VOLUME 53, NO. 1 | 2020 CHEMISTRY IN CHINA SPECIAL ISSUE (中国特刊 )

ALDRICHIMICA ACTA

CONTRIBUTORS TO THIS ISSUE (此特刊的贡献者 )

Xiaoming Feng (冯小明), Sichuan University Shu-Li You (游书力), SIOC, Chinese Academy of Sciences Xuefeng Jiang (姜雪峰 ), East China Normal University Wenjun Tang (汤文军 ), SIOC, Chinese Academy of Sciences

The life science business of Merck KGaA, Darmstadt, Germany operates as MilliporeSigma in the U.S. and Canada. DEAR READER:

1 Nature Index Country/Territory Outputs – By most measures, China’s transformation over the past half-century Chemistry (https://www.natureindex.com/ country-outputs/generate/Chemistry/global/ has been nothing short of spectacular, with its economy now ranked All/n_article) second in the world, an annual GDP north of USD 13 trillion, and 119 2 Nature Index 2019 Tables: Institutions – Chemistry (https://www.natureindex.com/ Chinese companies making it into Fortune magazine’s Global 500 list. annual-tables/2019/institution/all/chemistry) Noteworthy also are China’s commitment to, and remarkable advances in, basic and applied research in the natural sciences. Factors such as increased funding for scientific research, workforce qualification and size, and research output, quality, and innovation have propelled China to the #1 spot worldwide in terms of chemistry papers published,1 and Chinese Universities to occupy 5 of the top 10 spots in chemistry research quality worldwide.2

At Merck KGaA, Darmstadt, Germany, we laud China’s vigorous research efforts in chemistry and the life sciences, which we believe hold great promise for improving the quality of life for millions of people throughout the world. Moreover, we look forward to establishing strong collaborations with Chinese researchers to make their inventions more accessible worldwide to advance human health for all.

Sincerely yours,

Klaus-Reinhard Bischoff Executive Vice President, MilliporeSigma Head of Research Solutions Global Business Unit

The life science business of Merck KGaA, Darmstadt, Germany operates as MilliporeSigma in the U.S. and Canada. ALDRICHIMICA

ACTA VOL. 53, NO. 1 • 2020

“PLEASE BOTHER US.”

Dear Fellow Chemists,

Professor Xiaoming Feng of the College of Chemistry at Sichuan University kindly suggested that we offer Feng L -PiPr (904988) and Feng L -PrPr Merck KGaA, Darmstadt, Germany 3 2 3 2 (904961) as chiral, N,N’-dioxide ligands for metals such as nickel(II), Frankfurter Strasse 250 indium(III), scandium(III), cobalt(II), yttrium(III), and magnesium(II). 64293 Darmstadt, Germany The resulting stable complexes act as efficient catalysts for a number Phone +49 6151 72 0 of important asymmetric transformations such as ring opening–cycloaddition, Michael addition– alkylation, 1,3-dipolar cycloaddition, and homologation of α-keto esters—leading to the desirable To Place Orders / Customer Service products in high yields and very high diastereo- and enantioselectivities. Contact your local office or visit (1) Zhang, H. et al. Org. Lett. 2019, 21, 2388. (2) Kuang, Y. et al. Chem. Sci. 2018, 9, 688. SigmaAldrich.com/order (3) Zhang, D. et al. Chem. Commun. 2017, 53, 7925. (4) Li, W. et al. Angew. Chem., Int. Ed. 2013, 52, 10883. Technical Service Contact your local office or visit + + + + N – – N N – – N SigmaAldrich.com/techinfo O O O O H H O N H N O O N H N O i-Pr i-Pr i-Pr i-Pr i-Pr i-Pr General Correspondence i-Pr i-Pr Editor: Sharbil J. Firsan, Ph.D. [email protected] 904988 904961 Feng L3-PiPr2 Feng L3-PrPr2 (1R,1'R,2S,2'S) (1R,1'R,2S,2'S) Subscriptions 904988 Feng L3-PiPr2, ≥95% 100 mg Request your FREE subscription to the Aldrichimica Acta at SigmaAldrich.com/Acta 904961 Feng L3-PrPr2, ≥95% 100 mg

We welcome your product ideas. Email your suggestion to [email protected].

Udit Batra, Ph.D. CEO, Life Science

TABLE OF CONTENTS Asymmetric Catalysis Enabled by Chiral N,N'-Dioxide–Nickel(II) Complexes . 3 Zhen Wang, Xiaohua Liu,* and Xiaoming Feng,* Sichuan University Asymmetric Allylic Substitutions Catalyzed by Iridium Complexes Derived from C(sp2)–H Activation of Chiral Ligands . 11 Xiao Zhang and Shu-Li You,* SIOC, Chinese Academy of Sciences Recent Advances in Sulfuration Chemistry Enabled by Bunte Salts...... 19 Ming Wang, Yaping Li, and Xuefeng Jiang,* East China Normal University P-Chiral Phosphorus Ligands for Cross-Coupling and Asymmetric Hydrogenation Reactions . 27 Ting Wu, Guangqing Xu, and Wenjun Tang,* SIOC, Chinese Academy of Sciences

ABOUT OUR COVER The entire Aldrichimica Acta archive is available How did we in the West end up calling Zhōngguó (中国), China? Several theories exist, but what is at SigmaAldrich.com/Acta making the “Central State” a critical player on the world stage today is not fine china, silk, or tea; rather, it is the breathtaking advances it has made in the past few decades, particularly in science Aldrichimica Acta (ISSN 0002-5100) is a and technology. We, of course, are mostly interested in publication of Merck KGaA, Darmstadt, the life science and physical science advances there. What Germany. better to illustrate these advances than the small selection of world-class chemical research that we are featuring in this issue—research that is being carried out at some of Copyright © 2020 Merck KGaA, Darmstadt, the most prestigious Chinese institutions. We hope this gets Germany and/or its affiliates. All Rights you as excited about the promise of chemistry research in Reserved. MilliporeSigma, the vibrant M China and its benefit to mankind as it does us. and Sigma-Aldrich are trademarks of Merck One Hundred Flowers (ink and color on silk, 41.9 x 649 KGaA, Darmstadt, Germany or its affiliates. cm) is an unattributed, fine handscroll composed during the All other trademarks are the property of their Qing Dynasty after the style of the well-known Chinese artist Detail from One Hundred Flowers. Photo courtesy respective owners. Detailed information on The Metropolitan Museum of Art, New York, NY. Yun Shouping (1633–1690). It depicts a recurring theme in trademarks is available via publicly accessible earlier Chinese paintings—flowers in bloom in a seemingly natural setting. This, however, is clearly resources. Purchaser must determine the a composite scene of blooming peonies* with other blossoming flowers, not unlike the still-life-with- suitability of the products for their particular flowers genre in western paintings. use. Additional terms and conditions may This painting is a bequest of John M. Crawford Jr. to the Metropolitan Museum of Art, New apply. Please see product information on the York, NY. Sigma-Aldrich website at SigmaAldrich.com and/or on the reverse side of the invoice or * Peonies appear in many Chinese paintings of the past. What could the reason be? To find out, packing slip. visit SigmaAldrich.com/Acta Find your Lead Leverage DNA-encoded library technology for drug discovery Accelerate your drug discovery with the DNA-encoded library (DEL) technology, an alternative approach to high-throughput screening (HTS) compound libraries for effective hit and lead discovery.

Learn more about the DyNAbind off-the-shelf DNA-encoded library, visit SigmaAldrich.com/DEL

The life science business of Merck KGaA, Darmstadt, Germany operates as MilliporeSigma in the U.S. and Canada. Aldrichimica ACTA 3 VOL. 53, NO. 1 • 2020 Asymmetric Catalysis Enabled by Chiral N,N'-Dioxide–Nickel(II) Complexes

Zhen Wang, Xiaohua Liu,* and Xiaoming Feng* Key Laboratory of Green Chemistry and Technology Ministry of Education College of Chemistry Sichuan University 29 Wangjiang Road, Jiuyan Bridge Chengdu, Sichuan 610064, China Prof. Z. Wang Prof. X. M. Feng Email: [email protected]; [email protected]

Prof. X. H. Liu

Keywords. asymmetric catalysis; chiral N,N’-dioxide ligand; 1. Introduction nickel(II) complex; rearrangements; ene-type reactions; Friedel– Catalytic asymmetric reactions have been recognized as fundamental Crafts reaction; allylboration; Mannich reaction; Michael reaction; synthetic methods for the construction of optically active bioactive compounds. compounds.1–5 Impressive progress has been achieved by using sets of privileged synthetic chiral catalysts that include ligand−metal Abstract. The development of efficient catalysts and ligands bearing complexes and organocatalysts.3,5 In enantioselective coordination novel chiral backbones plays a crucial role in asymmetric catalysis. catalysis and organometallic catalysis, ligand–metal interactions 6 Our group has developed conformationally flexible, C2-symmetric play a key role in almost every event. An important property of N,N’-dioxide amide compounds as a new class of privileged ligands, the metal species is their ability to bind the substrate molecules via which form complexes with a number of metal salts leading to redistribution of electron density or cleavage in a specific array that efficient catalysts for a number of asymmetric reactions. In this is beneficial to high regio- and/or stereoselectivity. Meanwhile, the review, we highlight important asymmetric reactions that are nature of the chiral ligands plays a crucial role in constructing the promoted by chiral N,N’-dioxide–Ni(II) complexes, and shed some three-dimensional structures of the complexes and determining their light on their mode of action. catalytic activity and specificity. Over the past two decades, our group has developed a class of

Outline C2-symmetric amine oxide ligands, which are easily prepared from 1. Introduction optically active amino acids and amines (aliphatic or aromatic) 2. Catalytic Asymmetric Rearrangement Reactions (Figure 1). The two N-oxide amide units are linked in such a way

2.1. Propargyl, Allyl, and Allenyl Claisen Rearrangement that conformation-flexible, straight-chain alkanes [–(CH2)2,3,4,5…–] are 2.2. [2,3]-Wittig Rearrangement used. The structure is similar to nunchucks, pronounced “Shuangjie 2.3. Doyle−Kirmse Rearrangement Gun” in Chinese, a weapon in Kungfu fighting. There are four oxygen 2.4. [2,3]-Stevens and Sommelet–Hauser Rearrangements donor groups in N,N’-dioxide ligands, all of which can simultaneously 2.5. Allylboration/Oxy-Cope Rearrangement bond to the metal center, resulting in very stable complexes. The 3. Asymmetric Catalytic Nucleophilic Addition Reactions metal cations derive from main-group metals, transition metals, and 3.1. Ene-Type Reactions rare-earth metals. Our extensive investigations have shown that 3.2. Friedel–Crafts Reaction the resulting chiral N,N’-dioxide−metal complexes exhibit excellent 3.3. Michael and Mannich Reactions reactivity and enantiocontrol in more than 50 types of reactions 4. Miscellaneous Reactions with wide substrate scopes under mild reaction conditions. Their 4.1. Transformations Involving Hypervalent Iodine Salts discovery, structure information, and some applications have been 4.2. Reduction Reaction described in several accounts,7 and will not be discussed in details 5. Application in the Synthesis of Natural Products and Drug herein. This mini-review focuses on the catalytic aspects of the chiral Candidates N,N’-dioxide–nickel(II) complexes in asymmetric reactions. 6. Conclusion Nickel(II) forms a large number of complexes with complicated 7. Acknowledgments stereochemistry, encompassing coordination numbers 4, 5, and 6, 8. References and Notes and belonging to all the main structural types. On the other hand, Asymmetric Catalysis Enabled by Chiral N,N'-Dioxide–Nickel(II) Complexes 4 Zhen Wang, Xiaohua Liu,* and Xiaoming Feng*

nickel(II)–N,N’-dioxide complexes have a relatively simple distorted This flexibility in tuning the ligand structure permits the resulting octahedral 20-electron arrangement.8 The powders of such nickel(II) catalyst to satisfy the requirement of enantiocontrol in a variety

complexes—formed from Ni(BF4)2 or Ni(ClO4)2—are characteristically of reactions. The chiral nickel coordination sphere can restrict how green, and their X-ray crystal structures show that the chelating close the reactants can get to the center of the catalytic species by tetradentate ligands of the chiral N,N’-dioxides provide increased displacing the ancillary solvent or anion during the catalytic process. stability and a higher degree of control over the chiral coordination environment around the nickel center. The data related to the bite 2. Catalytic Asymmetric Rearrangement Reactions angles generated by coordination of the two carbonyl and the two 2.1. Propargyl, Allyl, and Allenyl Claisen Rearrangement amine oxide groups to nickel (i.e., the Oc-Ni-Oc angle and the ON- The Claisen rearrangement and its variants are some of the most Ni-ON angle) indicates that the fine conformation of the catalysts powerful stereoselective carbon–carbon bond-forming reactions.9 could be tuned by varying the length of the linker between the two If uncatalyzed, it usually requires higher reaction temperatures,

amine oxide units (e.g., L2-PiPr2 vs L3-PiPr2 vs L4-PiPr2), the amino while a Lewis acid catalyst might exert a positive influence on the

acid backbone (L3-PiPr2 vs L3-RaPr2), and/or the substituent on the reactivity. N,N’-Dioxide–nickel(II) salts offer several advantages

amide nitrogen (L3-PiPr2 vs L3-PiCHPh2, or L3-RaPr2 vs L3-RamBu2). in the Claisen rearrangement under mild reaction conditions. For instance, highly efficient and catalytic asymmetric propargyl and allyl Claisen rearrangements of O-propargyl and O-allyl β-keto esters were effected in the presence of the Ni(II) complexes of

the three-carbon-linked N,N’-dioxide L3-PiMe2, prepared from N N O O O– –O l-pipecolic acid and 2,6-dimethylbenzenamine (Scheme 1, Parts N N O O 10 N n N N H H N (a) and (b)). The enantioselective process gave a wide range of R O– –O R H H R R allenyl- or allyl-substituted all-carbon quaternary b-keto esters Label R n Label R in good yields (up to 99%), high diastereoselectivities (up to 2,6-i-Pr C H 0 2,6-Et C H L2-PiPr2 2 6 3 L3-RaEt2 2 6 3 19:1 dr), and excellent enantioselectivities (up to 99% ee). The L3-PiMe2 2,6-Me2C6H3 1 L3-RaPr2 2,6-i-Pr2C6H3 catalyst loading could be lowered to 0.5 mol % for the asymmetric L3-PiEt2 2,6-Et2C6H3 1 L3-RamBu2 3,5-t-Bu2C6H3

L3-PiPr2 2,6-i-Pr2C6H3 1 L3-RaPr3 2,4,6-i-Pr3C6H2 allyl Claisen rearrangement without deterioration of the yields L3-PioBr 2-BrC6H4 1 L3-RaPh Ph and stereoselectivities. Moreover, the chiral catalyst system was L3-PisEPh (S)-2-PhEt 1 extended to the allenyl Claisen rearrangement to form branched L -PiCHPh CHPh 1 3 2 2 1,3-dienyl substituted b-keto esters with high enantioselectivity but L4-PiPr2 2,6-i-Pr2C6H3 2 at higher reaction temperatures (Scheme 1, Part (c)).11 The major pathway of the Claisen rearrangement proceeds via a

Figure 1. A Selection of C2-Symmetric N,N'-Dioxide Ligands That Have cyclic chair conformation of the transition state (TS), whereas the Been Investigated by Our Group in the Featured Reactions. minor pathway proceeds via a boat conformation of the TS. Because chiral starting materials could give Claisen rearrangement products

of high optical purity, L3-PiMe2–Ni(OTf)2 was successfully applied to 12 2 the kinetic resolution of racemic propargyl vinyl ethers (eq 1). This R O L3-PiMe2–Ni(OTf)2 O O (1:1, 5–10 mol %) O catalyst system showed a preference for the (R)-configured cyclic (a) 1 1 o OR n OR CH2Cl2, 35 C n and linear propargyl vinyl ether through a bidentate bonding manner, 24–96 h 2 • n = 1–3 R leading to a diastereo- and enantioselective [3,3]-sigmatropic 1 R = Me, Et, t-Bu 70–96%, 73–99% ee rearrangement. Complete central-to-axial chirality transfer occurs in

3 O the propargyl Claisen rearrangement, and the chirality of the newly R O L3-PiMe2–Ni(BF4)2•6H2O O O 1 (1:1, 0.5 mol %) OR (b) formed stereogenic quaternary carbon is controlled, in some cases, OR1 o CH2Cl2, 35 C, 1–48 h by the chiral catalyst rather than by substrate induction. Moreover, n n R3 n = 1–3 86–99% the mismatched S isomer of the starting material could be recovered 93:7–99:1 dr R1 = Me, Et, t-Bu, allyl 92–98% ee

• R1O R O L3-PiMe2–Ni(OTf)2 O R O (1:1, 10 mol %) Kinetic Resolution of Racemic Propargyl Vinyl Ethers (c) 4 R4 n O R O P(OEt)2 F 1 n 1 NaBAr 4 (10 mol %) 1 L3-PiMe2–Ni(OTf)2 R (aR) Ar 2 OR R P(OEt)2 R o • n = 1, 2 ClCH2CH2Cl, 50 C O 2 (1:1, 5 mol %) O O R R (S) 1 10–96 h R O H 2 + R2 R = Me, Et, t-Bu CH Cl , H O R 2 1 2 2 2 2 R P(OEt)2 R 65–91%, 90–99% ee Ar R o 35 C, 3–24 h Ar F racemic O NaBAr 4 = NaB[3,5-(CF3)2C6H3]4; Tf = F3CSO2 1 R = Me, Et, n-Pr, i-Pr, n-Bu, Ph(CH2)2, MeS(CH2)2 36–48% 33–48% R2 = Me, Et, c-Pent, Cy 90–97% ee 98–99% ee Ar = XC6H4 (X = H, 4-Me, 4-MeO2C, 3-Br, 4-Br, 4-Cl), 1-Np

Scheme 1. The L3-PiMe2 Enabled Propargyl, Allyl, and Allenyl Claisen Rearrangement. (Ref. 10,11) eq 1 (Ref. 12) Aldrichimica ACTA 5 VOL. 53, NO. 1 • 2020

in high yield and enantiomeric excess. It is worth noting that 96% ee’s). There is an obvious ligand reaction-acceleration effect, enantioselective recognition enabled by chiral N,N’-dioxide–nickel(II) as only a trace amount of the product was obtained without the complexes has also been observed in visual or fluorescence sensing chiral ligand. The introduction of a pyrazoleamide unit into the of chiral α-hydroxycarboxylic acids and N-Boc amino acids.13 α-diazo compound enhances its electrophilicity, and facilitates the formation of the chiral Lewis acid bonded ylide intermediate and 2.2. [2,3]-Wittig Rearrangement stereocontrol via bidentate coordination. The latter hypothesis has

The [2,3]-Witting rearrangement proceeds via a five-membered been supported by the reaction of C2-symmetric diallyl sulfides with cyclic transition state and provides a direct route to homoallyl diazo pyrazoleamides, which led to the corresponding products with alcohols and related compounds. Using progargylic ethers of good enantioselecitivity. oxindole derivatives as substrates, the reaction delivers allene- substituted alcohols, but the reactivity is low due to the distorted 2.4. [2,3]-Stevens and Sommelet–Hauser Rearrangements transition-state geometries arising from the alkyne sp center. By The enantioselective [2,3]-Stevens and Sommelet–Hauser using L3-PiCHPh2–Ni(OTf)2 as catalyst, a highly enantioselective rearrangements of sulfonium ylides—generated from α-diazo variant was achieved (eq 2).14 Interestingly, a low yield (18%) was compounds and thioacetates—are much more complicated in obtained in the absence of the N,N’-dioxide ligand. Furthermore, comparison with the asymmetric Doyle–Kirmse reaction. There kinetic resolution of racemic oxindole derivatives was also achieved are vicinal S- and C-stereogenic centers in the ylide intermediates, with high efficiency and stereoselectivity.14 racemization or epimerization of ylide tautomers via 1,3-proton shifts, With respect to the modes of asymmetric catalysis of these chiral and a remote functionalization in the final [2,3]-rearrangement step. nickel complexes in the Claisen and [2,3]-Wittig rearrangements, it The L2-PiPr2–Ni(II) complex catalyzed the asymmetric has been proposed that they occur by similar bidentate activations. [2,3]-Stevens rearrangement of vinyl substituted a-diazo The b-keto esters, phosphonates, and oxindoles are 1,4-dioxygen- pyrazoleamides and aryl thioacetates. Initially, discrimination type substrates, which could bond to the nickel(II) center with of the heterotopic lone pairs on sulfur affords the (R)-configured the ether oxygen and the carbonyl group, forming a stable five- sulfonium ylide species I. Added 3-phenylpropanoic acid acts as membered cyclic transition state. The steric hindrance arising a mild proton shuttle, enabling the slower diastereoselective from the N,N’-dioxide ligand would then direct the subsequent tautomerization process to generate the (R,R)-ylide intermediate rearrangement enantioselectively to generate the stereogenic II, which undergoes an asymmetric [2,3]-rearrangement via an center vicinal to the carbonyl group in the products. envelope transition state, leading to the desired products with a (2R,3S,E) configuration (Scheme 3).17 2.3. Doyle−Kirmse Rearrangement This same chiral nickel complex also efficiently catalyzed The unique electronic and steric properties of chiral N,N’-dioxide– the asymmetric Sommelet–Hauser reaction of aryl-substituted metal complexes prompted us to design α-diazo pyrazoleamides a-diazo pyrazoleamides with (phenylthio)methylcarbamoates.17 for the asymmetric [2,3]-sigmatropic rearrangement of sulfonium This rearrangement is potentially more challenging because ylides generated from α-diazo compounds and allyl sulfides. The dearomatization and rearomatization steps are involved in the control of enantioselectivity in this type of [2,3]-sigmatropic process. The desired ortho-thioalkyl-substituted arylacetamides rearrangement relies on the formation of a metal-bonded ylide were isolated in 51–78% yield with 60–81% ee. The 1,3-proton intermediate or discrimination of the heterotopic lone pairs on shift results from a trace amount of water in the system, and the 15 sulfur. The chiral L2-PiPr2–Ni(II) complex efficiently catalyzed both the formation of the sulfide ylide intermediate and its subsequent

enantioselective rearrangement. Moreover, a combination of L2- Me Me Me 2 L2-PiPr2(10 mol %) Me PiPr2, NiCl2, and AgNTf2 efficiently catalyzed the enantioselective R S N2 NiCl2(10 mol %) Me + R2 * N Me Doyle−Kirmse reaction of a series of aryl- or vinyl-substituted 1 N N R N AgNTf2 (20 mol %) S 1 16 o R α-diazo pyrazoleamides with allyl aryl sulfides (Scheme 2). In O CH2Cl2, 40 C O most cases, the reactions were completed in 5−20 minutes in high 1.15 or 1.70 equiv 5–20 min 46–99%, 61–96% ee 1 2 yields and with excellent enantioselectivities (up to 99% yields and R = aryl, CH=CHR; R = aryl, allyl, alkyl Ph

S O Ar 3 Me R N Ni H O L3-PiCHPh2–Ni(OTf)2 HO • N (1:1, 5 mol %) 1 1 Me R O R3 R O Me N Et3N (1.2 equiv) N o R2 EtOAc, 35 C, 36 h R2 1 43–99%, 87 to >99% ee R = H, Me, Me2, MeO, F3CO, halogen chiral Ni(II)-bonded ylide R2 = H, Me, i-Pr, Bn; R3 = Me, Cy, aryl, heteroaryl Scheme 2. Doyle−Kirmse Reaction Catalyzed by Ni(II)–N,N’-Dioxide eq 2 (Ref. 14) Complexes. (Ref. 16) Asymmetric Catalysis Enabled by Chiral N,N'-Dioxide–Nickel(II) Complexes 6 Zhen Wang, Xiaohua Liu,* and Xiaoming Feng*

[2,3]-rearrangement process is slow and difficult due to the high which is suitable for the face-selective addition of the allylboronic activation energy of the dearomatization step. acid. It was found that the subsequent enantioselective oxy-Cope rearrangement is induced by the optically enriched vinyl- and 2.5. Allylboration/Oxy-Cope Rearrangement allyl-substituted alcohol intermediates, and the process could be

Recently, the complex L3-RaPr2–Ni(OTf)2 was used to catalyze an accelerated by the chiral Lewis acid at higher reaction temperature. allylboration–oxy-Cope rearrangement sequence of b,g-unsaturated The chirality transfer in the oxy-Cope rearrangement is via a rare, a-keto esters with allylboronic acids under mild conditions boat-like transition state. (Scheme 4).18 This protocol provides a facile and direct route to g-allyl-a-keto esters in moderate-to-good yields (65–92%) and 3. Asymmetric Catalytic Nucleophilic Addition excellent enantioselectivity (90–99% ee). The 1,2-allylboration Reactions products could also be isolated in good yields and excellent 3.1. Ene-Type Reactions diastereo- and enantioselectivities at lower reaction temperature. Ene-type reactions can provide access to polyfunctionalized The general catalytic mechanism is based on coordination of the b,g- compounds that are synthetically versatile intermediates by the unsaturated a-keto ester to the nickel center in a bidentate fashion, further transformation of the carbon–carbon double bond.19 The asymmetric carbonyl–ene reaction of glyoxals and glyoxylates can be used to construct chiral γ,δ-unsaturated α-hydroxy carbonyl compounds. The chiral N,N’-dioxide–nickel(II) complexes can O SAr O ArSCH2CO2Et (2.5 equiv) 1 * catalyze the asymmetric variant with remarkable results by employing R N L2-PiPr2–Ni(OTf)2 (1:1, 5 mol %) * N N Me EtO2C N Me 2 1 glyoxals, α-keto esters, or isatins as the enophiles, and alkenes, N2 R CO2H (20 mol %) R Me o Me Me MeCO2Me, 20 C, 35 min Me enamides, vinylogous hydrazine, or 5-methyleneoxazolines as the R1 = aryl, heteroaryl 39–84%, 78:22 to 88:12 dr 2 nucleophiles. The common catalytic pathway involves bidentate R = Ph(CH2)2 85–95% ee coordination of the 1,2-dicarbonyl compounds to the nickel center, acid-assisted 1,3-H transfer fast lowering the LOMO energy of the enophile. Subsequently, the ene 2 R1 R H component enantioselectively approaches the active carbonyl group H H O 1 EtO2C R CO2Et O via a cyclic transition state to yield the desired adduct. R1 CO Et H R H 2 R H block Ar S R H R blockS 1 3 For example, excellent enantioselectivities (up to >99% ee) were S Ph O R O H Ar obtained in the L3-PiPr2–Ni(BF4)2 catalyzed carbonyl-ene reaction N N Ni 2 N O Ni 20 N R CO2H of glyoxals and glyoxylates with various alkenes. The optically N N 2 Ni block active allyl-substituted α-hydroxy carbonyl products can undergo a L* subsequent, FeCl3–TBSCl catalyzed OH-selective Prins cyclization,

chiral sulfonium ylide I chiral sulfonium ylide II asymmetric catalytic leading to a broad range of substituted 4-hydroxytetrahydropyrans [2,3]-rearrangement highly stereoselectively (Scheme 5, Part (a).21 The N,N’-dioxide– nickel(II) catalysts also show remarkable performance in the carbonyl- Scheme 3. Catalytic, Asymmetric [2,3]-Stevens Rearrangement ene reaction of glyoxals and glyoxylates with a series of enamides22 Enabled by Ni(II)–N,N’-Dioxide Complexes. (Ref. 17) and 5-methyleneoxazolines23 as nucleophiles. The hetero-ene reaction of glyoxal derivatives and 5-methyleneoxazoline worked well even at 0.5 mol % loading of the catalyst, providing 2,5-disubstituted O L3-RaPr2–Ni(OTf)2 oxazole derivatives in 60–99% yields and 95 to >99% ee’s. HO CO Me R1 CO Me (1:1, 10 mol %) 3 2 2 1' Similarly, the asymmetric ene-type reaction of α-keto esters + 1 1 3' o R 2' 2 CH2Cl2, –20 C, 72 h 2 R B(OH)2 R2 with 5-methyleneoxazolines also works well under L3-PiPr2–Ni(BF4)2 23–24 1,2-allylboration 75–99%, >19:1 dr catalysis. Moreover, in the presence of L3-RaEt2–Ni(ClO4)2 as 97–98% ee L3-RaPr2–Ni(OTf)2 catalyst, a range of racemic β-halo-α-keto esters were efficiently (1:1, 10 mol %) o converted into the chiral β-halo-α-hydroxy esters via dynamic CH2Cl2, –20 C, 72 h then 35 oC, 48 h kinetic asymmetric transformations. The corresponding ene products containing vicinal tri- and tetrasubstituted carbon centers R1 O R2 oxy-Cope rearrangement were obtained in generally good yields and diastereoselectivity and CO2Me HO ‡ excellent ee values (Scheme 5, Part (b)).24 65–92%, 90–99% ee H CO2Me The valuable nucleophile vinylogous hydrazine underwent an H H 1 1 ene-type reaction with glyoxal derivatives. Subsequent treatment R = aryl, heteroaryl, vinyl H R R2 2 R = 4-MeOC6H4, thien-2-yl boat-like T.S. with magnesium monoperoxyphthalate hydrate (MMPP∙6H2O) gave the valuable, optically active 4-benzoyl-4-hydroxy-2- methylenebutanenitrile in 95% yield and 95% ee.25 This vinylogous Scheme 4. Application of Ni(II)–N,N’-Dioxide Complexes as Catalysts for an Asymmetric Allylboration and Oxy-Cope Rearrangement nitrile was elaborated in moderate yield and excellent ee into a Sequence. (Ref. 18) bioactive compound that is a potentially cytotoxic agent against 26 human leukemia HL-60 cells. Furthermore, L3-RaPr2–Ni(OTf)2 Aldrichimica ACTA 7 VOL. 53, NO. 1 • 2020

efficiently catalyzed the reaction of vinylogous hydrazine with an enantiodivergent Friedel–Crafts-type reaction of b,g-unsaturated isatins, and the product of the reaction was transformed in two α-keto esters with 2,5-dimethylpyrrole or 2-methylindole 30 steps into a spirocyclic lactone that is a potent antineoplastic agent (Scheme 6). For example, L3-RaPr2–Ni(OTf)2 catalyzes the against P-388 lymphocytic leukemia and human carcinoma of the addition of 2,5-dimthylpyrrole to b,g-unsaturated α-keto esters to 25 nasopharynx (Scheme 5, Part (c)). give the dextran product, while L3-RamBu2–Ni(OTf)2 catalyzes the In contrast to the preceding examples of the ene reaction, the same reaction to yield the right-handed enantiomer. The strategy asymmetric Alder–ene reaction using alkenes as enophiles remains was also successfully implemented in an enantiodivergent synthesis a challenge due to the low reactivity of the olefins along with of the corresponding indole adducts. The switch in enantioselectivity the required high activation energy of the ene reaction. Usually, results from the markedly different spatial environments in stoichiometric amounts of chiral Lewis acids are required to achieve a the seesawed amide units of the two catalyst complexes. Steric 27 satisfactory outcome. In this regard, L3-RaPr2–Ni(NTf2)2 efficiently hindrance around the enantiotopic face of the b,g-unsaturated promoted the asymmetric intramolecular Alder–ene reaction, α-keto ester causes its differentiation upon bidentate coordination leading to a series of 3,4-disubstituted chromans, thiochromans, to the nickel center. tetrahydroquinolines, and piperidines in high yields and with good- to-excellent diastereo- and enantioselectivities.28 3.3. Michael and Mannich Reactions Chiral N,N’-dioxide–Ni(II) complexes have also been used in classic 3.2. Friedel–Crafts Reaction addition reactions such as the oxa-Michael and Mannich reactions. The phenomenon of enantioselectivity reversal is interesting and For example, (2-hydroxyphenyl)propenone derivatives engage 29 has important applications in enantiodivergent synthesis. Using in two-point binding to the central metal in L3-RaPh–Ni(Tfacac)2, the chiral pool and slightly modifying the amide moiety of the N,N’- forming a chelate-ordered transition state that results in an 31 dioxide ligand in chiral N,N’-dioxide–Ni(OTf)2 complexes result in intramolecular oxa-Michael addition (Scheme 7, Part (a)). The reaction tolerated a relatively wide range of substrates to provide a series of flavanones in excellent yields (90–99%) and moderate- to-excellent enantioselectivities (40–99% ee). Significantly, the carbonyl–ene reaction optically active flavanones can be converted into versatile building 2 L3-PiPr2–Ni(BF4)2•6H2O R 2 HO 32 O R (1:1, 10 mol %) blocks such as hydrazones. (a) R' + R 1 R 3 1 o R Chiral L3-PiPr2-based Ni(II) and Mg(II) complexes are also R R CH2Cl2, 35 C, 48 h O O R3 2.0–3.0 equiv efficient catalysts for the asymmetric Mannich reaction employing 72–99% R = Me, Cy, EtO, aryl, heteroaryl; R' = H, EtO 97 to >99% ee 1,3,5-triazinanes as electrophilic reagents and imine precursors 1 O 33 R OH FeCl3–TBSCl (Scheme 7, Part (b)). The in situ generated imines react smoothly 2 3 R R (1:1, 20 mol %) R4 H with α-tetralone-derived β-keto esters or amides to give optically O o R4 O CH2Cl2, 10 C, 3–36 h active 2-(β-amino)-substituted tetralones in generally good- R R4 = alkyl, vinyl, aryl, heteroaryl to-excellent yields and enantioselectivities. However, the five- 42–92% 4:1 to >19:1 dr, 95–99% ee Prins reaction membered-ring β-keto amide analogue gave the corresponding product in 99% yield but with only 50% ee, while the seven- L3-RaEt2–Ni(ClO4)2•6H2O N O membered-ring β-keto amide counterpart gave 92% yield of the N (1:1, 10 mol %) HO (b) R + R O Ar CO2R' Ar o racemic product. O CH2Cl2, 30 C, 48 h CO2R' X H X 2.0 equiv X = Cl, Br; R = Bn, aryl 64–98% R' = Me, Et, i-Pr, n-Bu 67:33 to >95:5 dr Ar = Ph, 1-Np, substituted benzene 99% ee

R1 O NPip O L -RaPr –Ni(OTf) HO 2 3 2 2 Me CO2R (1:1, 10 mol %) HN (c) R O R O Me (+) N CH2Cl2, 5 Å MS N O (i) 68–94%, 86–99% ee R1 H2O (trace) R1 + o 35 C, 36 or 60 h 1 2 + NPip 86–98%, 96–99% ee R CO2R Me N Me H 1 O (ii) R O Me 3.0 equiv 2 1.3 equiv CO2R O 1. HCl (5 M) R1 = Cy, vinyl, aryl, heteroaryl Me I 2 HN 2. PCC R = Me, Et, t-Bu, Bn Me (–) O N R = 5-I, R1 = Me 78–95%, 20–96% ee o Me Pip = piperidinyl (i) L3-RaPr2–Ni(OTf)2 (1:1, 10 mol %), PhMe, –20 C, 48 h PCC = pyridinium chlorochromate o 40%, 99% ee (ii) L3-RamBu2–Ni(OTf)2 (1:1, 10 mol %), CH2Cl2, –20 C, 48 h antineoplastic spirolactone

Scheme 5. Asymmetric Ene-Type Reactions Catalyzed by Ni(II)–N,N’- Scheme 6. Enantiodivergent Friedel–Crafts Reaction Promoted by Dioxide Complexes. (Ref. 20,21,24,25) Chiral N,N'-Dioxide–Ni(OTf)2 Complexes. (Ref. 30) Asymmetric Catalysis Enabled by Chiral N,N'-Dioxide–Nickel(II) Complexes 8 Zhen Wang, Xiaohua Liu,* and Xiaoming Feng*

4. Miscellaneous Reactions Ni(OTf)2, a variety of spirocyclopropane-oxindoles with contiguous 4.1. Transformations Involving Hypervalent Iodine Salts one tertiary and two quaternary all-carbon centers are generated Hypervalent iodine salts, such as vinyl-, alkynyl-, and aryliodonium with excellent yields and stereoselectivities (up to 99% yield, > 19:1 salts are attractive reagents due to their low toxicity, high dr, and up to 99% ee). Based on EPR spectroscopic observations, 3 reactivity, and high stability. We previously found chiral N,N’- a free, triplet carbene intermediate, :C(CO2Me)2, was proposed as

dioxide–Sc(OTf)3 complexes to be efficient Lewis acid catalysts for resulting from the thermal decomposition of the phenyliodonium the enantioselective α-arylation of 3-substituted oxindoles with ylide. Bidentate coordination of the 3-alkenyloxindole to the chiral diaryliodonium salts through carbon–iodine bond formation and nickel center through the two carbonyl groups was also proposed subsequent [1,2]-rearrangement.34 When β-keto amides or esters to precede reaction with the triplet carbene. Ring closure of the

were used as substrates, it was observed that chiral L3-PisEPh–Ni(II) resulting singlet biradical intermediate leads to the cyclopropane was a much more efficient catalyst, which gave good results in the product, with the observed facial selectivity being attributed to the enantioselective vinylation, alkynylation, and arylation (Scheme 8, blocking of the nearby amide unit of the ligand. 35 Part (a)). A bidentate coordination of the 1,3-dicarbonyl compound The catalytic enantioselective Csp3–H a-alkylation of b-keto amides to the nickel center was proposed to rationalize the observed with phenyliodonium ylide has been achieved in the presence of 37 enantioselection. the chiral L3-PiEt2–Ni(OTf)2 complex. Notably, the catalytic radical A new strategy for the catalytic asymmetric cyclopropanation of process is insensitive to air and moisture, and the resulting products 3-alkenyloxindoles with phenyliodonium ylide malonate has been are obtained in good yields and with excellent enantioselectivities 36 developed (Scheme 8, Part (b)). In the presence of L3-PiPr2– even when the reaction is carried out on a gram scale (up to 91% yield and 97% ee).

4.2. Reduction Reaction (a) Intramolecular Oxa-Michael Addition The asymmetric reduction of secondary and primary a-amino 1. L3-RaPh–Ni(Tfacac)2•2H2O OH O R (1:1, 5 mol %), PhOMe O ketones has been achieved using N,N’-dioxide–Ni(II) complexes 1 1 R 30 oC, 12 h R and aqueous KBH4, confirming that such complexes can tolerate o 2 CO2t-Bu 2. p-TsOH, 80 C, 2 h 2 R R O R reducing agents and aqueous conditions. This approach provides R = Et, aryl; Tfacac =1,1,1-trifluoroacetylacetonate 90–99%, 40–99% ee easy access to chiral, β-amino alcohol based natural products and 1 2 1 2 R = H, Me; R = H, Me, MeO, Cl; R ,R = (CH2)4 drug candidates, such as β2-adrenoreceptor agonists. For example,

(b) All-Carbon Quaternary Stereocenter by a Novel Enantioselective Mannich Reaction chiral L3-PiEt2–Ni(OTf)2 catalyzed the reduction of a-(N-arylamino)- O O Ar O HNAr ketones to chiral b-amino alcohols in good-to-excellent yields (up to R L3-PiPr2–Ni(ClO4)2•6H2O R N 38 XR1 or L3-PiPr2–Mg(OTf)2 XR1 98%) and enantioselectivities (up to 97% ee) (eq 3). + NN Ar Ar (1:1, 5 mol %) O CH Cl , 0 oC, 12 h 2.9 equiv 2 2 50–99%, 81–99% ee 5. Application in the Synthesis of Natural Products and X = O, NH; R = H, Me, MeO, Br; R1 = t-Bu, 1-Ad Drug Candidates Hyperolactones A–C and (−)-biyouyanagin A, containing two chiral Scheme 7. Asymmetric Intramolecular Oxa-Michael Addition and vicinal quaternary carbon centers, are a family of spirolactone natural Mannich Reaction. (Ref. 31,33) products with significant activity against HIV. A short, catalytic, and stereodivergent synthesis of hyperolactones B and C has been achieved starting with an enantioselective dearomatization– (a) Claisen rearrangement of allyl furyl ethers in the presence of chiral 2 O L3-PisEPh–Ni(OTf)2 2 O R R L -PiMe –Ni(BF ) or ent-L -PiMe –Ni(BF ) (Scheme 9).39 The I+ (1:1.2, 10 mol %) R 3 2 4 2 3 2 4 2 COXR1 + Ar R COXR1 TfO– Na2CO3 (1.5 equiv) Ni(II)-catalyzed step was found to be generally applicable to allyl o X = O, NH 1.2 equiv CH2Cl2, 35 C, 12 h 40–99%, 94–99% ee furyl ethers, and, under the optimized conditions, a number of

1 2 R = t-Bu, 1-Ad; R = H, Me, Me2, MeO, F, Cl, Br Ar = Ph, monosubstituted benzene, Mes; R = (E)-R'CH=CH, R"C≡C, aryl

(b) 1 L3-PiEt2–Ni(OTf)2 R R1 O OH CO2Me H (1:1, 8 mol %) H L3-PiPr2–Ni(OTf)2 N + KBH4(aq) N CO2Me 1 1 CO2Me (1:1, 5 mol %) R Ar THF–CH Cl (1:1.2) R Ar 0.6 equiv 2 2 O + PhI O –20 oC, 4 h 70–98% N CO2Me Et2O–CH2Cl2 (4:1) N o 72–97% ee 2 Noteworthy Examples: 0 C, 20 h 2 25 oC, 24 or 48 h R R Boc 1.5 equiv Boc OH OH 1 H H R = COR', CO2R", Pr, t-Bu, CN, aryl 32–99%, 19:1 dr, 85–99% ee N N R2 = H, Me, MeO, Cl, Br, I OMe NHBoc 95%, 92% ee 70%, 84% ee (precursor of Scheme 8. Chiral N,N’-Dioxide–Ni(II) Catalyzed Reactions: (R,R)-β2-adrenoreceptor agonists) (a) α-Vinylation, Alkynylation, and Arylation of β-keto Acid Derivatives. (b) Cyclopropanation of 3-Alkenyloxindoles. (Ref. 35,36) eq 3 (Ref. 38) Aldrichimica ACTA 9 VOL. 53, NO. 1 • 2020

γ,δ-unsaturated carbonyl compounds were obtained in up to 99% Nickel and several other transition metals, with variable oxidation yield, 19:1 dr, and up to 99% ee. The steric hindrance arising from numbers, have considerable established organometallic chemistry, the bulky amide moiety of the ligand forces the alkene unit of the but the role of the catalyst is only beginning to be understood. substrate to preferentially approach the α position of the furan ring Improving our understanding of the geometry, ligands, active site, from one side. Thus, the stereogenic arrangement of the furanone and activation mode in such reactions would allow the development is catalyst-controlled, while the configuration of the quaternary of more efficient, and useful catalytic asymmetric reactions. carbon center is determined by the Z/E configuration of the allyl substituent. As a result, four enantiomers of the products could be 7. Acknowledgments prepared in excellent yields and stereoselectivities by a judicious We are sincerely indebted to a group of talented co-workers whose selection of the configuration of the catalyst and the alkene unit of names are listed in the relevant references. We also thank the the substrates.39 National Natural Science Foundation of China (Nos. 21625205 and N,N’-Dioxide–metal complexes have been successfully applied 21432006) for financial support. in asymmetric cycloaddition reactions.7c One of the noteworthy

examples is the N,N’-dioxide–Ni(OTf)2 catalyzed regio-, diastereo-, 8. References and Notes and enantioselective aza-Diels–Alder reaction of 3-vinylindoles with (1) Jacobsen, E. N., Pfaltz, A., Yamamoto H., Eds. Comprehensive isatin-derived ketimines. The reaction takes place by a concerted Asymmetric Catalysis I–III; Springer-Verlag: New York, NY, 1999. reaction pathway, and the regioselectivity and exo selectivity are (2) Mikami, K., Lautens, M., Eds. New Frontiers in Asymmetric attributed to the π–π interaction between the two indoline rings of the Catalysis; Wiley: Hoboken, NJ, 2007. two reactants. The transformation affords a series of spiroindolone (3) (a) Zhou, Q.-L., Ed. Privileged Chiral Ligands and Catalysts; derivatives in good yields and with excellent enantioselectivities.40 Wiley-VCH: Weinheim, Germany, 2011. (b) Stradiotto, M., Furthermore, the antimalarial drug candidate NITD609 was obtained Lundgren, R. J., Eds. Ligand Design in Metal Chemistry: Reactivity in three steps (40.6% overall yield and up to 99% ee) starting with and Catalysis; Wiley: U.K., 2016. the gram-scale, ent-L3-RaPr2–Ni(OTf)2 catalyzed aza-Diels–Alder (4) Sandoval, C. A.; Noyori, R. An Overview of Recent Developments cycloaddition of a suitably substituted 3-vinylindole and isatin- in Metal-Catalyzed Asymmetric Transformations. In Organic derived ketimine (Scheme 10).40 Chemistry – Breakthroughs and Perspectives; Ding, K.-L., Dai, L.-X., Eds.; Wiley-VCH: Weinheim, Germany, 2012; Chapter 9, 6. Conclusion pp 335–363. Chiral N,N’-dioxide ligand–Ni(II) complexes are now practical Lewis (5) Yoon, T. P.; Jacobsen, E. N. Science 2003, 299, 1691. acid catalysts in several well-known reactions. Additionally, a number (6) Yamamoto, H., Ed. Lewis Acids in Organic Synthesis; Handbook of chiral nickel(II) complexes—with ligands possessing functional of Chemoinformatics; Gasteiger, J., Ed.; Wiley-VCH: Weinheim, groups of other heteroatoms as electron-pair donors, such as Germany, 2000. amines and phosphines—have also been developed. For example, (7) (a) Liu, X. H.; Lin, L. L.; Feng, X. M. Acc. Chem. Res. 2011, chiral nickel(II)–PyBox or nickel(II)–bis(oxazoline) complexes 44, 574. (b) Liu, X. H.; Lin, L. L.; Feng, X. M. Org. Chem. Front. are efficient catalysts for enantioselective cross-couplings of 2014, 1, 298. (c) Liu, X. H.; Zheng, H. F.; Xia, Y.; Lin, L. L.; Feng, nucleophiles with racemic alkyl electrophiles via radical pathways.41 X. M. Acc. Chem. Res. 2017, 50, 2621. (d) Liu, X. H.; Dong, S. X.; The chiral nickel(II) complexes of diamines, salen, BINAP, and Lin, L. L.; Feng, X. M. Chin. J. Chem. 2018, 36, 791. TOX ligands promote various reactions as Lewis acid catalysts.

Me

BocN ent-L3-RaPr3–Ni(OTf)2 O R2 O cat or ent-cat F Cl (1:1, 10 mol %) (1:1, 10 mol %) CO2Me + O o 1 OTIPS 1 N CH Cl , –20 C, 6 days R CO2Me R O Cl N 2 2 O DCE, 35 oC, 4 days OTIPS H 2 Boc 1 R R = i-Pr, i-Bu, Cy, aryl Z: E = 1:2 80–99%, 8:1 to >19:1 dr R2 = H, Me, Et, i-Bu, BnCH , aryl 1.31 g (6.25 mmol) 0.95 g (2.5 mmol) 2 62–99% ee

cat = L3-PiMe2–Ni(BF4)2•6H2O; ent-cat = ent-L3-PiMe2–Ni(BF4)2•6H2O Me Me Cl Boc Cl NH N R1 = i-Pr, (R,S) F 2 steps F R1 = Ph, (S,S) O Me Cl N Cl N H O N H O N TMSBr (4.0 equiv) H Boc O MeOH–CH Cl (2:1) R1 O 2 2 0.391 g (1.01 mmol) 0.91 g (1.54 mmol) O 30 oC 40.6% (3 steps), >19:1 dr, 99% ee 62%, 20:1 dr, >99% ee 1 NITD609 hyperolactone B: R = i-Pr; 91%, 16:1 dr, 98% ee antimalarial drug candidate hyperolactone C: R1 = Ph; 91%, 10:1 dr, 99% ee

Scheme 10. Application of N,N’-Dioxide–Ni(II) Catalysts in a Three- Scheme 9. Application of N,N’-Dioxide–Ni(II) Catalysts in a Step, Gram-Scale Synthesis of the Antimalarial Drug Candidate Stereodivergent Synthesis of Hyperolactones B and C. (Ref. 39) NITD609. (Ref. 40) Asymmetric Catalysis Enabled by Chiral N,N'-Dioxide–Nickel(II) Complexes 10 Zhen Wang, Xiaohua Liu,* and Xiaoming Feng*

(8) The Cambridge Crystallographic Data Centre (CCDC) numbers (32) Savini, L.; Chiasserini, L.; Travagli, V.; Pellerano, C.; Novellino, E.; 1587231, 1834283, 759905, 1035849, 1035929, and 1849262 Cosentino, S.; Pisano, M. B. Eur. J. Med. Chem. 2004, 39, 113. contain the supplementary crystallographic data for the N,N’- (33) Lian, X. J.; Lin, L. L.; Fu, K.; Ma, B. W.; Liu, X. H.; Feng, X. M. dioxide complexes with nickel(II). Chem. Sci. 2017, 8, 1238. (9) (a) Martín Castro, A. M. Chem. Rev. 2004, 104, 2939. (b) Ilardi, (34) Guo, J.; Dong, S. X.; Zhang, Y. L.; Kuang, Y. L.; Liu, X. H.; Lin, E. A.; Stivala, C. E.; Zakarian, A. Chem. Soc. Rev. 2009, 38, L. L.; Feng, X. M. Angew. Chem., Int. Ed. 2013, 52, 10245. 3133. (35) Guo, J.; Lin, L. L.; Liu, Y. B.; Li, X. Q.; Liu, X. H.; Feng, X. M. (10) Liu, Y. B.; Hu, H. P.; Zheng, H. F.; Xia, Y.; Liu, X. H.; Lin, L. L.; Org. Lett. 2016, 18, 5540. Feng, X. M. Angew. Chem., Int. Ed. 2014, 53, 11579. (36) Guo, J.; Liu, Y. B.; Li, X. Q.; Liu, X. H.; Lin, L. L.; Feng, X. M. (11) Liu, Y. B.; Hu, H. P.; Lin, L. L.; Hao, X. Y.; Liu, X. H.; Feng, X. Chem. Sci. 2016, 7, 2717. M. Chem. Commun. 2016, 52, 11963. (37) Guo, J.; Liu, X. H.; He, C. Q.; Tan, F.; Dong, S. X.; Feng, X. M. (12) Liu, Y. B.; Liu, X. H.; Hu, H. P.; Guo, J.; Xia, Y.; Lin, L. L.; Feng, Chem. Commun. 2018, 54, 12254. X. M. Angew. Chem., Int. Ed. 2016, 55, 4054. (38) He, P.; Zheng, H. F.; Liu, X. H.; Lian, X. J.; Lin, L. L.; Feng, X. (13) He, X.; Zhang, Q.; Wang, W. T.; Lin, L. L.; Liu, X. H.; Feng, X. M. Chem.—Eur. J. 2014, 20, 13482. M. Org. Lett, 2011, 13, 804. (39) Zheng, H. F.; Wang, Y.; Xu, C. R.; Xu, X.; Lin, L. L.; Liu, X. H.; (14) Xu, X.; Zhang, J. L.; Dong, S. X.; Lin, L. L.; Lin, X. B.; Liu, X. Feng, X. M. Nat. Commun. 2018, 9, 1968. H.; Feng, X. M. Angew. Chem., Int. Ed. 2018, 57, 8734. (40) Zheng, H. F.; Liu, X. H.; Xu, C. R.; Xia, Y.; Lin, L. L.; Feng, X. (15) West, T. H.; Spoehrle, S. S. M.; Kasten, K.; Taylor, J. E.; Smith, M. Angew. Chem., Int. Ed. 2015, 54, 10958. A. D. ACS Catal. 2015, 5, 7446. (41)  (a) Cherney, A. H.; Kadunce, N. T.; Reisman, S. E. Chem. Rev. (16) Lin, X. B.; Tang, Y.; Yang, W.; Tan, F.; Lin, L. L.; Liu, X. H.; 2015, 115, 9587. (b) Choi, J.; Fu, G. C. Science 2017, 356, Feng, X. M. J. Am. Chem. Soc. 2018, 140, 3299. eaaf7230. (17) Lin, X. B.; Yang, W.; Yang, W. K.; Liu, X. H.; Feng, X. M. Angew. Chem., Int. Ed. 2019, 58, 13492. About the Authors (18) Tang, Q.; Fu, K.; Ruan, P. R.; Dong, S. X.; Su, Z. S.; Liu, X. H.; Zhen Wang received his B.S. (2009) and Ph.D. (2014) Feng, X. M. Angew. Chem., Int. Ed. 2019, 58, 11846. degrees from Sichuan University. From 2014 to 2015, he was a (19) Liu, X. H.; Zheng, K.; Feng, X. M. Synthesis 2014, 46, 2241. postdoctoral fellow in Professor Yixin Lu’s group at the National (20) Zheng, K.; Shi, J.; Liu, X. H.; Feng, X. M. J. Am. Chem. Soc. University of Singapore. In 2015, he joined the faculty of 2008, 130, 15770. Chongqing University, where he is now an associate professor. (21) Zheng, K.; Liu, X. H.; Qin, S.; Xie, M. S.; Lin, L. L.; Hu, C. W.; His research interest is in developing new catalytic methods for Feng, X. M. J. Am. Chem. Soc. 2012, 134, 17564. asymmetric synthesis. (22) Zheng, K.; Liu, X. H.; Zhao, J. N.; Yang, Y.; Lin, L. L.; Feng, X. Xiaohua Liu received her B.S. degree in 2000 from Hubei M. Chem. Commun. 2010, 46, 3771. Normal University. She then obtained her M.S. (2003) and (23) Luo, W. W.; Zhao, J. N.; Yin, C. K.; Liu, X. H.; Lin, L. L.; Feng, Ph.D. (2006) degrees from Sichuan University. She is now a X. M. Chem. Commun. 2014, 50, 7524. professor at Sichuan University. Her current research interests (24) Liu, W.; Cao, W. D.; Hu, H. P.; Lin, L. L.; Feng, X. M. Chem. include asymmetric catalysis and organic synthesis. Commun. 2018, 54, 8901. Xiaoming Feng was born in 1964. He received his B.S. (25) Zhang, H.; Yao, Q.; Cao, W. D.; Ge, S. L.; Xu, J. X.; Liu, X. H.; (1985) and M.S. (1988) degrees from Lanzhou University. Feng, X. M. Chem. Commun. 2018, 54, 12511. From 1988 to 1993, he worked at Southwest Normal University, (26) Janecki, T.; Błaszczyk, E.; Studzian, K.; Różalski, M.; Krajewska, where he became an associate professor in 1991. In 1996, U.; Janecka, A. J. Med. Chem. 2002, 45, 1142. he received his Ph.D. degree from the Chinese Academy of (27) (a) Desimoni, G.; Faita, G.; Righetti, P.; Sardone, N. Tetrahedron Sciences (CAS) under the supervision of Professors Zhitang 1996, 52, 12019. (b) Xia, Q.; Ganem, B. Org. Lett. 2001, 3, 485. Huang and Yaozhong Jiang. From 1996 to 2000, he was at the (28) Liu, W.; Zhou, P. F.; Lang, J. W.; Dong, S. X.; Liu, X. H.; Feng, Chengdu Institute of Organic Chemistry, CAS, where he was X. M. Chem. Commun. 2019, 55, 4479. appointed Professor in 1997. He did postdoctoral research at (29) Cao, W. D.; Feng, X. M.; Liu, X. H. Org. Biomol. Chem. 2019, Colorado State University from 1998 to 1999 with Professor Yian 17, 6538. Shi. In 2000, he moved to Sichuan University as a professor, (30) Zhang, Y. L.; Yang, N.; Liu, X. H.; Guo, J.; Zhang, X. Y.; Lin, L. and was selected as Academician of the Chinese Academy of L.; Hu, C. W.; Feng, X. M. Chem. Commun. 2015, 51, 8432. Sciences in 2013. He focuses on the design of chiral catalysts, (31) Wang, L. J.; Liu, X. H.; Dong, Z. H.; Fu, X.; Feng, X. M. Angew. development of new synthetic methods, and synthesis of Chem., Int. Ed. 2008, 47, 8670. bioactive compounds. m Aldrichimica ACTA 11 VOL. 53, NO. 1 • 2020 Asymmetric Allylic Substitutions Catalyzed by Iridium Complexes Derived from C(sp2)–H Activation of Chiral Ligands

Xiao Zhang and Shu-Li You* State Key Laboratory of Organometallic Chemistry Shanghai Institute of Organic Chemistry University of Chinese Academy of Sciences Chinese Academy of Sciences 345 Lingling Road Shanghai 200032, China Prof. X. Zhang Email: [email protected]

Prof. S.-L. You

Keywords. AAS; allylic substitution; asymmetric catalysis; 5. Ir-Catalyzed Asymmetric Allylic Substitutions with Nitrogen BHPphos; branch selectivity; chiral ligand; C(sp2)–H activation; Nucleophiles enantioselectivity; iridium; N‑heterocyclic carbene (NHC); 5.1. Aliphatic Amines and Arylamines THQphos. 5.2. Nitrogen-Containing Heterocycles 6. Ir-Catalyzed Asymmetric Allylic Substitutions with Oxygen Abstract. The iridium-catalyzed asymmetric allylic substitution Nucleophiles reaction has been developed into a reliable method for the 7. Conclusion and Outlook synthesis of highly enantioenriched molecules with an allylic 8. Acknowledgments stereocenter. The versatility of the reaction is largely attributed to 9. References the development of efficient catalysts. Some of these catalysts are iridium complexes derived from C(sp2)–H activation of chiral ligands 1. Introduction including THQphos (1,2,3,4-tetrahydroquinoline phosphoramidite), Transition-metal-catalyzed asymmetric allylic substitution (AAS) BHPphos (N-benzhydryl-N-phenyldinaphthophosphoramidite), reactions are among the most important transformations that and NHCs (N‑heterocyclic carbenes). These catalysts exhibit allow the construction of carbon–carbon or carbon–heteroatom exceptionally high regio-, diastereo-, and enantioselectivities as bonds in an enantioselective fashion.1 Early examples mainly well as good tolerance of sterically hindered substrates. In this focused on palladium catalysis, which is compatible with a wide article, we briefly review the design and mechanism of action range of nucleophiles and electrophiles and generally favors linear of these chiral ligands, and highlight their applications in the Ir- selectivity for mono-substituted allylic electrophiles. Catalysis catalyzed allylic substitution of various nucleophiles. by other metals has been less studied, but has shown promising control of selectivity. In particular, Ir-catalyzed asymmetric Outline allylic substitutions have received a lot of attention in the past 1. Introduction two decades owing to their unique reactivity profile that includes 2. Chiral Ligand Design a remarkably high branch selectivity for mono-substituted allylic 3. Mechanistic Studies electrophiles and nearly perfect enantioselective control.2 4. Ir-Catalyzed Asymmetric Allylic Substitutions with Carbon Since the first report by Janssen and Helmchen,3a various chiral Nucleophiles ligands—including oxazolinylphosphines, phosphoramidites, and 4.1. Enolates dienes—have been utilized in Ir-catalyzed allylic substitution 4.2. Electron-Rich Arenes reactions.3 Of these ligands, the phosphoramidites have 4.2.1. Indoles contributed significantly to the development of this area, and have 4.2.2. Pyrroles enabled a large number of valuable transformations with high 4.2.3. Naphthols levels of regio- and enantioselectivity. For instance, Carreira’s Asymmetric Allylic Substitutions Catalyzed by Iridium Complexes Derived from C(sp2)–H Activation of Chiral Ligands 12 Xiao Zhang and Shu-Li You*

bidentate P,olefin coordination ligands have demonstrated the found that K1, generated by mixing [Ir(cod)Cl]2 and P(OPh)3, 11 robustness of this approach by using unprotected allylic alcohols is unreactive. Upon addition of NaCH(CO2Me)2 and P(OPh)3 to as substrates in the presence of an acidic additive.2l,4 Under K1, complex K2 is formed via activation of the ortho C(sp2)–H 5a,b non-acidic conditions, the Feringa ligand and the Alexakis bond of one of the phenyl groups of P(OPh)3 (Scheme 1, Part 5c–e ligand are the most frequently employed ones in iridium- (a)). Subsequent dissociation of P(OPh)3 from K2 delivers the catalyzed allylic substitutions. Mechanistically, the active catalytically active species. Based on these early findings, we iridacycle catalyst is formed by bidentate P,C(sp3) coordination to developed a series of binaphthol-derived, P,C(sp2)-coordination Ir of the ligand, which is generated through C(sp3)–H activation phosphoramidite ligands, as exemplified by THQphos7 and of its methyl group.2d,6 BHPphos,8 which incorporate chiral elements. Later on, Our research efforts have been focused on developing a structurally distinct NHCs, bearing an N-aryl group at the ortho class of ligands that undergo C(sp2)–H activation during the position (e.g., the d-camphor-derived NHC9b) were found to be formation of the active catalytic iridium species. Specifically, suitable ligands for iridium-based catalytic systems following the we have developed THQphos (1,2,3,4-tetrahydroquinoline same C(sp2)–H activation mode (Scheme 1, Part (b)).9 phosphoramidite),7 BHPphos (N-benzhydryl-N-phenyldinaph- thophosphoramidite),8 and NHC (N‑heterocyclic carbene)9 3. Mechanistic Studies 7 ligands for the Ir-catalyzed asymmetric allylic substitution Among THQphos-type ligands, (R,Ra)-Me-THQphos (L1b) reactions (Figure 1). This class of chiral ligands exhibits unique outperforms in most cases. For example, its cinnamyliridium performance characteristics with respect to selectivity control complex, K3,7b was prepared following the procedure developed and substrate scope. Herein we highlight the evolution of these by Helmchen and co-workers.12 It is worth noting that an ligands with an emphasis on their applications in Ir-catalyzed exclusive exo isomer was formed at the very beginning; however, allylic substitutions with various nucleophiles. after equilibration, a 4:1 mixture of exo and endo isomers was finally isolated (Scheme 2, Part (a)). Using K3 in the allylic 2. Chiral Ligand Design alkylation reaction of sodium dimethyl malonate with cinnamyl The first iridium-catalyzed allylic substitution was reported by methyl carbonate led to comparable results with those obtained Takeuchi and Kashio in 1997.10 The allylic substitution reactions with the in situ generated catalyst, which supported the proposal of allylic acetates with sodium malonates proceeded with iridium that the (π-allyl)–Ir complex K3 is the catalytically active species

complexes generated in situ from [Ir(cod)Cl]2 and various (Scheme 2, Part (b)). Moreover, the crystal structure of K3 phosphites. It was also observed that utilization of the better showed that: (i) The iridacycle complex is formed via a C(sp2)–H 3 π-acceptor P(OPh)3 as ligand resulted in enhanced reactivity and bond insertion of the phenyl group rather than C(sp )–H bond favored the formation of branched products. In 2002, Helmchen activation of a methyl group in the ligand. (ii) Compared with and co-workers investigated the possible active species and the Ir-C(1) bond of K3, the Ir-C(3) bond is longer by 0.173 Å. The strong trans influence of the phosphorus atom, as well as the stabilizing ability of the attached phenyl ring, render C(3)

Me more electropositive than C(1). As a result, nucleophiles prefer O O Ar to attack at the C(3) position to afford highly branched allyl P N P N O O Ar alkylation products. (iii) Since the Re-face of C(3) is well shielded Me by the chiral pocket of the ligand, nucleophilic substitution

(Sa) (S,S,Sa) Carreira ligand Ar = Ph: Feringa ligand P,olefin coordination Ar = 2-MeOC H : Alexakis ligand 6 4 (a) Helmchen (2002) P,C(sp3) coordination P(OPh)3 P(OPh)3 + THF Cl NaCH(CO2Me)2 R Ir Ir P(OPh)2 1/2 [Ir(cod)Cl]2 P(OPh)3 P(OPh)3 (R )-L1a; R = R' = H O O O a Ph K1 P N (R,Ra)-L1b; R = H, R' = Me P N K2 O (S,Sa)-L1c; R = Ph, R' = Me O CHPh2 (b) You (2012–2016) R' R HO OH = (Ra)-BINOL (Sa)-L2 + ++ THQphos BHPphos O N O N NHCs Ph O N Ph O P Ir Me Ph P Ir Ir O N Me + O Ph t-Bu + N OTMS N Ph N – Ph N – Me N BF4 N N N BF4 – – – TfO BF4 – TfO Ph t-Bu Me O BF4 N N+ L3a L3b L3c Ph K3 K4 K5 2 2 2 P,,C(sp2) or NHC C(sp2) coordination P,,C(sp ) coordination P C(sp ) coordination NHC,C(sp ) coordination

Figure 1. Representative Ligands for the Ir-Catalyzed Asymmetric Scheme 1. Representative Iridium Complexes Formed by C(sp2)–H Allylic Substitution Reactions. (Ref. 7–9) Activation of Ligands. (Ref. 7b,8,9d,11) Aldrichimica ACTA 13 VOL. 53, NO. 1 • 2020 would occur from the Si-face to give the R configuration of the The corresponding α-quaternary β-keto ester products bearing branched product. Compared with Ir complexes derived from vicinal stereocenters were obtained in good yields and excellent Feringa-type ligands, K3 has a bigger pocket for the allyl ligand, stereoselectivities. Although diastereoselective control by thus permitting a good tolerance of sterically bulky substrates. a catalyst is problematic within this domain, the iridium

One possible explanation for the observed high enantioselectivity complex derived from (R,Ra)-Me-THQphos (L1b) resulted in is that the kinetically favorable exo form of K3 could be captured diastereoselectivities (>20:1 dr) that are much greater than those by nucleophiles prior to π-σ-π interconversion. The absolute from other privileged ligands (1:1 or 1:2 dr in each case).13,14 configuration of the chiral products is determined by the BINOL Stoltz’s group extended the use of the Ir/L1b catalytic system scaffolds. Interestingly, the reactions with THQphos and the further to address asymmetric transformations involving the more Feringa ligand derived from the same configuration of BINOL challenging acyclic β-keto esters.15 Employing LiOt-Bu as base, a afford the products with opposite absolute configurations. Further wide variety of nucleophiles—bearing substituents such as alkyl, investigations disclosed that the same C(sp2)–H activation mode allyl, propargyl, heteroaryl, and ketone functionalities at the operates in the iridium complexes derived from BHPphos and the α position—were tolerated, affording the expected products in NHCs bearing an N-Ar group.8,9 These three types of ligand have excellent yields and selectivities. When an electron-withdrawing found wide applications in iridium-catalyzed asymmetric allylic group was incorporated into the cinnamyl carbamate substrates, substitution reactions. a diminished regioselectivity was observed. When the logarithm of the B/L value was plotted vs the corresponding Brown σ+ 4. Ir-Catalyzed Asymmetric Allylic Substitutions with constant, a linear relationship was revealed, which corresponded Carbon Nucleophiles well with the experimental observations. 4.1. Enolates Stoltz’s group later employed enolates derived from α,β- In 2012, our group introduced a series of N-aryl phosphoramidites, unsaturated malonates or α,β-unsaturated keto esters as such as THQphos and BHPphos, as ligands for the iridium- substrates, and found that sequential α-alkylation and Cope catalyzed asymmetric allylic alkylation of sodium dimethyl rearrangement afforded linear γ-alkylated products in good 7b 16 malonates. (R,Ra)-Me-THQphos (L1b) proved to be the optimal yields and with excellent ee’s. (S,Sa)-diPh-THQphos (L1c) was ligand, with the corresponding reactions giving good yields and identified as the optimal ligand for α-alkylation (Scheme 3, Part excellent regio- and enantioselectivities. It is worth noting that ortho-substituted cinnamyl carbonates, which are typically unfavored substrates in iridium catalysis with Feringa-type NaNu Nu + + ligands, were well accommodated in this reaction.7b Recently, a Ar Ar Nu Ar OCO2Me B L chiral dihydroisoquinoline-type NHC was used as ligand for the using N-aryl phosphoramidite ligand using N-heterocyclic carbene ligand same transformation, resulting in excellent enantioselectivity (R,Ra)-L1b (4 mol %) L3c (5.0 mol %) but moderate regioselectivity being achieved for a wide range [Ir(cod)Cl]2 (2 mol %) [Ir(dncot)Cl]2 (2.5 mol %) 9f THF, rt, 1–30 h CH2Cl2, reflux, 12–47 h of allylic substrates. Preliminary mechanistic studies have B:L = 95:5 to >99:1 B:L = 28:72 to 91:9 suggested that the key active species results from the same 82–99% (B + L), 92–99% ee (B) 90–99% (B + L), 84–98% ee (B) 2 C(sp )–H activation mode. The modest regioselectivity is NuH = malonate, β-keto ester, 1,3-diketone, etc. presumed to be due to electronic effects, since the phosphorus dncot = dinaphthocyclooctatetraene; Ar = aryl, heteroaryl 7b,9f in THQphos is a stronger electron donor than an NHC (eq 1). eq 1 (Ref. 7b,9f) An iridium-catalyzed asymmetric allylic alkylation of cyclic β-keto esters has been reported by Stoltz and co-workers.13

MeO2C CO2Me 1. [Ir(cod)Cl]2 (2 mol %) MeO2C CO2Me (S,Sa)-L1c (4 mol %) OCO2Me TBD (10 mol %) 4 + Ar (a) (a) + Ph OCO2Me LiOt-Bu (1.2 equiv) O X n Ar X n (R,Ra)-L1b (3.8 equiv) o 2 THF, 20 C, 12–16 h + O P Ir Ph X = CH , O, S, NBn; n = 0, 1, 2 56–97%, 90–97% ee AgOTf, THF(anhyd) 2 o 1/2 [Ir(cod)Cl]2 2. PhMe, 100 C, 5 h argon, rt, overnight Me N 1 3 Ar = aryl, heteroaryl TfO– O Ar O HO OH = (Ra)-BINOL [Ir(cod)Cl]2 (2 mol %) RO2C K3 (exo-out) X OCO2Me (S,Sa)-L1b (4 mol %) X (b) + 63%, exo/endo = 4:1 RO2C n Ar TBD (10 mol %) n bond length (Å): Ir–C(1), 2.227; Ir–C(2), 2.241; Ir–C(3), 2.400 o X = CH2, NBn; n = 1, 2, 3; R = Me, Et THF, 20 C, 24 h B:L = 11:1 to >20:1 (b) Ar = XC6H4 (X = H, 4-Me, 3-MeO, 3-Cl, 4-Br) 40–99% (B + L) CH(CO Me) K3 (4 mol %) 2 2 TBD = 1,5,7-triazabicyclo[4.4.0]dec-5-ene dr = 1.2:1 to 5:1 Ph OCO2Me + NaCH(CO2Me)2 79–98% ee (major) THF, rt, 1h Ph 62–91% ee (minor) 2 equiv B:L = 99/1 92%, 95% ee

Scheme 2. Synthesis and Application of Iridium–THQphos Complex Scheme 3. Ir-Catalyzed Asymmetric Allylic γ-Alkylation of α,β- K3. (Ref. 7b) Unsaturated Malonates and Keto Esters. (Ref. 16) Asymmetric Allylic Substitutions Catalyzed by Iridium Complexes Derived from C(sp2)–H Activation of Chiral Ligands 14 Xiao Zhang and Shu-Li You*

(a)).16 The Cope rearrangement occurred with a high degree 4.2. Electron-Rich Arenes of chirality transfer via a chair-like transition state. However, 4.2.1. Indoles the reactions of endocyclic α,β-unsaturated β-keto esters only Apart from soft carbon nucleophiles, aromatic compounds gave modest dr values (Scheme 3, Part (b)). Moreover, the are also suitable substrates in iridium-catalyzed asymmetric pure diastereomers from the α-alkylation were isolated and allylic substitutions with ligands capable of undergoing C(sp2)–H subjected to the Cope rearrangement individually. The major activation. We reported the earliest examples back in 2009,

isomer delivered the product in a relatively better yield through when (R,Ra)-L1b and its analogues were synthesized and a chair-like transition state, while the minor isomer furnished a applied in the Ir-catalyzed asymmetric Friedel–Crafts reaction much lower yield via a boat-like transition state. of indoles with allylic carbonates.7a High levels of regioselectivity Alkyl-substituted allylic electrophiles are challenging for the branched alkylation product as well as high levels of substrates in iridium-catalyzed asymmetric allylic substitutions. enantioselectivity were observed. In particular, L1b exhibited Nevertheless, the Ir-catalyzed asymmetric allylic alkylation of superior performance to the Feringa-type ligands when ortho- β-keto esters with crotyl derivatives has been achieved by Stoltz substituted cinnamyl carbonates were used. When reacting and co-workers.17 Due to the counterion effect, crotyl chloride with substrates bearing an allylic carbonate side chain at the provided better regioselective control than crotyl carbonate. C(3) position of indoles, an intramolecular nucleophilic attack With diPh-THQphos (L1c) as ligand, the corresponding at the more-substituted C(3) of indoles took place resulting in a alkylated products were furnished in good-to-excellent yields spirocyclic product.20 Systematic evaluation of various reaction and selectivities. The same laboratory later reported that parameters established that the iridium catalyst generated in

masked acyl cyanide reagents were suitable nucleophiles in the situ from [Ir(cod)Cl]2 and L1b affords the desired dearomatized asymmetric allylic alkylation catalyzed by the iridium catalyst products bearing all-carbon quaternary stereogenic centers

derived from (S,Sa)-L1b. This led to vinylated α-aryl carbonyl in high yields and with remarkably high diastereo- and derivatives with high enantioselectivity (eq 2).18 enantioselectivity (up to >99:1 dr and 97% ee) (Scheme 4, Bos and Riguet reported that benzofuran-substituted Part (a)).20 The resultant spiroindolenines were amenable γ-lactones are competent substrates in Ir-catalyzed to further elaboration without loss of enantiomeric purity. asymmetric allylic substitutions in the presence of strong base Subsequently, an unprecedented Ir-catalyzed asymmetric such as LiHMDS that is required to generate the corresponding allylic dearomatization–N-Bn iminium migration sequence was 21 enolates. By using BHPphos (Sa)-L2 as the optimal ligand, unlocked when the electronic property of the tether was tuned. 1,5-hexadienes were delivered in good-to-excellent yields Synthesis of chiral tetrahydro-β-carbolines was achieved in a and selectivities (eq 3).19 Interestingly, a heteroaromatic highly enantioselective fashion with readily accessible L2 as Cope rearrangement of the resultant 1,5-hexadienes followed the chiral ligand. An aza-spiroindolenine intermediate was by rearomatization permitted the efficient alkylation of the proposed and detected via in situ infrared spectroscopy. benzofuran ring at the 3 position. Interestingly, by employing symmetric bis(indol-3-yl)- substituted allylic carbonates as substrates, the desymmetrizing allylic dearomatization of indoles was achieved.22 The spiroindolenines containing three contiguous stereogenic centers [Ir(cod)Cl]2 (2 mol %) OMOM OMOM (S,Sa)-L1b (4 mol %) NC + NC CN Ar OCO2Me NC TBD (10 mol %) Ar masked Ar = aryl, heteroaryl LiBr (2 or 4 equiv) acyl cyanide o 41–95% R' THF, 60 C, 18 h 89–98% ee (carbon monoxide R N equivalent) [Ir(cod)Cl]2 (2 mol %) NR' (R,Ra)-L1b (4 mol %) O (a) N Cs2CO3 (2 equiv) R H CH2Cl2, reflux, 1.5 h N X = OH, OR, NR'2 X 92–98% (isolated yield Ar of major diastereomer) MeO CO 2 dr = 96:4 to >99:1 eq 2 (Ref. 18) R = H, Me, MeO, BnO, F, Br 88–96% ee R' = Me, allyl, Bn, 4-BrC6H4CH2

n [Ir(cod)Cl]2 (2 mol %) R' XH OCO2Me (R,Ra)-L1b (4 mol %) [Ir(cod)Cl]2 (2 mol %) (b) R + n N TBD (10 mol %) X O (Sa)-L2 (4 mol %) R' 0.5 equiv R O Ar H Et3N (1 equiv) N TBD (10 mol %) H O n = 1, 2 THF, rt, 12 h + 40–85% (isolated yield LiHMDS (1.0 equiv) X = O, NMe, NBoc, NTs, NCO Me, NCO Et, NCO t-Bu O 2 2 2 of major diastereomer) Ar OCO2Me o O O THF, 50 C, 5 h C(CO2Me)2, C(CO2Et)2, C(CO2i-Pr)2 1.1 equiv dr = 4:1 to >20:1 B:L = 10:1 to >20:1 R = H, Me, MeO, Cl, Br; R' = aryl, heteroraryl, alkyl 91–99% ee Ar = aryl, heteroaryl dr = 68:32 to 83:17 LiHMDS = lithium hexamethyldisilazide 62–93%, 76–98% ee

Scheme 4. Ir-Catalyzed Asymmetric Allylic Alkylation of Indole eq 3 (Ref. 19) Derivatives. (Ref. 20,24) Aldrichimica ACTA 15 VOL. 53, NO. 1 • 2020 were obtained as single diastereoisomers with exceptionally inhibited. The dearomatized spironaphthalenones bearing two high enantioselectivity (up to 99% ee). The combination contiguous stereogenic centers were furnished with good-to- 23 of [Ir(dbcot)Cl]2 (dbcot = dibenzocyclooctatetraene) and excellent chemo-, diastereo-, and enantioselectivity (Scheme 26 (S,Sa)-L1c exerted crucial influence on the reaction outcome. 5, Part (b)). It is believed that the high C/O alkylation ratio When the products were subjected to a catalytic amount of might be caused by the restriction on ring size, as formation of p-toluenesulfonic acid in refluxing THF, a ring expansion six-membered rings is more facile than that of eight-membered of a six- to a seven-membered-ring occurred to deliver rings. It is worth noting that superior selectivities were achieved hexahydroazepino[4,5-b]indoles with high diastereoselectivity. when the nitrogen atom was protected with electron-deficient The configuration of the migrating carbon stereocenter was and sterically hindered groups. reversed, indicating a possible stepwise migration mechanism involving a free vinyliminium intermediate. 5. Ir-Catalyzed Asymmetric Allylic Substitutions with The intermolecular allylic dearomatization of indoles was also Nitrogen Nucleophiles explored using the iridium catalyst derived from (R,Ra)-L1b. 5.1. Aliphatic Amines and Arylamines Allylic substitution with allylic carbonates was selective for the In 2016, our research laboratory investigated the Ir- branched product and yielded polycyclic indolines possessing catalyzed asymmetric intermolecular allylic amination using contiguous tertiary and all-carbon quaternary stereocenters in a various nitrogen nucleophiles—namely, anilines, indolines, 24 highly chemo-, regio-, diastereo-, and enantioselective fashion. benzylamines, and 2-vinylanilines—in the presence of (S,Sa)- Tryptophols, tryptamines, indoles with a carbon nucleophile side L1c.7c To our delight, we observed a significant advantage over chain, and tryptophan derivatives were demonstrated to be the Feringa ligand with respect to regio- and enantioselective suitable substrates (Scheme 4, Part (b)). control when challenging ortho-substituted cinnamyl carbonates were employed as substrates. Remarkably, the utilization of

4.2.2. Pyrroles either (S,Sa)-L1c, its diastereomer (R,Sa)-L1c, or a mixture

Similarly, the [Ir(cod)Cl]2–(R,Ra)-L1b complex catalyzed the of equal amounts of the two resulted in the same reaction asymmetric allylic dearomatization of pyrroles tethered with an outcome, indicating that the stereocenter of 2-methyl-THQ was allylic carbonate. With THF as solvent, six-membered, spiro- not essential in this case. X-ray crystallographic analysis of the 2H-pyrrole derivatives were obtained in good yields with high catalyst complex further supported the proposal that the active levels of regio-, diastereo- and enantioselectivity (Scheme 5, iridacycle was generated via C(sp2)−H bond activation of the Part (a)).25 Further transformations of the resultant products THQ moiety of the ligand.7c afforded diverse pharmaceutically important spirocycles.

When (Ra)-L2 was used instead of (R,Ra)-L1b and the tether between the pyrrole ring and the allylic carbonate moiety was H R' [Ir(cod)Cl]2 (2 mol %) shortened by one CH2 group, a sequential dearomatization– R N N (R,Ra)-L1b (4 mol %) R (a) N in situ migration of the substituent from the C(2) to the C(3) N Cs2CO3 (1 equiv) R' position of the pyrrole ring occurred in a fashion similar to that THF, 50 oC of indoles.21 In combination with DFT calculations, it was found 61–90% (isolated yield of OCO2Me major diastereoisomer) that the N-Bn linkage enhances the migratory aptitude of the R = H, Et, aryl dr = 90:10 to >99:1 R' = Me, allyl, Bn, 4-BrC6H4CH2 84–96% ee methylene group. Employing (Ra)-L2 again and switching the substrates to the gem-diester-tethered analogues afforded Ts N stable five-membered-ring spiro-2H-pyrroles in good yields with [Ir(dbcot)Cl]2 (2 mol %) (S,S )-L1c (4 mol %) 8 a excellent diastereo- and enantioselectivity. Upon treatment with (b) A + B OH OCO2Me Cs2CO3 (1.0 equiv) a catalytic amount of TsOH, stereospecific allyl migration took R THF, 50 oC, 10–24 h place smoothly, yielding the enantioenriched polycyclic pyrrole derivatives with preserved ee’s. It is worth highlighting that the R = Me, MeO, Br, Ph, 4-FC6H4 Ts Ts Ir-complex derived from [Ir(cod)Cl]2 and (Ra)-L2 is critical for N N excellent control of both diastereo- and enantioselectivity. As + a consequence, the corresponding π-allyl iridium complex was O O R R prepared and characterized, further confirming the C(sp2)–H activation mode of the ligand.8 A B intramolecular O-allylation C-allylation–dearomatization cyclic ether 4.2.3. Naphthols product side-product A:B = 84:16 to >95:5; dr = 87:13 to >95:5 α-Substituted β-naphthols are challenging substrates in 70–88% (of isolated major diastereoisomer), 96–99% ee the Ir-catalyzed asymmetric allylic dearomatization, since etherification could be a facile competing reaction. Gratifyingly, Scheme 5. Ir-Catalyzed Asymmetric Allylic Alkylation of (a) Pyrrole by using [Ir(dbcot)Cl]2 as the iridium precursor and (S,Sa)-diPh- and (b) Naphthol Derivatives. (Ref. 25,26) THQphos (L1c), the allylic etherification pathway was largely Asymmetric Allylic Substitutions Catalyzed by Iridium Complexes Derived from C(sp2)–H Activation of Chiral Ligands 16 Xiao Zhang and Shu-Li You*

28–30 5.2. Nitrogen-Containing Heterocycles containing, electron-deficient heteroarenes. With (R,Ra)-L1b Our research efforts had demonstrated that indoles and pyrroles as the optimal ligand, a variety of heterocycles including pyrazines, with electron-donating or electron-neutral groups attached to quinolines, isoquinolines, benzoxazoles, benzothiazoles, and the core would undergo a dearomatization–migration reaction benzimidazoles underwent asymmetric allylic dearomatization sequence. However, when an electron-withdrawing group reactions smoothly, affording highly functionalized products is installed at the C(2) position, a highly enantioselective in good-to-excellent yields with excellent enantioselectivity intramolecular allylic amination of indoles and pyrroles is enabled (Scheme 6, Part (a)).28,29 In accordance with well-established

by an iridium complex generated in situ from [Ir(cod)Cl]2 and Ir-catalysis pathways, the allylic carbonate reacts first with the l-tert-butylalaninol-derived triazolium salt (L3a), first introduced chiral iridium catalyst. The liberated methoxide anion abstracts by the research group of Enders.9a For the first time, chiral NHC the α proton in the substrate, rendering the N-attack feasible carbenes were demonstrated as suitable ligands for Ir-catalyzed due to delocalization of the negative charge. Alternatively, asymmetric allylic substitutions.9d Preliminary mechanistic N-alkylation occurs prior to deprotonation. As supporting studies suggested that C(sp2)–H activation takes place at the evidence, and under certain conditions, the intermediate ortho C(sp2)–H bond of the N-aryl group of the ligand. Later, resulting from direct N-attack has been captured in situ

Ir–L3b prepared from [Ir(cod)Cl]2 and d-camphor-derived L3b, and isolated. The synthetic utility of this method has been was successfully applied in the same transformation. In both demonstrated by a facile synthesis of compound 2,29 which cases, the corresponding indolopiperazinones and piperazinones can be easily converted into (+)-gephyrotoxin31 through known were furnished in good yields and high enantioselectivities reaction steps32 (Scheme 6, Part (b)). (eq 4).9e To further broaden the substrate scope for pyrroles, The reaction was then extended to the more challenging the iridium catalysts derived from chiral phosphoramidites were hydroxyquinoline derivatives.33 However, the frequently used exploited. Particularly, the utilization of THQphos (L1b or L1c) phosphoramidites—including the Feringa and the Alexakis ligands, significantly improved the enantioselectivity of the reactions Me-THQphos, and BHPphos—failed to give satisfactory results. involving bromo-substituted pyrroles.27 However, to our great delight, the anticipated intramolecular C(sp2)–H activation ligands are also capable of promoting allylic alkylation reactions of 5- and 7-hydroxyquinolines were asymmetric allylic dearomatization reactions with nitrogen- achieved with good-to-excellent yields and enantioselectivities

with the iridium catalyst generated in situ from [Ir(dbcot)Cl]2 and the Enders NHC (L3a) (eq 5).33 Theoretical calculations supported the hypothesis that the aromatic character of the O O catalyst I or II Me two consecutive rings of the hydroxyquinoline was weakened. R DBU (10 mol %) R Me N NR' N NR' Ir Remarkably, performing the reaction directly in air and using H CH2Cl2 Cl rt or reflux N NPh undistilled THF as solvent led to comparable results, further Me N MeO2CO O highlighting the robustness of Ir–NHC catalysis. Based on this R' = Me, Bn, PMB, allyl; DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene Ir-L3b method, a key intermediate (a phenol variant of ent-2) for the

catalyst I: [Ir(cod)Cl]2 (2.5 mol %), L3a (5 mol %) 74–91%, 92–99% ee synthesis of (+)-gephyrotoxin was delivered in only two steps catalyst II: Ir-L3b (5 mol %) 75–95%, 88–94% ee from the product of the reaction. This method is also a rare

eq 4 (Ref. 9d,9e) example of allylic chlorides being viable precursors in the Ir- catalyzed asymmetric allylic substitution reaction.

6. Ir-Catalyzed Asymmetric Allylic Substitutions with [Ir(cod)Cl]2 (2–4 mol %) X X (R,Ra)-L1b (4–8 mol %) Oxygen Nucleophiles (a) R R THF, rt or 50 oC The catalytic, enantioselective construction of chiral N,O- N YH N Y 1.5–48 h MeO2CO heterocycles remains a challenging task in organic synthesis.

X = N, CH 53–99%, 57–99% ee Y = N, CCN, CCOZ (Z = Ar, OMe, OEt, Ot-Bu, F, Cl, Br)

OMe OMe OH O H [Ir(dbcot)Cl]2 (2 mol %) R 6 steps Ref. 32 L3a (4 mol %) (b) H H R R or DBU (1 equiv) N CO2Me N N N N O N Y H THF, rt, 12 h Cl

HO HO or 55–99% 85–99% 1, 96% ee 2, 91% ee (+)-gephyrotoxin R 82–97% ee 90–96% ee

R = H, Me, n-Pr, c-Pr, F, Cl, Br HO N Y Scheme 6. (a) The Iridium-Catalyzed Asymmetric Allylic Cl Dearomatization of Nitrogen-Containing Heterocycles and (b) Its Application to a Formal Synthesis of (+)-Gephyrotoxin, a Naturally Y = CH2, NTs Occurring Histrionicotoxin. (Ref. 28,29) eq 5 (Ref. 33) Aldrichimica ACTA 17 VOL. 53, NO. 1 • 2020

In 2014, Feringa and co-workers reported an unprecedented 8. Acknowledgments synthesis of such scaffolds through a highly efficient iridium- We thank the National Key R&D Program of China catalyzed intramolecular allylic substitution with the amide (2016YFA0202900), National Natural Science Foundation of group providing the oxygen nucleophile.34 By employing the China (91856201, 21572252, 21821002), Strategic Priority

catalyst generated from [Ir(cod)Cl]2 and (Sa)-L1a, Feringa’s Research Program (XDB20000000) and Key Research Program team was able to prepare differentially substituted oxazolines, of Frontier Sciences (QYZDY-SSW-SLH012) of the Chinese oxazines, and benzoxazines in good-to-excellent yields and with Academy of Sciences, and the Science and Technology high enantiomeric purity (Scheme 7).34 Commission of Shanghai Municipality (16XD1404300) for their generous financial support. 7. Conclusion and Outlook Chiral phosphoramidite and NHC ligands capable of undergoing 9. References C(sp2)–H activation have been widely employed in Ir-catalyzed (1) For selected reviews, see: (a) Trost, B. M.; van Vranken, D. L. asymmetric allylic substitution (AAS) reactions. Among them, Chem. Rev. 1996, 96, 395. (b) Trost, B. M. Chem. Pharm. Bull. THQphos and BHPphos participate in P,C(sp2) coordination with 2002, 50, 1. (c) Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, the Ir center. As a result of both electronic and steric influences, 103, 2921. (d) Milhau, L.; Guiry, P. J. Top. Organomet. Chem. high levels of branched regioselectivity and asymmetric induction 2012, 38, 95. are generally observed. Intriguingly, the newly developed (2) For selected reviews, see: (a) Helmchen, G.; Dahnz, A.; Dübon, catalysts tolerate well ortho-substituted cinnamyl carbonates, P.; Schelwies, M.; Weihofen, R. Chem. Commun. 2007, 675. (b) which were challenging substrates in prior similar studies. The Helmchen, G. In Iridium Complexes in Organic Synthesis; Oro, catalysts also display remarkable diastereoselective control when L. A., Claver, C., Eds.; Wiley-VCH: Weinheim, Germany, 2009; prochiral nucleophiles are employed. Furthermore, the C(sp2)–H pp 211–250. (c) Wu, Y.; Yang, D.; Long, Y. Chin. J. Org. Chem. activation mode has been extended to structurally distinct 2009, 29, 1522. (d) Hartwig, J. F.; Stanley, L. M. Acc. Chem. Res. N-heterocyclic carbene ligands, whereby the active iridium 2010, 43, 1461. (e) Hartwig, J. F.; Pouy, M. J. Top. Organomet. catalyst results from a bidentate NHC,C(sp2) coordination. Chem. 2011, 34, 169. (f) Liu, W.-B.; Xia, J.-B.; You, S.-L. Top. With NHC as the chiral ligand, Ir-catalyzed asymmetric allylic Organomet. Chem. 2012, 38, 155. (g) Tosatti, P.; Nelson, A.; substitution reactions can occur in a highly enantioselective Marsden, S. P. Org. Biomol. Chem. 2012, 10, 3147. (h) Hethcox, fashion. However, regioselective control is still problematic J. C.; Shockley, S. E.; Stoltz, B. M. ACS Catal. 2016, 6, 6207. (i) for the intermolecular variants. Nevertheless, NHCs show Qu, J.; Helmchen, G. Acc. Chem. Res. 2017, 50, 2539. (j) Zhang, significant advantages in some instances, as exemplified by the X.; You, S.-L. Chimia 2018, 72, 589. (k) Cheng, Q.; Tu, H.-F.; asymmetric allylic alkylation of challenging hydroxyquinolines. Zheng, C.; Qu, J.-P.; Helmchen, G.; You, S.-L. Chem. Rev. 2019, Despite considerable progress, the substrate scope for 119, 1855. (l) Rössler, S. L.; Petrone, D. A.; Carreira, E. M. Acc. currently available methods is still limited to commonly used Chem. Res. 2019, 52, 2657. (m) Qu, J.-P.; Helmchen, G.; Yang, nucleophiles, such as enolates or aromatic compounds, and Z.-P.; Zhang, W.; You, S.-L. Org. React. 2019, 99, 423. activated allylic electrophiles. In this regard, expanding the (3) (a) Janssen, J. P.; Helmchen, G. Tetrahedron Lett. 1997, 38, substrate scope is an important goal in our current investigations. 8025. (b) Defieber, C.; Grützmacher, H.; Carreira, E. M.Angew. On the other hand, efforts will also be directed to exploring Chem., Int. Ed. 2008, 47, 4482. structurally distinct ligands capable of C(sp2)–H activation, as (4) For selected early examples, see: (a) Lafrance, M.; Roggen, M.; well as exploring new types of asymmetric reactions beyond the Carreira, E. M. Angew. Chem., Int. Ed. 2012, 51, 3470. (b) Ir-catalyzed AAS.35 Rössler, S. L.; Krautwald, S.; Carreira, E. M. J. Am. Chem. Soc. 2017, 139, 3603. (5) (a) De Vries, A. H. M.; Meetsma, A.; Feringa, B. L. Angew. O R' Chem., Int. Ed. Engl. 1996, 35, 2374. (b) Teichert, J. F.; Feringa, [Ir(cod)Cl]2 (2.5 mol %) NH N R' B. L. Angew. Chem., Int. Ed. 2010, 49, 2486. (c) Langlois, J. (Sa)-L1a (5 mol %) (a) R R OCO2Me DABCO® (3 equiv) O B.; Alexakis, A. Top. Organomet. Chem. 2012, 38, 235 (DOI: THF, 50 oC, 24 h https://doi.org/10.1007/3418-2011-12). (d) Tissot-Croset, K.;

R = H, Cl, Br; R' = aryl, heteroaryl, t-Bu 63–93%, 83–97% ee Polet, D.; Alexakis, A. Angew. Chem., Int. Ed. 2004, 43, 2426. ® DABCO = 1,4-diazabicyclo[2.2.2]octane (e) Alexakis, A.; Polet, D. Org. Lett. 2004, 6, 3529. (6) For selected early examples, see: (a) Ohmura, T.; Hartwig, J. F. [Ir(cod)Cl]2 (2.5 mol %) O N (Sa)-L1a (5 mol %) n J. Am. Chem. Soc. 2002, 124, 15164. (b) Kiener, C. A.; Shu, C.; (b) OCO2Me Ph N DBU (0.5 equiv) Ph O H n Incarvito, C.; Hartwig, J. F. J. Am. Chem. Soc. 2003, 125, 14272. THF, rt, 24 h n = 1,2 n = 1, 60%, 95% ee (c) Madrahimov, S. T.; Hartwig, J. F. J. Am. Chem. Soc. 2012, n = 2, 65%, 92% ee 134, 8136. (d) Madrahimov, S. T.; Li, Q.; Sharma, A.; Hartwig, J.

Scheme 7. Feringa’s Ir-Catalyzed Intramolecular Asymmetric Allylic F. J. Am. Chem. Soc. 2015, 137, 14968. Substitution Reaction with Amide Oxygen Nucleophiles. (Ref. 34) (7) (a) Liu, W.-B.; He, H.; Dai, L.-X.; You, S.-L. Synthesis 2009, 2076. (b) Liu, W.-B.; Zheng, C.; Zhuo, C.-X.; Dai, L.-X.; You, Asymmetric Allylic Substitutions Catalyzed by Iridium Complexes Derived from C(sp2)–H Activation of Chiral Ligands 18 Xiao Zhang and Shu-Li You*

S.-L. J. Am. Chem. Soc. 2012, 134, 4812. (c) Zhang, X.; Liu, 3, 205. W.-B.; Cheng, Q.; You, S.-L. Organometallics 2016, 35, 2467. (26) Cheng, Q.; Wang, Y.; You, S.-L. Angew. Chem., Int. Ed. 2016, (8) Zhuo, C.-X.; Cheng, Q.; Liu, W.-B.; Zhao, Q.; You, S.-L. Angew. 55, 3496. Chem., Int. Ed. 2015, 54, 8475. (27) Zhuo, C.-X.; Zhang, X.; You, S.-L. ACS Catal. 2016, 6, 5307. (9) (a) Enders, D.; Kallfass, U. Angew. Chem., Int. Ed. 2002, 41, (28) Yang, Z.-P.; Wu, Q.-F.; You, S.-L. Angew. Chem., Int. Ed. 2014, 1743. (b) Li, Y.; Feng, Z.; You, S.-L. Chem. Commun. 2008, 53, 6986. 2263. (c) Li, G.-T.; Gu, Q.; You, S.-L. Chem. Sci. 2015, 6, 4273. (29) Yang, Z.-P.; Wu, Q.-F.; Shao, W.; You, S.-L. J. Am. Chem. Soc. (d) Ye, K.-Y.; Cheng, Q.; Zhuo, C.-X.; Dai, L.-X.; You, S.-L. 2015, 137, 15899. Angew. Chem., Int. Ed. 2016, 55, 8113. (e) Ye, K.-Y.; Wu, K.-J.; (30) Yang, Z.-P.; Zheng, C.; Huang, L.; Qian, C.; You, S.-L. Angew. Li, G.-T.; Dai, L.-X.; You, S.-L. Heterocycles 2017, 95, 304 (DOI: Chem., Int. Ed. 2017, 56, 1530. 10.3987/COM-16-S(S)19; https://www.heterocycles.jp/newlibrary/ (31) Daly, J. W.; Witkop, B.; Tokuyama, T.; Nishikawa, T.; Karle, I. L. libraries/journal/95/1). (f) Bao, C.-C.; Zheng, D.-S.; Zhang, X.; Helv. Chim. Acta 1977, 60, 1128. You, S.-L. Organometallics 2018, 37, 4763. (32) Ito, Y.; Nakajo, E.; Nakatsuka, M.; Saegusa, T. Tetrahedron Lett. (10) Takeuchi, R.; Kashio, M. Angew. Chem., Int. Ed. Engl. 1997, 1983, 24, 2881. 36, 263. (33) Yang, Z.-P.; Jiang, R.; Zheng, C.; You, S.-L. J. Am. Chem. Soc. (11) Bartels, B.; García-Yebra, C.; Rominger, F.; Helmchen, G. Eur. J. 2018, 140, 3114. Inorg. Chem. 2002, 2569. (34) Zhao, D.; Fañanás-Mastral, M.; Chang, M.-C.; Otten, E.; (12) (a) Spiess, S.; Raskatov, J. A.; Gnamm, C.; Brödner, K.; Feringa, B. L. Chem. Sci. 2014, 5, 4216. Helmchen, G. Chem.—Eur. J. 2009, 15, 11087. (b) Raskatov, J. (35) For an application of BHPphos in a Pd-catalyzed decarboxylation– A.; Spiess, S.; Gnamm, C.; Brödner, K.; Rominger, F.; Helmchen, cycloaddition sequence, see: Li, T.-R.; Tan, F.; Lu, L.-Q.; Wei, G. Chem.—Eur. J. 2010, 16, 6601. Y.; Wang, Y.-N.; Liu, Y.-Y.; Yang, Q.-Q.; Chen, J.-R.; Shi, D.- (13) Liu, W.-B.; Reeves, C. M.; Virgil, S. C.; Stoltz, B. M. J. Am. Q.; Xiao, W.-J. Nat. Commun. 2014, 5, Article No. 5500 (DOI: Chem. Soc. 2013, 135, 10626. https://doi.org/10.1038/ncomms6500). (14) The iridium complex was generated in situ by treatment of [Ir(cod)- ® Cl]2 and ligand with 1,5,7-triazabicyclo[4.4.0]undec-5-ene (TBD): Trademarks. DABCO (Evonik Degussa GmbH). (a) Lipowsky, G.; Miller, N.; Helmchen, G. Angew. Chem., Int. Ed. 2004, 43, 4595. (b) Shu, C.; Leitner, A.; Hartwig, J. F. About the Authors Angew. Chem., Int. Ed. 2004, 43, 4797. Xiao Zhang received her B.Sc. degree in chemistry in 2010 (15) Liu, W.-B.; Reeves, C. M.; Stoltz, B. M. J. Am. Chem. Soc. 2013, from Anhui Normal University, and completed her Ph.D. degree 135, 17298. in 2015 under the direction of Professor Shu-Li You at the (16) Liu, W.-B.; Okamoto, N.; Alexy, E. J.; Hong, A. Y.; Tran, K.; Shanghai Institute of Organic Chemistry (SIOC). She then spent Stoltz, B. M. J. Am. Chem. Soc. 2016, 138, 5234. two years as a Humboldt postdoctoral fellow with Professor Eric (17) Hethcox, J. C.; Shockley, S. E.; Stoltz, B. M. Angew. Chem., Int. Meggers at Philipps-Universität Marburg. In 2017, she joined Ed. 2016, 55, 16092. SIOC as Assistant Professor, and was promoted to Associate (18) Hethcox, J. C.; Shockley, S. E.; Stoltz, B. M. Org. Lett. 2017, Professor in June of 2018. Her research interests are in the 19, 1527. areas of transition-metal catalysis and photochemistry. (19) Bos, M.; Riguet, E. Chem. Commun. 2017, 53, 4997. Shu-Li You received his B.Sc. degree in chemistry in 1996 (20) Wu, Q.-F.; He, H.; Liu, W.-B.; You, S.-L. J. Am. Chem. Soc. from Nankai University. He obtained his Ph.D. degree in 2001 2010, 132, 11418. from the Shanghai Institute of Organic Chemistry (SIOC) under (21) Zhuo, C.-X.; Wu, Q.-F; Zhao, Q.; Xu, Q.-L.; You, S.-L. J. Am. the supervision of Professor Li-Xin Dai, and then carried out Chem. Soc. 2013, 135, 8169. postdoctoral studies with Professor Jeffery Kelly at The Scripps (22) Wang, Y.; Zheng, C.; You, S.-L. Angew. Chem., Int. Ed. 2017, Research Institute. From 2004 to 2006, he worked at the 56, 15093. Genomics Institute of the Novartis Research Foundation as a (23) Spiess, S.; Welter, C.; Franck, G.; Taquet, J.-P.; Helmchen, G. PI before joining SIOC as Professor in 2006. He is currently Angew. Chem., Int. Ed. 2008, 47, 7652. the director of the State Key Laboratory of Organometallic (24) Zhang, X.; Liu, W.-B.; Tu, H.-F.; You, S.-L. Chem. Sci. 2015, Chemistry. His research interests focus mainly on asymmetric 6, 4525. C–H functionalization and catalytic asymmetric dearomatization (25) Zhuo, C.-X.; Liu, W.-B.; Wu, Q.-F.; You, S.-L. Chem. Sci. 2012, (CADA) reactions. m Aldrichimica ACTA 19 VOL. 53, NO. 1 • 2020 Recent Advances in Sulfuration Chemistry Enabled by Bunte Salts

Ming Wang, Yaping Li, and Xuefeng Jiang* a State Key Laboratory of Estuarine and Coastal Research East China Normal University 3663 North Zhongshan Road Shanghai 200062, China b Shanghai Key Laboratory of Green Chemistry and Chemical Process East China Normal University 3663 North Zhongshan Road Prof. M. Wang Prof. X. Jiang Shanghai 200062, China Email: [email protected] Ms. Y. Li

Keywords. Bunte salt; S-aryl(alkyl) thiosulfate sodium 5. Application in Metal Nanoparticles salts; sodium thiosulfate; sulfuration reagent; sulfide; sulfur- 6. Conclusion containing heterocycles; dithiocarbamates; thiophosphates; 7. Acknowledgments metal nanoparticles; glycosyl. 8. References

Abstract. Bunte salts are easy-to-handle crystalline solids, 1. Introduction even when incorporating highly lipophilic organic moieties, and Alkyl and aryl thiosulfate sodium salts are known as Bunte generally have little-to-no odor. Due to the unique properties of salts, after Hans Bunte who first reported them in 1874.1 He Bunte salts, they have been frequently utilized in the synthesis of prepared the first such salt by reactiing ethyl bromide with sulfides, sulfur-containing heterocycles, thiophosphates, other sodium thiosulfate (Na2S2O3) to yield S-ethyl thiosulfate sodium compound classes, and metal nanoparticles. This short review salt as a crystalline solid. Bunte salts, as the easy-to-handle focuses on recent applications of Bunte salts in the synthesis crystalline solids, generally have little-to-no odor.2–3 The sulfur of sulfur-containing compounds with particular emphasis on the trioxide group in Bunte salts could be viewed as an electron- synthesis of sulfides. withdrawing group preventing strong coordination of the sulfur atom to metals. Moreover, we obtained the crystal structure of a Outline Bunte salt in 2015 and found that its sulfur–sulfur bond is longer 1. Introduction than the traditional S–S bond, which may be activated easily.4 2. Preparation of Bunte Salts Over the past few years, enormous efforts have been devoted to 2.1. Alkyl Bunte Salts developing synthetic methodologies for the application of Bunte 2.2. Aryl Bunte Salts salts. The present article concisely reviews recently reported 2.3. Glycosyl Bunte Salts methodologies for the application of Bunte salts, with particular 3. Bunte Salts for the Synthesis of Sulfides emphasis on the synthesis of sulfides. The presentation is 3.1. Coupling through C–X Bond Cleavage organized according to the structures of the reaction partners 3.2. Coupling through C–N Bond Cleavage of Bunte salts. 3.3. Coupling through C–O Bond Cleavage 3.4. Coupling through C–C Bond Cleavage 2. Preparation of Bunte Salts 3.5. Coupling through C–H Bond Cleavage 2.1. Alkyl Bunte Salts 3.6. Reactions with Grignard Reagents and Boronic Acids Alkyl Bunte salts have traditionally and conveniently been 3.7. Reaction with Organosilicon Reagents prepared by reaction of the inexpensive and odorless sodium 5–8 3.8. Sulfuration of Isoxazoles thiosulfate (Na2S2O3) with alkyl halides. More recently, various 4. Synthesis of Dithiocarbamates and Thiophosphates modifications of the reaction conditions have been developed for Recent Advances in Sulfuration Chemistry Enabled by Bunte Salts 20 Ming Wang, Yaping Li, and Xuefeng Jiang*

a diversity of alkyl halides. Both primary and secondary halides corresponding glycosyl Bunte salts in up to 94% yields. The are compatible with the transformation, and the desired Bunte utility of these S-glycosyl thiosulfates was then demonstrated salt products are obtained in generally excellent yields. by converting β-d-glucosyl Bunte salt into 1-thio-β-d-glucose, glucosyl disulfide, 1,6-anhydroglucose, and ethyl α-d- 2.2. Aryl Bunte Salts glucopyranoside. Janeba and co-workers reported a novel and facile route to polysubstituted aryl and heteroaryl Bunte salts by reaction of 3. Bunte Salts for the Synthesis of Sulfides aromatic thiocyanates with sodium sulfite.9 Their synthesis The main application of Bunte salts is in the synthesis of could be conducted under catalyst-free and room temperature sulfides, since these salts are stable, odorless, and green when conditions to generate the desired Bunte salts in good yields. compared with thiols as substrates. Monosubstituted thiocyanatobenzothiazole and polysubstituted thiocyanatopyrimidines, which contain labile hydrogens such as 3.1. Coupling through C–X Bond Cleavage

NH2 and OH, were compatible with the reaction conditions. In 2017, we developed a controlled sulfoxidation of diaryliodonium A year later, Reeves’s group disclosed the first direct and salts with Bunte salts in air and under photocatalytic conditions general method for the synthesis of a variety of aryl, heteroaryl, in which dual electron- and energy-transfer as well as single- and vinyl Bunte salts in 66–89% yields.8 The approach involves electron-transfer processes were involved (Scheme 1).14 When a Cu(I)-catalyzed reaction of the widely available halide the reaction was carried out under a nitrogen atmosphere, precursors with sodium thiosulfate (1.5 equiv) in DMSO at sulfenylation products were conveniently obtained. This approach 80 oC for 2–6 h. It is worth noting that, in the case of vinyl could be used in the late-stage modification of pharmaceuticals halides, the geometry of the carbon–carbon double bond was and sugar derivatives, which were highly compatibile with the preserved in the reaction. This synthetic method is currently reaction conditions. one of the most efficient routes to such Bunte salts because In the proposed mechanism, the excited-state catalyst Eosin of the wide availability and broad compatibility of the halide Y* (EY*) reacts with the diaryliodonium salt via a single-electron starting materials. transfer process to generate an aryl radical. The aryl radical In addition to the above strategies, several other original then couples with the Bunte salt to afford a sulfide radical. The methods have been developed for the synthesis of aryl Bunte electron-transfer process between the sulfide radical (ArS•R) and salts. For example, aryl Bunte salts were obtained by sulfonylation EY+• provides the sulfide product (ArSR) and regenerates the 10 of aryl thiols with N-pyridinium sulfonic acid (C5H5NSO3H) or photosensitizer EY. In the presence of air, an energy-transfer 11 3 1 with chlorosulfonic acid (ClSO3H), and by reaction of sodium process takes place between O2 and EY* to generate O2, the sulfite with aryl disulfides (or aryl sulfenyl chlorides).12 key active oxygen species, which was confirmed by fluorescent quenching experiments. Reaction of the in situ generated 1 2.3. Glycosyl Bunte Salts sulfide (ArSR) with O2 forms a persulfoxide intermediate (R(Ar)- + – Very recently, glycosyl Bunte salts (S-glycosyl thiosulfates) S –O–O ), which is stabilized by Zn(OAc)2. Reaction of the have been developed by Shoda and co-workers as a new class persulfoxide with a second in situ generated sulfide leads to two of synthetic intermediates in carbohydrate chemistry13 The molecules of the observed sulfoxide product (ArS(=O)R).

one-pot reaction is carried out in H2O–CH3CN, and it involves In 2014, our group developed a Pd-catalyzed double C–S the direct condensation of unprotected mono-, di-, and bond forming reaction for the synthesis of aryl alkyl sulfides.

polysaccharides with Na2S2O3 in the presence of 2-chloro-1,3- Aryl and heteroaryl iodides efficiently reacted with alkyl dimethylimidazolinium chloride (DMC) as dehydrating agent. chlorides to provide the desired sulfides in excellent yields.

Glucose, allose, xylose, mannose, rhamnose, and galactose In this transformation, Na2S2O3·5H2O was employed as an all underwent this mild reaction efficiently, giving rise to the environmentally friendly and odorless sulfur atom source to generate the Bunte salt in situ.15 Late-stage modification of pharmaceutical molecules was also achieved to demonstrate the O Zn(OAc)2 (2 equiv) synthetic potential of this protocol. S 18 W green LED ) Ar R MeOH–MeCN (3:1 43–84% air, rt, 24 h Eosin Y (2 mol %) 3.2. Coupling through C–N Bond Cleavage + – RS2O3Na + Ar2I BF4 DIPEA (2 equiv) An analogous Cu-catalyzed double C–S bond forming reaction 3.0 equiv Zn(OAc)2•2H2O has been developed for the synthesis of aryl alkyl sulfides (10 mol %) Ar = aryl, heteroaryl S from aromatic amines and alkyl halides via in situ generated R = n-Pent, functionalized alkyl, 23 W CFL Ar R propargyl, 3-MeOC H 16 6 4 MeOH, N2, rt, 24 h 46–87% Bunte salts. Heterocyclic substrates and active-hydrogen- CFL = compact flurorescent lamp LED = light emitting diode containing substrates were tolerated in this transformation, which permitted the late-stage sulfuration of functionalized aryl Scheme 1. Photocatalytic Sulfoxide and Sulfide Formation through Controlled Sulfoxidation and Sulfenylation of Diaryliodonium Salts. amines, including such interesting amines as sulfamethoxazole, (Ref. 14) sulfadiazine, and the antitumor drug lenalidomide. Axially chiral (R)-(+)-2,2′-diamino-1,1′-binaphthalene could also be Aldrichimica ACTA 21 VOL. 53, NO. 1 • 2020 transformed into the corresponding bis(benzyl sulfide) product An interesting extension of this approach has been disclosed without racemation (38% yield, 99% ee), which offers a facile by Jiang, Yi, and co-workers.19 In this instance, aromatic primary strategy for the synthesis of chiral, sulfur-containing ligands. amines were subjected to an efficient, Cu-catalyzed Sandmeyer- Moreover, amine derivatives of glucose and amino acids were type monofluoromethylthiolation by employing the Bunte salt tolerated in the reaction, hinting at its potential usefulness in sodium S-(fluoromethyl)sulfurothioate (FH2CS–SO2–ONa). The bioorthogonal reactions. intermediate aryldiazonium salts were generated in situ using Subsequently, we successfully extended this protocol to the tert-butyl nitrite (t-BuONO) and a variety of aryl and heteroaryl Cu-catalyzed reaction of substituted 1-aryltriazenes and alkyl primary amines, leading to the desired sulfides in moderate–to- chlorides in water at room temperature and in the absence of any good yields (43–77%). The late-stage monofluoromethylthiolation surfactant with the aim of developing an environmentally friendly of biologically relevant sulfonamides and the gastroprokinetic variant.17 We were also delighted to discover that the outcome of agent mosapride were also achieved in acceptable isolated the reaction was not significantly affected by the addition of such yields (41–73%). Interestingly, Bunte salt FH2CS–SO2–ONa was biomolecules as amino acids, nucleosides, oligosaccharides, also utilized in the monofluoromethylthiolation of substituted proteins, and HeLa cell lysates, highlighting again the promise of aryl thiols under similar conditions to provide the corresponding its potential applications in bioorthogonal studies. aryl monofluoromethyl disulfides in 58–78% isolated yields. A photocatalytic variant involved reacting diazonium salts with alkyl or aryl Bunte salts in the presence of Ru(bpy)3Cl2 3.3. Coupling through C–O Bond Cleavage (Scheme 2).18 The reaction did not proceed when the Bunte salt An efficient, catalytic, and metal-free sulfide synthesis from was replaced with BnSH or BnSSBn, demonstrating the unique allyl or propargyl alcohols and organic halides was reported by behavior of the Bunte salt in this system. Both alkyl and aryl Chu et al.20 The reaction takes place at 80 oC in air and in Bunte salts were well-tolerated in this transformation. Both an aqueous medium in the presence of two equivalents of tetra- oxidative and a reductive quenching process were possible in the n-butylammonium iodide (TBAI), leading to the formation of the transformation. At first, the Ru(II) catalyst is activated by visible two C–S bonds of the sulfide. TBAI plays the dual role of phase- 3 •- light to generate *[Ru(bpy)2(bpy )Cl2], which undergoes an transfer agent and a hydrolysis promoter of the Bunte salt oxidative quenching process with the diazonium salt to form Ru3+ initially formed from the halide. The hydrolysis gives rise to a • – and an aryl diazonium radical (Ar–N ≡N BF4 ). Bunte salt R’SSO3Na key intermediate mercaptan species, which then combines with releases an electron to the solvent and affords a thiosulfate radical the carbocation derived from the allylic or propargylic alcohol to cationic species, which couples with the aryl diazonium radical to provide the final sulfide product. A wide variety of functionalized provide the sulfide products. The solvent shuttles an electron to terminal and internal allylic alcohols as well as propargylic Ru3+ and regenerates the Ru(II) catalyst. A similar catalytic cycle alcohols and organic halides proved compatible with the eco- is proposed to operate in the reductive quenching process. friendly reaction conditions. These authors also demonstrated the value of their novel protocol by sulfurating important molecules (eq 1),20 including sulfur-modified epiandrosterone. A year later, the same laboratory described the efficient N2BF4 S photosensitizer R' (a) + S reaction of a wide variety of benzyl alcohols—including diaryl- R' SO3Na base (2 equiv) R 5 equiv DMSO–H2O (4.5:1) R methanol, triphenylmethanol, propynols, and allylic alcohols— 8 W CFL, N , rt, 5 h 50–86% 2 and alkyl halide derived Bunte salts in water at 100 oC.21 Both photosensitizer = [Ru(bpy)3Cl2]•6H2O (2 mol %) or methylene blue base = K2CO3 or Li2CO3 in situ generated Bunte salts and pre-prepared ones reacted R = H, Me, t-Bu, MeO, (MeO)3, 3-Pyr, CN, Cl, Br smoothly to provide unsymmetrical sulfides in moderate-to- R' = Bn, CH2CN, CH2CO2Et, XC6H4 (X = H, Me, MeO, CN, F, Cl) excellent yields. (b) Application to Late-Stage Modification of Pharmaceuticals with Free Amino Groups Very recently, Ma, Xu, and collaborators developed a Me S S scalable, one-pot reaction between alcohols, Na2S2O3·5H2O, and Bn Bn N O O heteroaryl chlorides under catalyst-, additive-, and solvent-free S S Me N N N N H O H O modified sulfamethazine modified sulfapyridine 59% 44% Bunte Salt Enabled Sulfide Synthesis through C–O Cleavage S S Bn O R' OH N O N O Me S S Me N N N Na S O (2.4 equiv) H O H O 2 2 3 (n-Bu)4NI (2 equiv) Me S Ph modified sulfamerazine modified sulfamethoxazole + o 52% R' = Bn (70%), 3-MeOC6H4 (67%) Me Br H2O, air, 80 C, 5 h Me Me

Me Me Ph 2 equiv 74% Scheme 2. Photocatalytic Sulfide Formation from Diazonium Salts thiogeraniol derivative and Alkyl and Aryl Thiosulfates and Its Application to the Late-Stage Modification of Pharmaceuticals. (Ref. 18) eq 1 (Ref. 20) Recent Advances in Sulfuration Chemistry Enabled by Bunte Salts 22 Ming Wang, Yaping Li, and Xuefeng Jiang*

conditions at 140 oC.22 Primary and secondary benzylic alcohols, 1H-indole-2-carboxylate,25 a potent tubulin polymerization heteroarylmethanols, and primary aliphatic alcohols were inhibitor, in 67% isolated yield (after chromatography), in competent substrates, giving rise to 31 desired unsymmetrical stark contrast to a prior method in which the carboxylate heteroaryl sulfides in 16–86% yields. was obtained in only 4% yield. More recently, a very similar mechanism has been proposed for the transition-metal-free and 3.4. Coupling through C–C Bond Cleavage regioselective sulfenylation of 4-anilinocoumarins catalyzed by An interesting, copper-catalyzed decarboxylative cross-coupling potassium iodide (20 mol %).26 This method provides access to of alkynyl carboxylic acids with Bunte salts for the synthesis 3-alkylthio-4-anilinocoumarins with potential biological activities of alkynyl chalcogenides has been disclosed by Liu and Yi.23 A in moderate-to-excellent yields. wide range of Bunte salts including benzyl, aryl, and alkyl ones, worked well to furnish the products in moderate-to-good yields. 3.6. Reactions with Grignard Reagents and Boronic Acids Alkyl Bunte salts provided only moderate yields due to the Reeves and co-workers developed the reaction of Bunte salts formation of the disulfide as byproduct. Both (hetero)aryl- and with Grignard reagents as a mild (THF, 0 oC to rt) and general alkylpropiolic acids were suitable partners, affording the desired route to sulfides that avoids using air-sensitive and malodorous alkynyl sulfides in good-to-excellent yields. Interestingly, seleno thiols as starting materials.8 The reaction is compatible with Bunte salts also proved applicable in the reaction, leading to the a broad range of alkyl, aryl, and vinyl Bunte salts and alkyl, construction of unsymmetrical alkynyl selenosulfides (eq 2).23 (hetero)aryl, vinyl, and alkynyl Grignard reagents and provides the sulfides in 68–99% isolated yields. The authors demonstrated 3.5. Coupling through C–H Bond Cleavage the usefulness of their approach by a straightforward and high Two efficient and C(3)-selective protocols for the sulfenylation of yield (82%) synthesis of a combretastatin analogue. It is also 1H-indoles24,25 and 1H-pyrrolo[2,3-b]pyridine25 with Bunte salts worth noting that an alkynyllithium, instead of the corresponding has been achieved under eco-friendly and metal-free conditions, Grignard Reagent, was also effective in the transformation. In leading to the corresponding 3-alkyl- and 3-arylthioindoles in 2015, the Cu-catalyzed direct oxidative cross-coupling between moderate-to-high yields. In the first protocol, a stoichiometric boronic acids and Bunte salts for the synthesis of unsymmetrical amount of tetra-n-butylammonium iodide is used, while in the sulfides was developed by our group (eq 4).27 Silver carbonate second 20 mol % of elemental iodine is utllized. In the proposed and di-tert-butyl peroxide (DTBP) were used as the oxidants,

mechanisms of both protocols, the catalytic cycle is initiated by and a CO2 atmosphere was required to suppress formation of

reaction of adventitious water with the Bunte salt (RS–SO3Na) the disulfide byproduct. This strategy was readily applied to – to form bisulfate (HSO4 ) and an intermediate thiol species, the late-stage diversification of biologically active molecules.

which is then oxidized by I2 to the actual thiolating species, Moreover, the unsymmetrical diaryl sulfide products can RSI. The latter then attacks the 3 position of the indole, giving undergo an oxidative dehydrogenative cyclization process to rise to the observed 3-thioindole products. The usefulness of provide unsymmetrical dibenzothiophenes (DBTs), which form the second protocol was demonstrated by a facile synthesis the core of photoactive compounds and conducting polymers. (eq 3) of methyl 5-methoxy-3-((3,4,5-trimethoxyphenyl)thio)- 3.7. Reaction with Organosilicon Reagents A novel and tunable Pd-catalyzed oxidative cross-coupling

Decarboxylative Cross-Coupling of Seleno Bunte Salts with Propiolic Acids of Bunte salts with aryl- or heteroaryl(triethoxy)silanes was recently disclosed by our group (Scheme 3).28 The selectivity CuI (20 mol %) CO2H SeR' Ag2CO3 (1.0 equiv) + Se R' SO3Na Ar K3PO4 (2.0 equiv) Ar 1.5 equiv DMF, air, 130 oC, 12 h 64–87% Cu(OTf)2 (20 mol %) 1,10-Phen (40 mol %) Ar = 4-XC6H4 (X = Me, MeO, CF3, Cl, Br) Ag2CO3 (1.2 equiv) R' = Cy, c-Hep, YC6H4CH2 (Y = H, Me, Cl, Br, CN, NO2), 2-Me-5-FC6H3 S S ArB(OH)2 + Ar' SO3Na Ar' Ar K3PO4 (1.4 equiv) 1.5 equiv eq 2 (Ref. 23) DTBP (1.0 equiv) CO2 atmosphere 41–85% DMF, 80 oC, 7 h Ar, Ar' = aryl, heteroaryl 1,10-Phen = 1,10-phenanthroline; DTBP = di-tert-butyl peroxide SAr Noteworthy Application Products: MeO MeO I2 (20 mol %) O CO2Me CO2Me Me N DMSO, argon N OMe O H o H H O Oi-Pr + 80 C, 16 h Me 67% (after chromatography) H H S Ph S O Ar SO3Na S Me Ar = 3,4,5-(MeO)3C6H2 S-fenofibrate 3 mmol (1.5 equiv) antitumor activity and potent S-estratrien (73% from bis(pinacolato)boron tubulin polymerization inhibition (67% from estratrien Bunte salt) fenofibrate)

eq 3 (Ref. 25) eq 4 (Ref. 27) Aldrichimica ACTA 23 VOL. 53, NO. 1 • 2020

30 for Hiyama-type coupling or one-carbon (C1) insertion was amines, and a thiocarbonyl surrogate (K2S + CHCl3). A wide controlled by the absence or presence of palladium ligand: range of amines—including 5- and 6-membered cyclic amines, Sulfides were afforded under ligand-free conditions, whereas dialkylamines, and methylaniline—reacted with alkyl and aryl thiol esters were formed with bidentate phosphine ligands Bunte salts in the presence of potassium sulfide and chloroform, under a carbon monoxide atmosphere. Aryl and alkyl Bunte furnishing the dithiocarbamates in moderate-to-high isolated salts were competent reactants in both protocols, providing yields (eq 6).30 Interestingly, some of the dithiocarbamates the corresponding products in moderate-to-excellent yields. exhibited promising selective bioactivity against human histone PhS-modified estratrien was also obtained by the Hiyama- deacetylase 8 (HDAC8), highlighting the potential of this type coupling reaction. Mechanistic studies of the C1-insertion method for the development of novel HDAC8 inhibitors with a reaction led to proposing a plausible pathway for thiol ester dithiocarbamate core. This stoichiometric process is believed formation. In this pathway, a chelated PdCl2 species is generated to occur via initial dichlorocarbene (generated from Ba(OH)2 with the bis(diphenylphosphino)alkane ligand. Transmetalation and CHCl3) insertion into the N–H bond of the amine to give through Cl– displacement by the Bunte salt is followed by CO a dichloromethylamine intermediate that is readily converted insertion. Loss of SO3, organosilicon transmetalation, and into the corresponding monochloromethylimine cation. Addition reductive elimination lead to the observed thiol ester product. of the alkyl or aryl thiol derived from the Bunte salt to this imine cation generates an α-alkyl/arylthioimine cation. Trisulfur •– 3.8. Sulfuration of Isoxazoles radical anion (S3 )—formed from K2S in NMP—addition, An interesting, atom- and step-economical, one-pot, three- intramolecular hydrogen atom transfer (HAT), and homolytic – component reaction cascade employing acetylenic oximes, S–S bond cleavage (with loss of S2 ) affords the dithiocarbamate

Na2S2O3, and aryl iodides has been reported by Li et al in the presence of base. (eq 5).29 The reaction sequence is carried out in air and in Lin, Yan, and co-workers have reported an efficient and 1-(3-cyanopropyl)-3-methylimidazolium chloride ([Cpmim]Cl) eco-friendly NaBr-catalyzed coupling reaction of Bunte salts ionic liquid under Pd-NHC catalysis. A variety of substituted aryl with phosphonates (R2P(O)H, where R = alkoxy or aryl) in the iodides and acetylenic oximes reacted smoothly with Na2S2O3 to presence of two equivalents of H2O2 as the oxidant and AcOH as afford highly substituted 4-arylthio-1,2-oxazoles in moderate- additive.31 The corresponding thiophosphates were obtained in to-high isolated yields. In contrast, alkyl iodides did not react 40–92% yields by a pathway that is initiated by the generation and, in the case of 1-iodobutane, the starting material was of the active alkyl/arylthiol species through hydrolysis of the recovered completely. In the proposed mechanism for the Bunte salt with water at 80 oC. reaction cascade, the isoxazole ring is formed first in a trans oxypalladation of the oxime. The resulting palladium–isoxazole intermediate undergoes a chloride–ArSSO – exchange with the 3 OH N O R2 Bunte salt generated in situ from the aryl iodide. The final two Pd(II)–NHC (0.25 mol %) N 1 + Ar–I + Na2S2O3 R o steps consist of loss of SO3 and reductive elimination to form [Cpmim]Cl, air, 80 C, 12 h 1 R2 1.5 equiv 2.0 equiv R SAr the observed isoxazole products. 56–87% R1 = alkyl, vinyl, aryl; R2 = alkyl, aryl, heteroaryl Ar = XC H (X = Me, t-Bu, MeO, CF , F, Cl, Br, Me , (MeO) , F , Cl ), 2-Np, thien-2-yl 4. Synthesis of Dithiocarbamates and Thiophosphates 6 4 3 2 2 2 2 i-Pr Recently, we developed a novel, efficient, and one-pot method for i-Pr the construction of dithiocarbamates from Bunte salts, secondary N N

– i-Pr i-Pr Cl + N Cl Pd Cl NC N Me N 1-(3-cyanopropyl)-3-methyl- Hiyama-type coupling imidazolium chloride ([Cpmim]Cl) N Pd(OAc)2 (5 mol %) Me Pd(II)–NHC S RAr CuF2•2H2O (1.1 equiv) CF3SO3H (1.5 equiv) 47–99% eq 5 (Ref. 29) DMA S N2 atmosphere ArSi(OEt)3 + RSO3Na o 2.0 or 100 C PdCl2•dppp (5 mol %) O 3.0 equiv dppm (15 mol %) R Ar S CuF2•2H2O (1.5 equiv) CO (balloon) 53–85% S S H K2S (2 equiv), CHCl3 (10 equiv) 2 C1 insertion + N R C R RSO3Na R1 R2 S N Ba(OH)2•8H2O (4.5 equiv) 1 2 equiv o R Ar = XC H (X = H, Me, F, Cl, MeO), thien-3-yl, 9H-fluoren-2-yl, estratrien-3-yl NMP, N2, 80 C, 8–12 h 6 4 43–85% R = XC6H4 (X = H, Me, MeO, Me2, CF3, Cl), Me, n-Bu, n-C12H25, Bn, 1-Np, 2-Np R = alkyl, Ph 1 2 dppp = 1,3-bis(diphenylphosphino)propane; dppm = bis(diphenylphosphino)methane R ,R = Me,Ph; Me,Bn; Bn2; Et2; heterocycle NMP = 1-methyl-2-pyrrolidinone

Scheme 3. Divergent Cross-Coupling of Organosilicon Reagents with Bunte Salts. (Ref. 28) eq 6 (Ref. 30) Recent Advances in Sulfuration Chemistry Enabled by Bunte Salts 24 Ming Wang, Yaping Li, and Xuefeng Jiang*

– 5. Application in Metal Nanoparticles particle surface followed by elimination of the SO3 fragment. Metal nanoparticles (MNPs) are used in biomedical assays Later, Shon and other co-workers reported a two-phase synthesis and treatments and for the construction of microscale optical of water-soluble, carboxylate-functionalized, and alkanethiolate- devices. A number of chemical strategies have been devised capped palladium nanoparticles (PdNPs) from Bunte salts for synthesizing functionalized metal nanoparticles of various (ω-carboxyl-S-alkanethiosulfate sodium salt).37,38 These PdNPs sizes.32 Since Bunte salts have no odor and lower reactivity were then investigated as catalysts for the hydrogenation of allyl than thiols, they are generally utilized for the synthesis of metal alcohol to 1-propanol versus its isomerization to propanal. Their nanoparticles with a sulfur-containing headgroup. Lukkari and results showed that the sulfur ligand structure, its conformation, co-workers found that Bunte salts can generate self-assembled and its degree of surface coverage were crucial in determining monolayers (SAMs) on gold under anaerobic conditions, and the activity and selectivity of the PdNP catalysts. 33 – chemisorb forming an Au–S bond. The S–SO3 bond in Bunte – salts (RS–SO3 ) is cleaved during adsorption of the RS moiety 6. Conclusion – onto the gold surface, releasing the SO3 group. The following The fact that Bunte salts are stable, easy-to-handle crystalline year, Murray’s group reported the first example of metal solids with generally little-to-no odor and unique chemical nanoparticles, in which alkanethiolate-protected AuNPs were properties has made them attractive thiol sources and desirable prepared by Bunte salts as ligand precursors (Scheme 4, Part substrates for a wide variety of chemical reactions. Not only (a)).34 Employing the same protocol, they later explored the have Bunte salts served as an important component of new preparation of water-soluble, monolayer-protected nanoparticles protocols for shorter and more efficient syntheses of known

(SO3–AuNP) by using the strong-acid-functionalized Bunte salt sulfur-containing compounds, but also as key precursors in the of 2-acrylamido-2-methyl-1-propanesulfonic acid as precursor synthesis of novel and bioactive sulfur-containing molecules and (Scheme 4, Part (b)).35 sulfur-modified drugs. Although quite a few effective strategies A thiosulfate approach was also utilized by Shon and Cutler have so far been devised for the application of Bunte salts in for the one-pot preparation of alkanethiolate-capped silver many types of reaction, there is still a need for even more nanoparticles (AgNPs) in aqueous media.36 The AgNPs, produced efficient and practical methods for their use in facilitating the

by borohydride (NaBH4) reduction of silver nitrate, were stabilized synthesis of structuraly diverse sulfur-containing compounds. – by adsorption of S-dodecylthiosulfate (n-C12H25S–SO3 ) onto the Drug discovery is one area that we believe Bunte salts, as optimal sulfurating agents, are poised to play an increasingly important role in. (a) Adsorption of S-Dodecylthiosulfate onto Gold Surface and Formation of Monolayer-Protected Gold Clusters 7. Acknowledgments slow HAuCl4•xH2O + RSSO3Na [–Au(I)SR–] n The authors are grateful for the financial support provided by R = CH (CH ) polymers 3 2 11 – SO3 The National Key Research and Development Program of China THF–H2O (2:1) (2017YFD0200500), NSFC (21971065, 21722202, 21672069, and rt, 10 min 21871089 for M. W.), S&TCSM of Shanghai (Grant 18JC1415600), – [Au(O3SSR)nCl4–n] the Professor of Special Appointment (Eastern Scholar) Program

NaBH4, H2O Me at Shanghai Institutions of Higher Learning, and the National rt, 16 h S 11 Me Au – S SO3 Au 11 Program for Support of Top-Notch Young Professionals. S S Me –O S Me – 3 11 SO3 11 8. References (1) Bunte, H. Chem. Ber. 1874, 7, 646. (b) Synthesis of Sulfonic Acid Functionalized, HO3S Monolayer-Protected, and Water-Soluble HO3S Me (2) Kunath, D. Chem. Ber. 1963, 96, 157. SO H Gold Nanoparticles (SO3-MPC) Me Me 3 Me NH Me O (3) Distler, H. Angew. Chem., Int. Ed. 1967, 6, 544. Me NH O HO3S NH O Me (4) Qiao, Z.; Jiang, X. Org. Biomol. Chem. 2017‚ 15, 1942, and Me NH OMe SO3H SO H Me references therein. 3 S N O S S H Me 1. HAuCl4•xH2O H S S O (5) Westlake, H. E., Jr.; Dougherty, G. J. Am. Chem. Soc. 1942, 64, Me H2O-HOAc (6:1) HO3S N Me Me HN rt, 10 min S Au S 149. Me Me N SO3H O O S S H 2. NaBH4, H2O, rt, 1.5 h (6) Gattow, G.; Hanewald, B. Z. Anorg. Allg. Chem. 1978, 444, 112. H S S O 3. HCl(conc) N S Me HN Me (7) Baker, R. H.; Barkenbaus, C. J. Am. Chem. Soc. 1936, 58, 262. S2O3Na HO3S Me O Me O SO3H (8) Reeves, J. T.; Camara, K.; Han, Z. S.; Xu, Y.; Lee, H.; Busacca, 2.40 mmol HN O O HN Me Me HN Me C. A.; Senanayake, C. H. Org. Lett. 2014, 16, 1196. Me Me HO3S Me SO3H (9) Jansa, P.; Čechová, L.; Dračínský, M.; Janeba, Z. RSC Adv. 2013, SO3H 3, 2650.

Scheme 4. The Synthesis of Gold Nanoparticles from Bunte Salts. (10) Baumgarten, P. Chem. Ber. (presently Eur. J. Inorg. Chem.) (Ref. 34,35) 1930, 63, 1330 (https://onlinelibrary.wiley.com/doi/epdf/10.1002/ cber.19300630606). Aldrichimica ACTA 25 VOL. 53, NO. 1 • 2020

(11) Tanaka, T.; Nakamura, H.; Tamura, Z. Chem. Pharm. Bull. 1974, M.; Lindström, M.; Kankare, J. Langmuir 1999, 15, 3529. 22, 2725. (34) Shon, Y.-S.; Gross, S. M.; Dawson, B.; Porter, M.; Murray, R. W. (12) Lecher, H. Z.; Hardy, E. M. J. Org. Chem. 1955, 20, 475. Langmuir 2000, 16, 6555. (13) Meguro, Y.; Noguchi, M.; Li, G.; Shoda, S. Org. Lett. 2018, 20, 76. (35) Shon, Y.-S.; Wuelfing, W. P.; Murray, R. W.Langmuir 2001, 17, (14) Li, Y.; Wang, M.; Jiang, X. ACS Catal. 2017, 7, 7587. 1255. (15) Qiao, Z.; Wei, J.; Jiang, X. Org. Lett. 2014‚ 16‚ 1212. (36) Shon, Y.-S.; Cutler, E. Langmuir 2004, 20, 6626. (16) Li, Y.; Pu, J.; Jiang, X. Org. Lett. 2014‚ 16‚ 2692. (37) Gavia, D. J.; Shon, Y.-S. Langmuir 2012, 28, 14502. (17) Zhang, Y.; Li, Y.; Zhang, X.; Jiang, X. Chem. Commun. 2015, 51, 941. (38) Gavia, D. J.; Maung, M. S.; Shon, Y.-S. ACS Appl. Mater. (18) Li, Y.; Xie, W.; Jiang, X. Chem.—Eur. J. 2015, 21, 16059. Interfaces 2013, 5, 12432. (19) Liu, F.; Jiang, L.; Qiu, H.; Yi, W. Org. Lett. 2018, 20, 6270. (20) Chu, X.-Q.; Xu, X.-P.; Ji, S.-J. Chem.—Eur. J. 2016, 22, 14181. About the Authors (21) Liu, B.-B.; Chu, X.-Q.; Liu, H.; Yin, L.; Wang, S.-Y.; Ji, S.-J. J. Ming Wang received his Ph.D. degree in 2011 from East China Org. Chem. 2017, 82, 10174. University of Science and Technology. From 2011 to 2014, he (22) Ma, X.; Yu, J.; Yan, R.; Yan, M.; Xu, Q. J. Org. Chem. 2019, 84, was a postdoctoral researcher under the guidance of Professor 11294. Yonggui Robin Chi at Nanyang Technological University, (23) Liu, F.; Yi, W. Org. Chem. Front. 2018, 5, 428. Singapore. In 2014, he joined East China Normal University as (24) Li, J.; Cai, Z.-J.; Wang, S.-Y.; Ji, S.-J. Org. Biomol. Chem. 2016, a lecturer, and is currently an associate professor at East China 14, 9384. Normal University. (25) Qi, H.; Zhang, T.; Wan, K.; Luo, M. J. Org. Chem. 2016, 81, Yaping Li received her B.S. degree in 2018 from Jiangxi Normal 4262. University. She is now working with Professor Xuefeng Jiang (26) Li, G.; Zhang, G.; Deng, X.; Qu, K.; Wang, H.; Wei, W.; Yang, toward her master‘s degree at East China Normal University. D. Org. Biomol. Chem. 2018, 16, 8015. Xuefeng Jiang is a professor at East China Normal (27) Qiao, Z.; Ge, N.; Jiang, X. Chem. Commun. 2015, 51, 10295. University. He received his B.S. degree in 2003 from Northwest (28) Qiao, Z.; Jiang, X. Org. Lett. 2016, 18, 1550. University (Xi'an, Shaanxi, China). He then joined Professor (29) Li, J.; Wu, Y.; Hu, M.; Li, C.; Li, M.; He, D.; Jiang, H. Green Shengming Ma’s research group at the Shanghai Institute of Chem. 2019, 21, 4084. Organic Chemistry, Chinese Academy of Sciences, where he (30) Tan, W.; Jänsch, N.; Öhlmann, T.; Meyer-Almes, F.-J.; Jiang, X. received his Ph.D. degree in 2008. From 2008 to 2011, Xuefeng Org. Lett. 2019‚ 21‚ 7484. worked as a postdoctoral researcher on the total synthesis (31) Min, C.; Zhang, R.; Liu, Q.; Lin, S.; Yan, Z. Synlett 2018, 29, of natural products in the research group of Professor K. C. 2027. Nicolaou at The Scripps Research Institute. His independent (32) San, K. A.; Shon, Y.-S. Nanomaterials 2018, 8, 346. research interests have focused on green sulfur chemistry and (33) Lukkari, J.; Meretoja, M.; Kartio, I.; Laajalehto, K.; Rajamäki, methodology-oriented total synthesis. m

product highlight Enrich Your Chemical Toolbox F I O Me The fluoroalkylation toolbox has now been Me expanded beyond the standard Togni Reagents. F F Ph Br CF0002 S The installation of highly fluorinated groups into drug and F F pesticide candidates is a powerful strategy to modulate their CF0014 properties. More elaborate fluoroalkylation is now possible F F with the development of a new suite of reagents— including TES hypervalent iodine perfluoroalkylation reagents as well as F fluoroalkyl bromides, silanes, carboxylates, and sulfonyl F F C2F5 I O fluorides—that allow late-stage fluoroalkylation of a variety of CF0021 Me functional groups through different reactivities. Me

To learn about the entire fluoroalkylation toolbox, visit CF0012 SigmaAldrich.com/fluoroalkylation Illuminated Synthesis From discovery to scale-up: Photoreactors and catalysts to deliver consistency and reproducibility to your research.

Chemists have long struggled with reproducibility in photoredox catalysis. Both varied reaction setups and individual reactions performed with the same setup can be tricky. Our new labware seeks to alleviate these issues by providing photoreactors for each stage of reaction development while ensuring high levels of consistency across reactions and between runs.

When combined with our broad portfolio of iridium and ruthenium catalysts and acridinium- based photocatalysts, these tools free synthetic chemists to focus on their next breakthrough.

To view our complete portfolio offering, visit SigmaAldrich.com/photocatalysis

The life science business of Merck KGaA, Darmstadt, Germany operates as MilliporeSigma in the U.S. and Canada.

2018-18261_MRK_Photoredox_Ad.indd 1 2/15/19 10:21 AM Aldrichimica ACTA 27 VOL. 53, NO. 1 • 2020 P-Chiral Phosphorus Ligands for Cross-Coupling and Asymmetric Hydrogenation Reactions

Ting Wu, Guangqing Xu, and Wenjun Tang*,a,b a State Key Laboratory of Bio-Organic and Natural Products Chemistry Center for Excellence in Molecular Synthesis Shanghai Institute of Organic Chemistry Chinese Academy of Sciences 345 Lingling Road Shanghai 200032, China

Ms. T. Wu Prof. W. Tang b School of Chemistry and Materials Science Hangzhou Institute for Advanced Study Prof. G. Xu University of Chinese Academy of Sciences 1 Sub-lane Xiangshan Hangzhou 310024, China Email: [email protected]

Keywords. P-chiral; phosphorus ligands; asymmetric cross- 3. Chiral Monophosphorus Ligands for Cross-Coupling coupling; Suzuki–Miyaura coupling; axial chirality; asymmetric 3.1. Asymmetric Suzuki–Miyaura Coupling dearomative coupling; α-arylation; asymmetric hydrogenation; 3.2. Asymmetric Dearomative Cross-Coupling all-carbon quaternary stereocenters. 3.3. Asymmetric α-Arylation of Carbonyl Compounds 4. Chiral Bisphosphorus Ligands for Asymmetric Hydrogenation Abstract. The asymmetric cross-coupling and asymmetric 5. Miscellaneous Asymmetric Transformations hydrogenation reactions are highly relevant to synthetic organic 6. Conclusion and Outlook chemists in both academia and industry. Chiral phosphorus 7. Acknowledgments ligands have played a central role in improving the efficiency, 8. References selectivity, and scope of these transition-metal-catalyzed asymmetric transformations. Nevertheless, the invention of 1. Introduction new phosphorus ligands and their applications in these two P-Chiral phosphorus ligands have played a significant role in the types of reaction are still urgently needed to further expand advancement and industrialization of asymmetric catalysis.1,2 their scope and improve their efficiency and enantioselectivity. For example, Knowles developed CAMP and DiPAMP ligands This mini-review summarizes our recent efforts in developing in the early 1970s, which not only set the bar high for highly P-chiral, mono- and bisphosphorus ligands that possess enantioselective rhodium-catalyzed asymmetric hydrogenation, unique structural motifs. It also highlights their powerful but also ushered in the era of asymmetric catalytic applications in promoting the asymmetric Suzuki–Miyaura transformations for industrial applications3,4 Imamoto later coupling, asymmetric dearomative cross-coupling, asymmetric developed a series of P-chiral bisphosphorus ligands—BisP*,5 α-arylation, and various asymmetric hydrogenations, with MiniPhos, and QuinoxP*®6—which are highly effective for various particular emphasis on practicality and efficiency of the Rh- or Pd-catalyzed carbon–carbon and carbon–hydrogen bond- transformations (low catalyst loading, good atom economy, forming reactions. In the meantime, Zhang developed a series and high enantioselectivity). of 1,2-bisphospholane ligands, TangPhos,7 DuanPhos,8 and ZhangPhos,9 which were successfully applied in asymmetric Outline hydrogenation, hydroformylation, and other reactions. Despite 1. Introduction these advances, the development of chiral phosphorus ligands 2. Design and Development of P‑Chiral Phosphorus Ligands with new structural motifs to address numerous unsolved Based on the 2,3-dihydrobenzo[d][1,3]oxaphosphole Motif challenges in asymmetric catalysis remains a necessary and P-Chiral Phosphorus Ligands for Cross-Coupling and Asymmetric Hydrogenation Reactions 28 Ting Wu, Guangqing Xu, and Wenjun Tang*

worthy pursuit. This mini-review highlights our group’s recent Chiral monophosphorus ligands have played increasingly efforts to design and synthesize novel P-chiral mono- and important roles in developing new and efficient asymmetric bisphosphorus ligands based on the 2,3-dihydrobenzo[d][1,3]- catalytic reactions.12 However, designing efficient chiral oxaphosphole (DHBOP) motif and to apply them in asymmetric monophosphorus ligands is much more difficult than designing cross-coupling and hydrogenation reactions.2,10,11 bisphosphorus ligands due to the lack of a conformationally defined and systematically tunable ligand framework. We have 2. Design and Development of P-Chiral Phosphorus been fortunate to have developed a library of conformationally Ligands Based on the 2,3-Dihydrobenzo[d][1,3]- well-defined and electron-rich P-chiral biaryl monophosphorus oxaphosphole Motif ligands based on the DHBOP motif (Figure 1). Structurally, The inspiration for employing this structural motif originated these are more stable and electron-rich ligands than chiral with TangPhos, a highly efficient but air-sensitive chiral monophosphoramide ligands, and most are also air-stable bisphospholane ligand.7 Preparation of both enantiomers crystalline solids, which are relatively easy to handle. Additionally, of TangPhos has remained a challenge owing to the use of the high tunability of the steric and electronic properties of the sparteine as the chiral reagent in the synthesis. Not only is P-chiral biaryl monophosphorus ligand structure enables the the natural (+)-sparteine expensive and in limited supply, but broad application of such ligands in various catalytic systems. an effective surrogate of its antipode, (–)-sparteine, is also The chiral, BIBOP-type bisphosphorus ligands also have scarce. To overcome the synthetic challenge and air-sensitivity unique structural features when compared to the well-known of TangPhos, we sought an air-stable, operationally simple, and bisphosphorus ligands such as BINAP and DuPhos. Variation modular version of TangPhos. Introducing two aryl rings into of the R' groups at the 4,4’ positions led to a series of chiral the oxaphosphole structure thus led to the DHBOP motif, which bisphosphorus ligands (Type I)—e.g., BIBOP, MeO-BIBOP, could be prepared from readily available starting materials in WingPhos, and ArcPhos—with various depths, shapes, and only three steps and could be resolved easily to provide both electronic properties of the chiral pocket. Another group enantiomers on a kilogram scale. Additionally, most ligands of chiral bisphosphorus ligands (Type II)—e.g., BABIBOP, derived from this structure are air-stable solids and thus Me-BABIBOP, and iPr-BABIBOP—are formally constructed operationally simple to handle. Furthermore, the excellent by dimerization at the 4 position of DHBOP (Figure 1). One

modularity and tunability of this unique structure have allowed interesting non-C2-symmetric bisphosphorus ligand is MeO- us to develop a series of chiral mono- and bisphosphorus ligands POP, which has proven a highly efficient ligand in rhodium- that have shown excellent reactivities and enantioselectivities catalyzed asymmetric hydrogenations. In addition to these in various asymmetric catalytic reactions. mono- and bisphosphorus ligands, a series of P,P=O ligands

O H O H R3 R3 P P 2 R1 R R1 t-Bu 2,3-dihydrobenzo[d][1,3]- monophosphorus ligands oxaphosphole 1 3 (S)-BIDIME (L2, R = 2,6-(MeO)2C6H3, R = H) (L1, DHBOP) 1 3 (S,S)-Me-BIDIME (L3, R = 2,6-(MeO)2C6H3, R = Me) 1 3 • stable ligand framework (S,S)-iPr-BIDIME (L4, R = 2,6-(MeO)2C6H3, R = i-Pr) • electron-rich P ligand (S)-AntPhos (L5, R1 = anthracen-9-yl, R3 = H) • highly tunable structure (S,S)-Me-AntPhos (L6, R1 = anthracen-9-yl, R3 = Me) (S,S)-iPr-AntPhos (L7, R1 = anthracen-9-yl, R3 = i-Pr) X 3 O H O R P t-Bu P P 4 H 4' P t-Bu R1 t-Bu t-Bu R1 R3 X bisphosphorus ligands (I) bisphosphorus ligands (II) (S,S,S,S)-BIBOP (L8, R1 = H) (S,S)-BABIBOP (L12, R3 = H, X = O) (S,S,S,S)-MeO-BIBOP (L9, R1 = OMe) (S,S,S,S)-Me-BABIBOP (L13, R3 = Me, X = O) (S,S,S,S)-WingPhos (L10, R1 = anthracen-9-yl) (S,S,S,S)-iPr-BABIBOP (L14, R 3 = i-Pr, X = O) (S,S,S,S)-N-BABIPhos (L15, R 3 = H, X = NPiv) O H O O H t-Bu P H P P P t-Bu O t-Bu t-Bu O Ph Ph OMe t-Bu i-Pr i-Pr (S,S,S,S,S,S)-ArcPhos (L11) (2R,3S)-MeO-POP (L16)

Figure 1. The Highly Tunable and Stable 2,3-dihydrobenzo[d][1,3]oxaphosphole (DHBOP) Motif and Novel, Air-Stable, Crystalline, and Highly Efficient Mono- and Bisphosphorus Ligands Derived from It. Aldrichimica ACTA 29 VOL. 53, NO. 1 • 2020 have been developed. The P=O moiety is designed to provide enantioselectivity, an effective noncovalent second interaction a hemilabile coordination to the metal center, thus inhibiting needed to be introduced. After screening a series of OPG’s, a β-hydride elimination or a second transmetalation, and we found that excellent enantioselectivity was achieved when promoting an effective aryl–alkyl cross-coupling. the bis(2-oxo-3-oxazolidinyl)phosphinyl (BOP) protecting group was employed. The significant increase in enantioselectivity

3. Chiral Monophosphorus Ligands for Cross-Coupling in going from O–P(O)Ph2 to O–BOP pointed to an important Cross-coupling is one of the most important carbon–carbon noncovalent interaction with the O–BOP group. The substrate bond-forming reactions, and has been widely applied in the scope further revealed the importance of the extended π electronics, materials, and pharmaceutical industries. Thanks system of the arylboronic acid for high enantioselectivity. All to the recent development of phosphorus ligands, the scope of these observations suggested the presence of a significant the cross-coupling reaction has been significantly expanded. polar–π interaction between the highly polarized BOP group Nevertheless, significant challenges remain such as tolerance and the extended π system of the arylboronic acid during of steric hindrance, compatibility of various functional groups, the reductive elimination step. The chiral ortho-O–BOP and excellent stereocontrol in forming axial chirality or all- biaryl products were subsequently applied to concise and carbon quaternary centers. To overcome these challenges, stereoselective total syntheses of the biologically active we developed a series of sterically hindered and electron- natural products korupensamine A and B, and michellamine B rich P-chiral monophosphorus ligands for the purpose of (Scheme 1, Part (b)).17 investigating the sterically hindered aryl–aryl and aryl–alkyl The trifluoromethanesulfonyl group can also be an effective cross-couplings.13 Moreover, an efficient, sterically hindered ortho OPG group in the asymmetric Suzuki–Miyaura coupling aryl–isopropyl coupling has also been developed for the first that uses Pd–(S,S)-Me-BIDIME (L3) as the catalyst system time by employing a sterically hindered P,P=O ligand.14 In the (Scheme 1, Part (c)).18 Utilizing this protocol, a series of chiral rest of this article, we will concisely highlight our recent results biaryl triflates were synthesized in excellent ee’s and yields. for the asymmetric Suzuki–Miyaura coupling,15–20 asymmetric dearomative cross-coupling,21–23 and α-arylation.24–25

3.1. Asymmetric Suzuki–Miyaura Coupling 1-NpB(OH)2 (2, 2.0 equiv) Br O Axially chiral biaryl structural motifs are found in a large Pd(OAc)2 (1 mol %) L3 (1.2 mol %) O number of biologically important natural products as well as in (a) N K3PO4 (3.0 equiv) O N thousands of ligands for asymmetric catalysis. Although there O THF, rt, 4 h 1 O O have been quite a few reported methods for the construction of Me Me Me 26 O 3, 95%, 96% ee chiral biaryl units, the asymmetric Suzuki–Miyaura coupling O remains of significant interest in this regard owing to its mild Me P Me O reaction conditions, broad functional group compatibility, and *P Pd Ar' Me 11 Pd nontoxic nature of the starting materials. To that end, we have Ar" O demonstrated the advantages of utilizing monophosphorus 2nd interaction ligands such as (S)-BIDIME (L2) and (S)-AntPhos (L5) in the N

Pd-catalyzed, sterically demanding Suzuki–Miyaura coupling O leading to tetra-ortho-substituted biaryls among others.15 π−π interaction O Ar We initially pursued the asymmetric construction of Br Pd(OAc)2 (1.0 mol %) ent-L3 or ent-L4 16 Ar OR chiral tri-ortho-substituted biaryls for which, and despite OR (1.2 mol %) (b) + considerable research efforts prior to our work, an efficient and K3PO4 (3.0 equiv) B(OH)2 PhMe–H2O (5:1) practical synthetic protocol utilizing the asymmetric Suzuki– 1.5 equiv rt, 12 h O 91–98%, 90–99% ee Miyaura coupling remained elusive. Our approach involved O P O R = N N Ar = acenaphthen-5-yl, ortho-substituted benzene incorporating a noncovalent π–π interaction between the two O O substituted naphthalen-1-yl aryl partners at the reductive elimination stage. Employing BOP this approach and monophosphorus ligand (S,S)-Me-BIDIME Ar Br (L3), an efficient, mild, and enantioselective Suzuki–Miyaura Pd(OAc)2 (1 mol %) OTf Ar L3 (1.2 mol %) OTf coupling between naphthyl bromide 1 and 1-naphthylboronic (c) + K PO (3 equiv) acid (2) was achieved, providing the biaryl coupling product 3 B(OH)2 3 4 PhMe, 30 oC, 8 h in 95% yield and 96% ee (Scheme 1, Part (a)).16 1.5 equiv ≤ 97%, ≤ 91% ee Since a large number of natural products feature chiral Ar = substituted benzene, acenaphthen-5-yl, phenanthren-9-yl, pyren-1-yl ortho-hydroxy- or ortho-methoxybiaryl structures, we then Scheme 1. Construction of Highly Sterically Hindered Biaryls by a Mild, developed an efficient asymmetric Suzuki–Miyaura coupling Efficient, and Highly Enantioselective Suzuki–Miyaura Coupling Enabled between arylboronic acids and aryl bromides bearing an by Chiral, Monophosphorus Ligands. (Ref. 16–18) ortho oxygen-protecting group (OPG).17 To achieve high P-Chiral Phosphorus Ligands for Cross-Coupling and Asymmetric Hydrogenation Reactions 30 Ting Wu, Guangqing Xu, and Wenjun Tang*

The biaryl triflate products underwent further elaborations such employing a chiral monophosphorus ligand.19 Although high as carbonylation, Suzuki–Miyaura coupling, Miyaura borylation, enantioselectivities were obtained for a few substrates with and Sonogashira coupling to forge a variety of chiral biaryl the employment of sterically hindered ligands, the asymmetric derivatives. Suzuki–Miyaura cross-coupling did not prove to be general. Tetra-ortho-substituted biaryls can also be accessed Low or no yield was obtained with slight variation of substrate by the asymmetric Suzuki–Miyaura or Negishi coupling by structure. The corresponding Negishi cross-coupling provided only slightly better yields of the tetra-ortho-substituted biaryls, but with lower enantioselectivities.19 Cl OH Compound 7 is a quinoline-based allosteric integrase inhibitor, OMe O O whose structure features an axially chiral biaryl backbone O N Me with an attached ortho-(α-(tert-butoxy)acetic acid) side chain. [Pd2dba3] (0.5 mol %) 4 L2 (1.1 mol %) N OH N OH A robust and practical synthesis was needed to support its + + n-C5H11OH–H2O CO2Me CO2Me advancement through the drug development process. Thus, O o Na2CO3, 60 C N Me N Me a diastereoselective Suzuki–Miyaura coupling of aryl chloride 6a (desired) 6b (undesired) N 4 and arylboronic acid 5 was exploited to install the chiral •HCl 6a:6b = 5:1, 73% yield of 6a B(OH)2 biaryl backbone, with the best result being obtained with ligand 5 20 O o (S)-BIDIME (L2) (Scheme 2). Under the optimized reaction (i) Cl3CC(NH)Ot-Bu, Tf2NH (4 mol %), PhF, 40 C (ii) NaOH (2 N), EtOH, 60 oC conditions (1-pentanol–water and 60 oC) a 5:1 diastereomeric

N Ot-Bu ratio of 6a to 6b was achieved, and the desired precursor (6a)

CO2H to 7 was isolated in 73% yield, which is significantly better than the 40% yield and 2:1 ratio of 6a to 6b obtained with SPhos.20 N Me 7, 88% (2 steps, multi-kg scale) dr > 99:1, 99% ee HIV integrase inhibitor 3.2. Asymmetric Dearomative Cross-Coupling Fused tricyclic skeletons containing chiral, all-carbon Scheme 2. Ligand (S)-BIDIME (L2) Enabled Suzuki Cross-Coupling as quaternary centers, such as chiral phenanthrenones, are a Key Step in a Concise, Robust, Safe, Economical, and Asymmetric Synthesis of an HIV Integrase Inhibitor. (Ref. 20) found in numerous complex terpenes and steroids that exhibit interesting biological activities.21,22 Complementing the asymmetric Heck reaction, the enantioselective intramolecular dearomative cross-coupling has become an important strategy [Pd(cinnamyl)Cl]2 Me (1 mol %) Me Br Me to assemble these chiral skeletons. Over the past several (S)-L17 (2 mol %) years, our research group has undertaken the total synthesis (a) HO + K2CO3 (1.5 equiv) O 8 o of terpenoids, steroids, alkaloids, and polyketide natural PhMe, N2, 90 C, 16 h 9, 92% ee OH O 94% (9 + 10) 10 products by taking advantage of the powerful, intramolecular, B: 9:10 = 96:4 P and enantioselective dearomative cross-coupling reaction. t-Bu HO Ph N Ph The program originated with the study of the asymmetric (S)-L17- a b b palladium-catalyzed cyclization of bromine-substituted phenol Pd(0) Br a (S)-L17 Pd (S)-L17 8, which can lead to the formation of the desired coupling 14 other examples: 11 35–99%, 83–99% ee product 9—containing a chiral, all-carbon quaternary center— as well as the achiral molecule 10 (Scheme 3, Part (a)).22

[Pd(cinnamyl)Cl]2 Products 9 and 10 arise from a common intermediate, 11, 4 Me Me (1 mol %) Me R Br N and, although 9 is thermodynamically less stable than 10, its 2' L5 (2 mol %) (b) + HO 1 N formation could be kinetically more favorable in the presence 2 R K2CO3 (2 equiv) O N PhMe, N , 90 oC, 16 h of a suitable catalyst. Among all the ligands screened, P-chiral 12 2 R OH 13 14 biaryl monophosphorus ligand (S)-L17 was found to promote R = P(O)(NMe2)2: 13:14 = 99:1; 13 (96% yield, 96% ee) the formation of the desired product, 9, smoothly in high yield and with the highest enantioselectivity (92% ee). In the OH N OH proposed stereochemical model for the cyclization, the high Et O H H N stereoselectivity observed with (S)-L17 is rationalized by N H Me O N N H H stipulating that the 2,5-diphenylpyrrole moiety of (S)-L17 and (–)-crinine (–)-aspidospermidine (–)-minfiensine its bulky tert-butyl group dictate the orientation of substrate coordination. Substrate 8, after oxidative addition to palladium Scheme 3. P-Chiral Biaryl Monophosphorus Ligands Enabling the to form 11 and nucleophilic substitution, could adopt two Efficient and Stereoselective Intramolecular Dearomative Cross- Coupling, a Key Step in the Synthesis of Fused Tricyclic Cores of major conformations, with the less strained one being more Biologically Active Natural Products. (Ref. 21–24) favored and leading to the observed R configuration of 9.22 By using this methodology, a series of biologically important Aldrichimica ACTA 31 VOL. 53, NO. 1 • 2020 terpenes, such as triptoquinone H,21 and (–)-totaradiol22 were we achieved the efficient and enantioselective synthesis of efficiently synthesized. In addition, this approach proved the antidepressant (S)-nafenodone (3 steps), the sceletium crucial in a nine-step, enantioselective synthesis of the strong alkaloid (+)-sceletium A-4 (4 steps), (–)-corynoline (5 steps), immunosuppressant (+)-dalesconol A that relied on the use and (–)-deN-corynoline (3 steps).25 of chiral (R)-AntPhos (ent-L5) as the chiral ligand.23 A steroid Carrying out an efficient cross-coupling between α-bromo skeleton was also constructed efficiently by using this method.21 carbonyl compounds and arylboron reagents under palladium The success we achieved in the all-carbon, fused tricyclic catalysis remains a tough challenge.26 Although such a systems prompted us to explore nitrogen-containing polycyclic transformation has been realized with chiral Ni27 or Fe28 catalysts, frameworks also incorporating a chiral, all-carbon quaternary palladium catalysis often features much lower catalyst loading center (Scheme 3, Part (b)).24 While the anticipated structural and is amenable to industrial applications. Nevertheless, the difference was simply the formation of a dihydrophenanthridinone palladium-catalyzed coupling of benzyl 2-bromopropionate with unit instead of a phenanthrenone one, it turned out that such phenylboronic acid in the presence of known ligands afforded a minor structural variation had a dramatic effect on the the undesired des-bromo ester and biphenyl in all cases chemoselectivity of the reaction. Substrate 12a (R = H) did without forming the desired cross-coupling product.29 Since not undergo the cyclization, while substrate 12b (R = Piv) monophosphorus ligands based on the DHBOP motif have been provided the undesired nonchiral compound 14b. We reasoned successfully applied in the coupling between aryl halides and that the chemoselectivity could be altered by changing the aryl- or alkylboronic acids, we surmised that the enantioselective N-R protecting group. Interestingly, after screening Piv, Ms, palladium-catalyzed coupling of α-bromo carbonyl compounds

Ts, Tris, Nos, Tf, SO2NMe2, and P(O)(NMe2)2 as the nitrogen with arylboronic acids could be accomplished by a judicious protecting group, we discovered that the bulky phosphoramide choice of ligand. The key to success would be the effective group P(O)(NMe2)2 led to the desired coupling product, 13, in inhibition of the homocoupling of the arylboronic acids, which excellent yield. When (S)-AntPhos (L5) was employed as ligand, results from a second transmetalation.30 Thus, we postulated the desired chiral dehydrophenanthridin-3(5H)-one product 13 that a bulky P,P=O ligand could offer a secondary hemilabile

[R = P(O)(NMe2)2] was isolated in 96% yield and 96% ee. interaction besides the Pd–P coordination, which would make DFT calculations helped rationalize the dramatic effect of the second transmetalation difficult due to steric hindrance.30 the N-R protecting group on the chemoselectivity. In substrate Careful ligand engineering and screening identified a bulky 30 12 [R = P(O)(NMe2)2], the C-2’ position (CBr) is in closer P, P = O l i g a n d, L18, as optimal. Using L18, the desired aryl– proximity to the C-4 position than is the case with substrate alkyl cross-coupling product was isolated in moderate yield 12 (R = Piv). NBO analysis also showed that the charge on and a decent ee. Because, in this case, the racemic α-bromo

C-4 in 12 [R = P(O)(NMe2)2] was –0.071, more negative than carboxamide was employed as substrate, the cross-coupling that on C-2 (–0.017). Thus the higher nucleophilicity of the C-4 position in substrate 12 [R = P(O)(NMe2)2] leads preferentially to the desired intramolecular dearomative cyclization forming O O Pd(OAc)2 (2 mol %) 24 compound 13. ent-L2 (4 mol %) R (a) R1 R + Ar Br R1 Finally, the asymmetric dearomative cross-coupling enabled n NaOt-Bu (2 equiv) Ar o the enantioselective synthesis of three distinct and challenging 15 16 PhMe, 80 C, 24 h 17 n = 1, 2 2 equiv 59–98%, 81–99% ee 24 biologically important polycyclic alkaloids: concise and gram- R = Me, Et, Bn, 4-MeBn, 2-Np, anthracen-9-yl scale total synthesis of (–)-crinine, an efficient total synthesis R1 = H, 5-Me, 5-MeO, 6-MeO; Ar = aryl, heteroaryl of indole alkaloid (–)-aspidospermidine, and a formal total O Me Me O O N N synthesis of (–)-minfiensine. H Me NMe2 O OMe Ph 3.3. Asymmetric α-Arylation of Carbonyl Compounds N O OH OMe The search for efficient asymmetric catalytic methods to (S)-nafenodone (3 steps) (+)-sceletium A-4 (4 steps) (–)-corynoline (5 steps) arylation step (L2): arylation step (L5): arylation step (L2): construct all-carbon quaternary stereocenters is gaining 75%, 80% ee 70%, 85% ee 70%, 92% ee significant momentum. The palladium-catalyzed, asymmetric ArB(OH)2 (2.0 equiv) α-arylation of carbonyl compounds remains one of most Pd(OAc) (1 mol %) Br 2 R Ph N Ad L18 (1.2 mol %) 2 O efficient and powerful methods to assemble chiral all-carbon NHR' NHR' Ad (b) R Ar P KF or K2CO3 (2.0 equiv) P O quaternary stereocenters, and the type of chiral ligand O O t-Bu PhMe, 60 oC, 48 h on palladium is key to achieving the desired reactivity and 42–80% Oi-Pr R = Me, Et, n-Bu, i-Bu, Ph(CH2)2 35–94% ee L18 enantioselectivity. Our group has found that (R)-BIDIME R' = CH(2-MeOC6H4)2 Ar = aryl, heteroaryl (ent-L2) is an exceptional ligand for the asymmetric α-coupling of indanones 15 with ortho-substituted 2-bromoarenes 16. Scheme 4. Chiral Quaternary Carbon Formation by the Catalytic, The ketone products, 17, incorporating a chiral quaternary Asymmetric α-Arylation Employing P-Chiral Biaryl Monophosphorus carbon center, are generated in up to 98% yield and 99% ee Ligands. (Ref. 25,30) (Scheme 4, Part (a)).25 Taking advantage of this methodology, P-Chiral Phosphorus Ligands for Cross-Coupling and Asymmetric Hydrogenation Reactions 32 Ting Wu, Guangqing Xu, and Wenjun Tang*

was essentially a dynamic kinetic resolution (DKR) process. and electronically by changing the substituents at the 4 and 4’ The base and the acidity of the substrates were important positions.31 Some of the novel bisphosphorus ligands that were parameters for both yield and enantioselectivity. Optimization developed in this way—e.g., BIBOP, MeO-BIBOP, and others— of the reaction parameters revealed that KF as the base and have proved to be excellent ligands for the enantioselective

CH(2-MeOC6H4)2 as the nitrogen protecting group were optimal catalytic hydrogenation reaction. for both yield and enantioselectivity (Scheme 4, Part (b)).30 Rh–BIBOP (Rh–L8) exhibited excellent catalytic efficiency in the asymmetric hydrogenation of various functionalized olefins 4. Chiral Bisphosphorus Ligands for Asymmetric such as α-(acylamino)acrylic acid derivatives, α-aryl enamides, Hydrogenation β-(acylamino)acrylic acid derivatives, and dimethyl itaconate The past few decades have seen significant advances in the (Scheme 5, Part (a)).31 Various functionalities were tolerated, asymmetric hydrogenation, and a number of important industrial and excellent enantioselectivities (up to 99% ee) and TONs (up processes have been implemented based on this reaction.1 Since to 2,000) were achieved in the synthesis of chiral α- and β-amino cost is a significant factor in judging whether a chemical reaction acids, chiral amines, and chiral carboxylic acid derivatives. is viable or not on an industrial scale, turnover numbers (TONs) MeO-BIBOP (L9) is another air-stable but more electron- must be considered for it and should be as high as possible. Our donating ligand. With Rh-L9 as the catalyst, a 200,000 TON belief that bisphosphorus ligands based on the DHBOP motif was achieved in the rhodium-catalyzed hydrogenation of could address these issues and other unmet challenges led us N-(1-(4-bromophenyl)vinyl)acetamide, which was the highest to develop three ligand frameworks for the catalytic asymmetric TON reported then for the hydrogenation of α-aryl enamides. hydrogenation. Our efforts led to BIBOP L8( ), which could be Similarly, a pyridine-substituted enamide was also hydrogenated prepared in two stereoisomeric forms and tuned both sterically with a Rh−MeO-BIBOP catalyst to provide the hydrogenation product in quantitative yield and 97% ee.32 By installing two 9-anthryl groups at the 4 and 4’ positions, a structurally R1 R1 interesting chiral bisphosphorus ligand—WingPhos (L10) was [Rh(nbd)(L8)]BF4 (1 mol %) (a) 2 2 designed and synthesized. The salient feature of WingPhos is R NH o R * NH CH2Cl2, H2 (100 psi), 0 C, 12 h the position of the two 9-anthryl groups that protrude directly R O R O 96 to >99% ee toward the coordinated substrate, forming a deep chiral pocket R = Me, t-Bu, CF3, N-morpholino capable of long-range stereochemical control. Notably, the two 1 R = H, XC6H4 (X = H, 4-MeO, 4-F, 2-Cl, 3-Br), 2-Np, thien-2-yl 2 diagonal quadrants bearing two tert-butyl groups no longer R = CO2Me, CO2H, XC6H4 (X = H, 3-Me, 4-MeO, 4-CF3, 4-Br), 2-Np, thien-3-yl provided a direct influence on substrate coordination, and the NHAc [Rh(nbd)(L10)]BF4 (0.5 mol %) NHAc (b) Ar Ar anthryl groups in the other two quadrants presumably influence o R CH2Cl2, H2 (750 psi), 50 C, 12 h R substrate coordination, leading to high enantioselectivities. > 99%, 93 to >99% ee The Rh−WingPhos complex was a highly efficient catalyst for or or NHAc NHAc the rhodium-catalyzed hydrogenation of (E)-β-aryl enamides, R' R' forming a variety of chiral cyclic and acyclic β-arylamines Z Z with different functionalities in excellent enantioselectivities > 99%, 94–98% ee at low catalyst loadings (TONs up to 10,000) (Scheme 5, Part R = Me, Et; R' = H, 5-MeO, 7-MeO, 6-Br, 8-Br; Z = O, CH2 33 Ar = XC6H4 (X = H, 2-Me, 2-MeO, 3-MeO, 4-MeO, 4-F, 2-Cl, 3-Br, 4-Br), (b)). Because (E)-β-aryl enamides could be conveniently 3,5-(BnO)2C6H3, 1-Np, 2-Np, thien-3-yl synthesized, this method provided a practical synthesis of [Rh(nbd) ]SbF (1 mol %) n 2 6 n various chiral β-arylamine derivatives. NHAc ent-L11 (1.2 mol %) NHAc (c) X X MeOH, H2 (500 psi), rt, 6 h ArcPhos (L11) is a conformationally defined, electron-rich, R R C -symmetric, P-chiral bisphosphorus ligand. It is highly n = 1–3; X = CH2, CMe2, O, S, NBn, NTs 97–99% 2 R = Me, Et, n-Pr, i-Pr, Bn, c-Pent, Cy, 22 to > 98% ee efficient in the rhodium-catalyzed asymmetric hydrogenation CH2CO2Et of carbocyclic and heterocyclic tetra-substituted enamides. [Rh(nbd)(ent-L11)]SbF6 Tf NHAc Tf NHAc Excellent enantioselectivities (up to 98% ee) and up to 10,000 N (0.025 mol %) (2.0 mg) N (d) MeOH, H (500 psi), rt, 6 h TON were achieved, which was the highest reported up until Me 2 Me 34 2.28 g 99% (2.27 g) then (Scheme 5, Part (c)). NMR experiments and X-ray Me 96% ee diffraction studies revealed that ent-L11 had a conformational Me N N CN preference whereby the flexible isopropyl groups are directed O N toward the rhodium center due to both stereoelectronic and

N N steric effects. Moreover, the asymmetric hydrogenation of a H (R)-tofacitinib heterocyclic starting material with [Rh(nbd)(ent-L11)]SbF6 as 62% (1.14 g), 96% ee catalyst led to N-trifluoromethanesulfonyl cis-3-acylamino-4-

Scheme 5. Efficient Enantioselective Olefin Hydrogenations Enabled by methylpiperidine (99% yield, 96% ee), and enabled an efficient Chiral Bisphosphorus Ligands. (Ref. 31,33,34) and practical synthesis of the Janus kinase inhibitor (R)- tofacitinib (Scheme 5, Part (d)).34 Aldrichimica ACTA 33 VOL. 53, NO. 1 • 2020

Our group has also developed a series of novel bisphosphorus additions of boron reagents to aldehydes, ketones, and ligands, L12–L14.35 This type of ligand possesses the following imines, to generate chiral homopropargylic alcohols,39 characteristics: (i) The chirality of the ligand arises from the tertiary alcohols,40 and α-tertiary amines41 in excellent central P-chirality instead of from the biaryl axial chirality. (ii) enantioselectivities. The Rh–(R)-BIDIME catalyst, Rh–ent-L2, The ligand adopts coordination modes with the metal similar enabled the asymmetric hydroboration of α-aryl enamides with to those of BINAP- or BIPHEP-type ligands. (iii) Its steric and B2(pin)2, providing a series of chiral α-amino tertiary boronic electronic properties can be highly modulated by varying the R3 esters in excellent ee’s and satisfactory yields.42 In the Pd- group at the 2 and 2′ positions. By employing Pd−iPr-BABIBOP catalyzed diboration of 1,1-disubstituted allenes, (S)-BIDIME (Pd−ent-L14) as catalyst, the hydrogenation of ethyl 3-oxo- (L2) performed the best among several chiral mono- and 3-phenylpropanoate proceeded in pentafluoropropanol–TFA bisphosphorus ligands tested, and led to the formation of a under 514 psi of H2 to form the chiral alcohol product in 93% series of chiral tertiary diboronic esters in excellent yields and ee and 99% yield with a TON of up to 10,000 (Scheme 6, Part ee’s.43 Using (S)-AntPhos (L5) or (S)-BIDIME (L2), our group (a)).35 Besides applications in palladium-catalyzed asymmetric effected the first Ni-catalyzed reductive coupling to generate, hydrogenation, other BABIBOPs have also been successfully in high yields and high ee’s, chiral tertiary allylic alcohols used in the rhodium-catalyzed asymmetric hydrogenation of attached to a tetrahydrofuran44 or to a pyrrolidine ring.45 di- and tri-substituted enamides (Scheme 6, Part (b))36 and the The reaction had a broad scope and permitted the efficient copper-catalyzed hydrogenation of 2-substituted 1-tetralones asymmetric synthesis of the lignan dehydroxycubebin as well via dynamic kinetic resolution (Scheme 6, Part (c)).37 The novel, C1-symmetric bisphosphorus ligand, MeO-POP, is an operationally convenient solid. It has proven equally effective (a) Asymmetric Nucleophilic Addition (Ref. 39) or even superior to the preceding C2-symmetric bisphosphorus PhCHO (1 equiv) Me Me Cu(II) isobutyrate (7 mol %) ligands in the rhodium-catalyzed asymmetric hydrogenation of Me ent-L9 (9 mol %) HO H TMS O α-(acylamino)acrylates and β-(acylamino)acrylates, providing Me Ph B LiOt-Bu (7 mol %) O TMS excellent enantioselectivities (up to >99% ee) and high TONs THF, –30 oC, 18 h 99%, 97% ee 9 other examples: (up to 10,000).38 For example, in the presence of 0.01 mol % 77–98%, 90–99% ee [Rh(nbd)(L16)]BF , methyl 2-acetamido-3-(2-chlorophenyl)- (b) Asymmetric Hydroboration (Ref. 42) 4 Me O acrylate was hydrogenated in methanol to provide the B2(pin)2 (1.5 equiv) [Rh(nbd)(ent-L2)]BF HN O HN Me 4 corresponding chiral α-amino acid derivative in 98% ee. (2 mol %) O Me B ® Me Me DABCO (20 mol %) O o Cl 5. Miscellaneous Asymmetric Transformations Cl C6F6, 60 C, 12 h Me Me 60%, 97% ee In addition to applications in the asymmetric cross-coupling 20 other examples: 31–72%, 83–99% ee and asymmetric hydrogenation, chiral phosphorus ligands (c) Asymmetric Diboration (Ref. 43) incorporating a DHBOP moiety have been extensively utilized B2(pin)2 (1.2 equiv) Me Me Bpin in a variety of other asymmetric transformations (Scheme 7). Pd2(dba)3 (1.0 mol %) L2 (2.5 mol %) Bpin BIBOP-type ligands have been successfully used in nucleophilic CyH, N2, rt, 24 h

Me Me 99%, 96% ee 31 other examples: Pd(ent-L14)(CF CO ) O O 3 2 2 OH O 76–98%, 8–94% ee (0.01 mol %) (a) (d) Reductive Coupling (Ref. 44) Ph OEt Ph OEt CF3CF2CH2OH–TFA (2.9:1) Ph Ph 2.39 g H (514 psi), 60 oC, 2 d 99% (2.39 g), 93% ee Ni(cod) (5 mol %) 2 O O 2 16 other examples: L2 (5 mol %) H 99%, 92 to >99% ee O OH Et3SiH (2 equiv) O O dioxane, N2, rt, 20 h [Rh(nbd)(L12)]BF4 (1 mol %) (b) Ph OMe Ph OMe MeOH, H (100 psi), 20 oC 95%, 97% ee NHBoc 2 NHBoc 19 other examples: 98%, >99% ee using L2 or L5 13 other examples: 86–98%, 91–99% ee (e) Alkene Aryloxyarylation (Ref. 46) 83–99%, 82 to >99% ee ArBr (2 equiv) O H2 (450 psi) OH R CuCl (5 mol %) Pd2(dba)3 (2 mol %) 2 X X Ph L15 (5 mol %) Ph ent-L6 (4 mol %) (c) Ar P(3,5-xylyl)3 (5 mol %) OH NaOt-Bu (2 equiv) O o R KOt-Bu (0.25 equiv) 92%, > 98% de, 94% ee X = O, N-Boc, CH2 C6F6, N2, 60 C, 18 h t-AmOH, 20 oC, 24 h 15 other examples: R = H, Me, Et, Ph 17 examples: 50–95%, 76 to >98% de, 52–94% ee Ar = aryl, heteroaryl, styryl 20–88%, 81–95% ee

Scheme 6. Asymmetric Hydrogenations Catalyzed by Biaryl Scheme 7. Miscellaneous Efficient Asymmetric Transformations Bisphosphorus Ligands. (Ref. 35–37) Enabled by P-Chiral Phosphorus Ligands Based on the DHBOP Motif. P-Chiral Phosphorus Ligands for Cross-Coupling and Asymmetric Hydrogenation Reactions 34 Ting Wu, Guangqing Xu, and Wenjun Tang*

as chiral dibenzocyclooctadiene skeletons. Finally, chiral biaryl Chem., Int. Ed. 2010, 49, 5879. monophosphorus ligand (R,R)-Me-AntPhos (ent-L6) led to good (14) Li, C.; Chen, T.; Li, B.; Xiao, G.; Tang, W. Angew. Chem., Int. yields and excellent enantioselectivities in the asymmetric Ed. 2015, 54, 3792. alkene aryloxyarylation.46 (15) Zhao, Q.; Li, C.; Senanayake, C. H.; Tang, W. Chem.—Eur. J. 2013, 19, 2261. 6. Conclusion and Outlook (16) Tang, W.; Patel, N. D.; Xu, G.; Xu, X.; Savoie, J.; Ma, S.; Hao, Over the last ten years, our research group has designed M.-H.; Keshipeddy, S.; Capacci, A. G.; Wei, X.; Zhang, Y.; Gao, and developed chiral phosphorus ligands based on the J. J.; Li, W.; Rodriguez, S.; Lu, B. Z.; Yee, N. K.; Senanayake, C. 2,3-dihydrobenzo[d][1,3]oxaphosphole (DHBOP) motif in order H. Org. Lett. 2012, 14, 2258. to address unmet challenges in asymmetric organic synthesis. (17) Xu, G.; Fu, W.; Liu, G.; Senanayake, C. H.; Tang, W. J. Am. High enantioselectivities and turnover numbers, low catalyst Chem. Soc. 2014, 136, 570. loadings, and generally mild conditions have been achieved (18) Yang, X.; Xu, G.; Tang, W. Tetrahedron 2016, 72, 5178. in a number of reactions by the judicious use of one of these (19) Patel, N. D.; Sieber, J. D.; Tcyrulnikov, S.; Simmons, B. J.; Rivalti, ligands and the metal catalyst. In this way, efficient asymmetric D.; Duvvuri, K.; Zhang, Y.; Gao, D. A.; Fandrick, K. R.; Haddad, cross-coupling, hydrogenation, hydroboration, cyclization, and N.; Lao, K. S.; Mangunuru, H. P. R.; Biswas, S.; Qu, B.; Grinberg, nucleophilic addition, among others, have been readily carried N.; Pennino, S.; Lee, H.; Song, J. J.; Gupton, B. F.; Garg, N. K.; out on a very wide range of substrates. Our continued efforts Kozlowski, M. C.; Senanayake, C. H. ACS Catal. 2018, 8, 10190. to design and develop novel and efficient phosphorus ligands (20) Fandrick, K. R.; Li, W.; Zhang, Y.; Tang, W.; Gao, J.; Rodriguez, for new applications in synthetic organic chemistry will help S.; Patel, N. D.; Reeves, D. C.; Wu, J.-P.; Sanyal, S.; Gonnella, transform the fields of catalysis and synthesis and make useful N.; Qu, B.; Haddad, N.; Lorenz, J. C.; Sidhu, K.; Wang, J.; contributions to the agrochemical and pharmaceutical industries. Ma, S.; Grinberg, N.; Lee, H.; Tsantrizos, Y.; Poupart, M.-A.; Busacca, C. A.; Yee, N. K.; Lu, B. Z.; Senanayake, C. H. Angew. 7. Acknowledgments Chem., Int. Ed. 2015, 54, 7144. We thank our co-workers from the Tang research group (21) Cao, Z.; Du, K.; Liu, J.; Tang, W. Tetrahedron 2016, 72, 1782. at SIOC, our previous colleagues at Boehringer Ingelheim (22) Du, K.; Guo, P.; Chen, Y.; Cao, Z.; Wang, Z.; Tang, W. Angew. Pharmaceuticals, and collaborators involved in this research Chem., Int. Ed. 2015, 54, 3033. topic. We are grateful for financial support from the Strategic (23) Zhao, G.; Xu, G.; Qian, C.; Tang, W. J. Am. Chem. Soc. 2017, Priority Research Program of the Chinese Academy of Sciences 139, 3360. (XDB20000000), CAS (QYZDY-SSW-SLH029), NSFC (21725205, (24) Du, K.; Yang, H.; Guo, P.; Feng, L.; Xu, G.; Zhou, Q.; Chung, L. 21432007, 21572246, and 21702223), and the K. C. Wong W.; Tang, W. Chem. Sci. 2017, 8, 6 247. Education Foundation. (25) Rao, X.; Li, N.; Bai, H.; Dai, C.; Wang, Z.; Tang, W. Angew. Chem., Int. Ed. 2018, 57, 12328. 8. References (26) Wencel-Delord, J.; Panossian, A.; Leroux, F. R.; Colobert, F. (1) Tang, W.; Zhang, X. Chem. Rev. 2003, 103, 3029. Chem. Soc. Rev. 2015, 44, 3418. (2) Xu, G.; Senanayake, C. H.; Tang, W. Acc. Chem. Res. 2019, 52, (27) Lundin, P. M.; Fu, G. C. J. Am. Chem. Soc. 2010, 132, 11027. 1101. (28) Iwamoto, T.; Okuzono, C.; Adak, L.; Jin, M.; Nakamura, M. (3) Knowles, W. S. Acc. Chem. Res. 1983, 16, 106. Chem. Commun. 2019, 55, 1128. (4) Vineyard, B. D.; Knowles, W. S.; Sabacky, M. J.; Bachman, G. L.; (29) Liu, C.; He, C.; Shi, W.; Chen, M.; Lei, A. Org. Lett. 2007, 9, Weinkauff, D. J. J. Am. Chem. Soc. 1977, 99, 5946. 5601. (5) Imamoto, T.; Watanabe, J.; Wada, Y.; Masuda, H.; Yamada, H.; (30) Li, B.; Li, T.; Aliyu, M. A.; Li, Z. H.; Tang, W. Angew. Chem., Int. Tsuruta, H.; Matsukawa, S.; Yamaguchi, K. J. Am. Chem. Soc. Ed. 2019, 58, 11355. 1998, 120, 1635. (31) Tang, W.; Qu, B.; Capacci, A. G.; Rodriguez, S.; Wei, X.; (6) Imamoto, T.; Sugita, K.; Yoshida, K. J. Am. Chem. Soc. 2005, Haddad, N.; Narayanan, B.; Ma, S.; Grinberg, N.; Yee, N. K.; 127, 11934, and references therein. Krishnamurthy, D.; Senanayake, C. H. Org. Lett. 2010, 12, 176. (7) Tang, W.; Zhang, X. Angew. Chem., Int. Ed. 2002, 41, 1612. (32) Reeves, J. T.; Tan, Z.; Reeves, D. C.; Song, J. J.; Han, Z. S.; Xu, (8) Liu, D.; Zhang, X. Eur. J. Org. Chem. 2005, 2005, 646. Y.; Tang, W.; Yang, B.-S.; Razavi, H.; Harcken, C.; Kuzmich, D.; (9) Zhang, X.; Huang, K.; Hou, G.; Cao, B.; Zhang, X. Angew. Mahaney, P. E.; Lee, H.; Busacca, C. A.; Senanayake, C. H. Org. Chem., Int Ed. 2010, 49, 6421. Process Res. Dev. 2014, 18, 904. (10) Li, C.; Chen, D.; Tang, W. Synlett 2016, 27, 2183. (33) Liu, G.; Liu, X.; Cai, Z.; Jiao, G.; Xu, G.; Tang, W. Angew. Chem., (11) Yang, H.; Tang, W. Chem. Rec. 2019, 19, 1 (DOI:10.1002/ Int. Ed. 2013, 52, 4235. tcr.201900003). (34) Li, C.; Wan, F.; Chen, Y.; Peng, H.; Tang, W.; Yu, S.; McWilliams, (12) Fu, W.; Tang, W. ACS Catal. 2016, 6, 4814. J. C.; Mustakis, J.; Samp, L.; Maguire, R. J. Angew. Chem., Int. (13) Tang, W.; Capacci, A. G.; Wei, X.; Li, W.; White, A.; Patel, N. Ed. 2019, 58, 13573. D.; Savoie, J.; Gao, J. J.; Rodriguez, S.; Qu, B.; Haddad, N.; Lu, (35) Jiang, W.; Zhao, Q.; Tang, W. Chin. J. Chem. 2018, 36, 153. B. Z.; Krishnamurthy, D.; Yee, N. K.; Senanayake, C. H. Angew. (36) Li, G.; Zatolochnaya, O. V.; Wang, X.-J.; Rodriguez, S.; Qu, B.; Aldrichimica ACTA 35 VOL. 53, NO. 1 • 2020

Desrosiers, J.-N.; Mangunuru, H. P. R.; Biswas, S.; Rivalti, D.; (46) Hu, N.; Li, K.; Wang, Z.; Tang, W. Angew. Chem., Int. Ed. 2016, Karyakarte, S. D.; Sieber, J. D.; Grinberg, N.; Wu, L.; Lee, H.; 55, 5044. Haddad, N.; Fandrick, D. R.; Yee, N. K.; Song, J. J.; Senanayake C. H. Org. Lett. 2018, 20, 1725. Trademarks. DABCO® (Evonik Degussa GmbH); QuinoxP*® (37) Zatolochnaya, O. V.; Rodriguez, S.; Zhang, Y.; Lao, K. S.; (Nippon Chemical Industrial Co., Ltd.). Tcyrulnikov, S.; Li, G.; Wang, X.-J.; Qu, B.; Biswas, S.; Mangunuru, H. P. R.; Rivalti, D.; Sieber, J. D.; Desrosiers, J.- About the Authors N.; Leung, J. C.; Grinberg, N.; Lee, H.; Haddad, N.; Yee, N. K.; Ting Wu received her B.S. degree in 2016 from Soochow Song, J. J.; Kozlowski, M. C.; Senanayake, C. H. Chem. Sci. University in Suzhou, Jiangsu (China). In the fall of 2016, 2018, 9, 4505. she moved to the Shanghai Institute of Organic Chemistry (38) Tang, W.; Capacci, A. G.; White, A.; Ma, S.; Rodriguez, S.; Qu, to pursue a doctoral degree under the direction of Professor B.; Savoie, J.; Patel, N. D.; Wei, X.; Haddad, N.; Grinberg, N.; Wenjun Tang. She is currently conducting research in the area Yee, N. K.; Krishnamurthy, D.; Senanayake, C. H. Org. Lett. of asymmetric catalysis. 2010, 12, 1104. Guangqing Xu obtained his Ph.D. degree in 2015 from the (39) Fandrick, D. R.; Fandrick, K. R.; Reeves, J. T.; Tan, Z.; Tang, W.; Shanghai Institute of Organic Chemistry, Chinese Academy Capacci, A. G.; Rodriguez, S.; Song, J. J.; Lee, H.; Yee, N. K.; of Sciences. He became a researcher in Professor Wenjun Senanayake, C. H. J. Am. Chem. Soc. 2010, 132, 7600. Tang’s group after graduation, and is currently an associate (40) Huang, L.; Zhu, J.; Jiao, G.; Wang, Z.; Yu, X.; Deng, W.-P.; Tang, professor at the Shanghai Institute of Organic Chemistry. His W. Angew. Chem., Int. Ed. 2016, 55, 45 27. research interests are in the areas of asymmetric catalysis (41) Zhu, J.; Huang, L.; Dong, W.; Li, N.; Yu, X.; Deng, W.-P.; Tang, and process chemistry. W. Angew. Chem., Int. Ed. 2019, 58, 16119. Wenjun Tang received his Ph.D. degree in 2003 from The (42) Hu, N.; Zhao, G.; Zhang, Y.; Liu, X.; Li, G.; Tang, W. J. Am. Pennsylvania State University (University Park, PA). After a two- Chem. Soc. 2015, 137, 6746. year postdoctoral research appointment at the Scripps Research (43) Liu, J.; Nie, M.; Zhou, Q.; Gao, S.; Jiang, W.; Chung, L. W.; Institute (La Jolla, CA), he worked for six years as a process Tang, W.; Ding, K. Chem. Sci. 2017, 8, 5161. chemist at Boehringer Ingelheim Pharmaceuticals (Ridgefield, (44) Fu, W.; Nie, M.; Wang, A.; Cao, Z.; Tang, W. Angew. Chem., Int. CT). In 2011, he accepted his current position as a research Ed. 2015, 54, 2520. professor at the Shanghai Institute of Organic Chemistry, (45) Liu, G.; Fu, W.; Mu, X.; Wu, T.; Nie, M.; Li, K.; Xu, X.; Tang, W. Chinese Academy of Sciences. His research interests are in Commun. Chem. 2018, 1, Article No. 90 (DOI: 10.1038/s42004- the areas of asymmetric catalysis, total synthesis of natural 018-0092). products, and development of efficient chemical processes. m

product highlight

Turn Research into Reality High-Quality Catalysis Products in Bulk P Going from research scale to production scale? We can provide bulk i-Pr quantities of high-quality catalysts, ligands, and precursors at the most competitive prices. Recent improvements to our processes allow us to quickly generate bulk quantities of Buchwald biaryl i-Pr i-Pr phosphine ligands and associated precatalysts. We’ll keep your work XPhos flowing with our full listing of bulk catalysis products! 638064 To learn more, visit SigmaAldrich.com/bulk Get Connected Get ChemNews

Get current news and information about chemistry with our free monthly ChemNews email newsletter. Learn new techniques, find out about late-breaking innovations from our collaborators, access useful technology spotlights, and share practical tips to keep your lab at the fore.

For more information, visit SigmaAldrich.com/ChemNews

The life science business of Merck KGaA, Darmstadt, Germany operates as MilliporeSigma in the U.S. and Canada. be sciencesational Bolder chemistry to empower your discovery

Scientific discovery is a revolution, not an evolution. It requires products you know and trust. But also, some you’ve never seen before.

Discover how we help you to stay sciencesational on: SigmaAldrich.com/ sciencesational

The life science business of Merck KGaA, Darmstadt, Germany operates as MilliporeSigma in the U.S. and Canada. MilliporeSigma P.O. Box 14508 St. Louis, MO 63178 USA

Join the tradition Subscribe to the Aldrichimica Acta, an open access publication for over 50 years.

In print and digital versions, the Aldrichimica Acta offers: • Insightful reviews written by prominent chemists from around the world • Focused issues ranging from organic synthesis to chemical biology • International forum for the frontiers of chemical research

To subscribe or view the library of past issues, visit SigmaAldrich.com/Acta

MS_BR5496EN 2020 – 30080 03/2020

The life science business of Merck KGaA, Darmstadt, Germany operates as MilliporeSigma in the U.S. and Canada.

Copyright © 2020 Merck KGaA, Darmstadt, Germany. All Rights Reserved. MilliporeSigma, Sigma- Aldrich, and the vibrant M are trademarks of Merck KGaA, Darmstadt, Germany or its affiliates. All other trademarks are the property of their respective owners. Detailed information on trademarks is available via publicly accessible resources.