiotopic-group-selective transmetalation of gem-diborylalkanes with chiral copper complexes and their reactions with various aldimines and ketimines to afford syn-β-aminoboronate esters with excellent enantio- and diastereoselectivity. Moreover, we developed the enantioselective allylation of gem-diborylalkanes that proceeded by reaction of in situ-generated chiral (α-borylalkyl)copper and allyl bromides. Mechanistic investigations revealed that the enantiotopic-group-selective transmetalation between gem-diborylalkanes and the chiral copper complex occurred through the open transition state rather than the closed transition state, thereby effectively generating chiral (α-borylmethyl)copper species. We also utilized (diborylmethyl)metallic species such as (diborylmethyl)silanes and (diborylmethyl)zinc halides in catalytic enantioselective reactions. We succeeded in developing the enantiotopic-group-selective cross-coupling of (diborylmethyl)silanes with aryl iodides to afford enantioenriched benzylic 1,1-silylboronate esters, which could be used for further consecutive stereospecific transformations to afford various enantioenriched molecules. In addition, we synthesized (diborylmethyl)zinc halides for the first time by the transmetalation of isolated (diborylmethyl)lithium and zinc(II) halides and their utilization to the synthesis of enantioenriched gem-diborylalkanes bearing a chiral center at the β-position via an iridium-catalyzed enantioselective allylic substitution process. In addition to our research efforts, we also include key contributions by other research groups. We hope that this Account will draw the attention of the synthetic community to gem-diboryl compounds and provide guiding principles for the future development of catalytic enantioselective reactions using gem-diboryl compounds.

Recent developments in catalytic asymmetric aldol reactions have been summarized. Enantioselective aldol reactions are important methods to synthesize β-hydroxy carbonyl compounds in optical pure form, and as such, numerous successful chiral catalysts were designed and applied for asymmetric aldol reactions. This review article is organized under the categories of: (1) catalytic enantioselective aldol reactions of preformed enolates, (2) catalytic enantioselective direct-type aldol reactions using chiral metal catalysts, (3) catalytic enantioselective direct-type aldol reactions using organocatalysts, (4) catalytic enantioselective aldol reactions in aqueous media. Examples of the aldol reactions that employ simple carbonyl compounds will be also the focus of this review.

Magnesium-catalyzed stereoselective transformations – A survey through recent achievements

Synergy makes it possible: Bifunctional cinchona alkaloids are found to promote the first highly enantioselective organocatalytic aza-Michael reactions with α,β-unsaturated ketones. In addition to utilizing practical catalysts, readily accessible substrates, and commercially available reagents, this reaction affords a synthetically valuable scope that is complimentary to existing methods catalyzed by chiral metal complexes. Supporting information for this article is available on the WWW under http://www.wiley-vch.de/contents/jc_2002/2008/z802785_s.pdf or from the author. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Biaryl atropisomers are key structural components in chiral ligands, chiral functional materials, natural products, and bioactive compounds, and their asymmetric syntheses have been reported by many groups. In contrast, although the scientific community has long been aware of atropisomers due to rotational restriction around N-C bonds, they have attracted scant attention and have remained an unexplored research area. In particular, their catalytic asymmetric synthesis and the synthetic applications were unknown until recently. This Account describes studies conducted by our group on the catalytic enantioselective syntheses of N-C axially chiral compounds and their applications in asymmetric reactions.In the presence of a chiral Pd catalyst, the reactions of achiral secondary ortho-tert-butylanilides with 4-iodonitrobenzene proceeded in a highly enantioselective manner (up to 96% ee), affording N-C axially chiral N-arylated ortho-tert-butylanilides in good yields. The application of the present chiral Pd-catalyzed N-arylation reaction to an intramolecular version gave N-C axially chiral lactams with high optical purity (up to 98% ee). These reactions were the first highly enantioselective syntheses of N-C axially chiral compounds with a chiral catalyst. Since the publication of these reactions, N-C axially chiral compounds have been widely accepted as new target molecules for catalytic asymmetric reactions. Furthermore, chiral-Pd-catalyzed intramolecular N-arylations were applied to the enantioselective syntheses of N-C axially chiral quinoline-4-one and phenanthridin-6-one derivatives. We also succeeded in the enantioselective syntheses of various N-C axially chiral compounds using other chiral Pd-catalyzed reactions. That is, optically active N-C axially chiral N-(2-tert-butylphenyl)indoles, 3-(2-bromophenyl)quinazolin-4-ones, and N-(2-tert-butylphenyl)sulfonamides were obtained through chiral Pd-catalyzed 5-endo-hydroaminocyclization, monohydrodebromination (reductive asymmetric desymmetrization), and Tsuji-Trost N-allylation, respectively. The study of the catalytic asymmetric synthesis of axially chiral indoles has contributed to the development of not only N-C axially chiral chemistry but also the chemistry of axially chiral indoles. Subsequently, the catalytic asymmetric syntheses of various indole derivatives bearing a C-C chiral axis as well as an N-C chiral axis have been reported by many groups. Moreover, axially chiral quinazlolin-4-one derivatives, which were obtained through chiral Pd-catalyzed asymmetric desymmetrization, are pharmaceutically attractive compounds; for example, 2-methyl-3-(2-bromophenyl)quinazolin-4-one product is a mebroqualone possessing GABA agonist activity.Most of the N-C axially chiral products have satisfactory rotational stability for synthetic applications, and their synthetic utility was also demonstrated through application to chiral enolate chemistry. That is, the reaction of various alkyl halides with the enolate prepared from the optically active anilide, lactam, and quinazolinone products proceeded with high diastereoselectivity by asymmetric induction due to the N-C axial chirality.At the present time, N-C axially chiral chemistry has become a popular research area, especially in synthetic organic chemistry, and original papers on the catalytic asymmetric syntheses of various N-C axially chiral compounds and their synthetic applications have been published.

Open AccessCCS ChemistryRESEARCH ARTICLE24 May 2022Inherently Chiral 6,7-Diphenyldibenzo[e,g][1,4]diazocine: Enantioselective Synthesis and Application as a Ligand Platform Yu Luo, Xilong Wang, Weiming Hu, Yan Peng, Chaoqin Wang, Ting Yu, Sidi Cheng, Jing Li, Yimiao He, Chunfang Gan, Shuang Luo and Qiang Zhu Yu Luo State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530 University of Chinese Academy of Sciences, Shijingshan District, Beijing 100049 , Xilong Wang State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530 University of Chinese Academy of Sciences, Shijingshan District, Beijing 100049 , Weiming Hu State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530 University of Chinese Academy of Sciences, Shijingshan District, Beijing 100049 , Yan Peng State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530 University of Chinese Academy of Sciences, Shijingshan District, Beijing 100049 , Chaoqin Wang State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530 University of Chinese Academy of Sciences, Shijingshan District, Beijing 100049 , Ting Yu State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530 University of Chinese Academy of Sciences, Shijingshan District, Beijing 100049 , Sidi Cheng State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530 University of Chinese Academy of Sciences, Shijingshan District, Beijing 100049 , Jing Li State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530 University of Chinese Academy of Sciences, Shijingshan District, Beijing 100049 , Yimiao He Guangxi Key Laboratory of Natural Polymer Chemistry and Physics, College of Chemistry and Materials, Nanning Normal University, Nanning 530001 , Chunfang Gan Guangxi Key Laboratory of Natural Polymer Chemistry and Physics, College of Chemistry and Materials, Nanning Normal University, Nanning 530001 , Shuang Luo *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530 University of Chinese Academy of Sciences, Shijingshan District, Beijing 100049 and Qiang Zhu *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530 University of Chinese Academy of Sciences, Shijingshan District, Beijing 100049 Guangxi Key Laboratory of Natural Polymer Chemistry and Physics, College of Chemistry and Materials, Nanning Normal University, Nanning 530001 https://doi.org/10.31635/ccschem.022.202201901 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail Inherently chiral 6,7-diphenyldibenzo[e,g][1,4]diazocine (DDD) has been synthesized enantioselectively for the first time via chiral phosphoric acid (CPA)-catalyzed cyclocondensation of readily available [1,1′-biphenyl]-2,2′-diamine ( 1a) and benzil ( 2a) in 82% yield, with 98% ee under mild reaction conditions. The strategy could also be applied to racemic biaryl diamines through kinetic resolution. The unexpectedly high interconversion energy barriers between the enantiomers (ΔG = 39.5 kcal/mol) and the chemical stability rendered DDD an ideal platform for developing new chiral ligands and catalysts. Unique inherently chiral DDD-based phosphoramidites, phosphoric acid, mono- and diphosphine ligands were prepared from optically pure diphenol derivative DDDOL as a common precursor. Preliminary asymmetric reactions catalyzed by Pd or Rh in the presence of newly developed ligands exhibited comparable or even better enantioselectivities than the corresponding BINOL- or SPINOL-derived ligands. Density functional theory calculation revealed the origin of the enantioselectivity during the process. Download figure Download PowerPoint Introduction The term "inherent chirality" was first introduced by Böhmer et al.1 in 1994 to describe chirality observed in calix[4]arene substituted non-symmetrically. Free interconversion between the concave conformers was restricted due to steric hindrance arising from the lower-rim modification. Thus, the stabilized curvature devoid of symmetry was not superimposable on its mirror image that was chiral by definition. In other words, inherent chirality was established as an intrinsic character of a cyclic molecule, even if it lacks conventional chiral factors such as central, axial, planar, and helical chirality (Figure 1a, left). From then on, the terminology has been gradually applied to macromolecules and supramolecules possessing similar structural characteristics, such as rotaxanes, catenanes, fullerenes, cavitands, and capsular assemblies.2–5 Since inherently chiral calixarenes and other macromolecules have played an increasingly important role in chiral recognition and asymmetric catalysis,6,7 accessing these molecules in enantiomerically pure form is of great significance but also a formidable challenge. For example, enantioenriched calix[4]arene derivatives are mainly obtained by high-performance liquid chromatography (HPLC) separation of racemic mixtures using a chiral stationary phase or by forming diastereomers with a chiral auxiliary.8 Attempts of enantioselective catalytic synthesis of inherently chiral macrocycles led to very poor results (up to 35% ee).9 In 2020, Tong et al.10 reported the first successful asymmetric synthesis of macrocyclic heteracalix[4]aromatics through Pd-catalyzed intramolecular C–N coupling with high enantioselectivity (Figure 1a, right). Figure 1 | Inherently chiral compounds and their asymmetric catalytic synthesis. Download figure Download PowerPoint Cyclic molecules with rigid non-planar conformation smaller than calix[4]arene can also exhibit inherent chirality. For instance, replacing the four methylene linkages in calix[4]arene by four σ-bonds and changing the linking substitution site from meta to ortho positions of the phenyl units leads to an eight-membered ring system named tetraphenylene which has a unique saddle-shaped structure with extraordinary rigidity (ΔG approximately 80 kcal/mol!).11,12 Non-symmetrically substituted tetraphenylenes are inherently chiral molecules, which have been studied extensively by Wong and coworkers.11,13–23 Although many methods have been developed to prepare racemic tetraphenylene derivatives; the enantioenriched ones are obtained mainly by HPLC separation or resolution of racemic mixtures. A breakthrough in the asymmetric synthesis of tetraphenylenes was realized by Shibata et al. in 2009, in which a novel Rh-catalyzed [2+2+2] cycloaddition of two phenylene-bridged 1,6,10-triynes was developed to deliver inherently chiral tetraphenylenes in up to 99% ee (Figure 1b).24,25 Overall, the study of inherently chiral small molecules, including their structural characteristics, enantioselective synthesis, and applications, has been long neglected. 6,7-Diphenyldibenzo[e,g][1,4]diazocine (DDD), an intuitively achiral eight-membered N-heterocycle, possesses an inflexible saddle-shaped configuration similar to that of tetraphenlene. Density functional theory (DFT) calculation suggests that the interconversion energy barrier is as high as 39.5 kcal/mol,26 indicating the existence of inherent chirality in this aza analog of tetraphenlene (Figure 1c, left). The first report for the synthesis of racemic DDD by thermal condensation of [1,1′-biphenyl]-2,2′-diamine and benzil dates back as early as 1892.27 In 1963, an optically pure 4,4′-diester derivative of DDD was obtained by resolution; a study of its enantiomeric stability showed that no reaction or racemization took place upon heating at 200 °C in mesitylene for 24 h.28 The ignored inherent chirality in DDD stimulated our interest in considering its enantioselective preparation and synthetic application. Our initial attempt relied on the hypothesis that a palladium-catalyzed double isocyanide insertion applying 2,2′-diisocyano-1,1′-biphenylbisisocyanide A would lead to a key dibenzo[e,g][1,4]diazocine-based palladium intermediate B. Transmetallation of B with aryl boronic acid, followed by reductive elimination would furnish 6,7-diaryldibenzo[e,g][1,4]diazocine, and in the presence of chiral ligand, enantioenriched DDD derivatives C will be obtained expectantly (Figure 1c, from A to C). Unfortunately, this hypothesized reaction sequence failed to give the desired product C in the presence of aryl boronic acid. Instead, another inherently chiral saddle-shaped product D was produced with high ee when cesium carboxylate was used (Figure 1c, from A to D).26 The failure of Pd-catalyzed enantioselective synthesis of DDD made us turn back to the century-old chemistry, condensation of [1,1′-biphenyl]-2,2′-diamine with benzyl. Inspired by recent achievements involving chiral phosphoric acid (CPA) in asymmetric catalysis,29–32 we hypothesized that optically pure DDD could be accessed by CPA-catalyzed asymmetric cyclocondensation of [1,1′-biphenyl]-2,2′-diamine and benzil under metal-free conditions (Figure 1d). When racemic biaryl diamines were used, it was possible to realize kinetic resolution to give value-added axially chiral diamines and DDD derivatives ready for ligand design. Experimental Methods In air, a 35 mL reaction tube was charged with [1,1′-biphenyl]-2,2′-diamines 1 (0.11 mmol), benzil 2 (0.1 mmol), and CPA (10 mol %). The tube was evacuated and filled with argon three times. Then, tetrahydrofuran (THF) or tetrahydropyran (THP) (0.1–0.2 mL) was added to the tube and sealed with a Teflon screwcap. The mixture was stirred at 35–75 °C for 24–72 h. After cooling to room temperature, the reaction mixture was directly loaded onto a low-pressure flash column (SYNTHWARE GLASS, C184171) packed with column chromatography silica gel (Qingdao Ocean, 100–200 mesh) by a minimal amount of CH2Cl2, and using petroleum ether/ethyl acetate as eluent to give the corresponding product 3. Following the procedure of phase separation mentioned in Supporting Information Figure S1, product 3 with increased optical purity was obtained. Results and Discussion To test our hypothesis, cyclocondensation of [1,1′-biphenyl]-2,2′-diamine ( 1a) with benzil ( 2a) catalyzed by CPA was investigated (Table 1). The result of the initial test with unsubstituted 1,1′-bi-2-naphthol (BINOL)-derived C1 (30 mol %) in dioxane at 65 °C for 24 h was encouraging, delivering the desired cyclization product 3aa in 63% yield with 22% ee (entry 1). Varying solvent revealed that the reaction proceeded more efficiently in THF; even the catalyst loading was reduced to 10 mol % (entry 4). Next, BINOL-based CPAs with substituents at the 3,3′-positions were screened. Except for bulky triphenylsilyl-substituted C3, 3,3′-diphenyl BINOL-CPA C2 and all of its aryl analogs were able to promote the cyclization but with low to moderate enantioselectivities (entries 5–14). Unfortunately, 1,1′-spirobiindane-7,7′-diol (SPINOL)-derived CPAs were ineffective in this case (entries 15–18). We found that H8-BINOL-based C16 could catalyze the reaction with slightly better ee than the BINOL analog C4 (entry 19 vs. entry 7). Intriguingly, the reaction was accelerated substantially at higher concentrations. When the amount of THF was minimized to 0.15 mL, 3aa was formed almost quantitatively with 68% and 76% ee in the presence of C16 and C18, respectively (entries 21–22). The enantioselectivity increased slightly to 81% ee when the reaction was carried out at 50 °C (entry 23). Accidentally, we found that the solubility of racemic and optically pure 3aa in isopropanol was quite different.33–35 After purification by column chromatography, 2 mL of isopropanol was added to the isolated product, followed by ultrasonic mixing for 2 min and precipitation of racemic 3aa. Subsequently, the product, which remained in solution, was obtained by removing solvent to give 3aa in 82% yield with excellent optical purity (98% ee, entry 24; see the detailed procedures in Supporting Information Figure S1). Interestingly, CPAs C18 and C19 had opposite asymmetric induction, although both catalysts had the same configuration (entry 23 vs entry 24).36–40 Table 1 | Optimization of the Reaction Conditionsa Entry Catalyst Solvent Yield (%) ee (%) 1 C1b Dioxane 63 −22 2 C1b DME 56 −14 3 C1b THF 77 −31 4 C1 THF 60 −21 5 C2 THF 54 61 6 C3 THF 0 / 7 C4 THF 61 64 8 C5 THF 78 −59 9 C6 THF 69 26 10 C7 THF 59 33 11 C8 THF 63 −16 12 C9 THF 52 −57 13 C10 THF 50 −57 14 C11 THF 76 −29 15 C12 THF 0 / 16 C13 THF 34 −3 17 C14 THF Trace −11 18 C15 THF 15 5 19 C16 THF 60 66 20 C17 THF 61 65 21c C16 THF 99 68 22c C18 THF 99 76 23 c, d C18 THF 98(82) e 81(98) e 24 C19 THF 51 −40 aReaction conditions: 1a (0.11 mmol), 2a (0.10 mmol), CPA (10 mol %) in 1.0 mL of solvent, 65 °C, 24 h, isolated yield, ee was determined by HPLC analysis using a chiral stationary phase. DME, 1,2-dimethoxyethane. b30 mol %. c0.15 mL of THF. d50 °C. ePhase separation. Following the identification of optimal reaction conditions and postreaction procedures (entry 23), the scope of benzils ( 2) was first explored in reactions with 1a. The substrates were insoluble in 0.15 mL THF; thus, we increased the volume to 0.2 mL of the solvent. As shown in Scheme 1, as expected, symmetric benzils with electron-withdrawing groups, including F, Cl, and Br, at the para-positions were more reactive than those with electron-donating groups. Although an extended reaction time and a higher temperature were required for OMe-substituted benzil, all of the corresponding products 3aa–3af were obtained in 68%–82% yields with excellent enantioselectivities (94–98% ee). The reaction was sluggish for ortho-methyl-substituted benzil 1g, which required 72 h at 65 °C to give 3ag in 73% yield with 72% ee without phase separation. Interestingly, in the case of 3ah, an optically pure product was precipitated after treatment with isopropanol instead of the racemate. For unsymmetric benzil 2i, cyclocondensation also proceeded smoothly ( 3ai, 72% yield, 96% ee). However, when phenyl methyl 1,2-diketone was applied, no enantioselectivity was observed for the corresponding cyclization product 3aj. Importantly, the unique pyridine-containing structure of 3ak, a potential chiral N,N-ligand,41 was accessed with 99% ee, albeit in low yield due to unidentified side-product formation. It's worth mentioning that when using symmetric tetraketone 2,2′-(1,4-phenylene)bis(1-phenylethane-1,2-dione) 2l in condensation with 1.0 equiv of 1a, 3al containing unreacted 1,2-diketone moiety was obtained in 82% yield with 80% ee. When 2l reacted with an excess amount of 1a, double condensation occurred smoothly, giving a mixture of diastereomers 3am in 98% ee and 3an as a meso-isomer in a 5∶1 ratio. Scheme 1 | The scope of benzyls.aaReaction conditions: 1a (0.11 mmol), 2 (0.10 mmol), (R)-C18 (10 mol %), THF (0.15 mL), 50 °C, 24 h, in a sealed tube, isolated yield, ee was determined by HPLC analysis using a chiral stationary phase. bTHF (0.2 mL). c40 °C. d36 h. e65 °C, 48 h. f65 °C, 72 h, without phase separation. g(R)-C19, 48 h, the optical product was precipitated. h(R)-C16. i1a (0.1 mmol), 2 (0.3 mmol), THP (0.1 mL), 35 °C, 72 h, without phase separation. j1a (0.3 mmol), 2 (0.1 mmol), THP (0.1 mL), 35 °C, 72 h, without phase separation. kNo racemization and decomposition were observed upon heating in dry mesitylene at 250 °C for 24 h. THP, tetrahydropyran. Download figure Download PowerPoint Next, the compatibility of substituted [1,1′-biphenyl]-2,2′-diamines ( 1) was investigated (Scheme 2). When diamines ( 1) bearing OMe, Me, or F at the 4,4′ positions were applied, the corresponding cyclocondensation products 3ba, 3ca, and 3fa were obtained in moderate yields with excellent enantioselectivities catalyzed by C19 following the standard phase separation. However, diamines 1d and 1g substituted with strong electron-withdrawing CF3 or CN groups were found unsuitable in condensation with 2a, resulting in low yields of 3da and 3ga. Less electron-deficient 4,4′-diester-substituted derivative 3ea was accessed in 80% yield with 82% ee. We found that substituents at the para positions of 1 had little effect on both yield and enantioselectivity. For example, the yield for electron-withdrawing F substituted 1h was slightly lower than that for 1k substituted with electron-donating OMe ( 3ha vs. 3ka). Both 3ia (Cl) and 3ja (Me) were obtained in excellent yields with high ee. Unsymmetrical isopropyl-substituted 1l could cyclize with 2a very efficiently; however, the enantiomeric purity of the corresponding product 3la could not be enriched by precipitation of the racemate (99% yield, 86% ee). It was not surprising that condensation of sterically hindered 1m with 2a was inefficient in terms of both yield and enantioselectivity ( 3ma, 42% yield, 60% ee). Scheme 2 | The scope of [1,1′-biphenyl]-2,2′-diamines.aaReaction conditions: 1 (0.11 mmol), 2a (0.10 mmol), (R)-C19 (10 mol %), THF (0.15 mL), 50 °C, 36 h, in a sealed tube, isolated yield, ee was determined by HPLC analysis using a chiral stationary phase. b48 h. c(R)-C16, THF (0.2 mL), 65 °C. d(R)-C18. e1 (0.1 mmol), 2a (0.3 mol), THP (0.1 mL), 72 h. f1 (0.1 mmol), 2a (0.3 mol), THP (0.1 mL), 35 °C, 48 h. gWithout phase separation. Download figure Download PowerPoint Next, 6,6′-mono- and disubstituted [1,1′-biphenyl]-2,2′-diamines in which rotation around the aryl-aryl axis was hindered under varying degrees were investigated in condensation with 2a (Scheme 3). Racemic 6,6′-difluoro-[1,1′-biphenyl]-2,2′-diamine 1n reacted with 2a smoothly to give 3na in 86% yield with 85% ee through dynamic kinetic resolution (DKR) (for enantiomerization study of 1n see the Supporting Information Tables S2 and S3 and Figures S2 and S3). In addition, other biaryldiamines with unstable chiral axis such as 6-methyl-[1,1′-biphenyl]-2,2′-diamine 1o and 1-(2-aminophenyl)naphthalen-2-amine 1p were also fully converted to the corresponding products 3oa and 3pa in good yields, with 90% and 97% ee, respectively. After the DKR of biaryldiamines with unstabilized axial chirality, the kinetic resolution of stabilized biaryldiamines was studied. Unfortunately, only moderate enantioselectivities (50%–55% ee) were observed for DDD analogs 3qa– 3sa, and unreacted 1q– 1s were recovered in low enantiomeric purity (30–36% ee). However, when 6,6′-dimethoxy-[1,1′-biphenyl]-2,2′-diamine 1t was applied to condense with 2a in the presence of (R)- C18 as a catalyst, 3ta was isolated in 49% yield with a moderate 68% ee. Enantioenriched 3ta (35% yield, 99% ee) was obtained through the simple operation of phase separation in sacrificing an acceptable amount of the racemate. The absolute configuration of 3ta was confirmed by X-ray diffraction.a Notably, the other enantiomer of 3ta could be accessed by reaction of the recovered (R)- 1t (57% ee) with 2a in the presence (S)- C18 under otherwise identical conditions (see the detailed requirements in the Supporting Information). Therefore, both of the enantiomers of 3ta were accessed in excellent optical purity (99% ee). Scheme 3 | Kinetic resolution of racemic 1.aaReaction conditions: 1 (0.1 mmol), 2a (0.3 mol), (R)-C18 (10 mol %), THP (0.1 mL), 35 °C, 48 h, in a sealed tube, isolated yield, ee was determined by HPLC analysis using a chiral stationary phase. b(R)-C4, rt, 3 days. c(R)-C4, 35 °C, 48 h. d(R)-C4, rt, 4 days. e1t (0.5 mmol), 2a (1 mmol), THF (0.35 mL), 50 h. fphase separation. gs = ln[(1 − C)(1 − ees)]/ln[(1 − C)(1 + ees)], Conversion (C) = ees/(ees + eep). Download figure Download PowerPoint Scheme 4 | Preparation of DDD-based phosphoramidites, CPA, and phosphorus ligands. Conditions: (a) hexamethylphosphorous triamide (HMPT), toluene, 115 °C, 6 h; or hexaethylphosphoruo triamide (HEPT), toluene, 115 °C, 6 h; or (1) diisopropylamine, PCl3, NEt3, DCM, 0 °C, 7 h, (2) (-)-DDDOL, NEt3, DCM, rt, 18 h; or (1) (R)-bis((R)-1-phenylethyl)amine, PCl3, NEt3, DCM, 0 °C, 7 h, (2) (-)-DDDOL, NEt3, DCM, rt, 18 h. (b) (1) POCl3, pyridine, 80 °C, 5 h, (2) H2O, 50 °C, 12 h, (3) 3 N HCl, 100 °C, 30 min. (c) (1) Tf2O, C5H5N, DCM, rt, 24 h, (2) Pd(OAc)2, dppp, DIPEA, HP(O)Ph2, DMSO, 100 °C, 24 h, (3) toluene, 100 °C, 24 h, Pd(OAc)2, DIPEA, HP(O)Ph2, DMSO, 100 °C, 14 h. (1) Tf2O, C5H5N, DCM, rt, 24 h, (2) Pd(OAc)2, DIPEA, DMSO, °C, 18 h. (1) Tf2O, C5H5N, DCM, rt, 24 h, (2) Pd(OAc)2, dppp, DIPEA, HP(O)Ph2, DMSO, 100 °C, 24 h, (3) toluene, 100 °C, 24 h. DMSO, DIPEA, Download figure Download PowerPoint The structure of 3ta that the biaryl was approximately which was similar to that of The rigid configuration and of enantiomeric 3ta us to new ligands on this As shown in Scheme of 3ta as a key intermediate in 72% yield with of the ( (Scheme 4). a of ligands were readily prepared by from DDDOL in Next, CPA was prepared with a moderate DDD-based mono- and ligands were synthesized in in In addition, 4 could also as a to form ligand in 63% yield after three of It is worth mentioning that racemization decomposition was observed during these although conditions were applied, such as heating at °C for 18 h in Pd-catalyzed using in and using in of to the absolute of and were confirmed by X-ray (Scheme Scheme 5 | of in asymmetric Download figure Download PowerPoint these DDDOL derivatives in their as potential chiral ligands in asymmetric reactions were Rh-catalyzed asymmetric of 5 was to test with three other available as ligands (Scheme the reaction giving derivative 6 quantitatively in ee. The used and led to or slightly better Importantly, the moiety in DDD was upon even under high Next, the of as a ligand was in the of acid to 7 catalyzed by (Scheme Although and the ligand showed comparable asymmetric induction, the yield of 9 was better for the reaction using as a To our in the asymmetric reaction catalyzed by was to be an excellent ligand, delivering 12 in 98% yield with ee (Scheme The of in Pd-catalyzed reaction was also investigated to C–N derivatives (Scheme results for the reactions of with acetate catalyzed by in the presence of and that both of the ligands could promote the reaction in high yields but with poor enantioselectivities ( ee). We found that a methyl on the of acetate was for the of the corresponding ee). However, when acetate was used as the both the yield and ( yield, 42% ee). when a acetate derivative was applied, in which an chiral was the enantioselectivity for the ee ( after both of and Pd-catalyzed reaction in the presence of derivative containing both C–N axial chirality and chirality in excellent yield enantioselectivity ee) and It is that was produced in a lower yield with as the ligand under otherwise identical conditions. Although methods have been developed to axially chiral C–N compounds to the of our of and axis chirality through Pd-catalyzed has not been reported results that could be a chiral ligand to in catalyzed asymmetric Scheme 6 | Application of in the asymmetric of C–N axis configuration is from similar DCM, Download figure Download PowerPoint The result of these inherently chiral DDD-based ligands in of reactions us to study the of with ligands in To this mixing and in a that was from X-ray analysis of the revealed that the was smaller than that in and to that in (Scheme As we the of a ligand a role in the chiral of an asymmetric Therefore, to the of the in these palladium with asymmetric induction, a Pd-catalyzed of 15 was investigated (Scheme the same reaction in the presence of and ligand derivative 16 bearing axial chirality was obtained with 0 and 60% ee, respectively. When was 16 was obtained in ee. result that could be an ideal to and when chiral ligands for asymmetric catalytic Scheme 7 | and of Download figure Download PowerPoint Next, we explored the reaction and of enantioselectivity with 1a and benzil 2a as Since the first was not for the chirality the calculation with (Figure 2). The energy of the for the condensation was (Figure After by CPA ( ( the moiety of an intramolecular by the via the by the CPA with chiral were including two of ( The rotation barrier of the biaryl in was the energy between the diastereomers and was (Figure As a could be by

Catalytic enantioselective Strecker-type reactions of aldimines with tributyltin cyanide (Bu3SnCN) proceeded smoothly in the presence of a novel chiral zirconium catalyst. High levels of enantioselectivities in the synthesis of α-amino nitrile derivatives with wide substrate generality were obtained via these reactions. In addition, hydrogen cyanide (HCN) was successfully used instead of Bu3SnCN as the cyanide source. Catalytic asymmetric Strecker amino acid synthesis starting from achiral aldehydes, amines, and HCN using a chiral zirconium catalyst has also been achieved. The three-component asymmetric process reported here significantly improves upon the original Strecker reaction, and has advantages over previous reactions using unstable imines (Schiff bases) as starting materials. Moreover, high yields and enantioselectivities have been obtained even in the reactions using aliphatic aldehydes, and both enantiomers of various types of α-amino acid derivatives can be prepared. As demonstrations to show the utility of this reaction, efficient syntheses of homophenylalanine, leucine amide, and pipecolic acid derivatives have been performed. Finally, two novel binuclear zirconium complexes (3 and 4) are postulated to be active chiral catalysts in the reactions of aldimines with Bu3SnCN and the three-component reactions, respectively, and low loading levels of the chiral catalysts (1−2.5 mol %) have been accomplished in both cases.

Although arynes are usually considered fleeting intermediates, they are highly valuable synthons because they enable the introduction of aromatic rings and the simultaneous formation of new bonds at two sites. Although catalytic reactions using transition metals are excellent method for constructing complex polycyclic aromatic molecules in a single step, the use of asymmetric catalysis for the capture of arynes remains a crucial goal for the progress of aryne chemistry. Catalytic asymmetric reactions of arenes are challenging, requiring sufficient interactions between the neutral and highly reactive short-lived aryne intermediates in a stereo-controlled fashion. In addition, spontaneous decomposition, as well as side reactions, has hindered their development and, until recently, highly enantioselective reactions using arynes had remained elusive. This Review highlights asymmetric reactions using arynes, featuring diastereoselective, enantioselective and catalytic enantioselective reactions.

The first catalytic enantioselective Reissert reaction of pyridine derivatives that affords products with excellent regio- and enantioselectivity is described. The key for success is the development of new Lewis acid-Lewis base bifunctional asymmetric catalysts containing an aluminum as a Lewis acid and sulfoxides or phosphine sulfides as a Lewis base. These reactions are useful for the synthesis of a variety of chiral piperidine subunits, and catalytic enantioselective formal synthesis of CP-293,019, a selective D4 receptor antagonist, was achieved. Preliminary mechanistic studies indicated that both sulfoxides and phosphine sulfides can activate TMSCN as a Lewis base. In addition, the sulfoxides with appropriate stereochemistry might stabilize a highly enantioselective bimetallic complex (a presumed active catalyst) through internal coordination to aluminum.

Full details of the first catalytic enantioselective Reissert-type reaction are described. Utilizing the Lewis acid-Lewis base bifunctional catalyst 5 or 6 (9 mol %), the Reissert products were obtained in 57 to 99% yield with 54 to 96% ee. Electron-rich quinolines produced better yields and enantioselectivities than electron-deficient substrates. Kinetic studies indicated that the reaction should proceed via the rate-determining acyl quinolinium formation, followed by the attack of a cyanide. The catalyst does not facilitate the first rate-determining step; however, it strongly facilitates the second cyanation step. The reaction was successfully applied to an efficient catalytic asymmetric synthesis of a potent NMDA receptor antagonist (-)-L-689,560. A key step is the one-pot process using the Reissert-type reaction from quinoline 1f, followed by stereoselective reduction of the resulting enamine 2f. This step gave the key intermediate 20 in 91% yield with 93% ee, using 1 mol % of 6. The enantiomerically pure target compound was obtained through 10 operations (including recrystallization) in total yield of 47%. Furthermore, 6 was immobilized to JandaJEL, and the resulting solid-supported catalyst 11 afforded 20 in a comparable yield to the homogeneous 6, but with slightly lower enantioselectivity.

General and practical catalytic enantioselective Strecker reaction of ketoimines: significant improvement through catalyst tuning by protic additives

The development of a new enantioselective catalytic anti aldol reaction is described. In this Lewis acid-catalyzed process, a chiral metal-ligand enolate complex is accessed through soft-enolization and reacts with an aldehyde to form aldol adducts in good enantioselectivity and anti diastereoselection. Mechanistic studies confirm the non-Mukaiyama pathway involving a reactive metal enolate species. Investigations have shown that the choice of amine base has a remarkable effect on the mechanism and outcome of the reaction. The development of the first enantioselective organocatalytic [1,3]-dipolar cycloaddition reaction is also reported. In this imidazolidinone-catalyzed process, nitrones react with a,b-unsaturated aldehydes to form chiral isoxazolidines in excellent yield, enantioselectivity, and diastereoselection. The scope of this process appears quite general with respect to both the nitrone and aldehyde components of the reaction. A second-generation imidazolidinone catalyst offers improved reaction rates and selectivities and has also facilitated the development of the first exo selective organocatalytic [1,3]-dipolar and Diels-Alder cycloaddition reactions. A synthetic approach towards the marine natural product callipeltoside A is described. The synthesis relies upon rapid construction of the stereochemical backbone through a novel tandem amino-sulfide acyl-Claisen rearrangement. Subsequent elaboration towards the macrolide has involved a highly diastereoselective reductive opening of a spirocyclic intermediate, highly diastereoselective Ireland Claisen rearrangement, and synthesis of the tetrahydropyran moiety through a palladium catalyzed carbonylative cyclization. Completion of the synthesis has yet to be achieved due to difficulties in removal of a benzyl ether protecting group.

Asymmetric catalytic cyclopropanation reactions in water

phosphate. 5 Although there have been reports for the catalytic enantioselective conjugate addition reaction of 3-aryl-substituted oxindoles to vinyl ketones, 5 a few examples for the catalytic enantioselective conjugate addition reaction of 3alkyl-substituted oxindoles to cyclic enones were reported using chiral primary or secondary amine catalysts. 6 Therefore, the development of alternative catalysts for the catalytic enantioselective conjugate addition reaction of 3-alkyl-substituted oxindoles to vinyl ketones would be highly desirable. As part of the research program toward the development of synthetic methods for the catalytic carbon-carbon bond formations, 7 we recently reported the organocatalytic conjugate addition reaction to α,β-unsaturated carbonyl compounds 8 and the other Michael acceptors. 9 In this communications, we wish to describe the enantioselective conjugate addition reaction of prochiral 3-alkyl-substituted oxindoles with vinyl ketones catalyzed by binaphthyl-modified bifunctional organocatalysts bearing both central and axial chiral elements. In an attempt to validate the feasibility of the organocatalytic enantioselective conjugate addition reaction of 3substituted oxindoles, we first investigated the reaction system with 3-benzyl oxindole 1a with methyl vinyl ketone (2a) in the presence of 10 mol % of catalyst in toluene at room temperature. We examined the impact of the structure of catalysts I-IV on enantioselectivities (Table 1, entries 1-4). Quinine-derived thiourea catalyst I was ineffective (Table 1, entriry 1). While binaphthyl-modified chiral bifunctional organocatalysts II-III bearing both central and axial chiral