Practical asymmetric amine nucleophilic approach for the modular construction of protected α-quaternary amino acids

We report the first amine nucleophilic approach for the modular construction of enantioenriched protected α-quaternary amino acids. The key to success is the use of an alcohol solvent, which makes a rationally designed COOMe-bonded Cu-allenylidene electrophilic intermediate stable enough to couple with amine nucleophiles before its decomposition. The reaction features wide functional group tolerance with high enantioselectivity, typically >90% ee, and is amenable to the modification of commercially available bioactive molecules. The resultant protected α-amino acids could be readily converted into a number of precious enantioenriched amines featuring α-hindered tertiary carbon centers, which are otherwise synthetically quite challenging, including those of α-amino aldehyde, peptides or α-vinyl amino ester with >92% ee in excellent yields. This protocol could be utilized for the synthesis of the protected bioactive α-ethylnorvaline in 3 steps, a significant advancement in comparison to an 11-step sequence reported previously.

We report the first amine nucleophilic approach for the modular construction of enantioenriched protected α-quaternary amino acids.     

Scalable synthesis and coupling of quaternary α-arylated amino acids: α-aryl substituents are tolerated in α-helical peptides

Quaternary amino acids are important tools for the modification and stabilisation of peptide secondary structures. Here we describe a practical and scalable synthesis applicable to quaternary alpha-arylated amino acids (Q4As), and the development of solid-phase synthesis conditions for their incorporation into peptides. Monomeric and dimeric α-helical peptides are synthesised with varying degrees of Q4A substitution and their structures examined using biophysical methods. Both enantiomers of the Q4As are tolerated in folded monomeric and oligomeric α-helical peptides, with the (R)-enantiomer slightly more so than the (S).

Both R and S enantiomers of Fmoc-protected amino acids bearing α-aryl substituents may be made on gram scale. Solid-phase synthesis leads to helical peptides unperturbed by the presence of these additional α-aryl groups.     

Introduction of a quaternary stereogenic center to oxindole using cholinesterase-catalyzed asymmetric hydrolysis

Prochiral diesters bearing an oxindole skeleton were efficiently prepared from oxindole. Cholinesterase-catalyzed hydrolysis of prochiral dipropionate afforded an optically active monoalcohol of 95% e.e. The obtained monoalcohol might find use as a versatile intermediate in the enantioselective synthesis of indole alkaloids.     

Construction of a chiral quaternary carbon center by indium-catalyzed asymmetric alpha-alkenylation of beta-ketoesters

Construction of a nonracemic all-carbon quaternary stereocenter at the alpha-position of beta-ketoesters was achieved by way of an indium(III)-catalyzed diastereoselective alpha-alkenylation reaction of chiral enamines with 1-alkynes. The enamine bearing a chiral auxiliary derived from l-isoleucine was added to the alkyne to give an alpha-alkenylated product in excellent yield and with a stereoselectivity better than 90% ee. One can ascribe the high selectivity to a chelate intermediate involving the auxiliary and the metal atom and the high yield to efficient interactions between the indium(III) atom and the alkyne. The selectivity increased as the reaction temperature was raised to 120 degrees C and decreased at higher temperatures.     

Radical 1,2,3-tricarbofunctionalization of α-vinyl-β-ketoesters enabled by a carbon shift from an all-carbon quaternary center

Herein, we report an intermolecular, radical 1,2,3-tricarbofunctionalization of α-vinyl-β-ketoesters to achieve the goal of building molecular complexity via the one-pot multifunctionalization of alkenes. This reaction allows the expansion of the carbon ring by a carbon shift from an all-carbon quaternary center, and enables further C–C bond formation on the tertiary carbon intermediate with the aim of reconstructing a new all-carbon quaternary center. The good functional group compatibility ensures diverse synthetic transformations of this method. Experimental and theoretical studies reveal that the excellent diastereoselectivity should be attributed to the hydrogen bonding between the substrates and solvent.

Herein, we report an intermolecular, radical 1,2,3-tricarbofunctionalization of α-vinyl-β-ketoesters to achieve the goal of building molecular complexity via the one-pot multifunctionalization of alkenes.

A leading motive for the impressive achievements in the area of assembling molecular complexity is the transformation of simple feedstock chemicals into complex molecular skeletons with superior bioactive properties. In this respect, the direct functionalization of alkenes has been demonstrated as one of the most effective and simple strategies to meet this criterion at a high level. While the difunctionalization of alkenes in a one-pot process is the major theme of considerable interest in this field,¹ the multifunctionalization of alkenes,² for example, a 1,2,3-trifunctionalization of alkenes, has the power to simultaneously incorporate multifunctional groups. Therefore, this multifunctionalization reaction model can be regarded as an efficient and novel strategy to afford molecules with high structural diversity and complexity. However, such methods are elusive.During the last decades, radical alkene functionalizations have been revealed to be a powerful tool for building complex molecular frameworks by employing a radical initiator, a transition metal catalyst, or a photocatalyst.^1f–i However, only several successful methods for the radical multifunctionalization of alkenes have been achieved. For example, the Studer group reported an elegant 1,2-boryl shift-enabled radical 1,2,3-trifunctionalization of allylboronic esters using AIBN as the radical initiator (Fig. 1a).³ Shi et al. disclosed an excellent photocatalytic perfluoroalkylation of a vinyl-substituted all-carbon quaternary center through 1,2-aryl migration (Fig. 1b).⁴ Herein, we report a new one-pot protocol to realize an intermolecular, radical 1,2,3-tricarbofunctionalization of α-vinyl-β-ketoesters through a cascade process of deconstruction–reconstruction of the all-carbon quaternary center (Fig. 1c).⁵Open in a separate windowFig. 1Radical 1,2,3-trifunctionalization of alkenes. (a) Studer''s work; (b) Shi''s work; (c) This work.The direct incorporation of a fluorine atom or fluorinated moieties into organic compounds has been extensively investigated and proved to be an significant synthetic strategy in the field of discovering new pharmaceuticals.⁶ Recently, we are interested in the radical functionalization of alkenes with fluoroalkyl groups,⁷ and we envisioned that, different from the typical Dowd–Beckwith⁸ ring expansion reaction,⁹ the addition of a fluoroalkyl radical to the C C double bond would generate an adduct radical species I, which will transform into the radical intermediate II upon ring expansion (Fig. 1c). Finally, the cascade C–C coupling affords the product with a reconstructed all-carbon quaternary center. However, there are several challenging issues that need to be addressed: (1) the carbon shift from an all-carbon quaternary center to afford a tertiary carbon center which is bulkier than the tertiary carbon center formed in a typical Dowd–Beckwith ring expansion reaction; (2) the reconstruction of all-carbon quaternary center from tertiary carbon radical II will meet the associated conformational restriction and steric congestion; (3) side reactions, such as 1,2-radical addition to the alkenyl group, homolytic couplings of the carbon radical intermediates I and II, and direct H-atom abstraction;¹⁰ (4) how to control the diastereomeric ratio of the products. To meet these challenges, we developed a novel method for the 1,2,3-trifunctionalization of alkenes using alkynyl triflones as both the CF₃ (ref. 6) and alkynyl sources, providing the ring-expanded cyclic β-ketoesters with excellent diastereoselectivity and functional group diversity. In addition, good functional group compatibility of this method was observed, which ensures the diverse synthetic transformations. Moreover, hydrogen bonding between the substrates and 2,2,2-trifluoroethanol solvent was revealed to be the key factor for the excellent diastereoselectivity obtained in this reaction, and this result was confirmed by both experimental and theoretical studies.This study began by surveying radical initiators for 1,2,3-tricarbofunctionalizing α-vinyl-β-ketoester 1a with alkynyl triflone 2a¹¹ (12 (13 dramatically increased the diastereoselectivity and (±)-3a could be obtained in an identical yield with an even higher dr value (dr > 20 : 1) (14 Without the addition of a radical initiator, a reaction did not happen (

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.     

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.     

Enantioselective synthesis of quaternary stereogenic centers through catalytic asymmetric addition of dimethylzinc to α-ketoesters with chiral cis-cyclopropane-based amide alcohol as ligand

A new amino alcohol with a chiral cyclopropane backbone has been developed and used in the catalytic asymmetric diethylzinc addition to various types of α-ketoesters. This cyclopropane-based chiral amino alcohol shows moderate enantioselectivity in the addition of organozinc to α-ketoesters. For dimethylzinc addition to α-ketoesters, up to 81% ee are obtained, respectively.     

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 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.     

Primary trifluoroborate-iminiums enable facile access to chiral α-aminoboronic acids via Ru-catalyzed asymmetric hydrogenation and simple hydrolysis of the trifluoroborate moiety

This work describes the first preparation and application of primary trifluoroborate-iminiums (pTIMs) as a new, easily accessible and valuable class of organoboron derivatives. An array of structurally diverse pTIMs was prepared from potassium acyltrifluoroborates in excellent yields. Highly efficient and enantioselective [(R,R)-TethTsDpen-RuCl] complex-catalyzed hydrogenation of pTIMs provided direct access to chiral primary trifluoroborate-ammoniums (pTAMs). Moreover, facile synthesis of a series of structurally diverse chiral α-aminoboronic acids from chiral pTAMs was accomplished through novel, operationally simple and efficient conversion using hexamethyldisiloxane/aqueous HCl. Using no chromatography at any point, this work allowed easy access to chiral α-aminoboronic acids, as exemplified by the synthesis of optically pure anti-cancer drugs bortezomib and ixazomib.

Starting with potassium acyltrifluoroborates (KATs), N-unprotected chiral α-aminoboronic acids are prepared in three simple steps without chromatography. This facile methodology will tap the broad potential of these valuable compounds.     

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.     

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.     

Synthesis of chiral α-amino acids

A novel method for the synthesis of chiral α-amino acids has been developed where the acid functionality was constructed by oxidizing a hydroxymethyl group introduced by Evans’ method in the α-position of an appropriate acid substrate and the amino part came from the amide of the original carboxyl group following a modified Hofmann rearrangement reaction.     

Asymmetric hydroalkylation of alkynes and allenes with imidazolidinone derivatives: α-alkenylation of α-amino acids

This work reports a new method for the synthesis of quaternary α-alkenyl substituted amino acids by the enantio- and diastereoselective addition of imidazolidinone derivatives to alkynes and allenes. Further hydrolysis of the imidazolidinone products under acidic conditions afforded biologically relevant amino acid derivatives. This method is geometry-selective (E-isomer), enantio- and diastereoselective, and products were obtained in good to excellent yields. The utility of this new methodology is proved by its operational simplicity and the successful accomplishment of gram-scale reactions. Experimental and computational studies suggest the key role of Li in terms of selectivity and support the proposed reaction mechanism.

Enantio-, diastereoselective, geometry-selective addition of imidazolidinone derivatives to alkynes and allenes in the presence of LiHMDS in order to obtain quaternary α-alkenyl substituted amino acids in high isolated yields.     

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.     

Preparation of α-amino acids via Ni-catalyzed reductive vinylation and arylation of α-pivaloyloxy glycine

This work emphasizes easy access to α-vinyl and aryl amino acids via Ni-catalyzed cross-electrophile coupling of bench-stable N-carbonyl-protected α-pivaloyloxy glycine with vinyl/aryl halides and triflates. The protocol permits the synthesis of α-amino acids bearing hindered branched vinyl groups, which remains a challenge using the current methods. On the basis of experimental and DFT studies, simultaneous addition of glycine α-carbon (Gly) radicals to Ni(0) and Ar–Ni(ii) may occur, with the former being more favored where oxidative addition of a C(sp²) electrophile to the resultant Gly–Ni(i) intermediate gives a key Gly–Ni(iii)–Ar intermediate. The auxiliary chelation of the N-carbonyl oxygen to the Ni center appears to be crucial to stabilize the Gly–Ni(i) intermediate.

We have developed Ni-catalyzed reductive coupling of N-carbonyl protected α-pivaloyloxy glycine with Csp²-electrophiles that enabled facile preparation of α-amino acids, including those bearing hindered branched vinyl groups.     

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

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.