Catalytic asymmetric synthesis of enantioenriched α-deuterated pyrrolidine derivatives

The recent promising applications of deuterium-labeled pharmaceutical compounds have led to an urgent need for the efficient synthetic methodologies that site-specifically incorporate a deuterium atom into bioactive molecules. Nevertheless, precisely building a deuterium-containing stereogenic center, which meets the requirement for optimizing the absorption, distribution, metabolism, excretion and toxicity (ADMET) properties of chiral drug candidates, remains a significant challenge in organic synthesis. Herein, a catalytic asymmetric strategy combining H/D exchange (H/D-Ex) and azomethine ylide-involved 1,3-dipolar cycloaddition (1,3-DC) was developed for the construction of biologically important enantioenriched α-deuterated pyrrolidine derivatives in good yields with excellent stereoselectivities and uniformly high levels of deuterium incorporation. Directly converting glycine-derived aldimine esters into the deuterated counterparts with D₂O via Cu(i)-catalyzed H/D-Ex, and the subsequent thermodynamically/kinetically favored cleavage of the α-C–H bond rather than the α-C–D bond to generate the key N-metallated α-deuterated azomethine ylide species for the ensuing 1,3-DC are crucial to the success of α-deuterated chiral pyrrolidine synthesis. The current protocol exhibits remarkable features, such as readily available substrates, inexpensive and safe deuterium source, mild reaction conditions, and easy manipulation. Notably, the synthetic utility of a reversed 1,3-DC/[H/D-Ex] protocol has been demonstrated by catalytic asymmetric synthesis of deuterium-labelled MDM2 antagonist idasanutlin (RG7388) with high deuterium incorporation.

A strategy of combining H/D-Ex and azomethine ylide-involved 1,3-DC was developed for the construction of α-deuterated pyrrolidine derivatives in good yields with excellent stereoselectivities and uniformly high levels of deuterium incorporation.     

Catalytic asymmetric hydrogenation of (Z)-α-dehydroamido boronate esters: direct route to alkyl-substituted α-amidoboronic esters

The direct catalytic asymmetric hydrogenation of (Z)-α-dehydroamino boronate esters was realized. Using this approach, a class of therapeutically relevant alkyl-substituted α-amidoboronic esters was easily synthesized in high yields with generally excellent enantioselectivities (up to 99% yield and 99% ee). The utility of the products has been demonstrated by transformation to their corresponding boronic acid derivatives by a Pd-catalyzed borylation reaction and an efficient synthesis of a potential intermediate of bortezomib. The clean, atom-economic and environment friendly nature of this catalytic asymmetric hydrogenation process would make this approach a new alternative for the production of alkyl-substituted α-amidoboronic esters of great potential in the area of organic synthesis and medicinal chemistry.

The direct catalytic asymmetric hydrogenation of (Z)-α-dehydroamino boronate esters was realized.

Since FDA approval of bortezomib¹ for the treatment of multiple myeloma, chiral α-aminoboronic acids have been recognized as key pharmacophores for the design of proteasome inhibitors.² The incorporation of chiral α-aminoboronic acid motifs at the C-terminal position of a peptide³ to develop potential clinical drug candidates has drawn increasing interest⁴ (Fig. 1). Meanwhile, chiral α-amidoboronic acids and their derivatives are useful synthetic building blocks for the stereospecific construction of chiral amine compounds.⁵ The biological and synthetic value of α-amidoboronates has led to considerable efforts for the development of efficient synthetic methods. However, up to now, limited transition-metal-catalyzed asymmetric approaches have been reported. The widely used strategies to synthesize these compounds are stepwise Matteson homologation/N-nucleophilic replacement,⁶ borylation of imines,⁷ and alkene functionalization.⁸ Recently, two other elegant approaches, Ni-catalyzed decarboxylative borylation of α-amino acid derivatives⁹ and enantiospecific borylation of lithiated α-N-Boc species,¹⁰ were reported by the Baran and Negishi groups, respectively. To the best of our knowledge, the majority of the methods relied on either stoichiometric amounts of chiral auxiliaries^6,7a,b or substrate-control strategies⁹ and most of these methods enable the construction of aryl-substituted α-aminoboronates. Enantioselective methods to access unfunctionalized alkyl-substituted α-aminoboronic esters are still rarely developed and so far only two examples have been realized by the Miura^8a and Scheidt^7f groups, respectively. Considering that most therapeutically relevant α-amidoboronic acid fragments contain an alkyl subunit and the fact that the options for the synthesis of alkyl-substituted α-amidoboronic esters in an enantioselective manner are still rare, the development of other distinct approaches would be highly desirable. Herein, we report a new alternative to access these compounds by catalytic asymmetric hydrogenation of (Z)-α-dehydroamidoboronate esters. With this approach, the desired chiral alkyl-substituted α-amidoboronic esters could be obtained in high yields and generally excellent enantioselectivities (up to 99% yield and 99% ee) with simple purification.Open in a separate windowFig. 1Selected inhibitors containing chiral alkyl-substituted α-amidoboronic acids.Catalytic asymmetric hydrogenation of olefins is an atom-economic, environmentally friendly and clean process for the synthesis of valuable pharmaceuticals, agricultural compounds and feedstock chemicals.¹¹ Recently, hydrogenation of vinylboronic compounds has emerged for the preparation of chiral boronic compounds in a regiodefined manner.^12,13 However, surprisingly α-dehydroamido boronate esters and their derivatives, as elegant precursors to access alkyl-substituted α-amidoboronic compounds, have never been used as substrates in asymmetric hydrogenation and remain a challenging project. To our knowledge, only one efficient hydrogenation approach to (1-halo-1-alkenyl) boronic esters was reported for indirect synthesis of alkyl-substituted α-aminoboronic esters but it was accompanied by inevitable de-halogenated by-products¹⁴ (Scheme 1). Given the catalytic efficiency and atom economy of the hydrogenation method, the development of a new direct hydrogenation approach to construct these important chiral alkyl-substituted α-amidoboronic esters would be very appealing.Open in a separate windowScheme 1Approaches towards the synthesis of chiral alkyl-substituted α-aminoboronic esters.The inspiration for our approach to the hydrogenation of α-dehydroamido boronates came from the molecular structures of relevant biologically active inhibitors containing alkyl-substituted α-amidoboronic acid fragments. Due to the limited stability of free α-aminoboronic acids, an electron-withdrawing carboxylic N-substituent is often required.¹⁵ Thus, we envisaged that N-carboxyl protected α-dehydroamido boronate esters could serve as a potential precursor for the synthesis of alkyl-substituted α-amidoboronates through Rh-catalyzed asymmetric hydrogenation of the C C bond¹⁶ (Fig. 1), a strategically distinct approach to the construction of unfunctionalized alkyl-substituted α-amidoboronic esters. However, challenges still remain, including: (1) how to synthesize α-dehydroamido boronates; (2) the facile transmetalation process of the starting materials leading to deboronated by-products in the hydrogenation process;¹⁷ (3) the unknown stability of α-amidoboronic compounds in the presence of a transition-metal catalyst and hydrogen molecules. As part of our continuous efforts to develop efficient hydrogenation approaches to construct valuable motifs,¹⁸ here we present the results of the investigation to address the aforementioned challenges.The desired aryl-substituted (Z)-α-dehydroamido boronates could be obtained by Cu-catalyzed regioselective hydroborylation of ynamide according to a previous report.¹⁹ However, different α/β-regioselectivity was observed for the preparation of alkyl-substituted (Z)-α-dehydroamido boronate esters and a new synthetic route was developed (Scheme 2, see the ESI^† for details). Of note, (Z)-α-dehydroamido boronate esters should be purified with deactivated silica gel,^7c or else protodeborylation would occur readily with flash chromatography.Open in a separate windowScheme 2Synthetic route to (Z)-α-dehydroamino boronates.In order to check the feasibility of our hypothesis, three substrates were prepared with Rh(NBD)₂BF₄ and examined and our group prepared (Rc,Sp)-DuanPhos under 50 atm hydrogen pressure (Table 1). Gratifyingly, substrate 1b reacted smoothly to provide the desired product 2b in high yield and enantioselectivity (>99% conv., 98% ee, entry 2) whilst the reaction with substrate 1a yielded a mixture of deborylation products and 1c did not work at all (entries 1 and 3). Of note, we did not observe deborylation products with 1b under the current reaction conditions and we did not select (Z)-α-dehydroamido boronic acid 1a as the model substrate because of its poor solubility in most solvents. Then, a variety of chiral diphosphine ligands were investigated along with Rh(NBD)₂BF₄ and the results are shown in Table 1. In most cases, the reaction proceeded smoothly to furnish the desired products and the best results were obtained when (Rc,Sp)-DuanPhos was used as the ligand (entries 2 and 4–12). Poor results were obtained with axially bidentate phosphine ligands (entries 5, 6 and 9). (R,R)-QuinoxP* and (R,R)-Ph-BPE also gave good conversion with a slightly decreased ee whilst (R,R)-ⁱPr-DuPhos exhibited poor results (entries 4, 7 and 10). Subsequent solvent screening revealed that the desired products could be obtained in most of the solvents and 1,2-DCE was the best solvent. (Entry 13, see the ESI^†).Condition optimization for catalytic asymmetric hydrogenation of 1^a

Asymmetric hydrogenation of exocyclic γ,δ-unsaturated β-ketoesters to functionalized chiral allylic alcohols via dynamic kinetic resolution

An iridium catalyzed asymmetric hydrogenation of racemic exocyclic γ,δ-unsaturated β-ketoesters via dynamic kinetic resolution to functionalized chiral allylic alcohols was developed. With the chiral spiro iridium catalysts Ir-SpiroPAP, a series of racemic exocyclic γ,δ-unsaturated β-ketoesters bearing a five-, six-, or seven-membered ring were hydrogenated to the corresponding functionalized chiral allylic alcohols in high yields with good to excellent enantioselectivities (87 to >99% ee) and cis-selectivities (93 : 7 to >99 : 1). The origin of the excellent stereoselectivity was also rationalized by density functional theory calculations. Furthermore, this protocol could be performed on gram scale and at a lower catalyst loading (0.002 mol%) without the loss of reactivity and enantioselectivity, and has been successfully applied in the enantioselective synthesis of chiral carbocyclic δ-amino esters and the β-galactosidase inhibitor isogalactofagomine.

An iridium catalyzed asymmetric hydrogenation of exocyclic γ,δ-unsaturated β-ketoesters via dynamic kinetic resolution was developed, providing efficient protocol for enantioselective synthesis of functionalized chiral allylic alcohols.     

Catalytic asymmetric synthesis of quaternary trifluoromethyl α- to ε-amino acid derivatives via umpolung allylation/2-aza-Cope rearrangement

In this study, we developed an efficient Ir-catalyzed cascade umpolung allylation/2-aza-Cope rearrangement of tertiary α-trifluoromethyl α-amino acid derivatives for the preparation of a variety of quaternary α-trifluoromethyl α-amino acids in high yields with excellent enantioselectivities. The umpolung reactivity empowered by the activation of the key isatin-ketoimine moiety obviates the intractable enantioselectivity control in Pd-catalyzed asymmetric linear α-allylation. In combination with quasi parallel kinetic resolution or kinetic resolution, the generality of this method is further demonstrated by the first preparation of enantioenriched quaternary trifluoromethyl β-, γ-, δ- and ε-amino acid derivatives.

In this study, we developed an efficient Ir-catalyzed cascade umpolung allylation/2-aza-Cope rearrangement for the preparation of a variety of quaternary trifluoromethyl α-ε-amino acids in high yields with excellent enantioselectivities.     

Catalytic asymmetric reductive amination of aldehydes via dynamic kinetic resolution

A novel organocatalytic asymmetric reductive amination of aldehydes has been developed. Treating racemic alpha-branched aldehydes with p-anisidine and a Hantzsch ester in the presence of our previously developed phosphoric acid catalyst, TRIP, gave beta-branched secondary amines in excellent yields and enantioselectivities via an efficient dynamic kinetic resolution. The process is applicable to several different aromatic aldehydes and amines but gives slightly reduced enantiomeric ratios with aliphatic aldehydes.     

Dynamic kinetic resolution of γ,γ-disubstituted indole 2-carboxaldehydes via NHC-Lewis acid cooperative catalysis for the synthesis of tetracyclic ε-lactones

The ubiquity of ε-lactones in various biologically active compounds inspired the development of efficient and enantioselective routes to these target compounds. Described herein is the enantioselective synthesis of indole-fused ε-lactones by the N-heterocyclic carbene (NHC)-Lewis acid cooperative catalyzed dynamic kinetic resolution (DKR) of in situ generated γ,γ-disubstituted indole 2-carboxaldehydes. The Bi(OTf)₃-catalyzed Friedel–Crafts reaction of indole-2-carboxaldehyde with 2-hydroxy phenyl p-quinone methides generates γ,γ-disubstituted indole 2-carboxaldehydes, which in the presence of NHC and Bi(OTf)₃ afforded the desired tetracyclic ε-lactones in up to 93% yield and >99 : 1 er. Moreover, preliminary studies on the mechanism of this formal [4 + 3] annulation are also provided.

NHC-Lewis acid cooperative catalyzed dynamic kinetic resolution (DKR) of transiently generated γ,γ-disubstituted indole 2-carboxaldehydes leading to the enantioselective synthesis of tetracyclic ε-lactones is reported.     

Enantioselective synthesis of α-amino ketones through palladium-catalyzed asymmetric arylation of α-keto imines

Chiral α-amino ketones are common structural motifs in natural products and pharmaceuticals, as well as important synthons in organic synthesis. Thus, establishing efficient methods for preparing compounds with these privileged scaffolds is an important endeavor in synthetic chemistry. Herein we disclose a new catalytic asymmetric approach for the synthesis of chiral α-amino ketones through a chiral palladium-catalyzed arylation reaction of in situ generated challenging α-keto imines from previously unreported C-acyl N-sulfonyl-N,O-aminals, with arylboronic acids. The current reaction offers a straightforward approach to the asymmetric synthesis of acyclic α-amino ketones in a practical and highly stereocontrolled manner. Meanwhile, the multiple roles of the chiral Pd(ii) complex catalyst in the reaction were also reported.

Chiral α-amino ketones are common structural motifs in natural products and pharmaceuticals, as well as important synthons in organic synthesis.     

Stereodivergent entry to β-branched β-trifluoromethyl α-amino acid derivatives by sequential catalytic asymmetric reactions

Currently, conventional reductive catalytic methodologies do not guarantee general access to enantioenriched β-branched β-trifluoromethyl α-amino acid derivatives. Herein, a one-pot approach to these important α-amino acids, grounded on the reduction – ring opening of Erlenmeyer–Plöchl azlactones, is presented. The configurations of the two chirality centers of the products are established during each of the two catalytic steps, enabling a stereodivergent process.

A one-pot approach to β-branched β-trifluoromethyl α-amino acids, grounded on the reduction – ring opening of Erlenmeyer–Plöchl azlactones, and complementary to conventional catalytic asymmetric hydrogenation, is presented.     

Nickel-catalyzed asymmetric reductive cross-coupling of α-chloroesters with (hetero)aryl iodides

An asymmetric reductive cross-coupling of α-chloroesters and (hetero)aryl iodides is reported. This nickel-catalyzed reaction proceeds with a chiral BiOX ligand under mild conditions, affording α-arylesters in good yields and enantioselectivities. The reaction is tolerant of a variety of functional groups, and the resulting products can be converted to pharmaceutically-relevant chiral building blocks. A multivariate linear regression model was developed to quantitatively relate the influence of the α-chloroester substrate and ligand on enantioselectivity.

A Ni-catalyzed enantioselective reductive cross-coupling of α-chloroesters and (hetero)aryl iodides is reported. A MLR model was developed to quantitatively relate the influence of the α-chloroester substrate and ligand on enantioselectivity.     

光氧化还原催化自由基偶联合成β-氟代-α-氨基酸衍生物

通过可见光驱动光氧化还原催化, 发展了一种新颖、便利的β-氟代-α-氨基酸衍生物的合成方法. 以非金属的二氰基吡嗪衍生物(DPZ)为光催化剂, 以易于制备的N-芳基甘氨酸酯和芳基乙酸氧化还原酯为原料, 通过单电子氧化还原分别生成酯基取代α-氨烷基自由基及α-氟代苄基自由基. 经过高反应活性自由基的交叉偶联, 高产率地得到目标产物. 该方法由于氧化还原中性反应途径而无需额外的氧化剂或还原剂, 且属于绿色、可持续的有机催化合成策略.     

镍催化α,β-不饱和醛的选择性α,β-双芳基化反应

三组分双官能化反应是一种高效、简便构建C―C键、C―X键的方式. 双键广泛存在于众多有机化合物中, 对双键的双官能化反应研究有巨大的应用潜力. 本工作以Ni(COD)₂为催化剂, 以芳基溴化镁、芳基溴化物为芳基化试剂, 实现了3-芳基-2-丙烯醛亚胺中碳碳双键的双芳基化反应. 该反应建立了一个新的镍催化α,β-不饱和醛的α,β-双芳基化方法, 可以高度区域选择性地向底物分子中引入两个不同取代的芳环, 得到多种2,3,3-三芳基丙醛骨架的产物. 利用这一反应作为核心步骤实现了天然产物Quebecol的简便合成. 机理研究表明, 该反应可能经历了亲核加成、金属交换、还原消除的历程.     

Efficient kinetic resolution of racemic 3-nitro-cyclopent(or hex)-2-en-1-yl acetates

The kinetic resolution of 3-nitro-cyclopent(or hex)-2-en-1-yl acetates via enzymatic hydrolysis using Pseudomonas cepacia lipase is described. A model, based on a strong interaction between the nitro group and the active site, accounts for the structural selectivity and the stereoselectivity observed.     

Estrogenic Activity of Mycoestrogen (3β,5α,22E)-Ergost-22-en-3-ol via Estrogen Receptor α-Dependent Signaling Pathways in MCF-7 Cells

Armillariella tabescens (Scop.) Sing., a mushroom of the family Tricholomataceae, has been used in traditional oriental medicine to treat cholecystitis, improve bile secretion, and regulate bile-duct pressure. The present study evaluated the estrogen-like effects of A. tabescens using a cell-proliferation assay in an estrogen-receptor-positive breast cancer cell line (MCF-7). We found that the methanol extract of A. tabescens fruiting bodies promoted cell proliferation in MCF-7 cells. Using bioassay-guided fractionation of the methanol extract and chemical investigation, we isolated and identified four steroids and four fatty acids from the active fraction. All eight compounds were evaluated by E-screen assay for their estrogen-like effects in MCF-7 cells. Among the tested isolates, only (3β,5α,22E)-ergost-22-en-3-ol promoted cell proliferation in MCF-7 cells; this effect was mitigated by the ER antagonist, ICI 182,780. The mechanism underlying the estrogen-like effect of (3β,5α,22E)-ergost-22-en-3-ol was evaluated using Western blot analysis to detect the expression of extracellular signal-regulated kinase (ERK), phosphatidylinositol 3-kinase (PI3K), Akt, and estrogen receptor α (ERα). We found that (3β,5α,22E)-ergost-22-en-3-ol induced an increase in phosphorylation of ERK, PI3K, Akt, and ERα. Together, these experimental results suggest that (3β,5α,22E)-ergost-22-en-3-ol is responsible for the estrogen-like effects of A. tabescens and may potentially aid control of estrogenic activity in menopause.     

A general strategy for the synthesis of α-trifluoromethyl- and α-perfluoroalkyl-β-lactams via palladium-catalyzed carbonylation

β-Lactam compounds play a key role in medicinal chemistry, specifically as the most important class of antibiotics. Here, we report a novel one-step approach for the synthesis of α-(trifluoromethyl)-β-lactams and related products from fluorinated olefins, anilines and CO. Utilization of an advanced palladium catalyst system with the Ruphos ligand allows for selective cycloaminocarbonylations to give diverse fluorinated β-lactams in high yields.

β-Lactam compounds play a key role in medicinal chemistry, specifically as the most important class of antibiotics.     

Catalytic enantioselective allene–anhydride approach to β,γ-unsaturated enones bearing an α-all-carbon-quarternary center

A protocol of highly regio- and enantioselective copper-catalyzed hydroacylation of the non-terminal C C bond in 1,1-disubstituted terminal allenes with anhydrides has been developed. Both aromatic and aliphatic carboxylic anhydrides are applicable to the efficient construction of all carbon quarternary centers connected with a versatile C C bond and a useful ketone functionality. The synthetic potentials of the enantioenriched products have also been demonstrated. Density functional theory (DFT) calculations were performed to explain the steric outcome of the products: the hydroacylation proceeds through a six-membered transition state and the ligand-substrate steric interactions account for the observed enantioselectivity although the chiral ligand is far away from the to-be-genetated chiral center.

A protocol of highly regio- and enantioselective copper-catalyzed hydroacylation of the non-terminal C C bond in 1,1-disubstituted terminal allenes with anhydrides has been developed.     

Trityl Cation-Catalyzed Hosomi-Sakurai Reaction of Allylsilane with β,γ-Unsaturated α-Ketoester to Form γ,γ-Disubstituted α-Ketoesters

(Ph₃C)[BPh(^F)₄]-catalyzed Hosomi-Sakurai allylation of allylsilanes with β,γ-unsaturated α-ketoesters has been developed to give γ,γ-disubstituted α-ketoesters in high yields with excellent chemoselectivity. Preliminary mechanistic studies suggest that trityl cation dominates the catalysis, while the silyl cation plays a minor role.     

Construction of chiral α-tert-amine scaffolds via amine-catalyzed asymmetric Mannich reactions of alkyl-substituted ketimines

Stereoselective Mannich reactions of aldehydes with ketimines provide chiral β-amino aldehydes that bear an α-tert-amine moiety. However, the structural variation of the ketimines is limited due to the formation of inseparable E/Z isomers, low reactivity, and other synthetic difficulties. In this study, a highly diastereodivergent synthesis of hitherto difficult-to-access β-amino aldehydes that bear a chiral α-tert-amine moiety was achieved using the amine-catalyzed Mannich reactions of aldehydes with less-activated Z-ketimines that bear both alkyl and alkynyl groups.

Stereoselective Mannich reactions of aldehydes with ketimines provide chiral β-amino aldehydes that bear an α-tert-amine moiety.     

DFT insight into asymmetric alkyl–alkyl bond formation via nickel-catalysed enantioconvergent reductive coupling of racemic electrophiles with olefins

A DFT study has been conducted to understand the asymmetric alkyl–alkyl bond formation through nickel-catalysed reductive coupling of racemic alkyl bromide with olefin in the presence of hydrosilane and K₃PO₄. The key findings of the study include: (i) under the reductive experimental conditions, the Ni(ii) precursor is easily activated/reduced to Ni(0) species which can serve as an active species to start a Ni(0)/Ni(ii) catalytic cycle. (ii) Alternatively, the reaction may proceed via a Ni(i)/Ni(ii)/Ni(iii) catalytic cycle starting with a Ni(i) species such as Ni(i)–Br. The generation of a Ni(i) active species via comproportionation of Ni(ii) and Ni(0) species is highly unlikely, because the necessary Ni(0) species is strongly stabilized by olefin. Alternatively, a cage effect enabled generation of a Ni(i) active catalyst from the Ni(ii) species involved in the Ni(0)/Ni(ii) cycle was proposed to be a viable mechanism. (iii) In both catalytic cycles, K₃PO₄ greatly facilitates the hydrosilane hydride transfer for reducing olefin to an alkyl coupling partner. The reduction proceeds by converting a Ni–Br bond to a Ni–H bond via hydrosilane hydride transfer to a Ni–alkyl bond via olefin insertion. On the basis of two catalytic cycles, the origins for enantioconvergence and enantioselectivity control were discussed.

The enantioconvergent alkyl–alkyl coupling involves two competitive catalytic cycles with nickel(0) and nickel(i) active catalysts, respectively. K₃PO₄ plays a crucial role to enable the hydride transfer from hydrosilane to nickel–bromine species.     

Nonenzymatic kinetic resolution of racemic 2,2,2-trifluoro-1-aryl ethanol via enantioselective acylation

Kinetic resolution of a series of 2,2,2-trifluoro-1-aryl ethanol with (R)-benzotetramisole as the catalyst has been investigated. The result showed that when the aryl group in the substrate was a phenyl (or a phenyl substituted by an electron-donating group) or a naphthyl (an extended phenyl) group, the system could give an s value higher than 20. Preparative KR examples demonstrated the applicability of this method in the preparation of some of enantiomerically pure 2,2,2-trifluoro-1-aryl ethanol or 2,2,2-trifluoro-1-aryl-ethyl iso-butyrate.