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Synthesis 2022; 54(21): 4784-4794
DOI: 10.1055/a-1802-6793
special topic
Asymmetric C–H Functionalization

Synthesis of P- and S-Stereogenic Compounds via Enantioselective C–H Functionalization

Pu-Fan Qian  ‡
a   Center of Chemistry for Frontier Technologies, Department of Chemistry, Zhejiang University, Hangzhou, 310027, P. R. of China
,
Jun-Yi Li‡
a   Center of Chemistry for Frontier Technologies, Department of Chemistry, Zhejiang University, Hangzhou, 310027, P. R. of China
,
Tao Zhou∗
a   Center of Chemistry for Frontier Technologies, Department of Chemistry, Zhejiang University, Hangzhou, 310027, P. R. of China
,
Bing-Feng Shi  ∗
a   Center of Chemistry for Frontier Technologies, Department of Chemistry, Zhejiang University, Hangzhou, 310027, P. R. of China
b   Green Catalysis Center, College of Chemistry, Zhengzhou University, Zhengzhou, Henan, 450001, P. R. of China
c   School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan, 453007, P. R. of China
› Author Affiliations

Financial support from the National Natural Science Foundation of China (NSFC) (21925109 and 21801223), the Open Research Fund of the School of Chemistry and Chemical Engineering of Henan Normal University and the Center of Chemistry for Frontier Technologies of Zhejiang University is gratefully acknowledged.
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Abstract

Transition metal-catalyzed enantioselective C–H functionalization has emerged as an efficient and powerful strategy to access various chiral molecules. Recently, this strategy has also provided a complementary pathway to the construction of P- and S-stereogenic compounds. In this short review, we summarize the development and applications of various catalytic systems: Pd(II)/mono-N-protected amino acids (MPAA), Pd(0)/trivalent phosphorus chiral ligands, chiral cyclopentadienyl-ligated metal catalysts [CpxM(III)] (M = Rh, Ir), half-sandwich d6 Ir(III) and Ru(II) with a chiral carboxylic acid (CCA) ligand, Ir(I)/chiral bidentate boryl ligand, and Ir(I)/chiral cation, for accessing these chiral compounds via enantioselective C–H functionalization.

1 Introduction

2 Pd(II)/Mono-N-protected Amino Acids

3 Pd(0)/Trivalent Phosphorus Chiral Ligands

4 Chiral Cyclopentadienyl-Ligated Metal Catalysts [CpxM(III)] (M = Rh, Ir)

5 Half-sandwich d6 Ir(III) and Ru(II) with a Chiral Carboxylic Acid (CCA) Ligand

6 Ir(I)/Chiral Bidentate Boryl Ligand

7 Ir(I)/Chiral Cation

8 Conclusion and Outlook


#

Key words

enantioselectivity - C–H functionalization - P- and S-stereogenic compounds - chiral ligands - transition metals
1

Introduction

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Pu-Fan Qian(left) was born in Zhejiang, China. He is currently an undergraduate student at the Department of Chemistry, Zhejiang University. He joined the group of Prof. Bing-Feng Shi in 2019, where he focuses on the development of transition-metal-catalyzed asymmetric C–H functionalization reactions. Jun-Yi Li (second left) was born in 2000 in Zhejiang, China. He is an undergraduate student at the Department of Chemistry, Zhejiang University. In the summer of 2020, he joined the laboratory of Prof. Bing-Feng Shi, researching the development and applications of asymmetric C–H activation. Tao Zhou (second right) was born in 1989 Hubei, China. He received his B.Sc. degree (2012) from Shandong University and his Ph.D. (2017) from Nankai University under the supervision of Prof. Bai-Quan Wang. He subsequently worked as a postdoctoral fellow in the group of Prof. Bing-Feng Shi at Zhejiang University. He was promoted to assistant professor in 2021. His current research interests are focused on transition-metal-catalyzed asymmetric C–H activation. Bing-Feng Shi (right) was born in Shandong, China. He received his B.S. degree from Nankai University in 2001 and his Ph.D. in 2006 from the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences under the guidance of Professor Biao Yu. Following time as a postdoctoral fellow at the University of California, San Diego (2006–2007), he moved to The Scripps Research Institute to work with Professor Jin-Quan Yu as a research associate. In 2010, he joined the Department of Chemistry at Zhejiang University as a professor. His research focus is directed toward transition-metal-catalyzed C–H functionalization and its application in the synthesis of biologically important small molecules.

P- and S-stereogenic compounds are highly important motifs in pharmaceuticals and bioactive compounds.[1] [2] They also serve as privileged chiral ligands and catalysts in asymmetric synthesis.[3,4] Thus, significant efforts have been made to develop efficient methodologies for the preparation of these valuable chiral skeletons.[5,6]

In the past decade, transition-metal-catalyzed enantioselective C–H functionalization has emerged as an efficient and powerful strategy to access various chiral molecules.[7] Tremendous progress has been achieved toward the formation of carbon stereogenic centers,[8] axial chirality,[9] and planar chirality.[10] Recently, the construction of P- and S-stereogenic compounds via asymmetric C–H activation has also gained considerable attention.[11] The most commonly used strategy is the desymmetrizing C–H activation of substrates with a prochiral phosphorus or sulfur atom.[12] As demonstrated in Scheme [1], in the desymmetrizing C–H activation strategy, a chiral metallacycle intermediate can be formed via an enantiodetermining C–H cleavage, which can then undergo an inter- or intramolecular functionalization to give the chiral P- and S-stereogenic products. Two other strategies are kinetic resolution (KR) and parallel kinetic resolution (PKR) of racemic P- or S-stereogenic compounds (Scheme [2]).[13] In an asymmetric C–H activation/KR process, one enantiomer is recognized by the chiral catalyst and reacts faster than the other enantiomer to give the chiral metallacycle, which can then be functionalized to give the desired product and residual starting material in enantioenriched form (Scheme [2a]). While in an asymmetric C–H activation/PKR process, both enantiomers of the starting material can be transformed into different enantiomerically enriched products in one pot (Scheme [2b]).

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Scheme 1 Synthesis of P- and S-stereogenic compounds via desymmetric C–H functionalization
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Scheme 2 Synthesis of P- and S-stereogenic compounds via KR and PKR

In this short review, we summarize recent advances on the synthesis of these valuable chiral compounds via enantioselective C–H functionalization. For clarity, this review is classified according to the type of catalytic system: Pd(II)/mono-N-protected amino acids, Pd(0)/trivalent phosphorus chiral ligands, chiral cyclopentadienyl-ligated metal catalysts [CpxM(III)] (M = Rh, Ir), half-sandwich d6 Ir(III) and Ru(II) with a chiral carboxylic acid (CCA) ligand, Ir(I)/chiral bidentate boryl ligand, and Ir(I)/chiral cation.


# 2

Pd(II)/Mono-N-protected Amino Acids

Palladium has received extensive attention in C–H functionalization reactions because of the diverse reactivities of palladacycles, which can be transformed into various synthetically useful products with new C–C, C–N, C–O, and C–X bonds.[14] In 2008, Yu and co-workers pioneeringly developed Pd(II)-catalyzed enantioselective C–H functionalization using mono-N-protected amino acids (MPAA) as chiral ligands.[15] MPAA-type ligands have been recognized as one of the most successful types of chiral ligands in Pd(II)-catalyzed asymmetric C–H functionalizations.[16]

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Scheme 3 Pd(II)/MPAA-catalyzed enantioselective C–H arylation of arylphosphinamides

In 2015, the Han group successfully applied such a catalytic system for the synthesis of P-stereogenic phosphinamides (Scheme [3a]).[17] This work represents the first asymmetric synthesis of P-chiral organophosphorus compounds via enantioselective C–H activation. In their previous work, the stable palladacycle 4 was isolated from DMF, which could react smoothly with p-tolylboronic acid (2a) to give the arylated product rac-3a (Scheme [3b]).[18] Based on the racemic version, Han’s group successfully realized the asymmetric synthesis of chiral phosphinamides 3 in up to 98% ee when MPAA L1 was used as the chiral ligand. Various phosphinamides 1 and arylboronic acids 2 bearing both electron-donating and electron-withdrawing groups were well tolerated in this protocol. Recently, Han and Qin reported that the P-stereogenic phosphinamides 3 could be used as chiral organocatalysts in the desymmetric enantioselective reduction of cyclic 1,3-diketones (Scheme [4]),[19] which served as strategic transformations in the synthesis of four cyathane-type and two hamigeran-type terpenoids.[11c]

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Scheme 4 Desymmetric enantioselective reduction of cyclic 1,3-diketones

In 2018, Wang and co-workers reported a Pd(II)-catalyzed enantioselective C–H olefination of diaryl sulfoxides via desymmetrization and PKR (Scheme [5]).[20] The optimization of a range of different MPAAs revealed that Ac-Leu-OH was the best ligand for this transformation. It should be noted that pre-stirring of Pd(OAc)2 and Ac-Leu-OH in HFIP for 2 hours was necessary, which prevented the deactivation of catalyst by coordination of the Pd(II) catalyst with sulfoxide. A wide range of diaryl sulfoxides 7 bearing both electron-donating and weakly electron-withdrawing groups at the para-, meta-, and ortho-positions were all well tolerated, affording the olefination products 9 in moderate yields and with good ee values (Scheme [5a]). All of the diaryl sulfoxides with meta-substituents on the phenyl groups were regioselectively olefinated at the sterically less hindered ortho position. The PKR of rac-10 afforded a pair of enantiomers, (S)-11 and (R)-12, in excellent enantioselectivities when the reaction temperature was increased to 100 °C (Scheme [5b]). Although a small amount of methyl (E)-3-(2-phenylsulfonyl)phenylacrylate was detected in the reaction of 7a (Scheme [5a]) (R1 = H, R = CO2Me), the investigation of the time dependence on the ee values and the relative yields of 9b (R1 = H, R = CO2Et) ruled out the possibility of selective oxidation of one of the olefinated sulfoxides via a KR process and the enantioselectivity was induced during the Pd(II)/MPAA-catalyzed C–H cleavage step.

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Scheme 5 Palladium(II)-catalyzed enantioselective C–H olefination of diaryl sulfoxides
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Scheme 6 Pd(II)-catalyzed enantioselective C–H alkynylation/kinetic resolution of 2-(arylsulfinyl)pyridines
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Scheme 7 Pd(II)-catalyzed C–H arylation and olefination of sulfoximines

Previously, Shi and co-workers realized that readily available and inexpensive l-pyroglutamic acid (L3) was an efficient chiral ligand in Pd(II)-catalyzed atroposelective C–H activation.[21] In 2021, they further extended the Pd(II)/l-pyroglutamic acid catalytic system to the construction of S-stereocenters.[22] They reported a Pd(II)-catalyzed enantioselective C–H alkynylation of 2-(arylsulfinyl)pyridines via kinetic resolution, giving the alkynylated sulfoxides 15 and recovered (S)-13 in excellent yields and high stereospecificities with s-values of up to 354 (Scheme [6]). The reaction could be conducted on gram scale and the alkynylation products could be easily transformed into several other types of potentially useful chiral sulfoxide scaffolds.

Almost at the same time, Sahoo and co-workers reported the kinetic resolution of sulfur-stereogenic sulfoximines via Pd(II)/MPAA-catalyzed C–H arylation and olefination (Scheme [7]).[23] Boc-l-Thr(Bn)-OH was the optimal ligand for this transformation. A variety of sulfoxides rac-16 were compatible with this protocol, giving access to a range of highly functionalized sulfoximines in good yields and excellent enantioselectivities.


# 3

Pd(0)/Trivalent Phosphorus Chiral Ligand

Trivalent phosphorus chiral ligands are privileged ligands in palladium(0)-catalyzed asymmetric C–H activation.[24] In 2015, the Duan group presented a Pd(0)-catalyzed intramolecular C–H arylation to construct P-chiral phosphinic amides (Scheme [8a]).[25] A range of chiral phosphinic amides was obtained in good yields (58–94%) and enantioselectivities (83–93% ee) via intramolecular arylation/cyclization of N-(o-bromoaryl)diarylphosphinic amides 19 in the presence of Pd(OAc)2 and TADDOL-based phosphoramide L5. Substrates with both electron-donating and electron-withdrawing groups were well tolerated. Moreover, the P–N bond in the products could be cleaved by organolithium compounds to access P-chiral biphenyl monophosphine ligands. For example, compound 20a could be converted into ligands 21a and 21b with the enantiomeric ratio maintained (Scheme [8c]). Liu, Ma and co-workers independently disclosed the same reaction using a similar ligand L6, furnishing the corresponding P-chiral products in up to 99% yield and 99% ee (Scheme [8b]).[26]

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Scheme 8 Pd(0)-catalyzed enantioselective C–H arylation of phosphinic amides

Shortly after, the Tang group developed a Pd(0)-catalyzed enantioselective C–H arylation/cyclization for the synthesis of P-chiral biaryl phosphonates (Scheme [9]).[27] The P-chiral mono-phosphorus ligand L7, which was first developed by Tang and co-workers in 2010,[28] was used as the chiral ligand. Both electron-poor and electron-rich substrates reacted smoothly to afford the desired products in up to 92% yield and 88% ee (Scheme [9a]). P-Chiral biaryl phosphonate 23a could be transformed into phosphine oxide 25 and its enantiomer ent-25 by reversing the addition order of the alkyl lithium. Compounds 25 and ent-25 could be stereospecifically reduced to give P-chiral dialkylphosphines following a literature procedure (Scheme [9b]).[29]

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Scheme 9 Pd(0)-catalyzed enantioselective C–H arylation of biaryl phosphonates

In 2017, Cui, Xu and co-workers reported a desymmetric synthesis of P-stereogenic phosphole oxides 28 via enantioselective intramolecular C–H arylation using (S,S)-Me-Duphos (L8) as a chiral ligand (Scheme [10a]).[30] However, only moderate enantioselectivities were achieved for most examples. In 2019, the Duan group realized the same reaction with superior results (Scheme [10b]).[31] Both enantiomers of the P-stereogenic dibenzophospholes 28 were obtained by employing two different catalytic systems. Products (S)-28 could be obtained in up to 95% yield and 90% ee when using Pd(PCy3)2 in the presence of chiral phosphoric acid/amide ligands (Conditions A: L9/L10 = 1:1), while the opposite enantiomer (R)-28 could be gained in moderate yields and good enantioselectivities when using Pd(OAc)2 and (R)-Segphos (L11) (Conditions B).

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Scheme 10 Pd(0)-catalyzed enantioselective C–H arylation of phosphine oxides

# 4

Chiral Cyclopentadienyl-Ligated Metal Catalysts [CpxM(III)] (M = Rh, Ir)

The use of chiral cyclopentadienyl (Cpx)-ligated metal catalysts [CpxM(III)] in asymmetric C–H activation was first reported by the groups of Rovis[32] and Cramer in 2012,[33] with the reactions proceeding via Rh(III)-catalyzed enantioselective C–H functionalization. This strategy has been developed rapidly.[34]

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Scheme 11 Chiral CpxIr(III)-catalyzed asymmetric C–H amidation assisted by a chiral carboxylic acid

In 2017, Cramer and co-workers reported the synthesis of P-stereogenic organophosphine oxides via chiral CpxIr(III)-catalyzed asymmetric C–H amidation (Scheme [11]).[35] P-Chiral compounds 31 were obtained in excellent yields and ee values (up to 95% yield and 98% ee) when N-phthaloyl tert-leucine (S)-L12 was used in combination with chiral catalyst (R)-Ir1. Substrates with electron-rich arenes were more reactive than those with electron-poor arenes. Both the reactivity and selectivity were significantly improved with sterically bulkier R2 groups. Moreover, both the reactivity and enantioselectivity of this reaction were mainly controlled by the chiral Cpx ligand, as the achiral catalyst [Cp*IrCl2]2 led to only a marginal yield and ee value in the presence of chiral acid (S)-L12. On the other hand, when (R)-L12 was used instead of (S)-L12, the ee of 31a dropped dramatically (from 92% to 20%), accompanied with a sharp decrease of the yield. Consequently, a matched–mismatched cooperation was proved to exist between the chiral catalyst (R)-Ir1 and the chiral carboxylic acid. In 2018, Cramer reported the asymmetric C–H arylation of phosphine oxides 29 using the same catalytic system (Scheme [12]).[36] Three types of chiral products, including P-chiral products, both P- and axially chiral products, and axially chiral products, were obtained in high yields and enantioselectivities. The phosphine oxides 33 could be reduced to chiral monodentate phosphine (MOP) ligands 35 with the ee values maintained.

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Scheme 12 Chiral CpxIr(III)-catalyzed asymmetric C–H arylation assisted by a chiral carboxylic acid

The Cramer group have also reported the construction of P-stereogenic phosphine amides via chiral CpxRh(III)-catalyzed desymmetrizing C–H annulation with alkynes (Scheme [13a]).[37] By using (R)-Rh1 as the chiral catalyst and Ag2CO3 as the oxidant, the target compounds 38 were formed in up to 86% yield and 92% ee. Unsymmetrical diaryl alkynes also worked well. Deuteration studies revealed that the reversibility of C–H activation was significantly reduced by the additive K2CO3, distinctly contributing to the promotion of enantioselectivity. Subsequently, Cramer successfully realized the synthesis of P-stereogenic phosphine amides via kinetic resolution of rac-39 using (R)-Rh2 as the chiral catalyst (Scheme [13b]).[38] The introduction of a bulky third substituent at the central position of the chiral Cp ring led to a substantially increased selectivity for the kinetic resolution, whilst the presence of a tert-butyl group allowed for an s-factor of up to 50.

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Scheme 13 Chiral CpxRh(III)-catalyzed asymmetric C–H annulation of phosphinamides via desymmetrization/kinetic resolution

In 2021, Wang, Li and co-workers reported the 1:2 coupling of phosphinamides with diarylacetylenes for the enantio- and diastereoselective synthesis of axially chiral biaryls bearing a P-stereogenic center. (Scheme [14]).[39] Employing chiral (R)-Rh3 as the catalyst, the desired products were obtained in good yields and enantioselectivities. Both para- and meta-substituted diarylphosphinic amides were compatible, while the C–H arylation was inhibited by ortho-substituted substrates 41 and meta- or ortho-substituted diarylacetylenes. Remarkably, the stereochemistry of the final product 42 was suggested to be determined by the twofold C–H activation steps together, instead of the first desymmetrizing C–H cleavage step only. Additionally, the obtained compound 42a could be transformed into monophosphine ligand 44, which was used as an efficient chiral ligand in a Pd-catalyzed asymmetric allylic alkylation to provide 47 in 81% yield and 90% ee.

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Scheme 14 Chiral CpxRh(III)-catalyzed asymmetric C–H arylation of phosphinamides

In 2018, Li and co-workers reported a chiral CpXRh(III)-catalyzed enantioselective C–H activation/annulation of sulfoximines with diazo compounds.[40] In their original design, the left section of the metal intermediate is shielded by an R-configured binaphthyl backbone, and the top front and the bottom back sections are blocked by the 2- and 2′-substituents, respectively, which orients the large substrate (SL) distal to the bottom blocking group (Scheme [15]). Therefore, the steric bulk of the carboxylic acid should have a direct impact on the stereochemical outcome, which means changing the substituent structure of the carboxylic acid may result in configuration inversion of the desired products. As expected, the use of Rh4 with 2-methoxybenzoic acid gave (R)-50 in high yields and with good enantioselectivities (Scheme [16a]). Meanwhile, the use of sterically more hindered 2,6-dimethoxybenzoic acid afforded products (S)-50 in high yields and good enantioselectivities (Scheme [16b]). A wide range of diaryl sulfoximines and diazo compounds were well tolerated. The H/D exchange experiments suggested that the C–H activation process was irreversible, which was also the rate-determining step as indicated by measurement of the KIEs in intermolecular competition experiments.

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Scheme 15 Rationale behind the enantioselective control by the chiral CpXRh(III) catalyst
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Scheme 16 Chiral CpXRh(III)-catalyzed enantioselective C–H annulation of sulfoximines

Also in 2018, the Cramer group independently reported the synthesis of chiral sulfoximines in high yields and with good enantioselectivities by using isopropyl-substituted chiral Cpx ligand Rh5 in combination with chiral tert-leucine-derived ligand L13 (Scheme [17]).[41] Broad ranges of diaryl sulfoximines and diazo compounds with different substitution patterns were well tolerated. In 2019, the Cramer group reported the asymmetric synthesis of sulfur-stereogenic sulfoximines by exploiting CpXRh(III)-catalyzed C–H annulation/kinetic resolution (Scheme [18]).[42] Sulfoximines rac-51 could be transformed into (R)-52 and unreacted (S)-51, with high enantioselectivities, by the use of cationic Rh6 in combination with L14. Wide ranges of diaryl sulfoximines and diazo compounds were well tolerated, ensuring s-values of up to 200. The reaction kinetics were obtained by 1H NMR, which suggested that the (R)-isomer reacted 20 times faster than the (S)-isomer and reached complete conversion at 6.5 hours during this transformation, corresponding well to the observed resolution selectivity. A control experiment showed that the transformation would not occur in the absence of L14.

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Scheme 17 Chiral CpxRh(III)/CCA-catalyzed enantioselective C–H functionalization of sulfoximines

# 5

Half-sandwich d6 Ir(III) and Ru(II) with a Chiral Carboxylic Acid (CCA) Ligand

Carboxylate additives generally play an important role in trivalent group 9 metal-catalyzed C–H functionalization reactions by a carboxylate-assisted concerted metalation–deprotonation (CMD) pathway.[43] Stimulated by their preceding work on the diastereoselective synthesis of arylphosphoryls controlled by chiral auxiliaries,[44a] Chang and co-workers studied the role of carboxylic acid additives in Ir(III)-catalyzed C–H aminations. In this seminal study, the authors realized the achiral Cp*Ir(III)-catalyzed enantioselective C–H amination of prochiral diphenylphosphoryl compounds 29 by using O,O-dipivaloyl-l-tartaric acid L15 as the external chiral ligand (Scheme [19]).[44b] However, the corresponding products were generated in low enantioselectivities (11–32% ee). Recently, highly enantioselective C–H functionalization enabled by the combination of achiral Cp*M(III) (M = Co, Rh, Ir) or (p-cymene)Ru(II) and an external chiral ligand has become an enabling catalytic system to access various chiral molecules.[45]

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Scheme 18 Chiral cationic CpXRh(III)-catalyzed kinetic resolution of sulfur-stereogenic sulfoximines
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Scheme 19 Achiral Cp*Ir(III)/CCA-catalyzed enantioselective C–H amination

Recently, the Duan group progressed the construction of biaryl phosphine oxides with both P-central and axial chirality (Scheme [20]).[46] By combining an achiral Cp*Ir(III) species and chiral carboxylic amide L16, the phosphine oxides 53 could be obtained in moderate to good yields and with high enantioselectivities. Interestingly, when replacing N-methyl-substituted amide L17 with the N-OMe-substituted amide L18, the enantioselectivity increased dramatically (from 4% to 60%) along with an obvious improvement in the yield and dr value. This transformation can be conducted on gram scale, affording product 53a in 69% yield (1.05 g), 90% ee and 14:1 dr. The corresponding products could be reduced to trivalent phosphines by MeOTf/LiAlH4 without erosion of the ee value.

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Scheme 20 Achiral Cp*Ir(III)-catalyzed asymmetric C–H functionalization enabled by chiral carboxylic amides

In 2020, He and co-workers reported a dual-ligand-enabled Ir(III)-catalyzed highly enantioselective C–H amidation of diaryl sulfoxides (Scheme [21]).[47] The N-Piv-Me-Pro-OH (L19) and the sterically hindered ligand Cp*tBu were crucial for obtaining high yields and ee values. A wide range of chiral sulfoxides was obtained via desymmetrization (Scheme [21a]) and parallel kinetic resolution (Scheme [21b]) in good yields and ee values. Unlike the phosphine oxides 29, in which the O atom coordinates with the iridium catalyst, The S atom in sulfoxides 54 may coordinate with iridium(III). Derivatization of S-stereogenic amides into several potentially useful S-chiral bidentate and tridentate ligands was also achieved, which shows the high value of utility of this transformation. Kinetic isotope effect experiments suggested that C–H cleavage may occur as part of the turnover-limiting step.

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Scheme 21 Ir(III)/CCA-catalyzed enantioselective C–H amidation for the synthesis of chiral sulfoxides

In 2021, Shi and co-workers reported the first (p-cymene)Ru(II)-catalyzed asymmetric C–H activation enabled by CCA ligands.[48] They successfully achieved the synthesis of sulfur-stereogenic sulfoximines via ruthenium(II)-catalyzed enantioselective C–H functionalization assisted by C 1-symmetric binaphthyl monocarboxylic acids L20 and L21 (Scheme [22]).[48] This was the first report of a ruthenium(II)-catalyzed asymmetric C–H functionalization via an enantiodetermining C–H cleavage step. A wide range of chiral sulfoximines was obtained in good to excellent yields and enantioselectivities via desymmetrization (Scheme [22a]), kinetic resolution (Scheme [22b]) and parallel kinetic resolution (Scheme [22c]). Hydrogen bond interactions between the amide group on the ligand and the hydrogen atom on sulfoximine 48 were proposed to explain the high stereospecificity of this transformation (Figure [1]). Shortly after, Matsunaga and co-workers independently reported a similar Ru(II)-catalyzed enantioselective C–H functionalization using L22 as the chiral ligand, giving the products with significantly lower ee values.[49]

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Scheme 22 Ru(II)-catalyzed enantioselective C–H functionalization enabled by C 1-symmetric monocarboxylic acids
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Figure 1 Postulated stereoinduction model involving N–H…O hydrogen bonding interactions

# 6

Ir(I)/Chiral Bidentate Boryl Ligand

In 2021, Ke, Xu, and co-workers demonstrated an Ir(I)-catalyzed enantioselective C–H borylation of diarylphosphinates 66 using the chiral bidentate boryl ligand (CBL) L23 as a chiral ligand (Scheme [23]).[50] Borylated phosphorus compounds 68, substituted with a variety of functional groups, were obtained in up to 92% ee. Surprisingly, when the iso-hexafluoropropyl group in substrate 66 was changed to trifluoroethyl, the ee value of the product reduced dramatically to 66%, and even lower ee values were obtained by using simple alkyl diarylphosphinates, indicating that the fluorinated alkoxy moiety was essential for acquiring high enantioselectivity. This was supported by density functional theory (DFT) studies. Additionally, the gram-scale borylation of diphenylphosphinate 66a was also feasible, generating the desired product 68a in 67% yield with only a slight decrease in the ee value. Further transformations of the resulting borylated phosphorus compounds could also be performed.

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Scheme 23 Iridium-catalyzed enantioselective C–H borylation of diarylphosphinates

# 7

Ir(I)/Chiral Cation

All of the above-mentioned examples on the synthesis of P- and S-stereogenic compounds were achieved via asymmetric functionalization of ortho-C–H bonds. In 2020, Phipps and co-workers realized the first synthesis of chiral phosphinamides via Ir-catalyzed enantioselective remote C–H activation enabled by a chiral cation ligand (Scheme [24]).[51] A common bipyridine anionic ligand paired with a chiral cation derived from quinine was used as the ligand (L24). This ion-paired complex afforded chiral borylated phosphinamides with high enantioselectivities via long-range asymmetric induction. A substrate test revealed that ortho-substituted symmetrical phosphinamides gave poor outcomes, probably due to the fact that the bulky ortho-substituted aromatic ring affects the substrate–ligand interactions.

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Scheme 24 Iridium-catalyzed, enantioselective, remote C–H borylation of phosphinamides

# 8

Conclusion and Outlook

In this short review, we have described recent progress on asymmetric C–H activation for the synthesis of P- and S-stereogenic compounds. Although enantioselective C–H functionalization has proved to be an efficient strategy to access valuable P- and S-stereogenic compounds, several critical issues remain to be addressed. First, these reactions rely on the use of noble-metal catalysts, such as Pd, Rh, and Ir, hence the development of base-metal-catalyzed asymmetric C–H activation is highly desirable. Second, no reports on the construction of P- and S-stereocenters via C(sp3)–H activation have been reported, despite the burgeoning of enantioselective C(sp3)–H activation. Finally, significant efforts should be devoted to the use of these P- and S-stereogenic compounds in drug discovery and asymmetric synthesis. Innovative strategies for the synthesis of P- and S-stereogenic compounds via enantioselective C–H functionalization will continue to be discovered and stimulate advances in related fields.


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Conflict of Interest

The authors declare no conflict of interest.


Corresponding Authors

Tao Zhou
Center of Chemistry for Frontier Technologies, Department of Chemistry, Zhejiang University
Hangzhou, 310027
P. R. of China   

Bing-Feng Shi
Center of Chemistry for Frontier Technologies, Department of Chemistry, Zhejiang University
Hangzhou, 310027
P. R. of China   

Publication History

Received: 22 February 2022

Accepted after revision: 18 March 2022

Accepted Manuscript online:
18 March 2022

Article published online:
12 May 2022

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Pu-Fan Qian(left) was born in Zhejiang, China. He is currently an undergraduate student at the Department of Chemistry, Zhejiang University. He joined the group of Prof. Bing-Feng Shi in 2019, where he focuses on the development of transition-metal-catalyzed asymmetric C–H functionalization reactions. Jun-Yi Li (second left) was born in 2000 in Zhejiang, China. He is an undergraduate student at the Department of Chemistry, Zhejiang University. In the summer of 2020, he joined the laboratory of Prof. Bing-Feng Shi, researching the development and applications of asymmetric C–H activation. Tao Zhou (second right) was born in 1989 Hubei, China. He received his B.Sc. degree (2012) from Shandong University and his Ph.D. (2017) from Nankai University under the supervision of Prof. Bai-Quan Wang. He subsequently worked as a postdoctoral fellow in the group of Prof. Bing-Feng Shi at Zhejiang University. He was promoted to assistant professor in 2021. His current research interests are focused on transition-metal-catalyzed asymmetric C–H activation. Bing-Feng Shi (right) was born in Shandong, China. He received his B.S. degree from Nankai University in 2001 and his Ph.D. in 2006 from the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences under the guidance of Professor Biao Yu. Following time as a postdoctoral fellow at the University of California, San Diego (2006–2007), he moved to The Scripps Research Institute to work with Professor Jin-Quan Yu as a research associate. In 2010, he joined the Department of Chemistry at Zhejiang University as a professor. His research focus is directed toward transition-metal-catalyzed C–H functionalization and its application in the synthesis of biologically important small molecules.
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Scheme 1 Synthesis of P- and S-stereogenic compounds via desymmetric C–H functionalization
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Scheme 2 Synthesis of P- and S-stereogenic compounds via KR and PKR
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Scheme 3 Pd(II)/MPAA-catalyzed enantioselective C–H arylation of arylphosphinamides
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Scheme 4 Desymmetric enantioselective reduction of cyclic 1,3-diketones
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Scheme 5 Palladium(II)-catalyzed enantioselective C–H olefination of diaryl sulfoxides
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Scheme 6 Pd(II)-catalyzed enantioselective C–H alkynylation/kinetic resolution of 2-(arylsulfinyl)pyridines
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Scheme 7 Pd(II)-catalyzed C–H arylation and olefination of sulfoximines
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Scheme 8 Pd(0)-catalyzed enantioselective C–H arylation of phosphinic amides
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Scheme 9 Pd(0)-catalyzed enantioselective C–H arylation of biaryl phosphonates
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Scheme 10 Pd(0)-catalyzed enantioselective C–H arylation of phosphine oxides
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Scheme 11 Chiral CpxIr(III)-catalyzed asymmetric C–H amidation assisted by a chiral carboxylic acid
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Scheme 12 Chiral CpxIr(III)-catalyzed asymmetric C–H arylation assisted by a chiral carboxylic acid
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Scheme 13 Chiral CpxRh(III)-catalyzed asymmetric C–H annulation of phosphinamides via desymmetrization/kinetic resolution
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Scheme 14 Chiral CpxRh(III)-catalyzed asymmetric C–H arylation of phosphinamides
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Scheme 15 Rationale behind the enantioselective control by the chiral CpXRh(III) catalyst
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Scheme 16 Chiral CpXRh(III)-catalyzed enantioselective C–H annulation of sulfoximines
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Scheme 17 Chiral CpxRh(III)/CCA-catalyzed enantioselective C–H functionalization of sulfoximines
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Scheme 18 Chiral cationic CpXRh(III)-catalyzed kinetic resolution of sulfur-stereogenic sulfoximines
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Scheme 19 Achiral Cp*Ir(III)/CCA-catalyzed enantioselective C–H amination
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Scheme 20 Achiral Cp*Ir(III)-catalyzed asymmetric C–H functionalization enabled by chiral carboxylic amides
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Scheme 21 Ir(III)/CCA-catalyzed enantioselective C–H amidation for the synthesis of chiral sulfoxides
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Scheme 22 Ru(II)-catalyzed enantioselective C–H functionalization enabled by C 1-symmetric monocarboxylic acids
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Figure 1 Postulated stereoinduction model involving N–H…O hydrogen bonding interactions
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Scheme 23 Iridium-catalyzed enantioselective C–H borylation of diarylphosphinates
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Scheme 24 Iridium-catalyzed, enantioselective, remote C–H borylation of phosphinamides