Substrate Directed Asymmetric Reactions - American Chemical Society

Review Cite This: Chem. Rev. 2018, 118, 3391−3446

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Substrate Directed Asymmetric Reactions Sukalyan Bhadra*,† and Hisashi Yamamoto*,‡ †

Inorganic Materials and Catalysis Division, Academy of Scientific and Innovative Research, CSIR-Central Salt and Marine Chemicals Research Institute, G. B. Marg, Bhavnagar, 364002 Gujarat, India ‡ Molecular Catalyst Research Center, Chubu University, 1200, Matsumoto-Cho, Kasugai, Aichi 487-8501, Japan ABSTRACT: Historically, reagent controlled reactions (mechanism controlled reactions) have played a significant role in the asymmetric synthesis of complex structures. In contrast, today’s asymmetric synthesis is greatly dependent on substrate directed approaches. In this approach, a polar functional group, namely, a “directing group”, in the vicinity of the reactive site inside the substrate has been documented to preassociate with the chiral catalyst, which exerts stereodirecting influence by directing the reacting partner toward one of the enantiotopic faces of the reaction center. Those reactions usually proceed through exceptionally ordered transition states and result in extraordinary levels of stereoselection. Within the last four decades, the substrate directed approach has become an indispensible tool for the preparation of complex chiral frameworks starting directly from relatively simple achiral substrate molecules via asymmetric induction or various resolution techniques or both. Likewise, the substrate directed approach has been applied to functionalize enantiopure substrates bearing pre-exisiting stereocenters into complex structures as a single diastereomer. A classical example is Sharpless asymmetric epoxidation of allylic alcohols in which the free hydroxy function acts as an active anchor to a dimeric Ti-catalyst that controls the stereochemical outcome of the epoxidation process by transferring the oxidant enantioselectively. The principal aim of the present review is to give a general overview of substrate directed asymmetric transformations, a topic that has not yet been documented in the form of a concise review of recently developed approaches. Due to the large number of related applications, only recent advances that have been documented within the last two decades have been reviewed. Furthermore, in the current review, we have mainly highlighted asymmetric reactions that are controlled by abundant and frequently used directing groups such as hydroxy, amide, and sulfonamide groups. In addition, selected examples of a few important substrate-directed chemo-, regio-, and diastereoselective reactions have also been included in this review.

CONTENTS 1. Introduction 2. Hydroxy-Directed Asymmetric Reactions 2.1. Asymmetric Oxidations 2.1.1. Asymmetric Epoxidation of Hydroxy 2,3Olefins 2.1.2. Asymmetric Epoxidation of Longer Hydroxy Olefins 2.1.3. Hydroxy-Directed Asymmetric S- and NOxidations 2.2. Asymmetric Halogenation of Hydroxy Olefins 2.3. Asymmetric Cyclopropanation of Hydroxy Olefins 2.4. Stereoselective Ring Opening of Epoxy Alcohols 2.5. Asymmetric Direct Aldol and Mannich Reactions 2.6. Asymmetric Diels−Alder Reaction 2.7. Asymmetric Hydrogenation 3. Amide-Directed Asymmetric Reactions 3.1. Asymmetric Fluorination 3.2. Asymmetric C−H Functionalization 4. Sulfonamide-Directed Asymmetric Reactions 4.1. Asymmetric Epoxidation

© 2018 American Chemical Society

4.2. Stereoselective Ring Opening of Epoxy Sulfonamides 4.3. Asymmetric C−H Functionalization 5. Miscellaneous Examples 5.1. Atroposelective Biaryl Synthesis 5.2. Stereoselective Borocyclopropanation 5.3. Amidation of Carboxylic Acid Esters 6. Conclusion and Future Prospects Author Information Corresponding Authors ORCID Notes Biographies Acknowledgments References

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1. INTRODUCTION Historically, reagent controlled reactions (mechanism controlled reactions) have played a significant role in the asymmetric synthesis of complex structures. In contrast, today’s asymmetric synthesis is greatly dependent on substrate directed approaches. Received: August 28, 2017 Published: March 23, 2018 3391

DOI: 10.1021/acs.chemrev.7b00514 Chem. Rev. 2018, 118, 3391−3446

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In this approach, a polar functional group, namely, a “directing group”, in the vicinity of the reactive site inside the substrate has been documented to preassociate with the chiral catalyst, which exerts stereodirecting influence by directing the reacting partner toward one of the enantiotopic faces of the reaction center. Those reactions usually proceed through exceptionally ordered transition states and result in extraordinary levels of stereoselection.1 One of the major advantages of these reactions is that new functionalities or substituents are stereoselectively installed at a predefined position in the substrate without affecting the directing functionality, which can be further manipulated to a synthetic structure of particular interest. A classical example is Sharpless asymmetric epoxidation of allylic alcohols in which the free hydroxy function acts as an active anchor to a dimeric Ticatalyst that controls the stereochemical outcome of the epoxidation process by transferring the oxidant enantioselectively. Within the last four decades, the substrate directed approach has appeared as an indispensible tool for the preparation of complex chiral frameworks directly starting from relatively simple achiral substrate molecules via asymmetric induction or various resolution techniques or both. Likewise, the “substratedirected” concept has been applied to functionalize enantiopure substrates bearing pre-existing stereocenters into complex structures as a single diastereomer. While progress in the field of substrate directed asymmetric reactions has been immense, a review has never documented the recently developed approaches.2 The principal goal of the current review is to give a general overview of substrate-directed asymmetric induction by privileged chiral catalysts. Due to the large number of related applications only recent developments that have appeared in the last two decades have been reviewed. Developments that unambiguously exhibit transient interaction of the substrate’s directing functionality with a chiral catalyst via either covalent or noncovalent or hydrogen bonding have been described in the current review. Thus, the review does not cover reactions where the directing group is finally converted into another functional group within the same reaction step. Furthermore, in this review, we mainly highlight enantioselective reactions that are either actively or passively controlled by abundant and frequently used directing groups, such as hydroxy, amide, and sulfonamide functional groups. In addition, selected examples of a few important substrate-directed chemo-, regio-, and diastereoselective reactions have also been discussed in this review.

alcohols has high synthetic significance due to the following reasons: (1) The starting allylic alcohols are either commercially available or can be readily prepared in both E- and Z-isomeric forms; (2) In general, the metal-catalyzed or organocatalyzed epoxidation employs mild reaction conditions that tolerate a range of functional groups; (3) The reaction allows for the creation of three successive oxygenated carbon atoms, which can be easily converted into other functionalities of specific interest. The Sharpless asymmetric epoxidation (SAE) of allylic alcohols is the most straightforward method to obtain the corresponding chiral epoxy alcohols using a titanium/tartrate/tbutyl hydroperoxide-based system (Scheme 1).6,7 Only Scheme 1. Sharpless Asymmetric Epoxidation of Allylic Alcohols

commercially available reagents are required to generate, with excellent and reliable enantio- and diastereocontrol, synthetically useful epoxy alcohols from a variety of substrates.8 Subsequently, this process has become a classical tool for the synthesis of enantiomerically pure target molecules, especially in the field of complex natural products. In comparison with the titanium catalysts, only a few chiral vanadium catalysts for the epoxidation of allylic alcohols have been developed. The first example of vanadium-catalyzed epoxidation was demonstrated by Sharpless in 1977 in the presence of a hydroxamic acid ligand.9,10 However, progress in the field of V-catalyzed AE of allylic alcohol ceased for the next two decades due to ligand deceleration along with dynamic ligand exchange processes in this system. The major drawback was associated with the fact that to obtain high enantioselectivity an excess of chiral ligand was necessary to suppress background reaction, but such excess would rather favor the formation of catalytically inactive species and hence decrease the reactivity. Nonetheless, the advantages of vanadium catalysts over titanium catalysts were gradually resurveyed: lower catalyst loading, better moisture tolerance, easier workup procedures, and higher selectivity for a wide range of substrates, often complementary to the SAE.11 It was believed that during the catalyst generation stage, metal−ligand complexes remain in equilibrium (Scheme 2).12 The 1:1 complex of metal and ligand 4 was considered to be the active species. To eliminate the racemic background reaction, an excess of ligand had to be used in order to minimize the extent of achiral vanadium species 3, while such excess could also lead to unreactive intermediates 5 and 6 that might alter the reactivity.

2. HYDROXY-DIRECTED ASYMMETRIC REACTIONS Among numerous diastereo- and enantioselective transformations that have been developed to date, hydroxy-directed reactions are most widespread, given the abundance of hydroxy substituents in naturally occurring and biologically active compounds.3,4 Furthermore, the hydroxy function acts as an efficient anchor to various organocatalysts via H-bonding as well as to metal catalysts via covalent or nonbonding interaction that facilitates various enantioselective processes.

Scheme 2. Ligand-Deceleration Effect in Vanadium− Hydroxamic Acid Catalysis

2.1. Asymmetric Oxidations

2.1.1. Asymmetric Epoxidation of Hydroxy 2,3-Olefins. Optically active chiral epoxy alcohols are regarded as versatile synthetic intermediates that deliver C2-building blocks in an efficient manner. Thus, the direct synthesis of those molecules via asymmetric epoxidation (AE) of hydroxy olefins is of fundamental importance.5 In particular, the epoxidation of allylic 3392


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Yamamoto et al. developed a solution to this problem in 1999 based on an assumption that a sterically demanding ligand would not prefer the formation of metal complexes containing two or more ligands.12,13 Thus, hydroxamic acids bearing bulky substituents on both carboxyl and hydroxylamine components were synthesized and applied as catalysts for AE of allylic alcohols (Figure 1).

Figure 1. Yamamoto’s first generation hydroxamic acid ligands.

The required bulky ligand was obtained via the conversion of an optically active binaphthyl-derived carboxylic acid into a hydroxamic acid group that has high affinity to vanadium complexes as outlined in Figure 1. Gratifyingly, it was observed that a 1:1 ratio of vanadium to ligand 7 is crucial to obtain the best result for the AE of allylic alcohols. Thus, a diverse range of allylic alcohols with various substitution patterns was successfully epoxidized with triphenylmethyl hydroperoxide (TrOOH) by means of the vanadium/ hydroxamic acid catalyst system in satisfactory yields and enantioselectivities (Scheme 3).

Figure 2. Iterative positional optimization approach.

Scheme 4. VO(OiPr)3−9-Catalayzed Asymmetric Epoxidation of Allylic Alcohols

Scheme 3. VO(OiPr)3−7-Catalyzed Asymmetric Epoxidation of Allylic Alcohols

Although vanadium in combination with a chiral hydroxamic acid ligand constitutes an effective catalyst system for AE of allylic alcohols, some achiral vanadium precursors were also used in the presence of chiral hydroperoxide reagents. In 2003, Adam and co-workers described an oxovanadium-substituted sandwichtype polyoxometalate [ZnW(VO)2(ZnW9O34)2]12− that enables the catalytic enantioselective epoxidation of allylic alcohols in the presence of a sterically demanding chiral TADDOL-derived hydroperoxide (TADOOH).15 The reaction showed remarkably high catalytic efficiency (up to 42000 TON), giving excellent levels of enantioselectivity in the epoxide products (up to er = 95:5) (Scheme 5). The reaction was believed to proceed via the formation of a vanadium(V)-template generated in situ from the oxovanadium(IV)−polyoxometalate catalyst, the chiral hydroperoxide, and allylic alcohol. The chiral hydroperoxide (TADOOH) could be regenerated from the resulting TADDOL without loss of optical purity by a known procedure.16

The structure of the ligand has been shown to be the key to a successful epoxidation process. Although the binaphthyl-derived ligands constitute a relatively effective catalyst system, the chiral binaphthyl group is rather challenging to modify. In search of more efficient and easily accessible chiral ligands, the binaphthyl group was replaced with novel (R)-amino acid-based substituents in the hydroxamic acids.14 Based on initial results an iterative positional optimization approach was applied for ligand synthesis and subsequent screening. In this approach, the ligands were considered to have three variable components: L-α-amino acids as the chiral core in place of binaphthyl, dicarboxylimide as the N-protecting group, and a free hydroxylamine (Figure 2). Allylic alcohols with various substituent patterns were epoxidized with VO(OiPr)3 in the presence of the optimal ligand system in high efficiency and enantioselectivity (Scheme 4). Furthermore, the catalyst was shown to be effective even at a very low catalyst concentration (0.1 mol %), with a slight loss of enantioselectivity. 3393


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Scheme 5. Chiral TADOOH-Mediated Epoxidation of Allylic Alcohols

Scheme 7. Asymmetric Epoxidation of Allylic Alcohols in Water

Lattanzi et al. developed a (S)-norcamphor-based chiral tertiary alkyl hydroperoxide 13, in which (unlike TADOOH) the oxidizing hydroperoxyl group is directly attached to a stereogenic center.17 This chiral oxidant was used in the AE of allylic alcohol in the presence of VO(acac)2 and commercially available achiral hydroxamic acid ligand 12 (Scheme 6). However, moderate enantioselectivity was achieved.

To accomplish the AE of allylic alcohols in an aqueous medium with practically useful enantioselectivity, the necessity of further modification of the ligand became apparent. The same group developed a new class of chiral hydroxamic acid ligand built around the chiral 1,2-diamine scaffold (16 and 17, Scheme 8).19 Consequently, it was found that ligand 17 in the presence of

Scheme 6. Chiral tert-Hydroperoxide Promoted Asymmetric Epoxidation

Scheme 8. Modified Hydroxamic Acid Ligands for AE of Allylic Alcohols in Aqueous Medium

Despite steady progress in the V-catalyzed AE in terms of designing a hydroxamic acid ligand and chiral peroxide oxidant, one issue still remained unsolved. All these methods demand absolutely anhydrous reaction conditions due to the ligand deceleration effect of vanadium catalyst by water molecules. Use of water as a solvent offers numerous advantages over traditional organic solvents, including favorable environmental impact, low cost, and operational simplicity. In this context, Malkov and Bourhani have introduced a set of sulfonamide-based chiral hydroxamide ligands for V-catalyzed AE of allylic alcohols in water.18 They demonstrated that in the presence of those ligands, the epoxidation process in water becomes rather ligandaccelerated and an excess of ligand is no longer necessary. It was found that while the epoxidation in water proceeded at a slower rate than that in toluene, the enantioselectivity was not altered. Consequently, the epoxidation of allylic alcohols was exemplified with 2-methyl cinnamyl alcohol separately in water and in toluene in the presence of a V-precursor and ligands 14 or 15 with comparable enantiomeric excess of the epoxide product (Scheme 7). However, this method provided only an acceptable level of reactivity and selectivity of the epoxide products (up to 72% ee).

water-soluble VOSO4, can be used for the AE of a range of trisubstituted allylic alcohols giving satisfactory enantioselectivity (83−94% ee). Despite the many successes of vanadium/monohydroxamic acid catalysts, ligand deceleration effect still appeared to be a major problem and various classes of allylic alcohols remained that were not amenable to epoxidation in high yields and enantioselectivities. As a possible solution, in 2005 Yamamoto and co-workers designed a novel class of C2-symmetric bishydroxamic acid (BHA) ligands 22 having the following features to minimize the ligand deceleration effect: (1) an extra binding 3394


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site through which 22 chelates to the vanadium center to complete the formation of a chiral vanadium/ligand complex more efficiently than the monohydroxamic acid and (2) an R group of the amide in 22 that is large enough to direct the oxygen atom of the carbonyl group toward the cyclohexane ring to minimize steric crowding and hinders its interaction with the metal center.20 Furthermore, the attachment of additional ligands to the vanadium center would not be facilitated due to steric reasons. Consequently, a ligand deceleration effect resulting from doubly or triply coordinated catalytically inactive vanadium species within the vanadium/22 catalyst system could be avoided. The required ligand was prepared starting from readily available diamine tartrate salt via the synthesis of a platform molecule 21, which upon treatment with an acid chloride further gives a range of desired BHA ligands (Scheme 9).

Scheme 10. VO(OiPr)3/BHA-Catalyzed AE of Allylic Alcohols

Scheme 9. Synthesis of Bis-hydroxamic Acid (BHA) Liganda

Scheme 11. V-Catalyzed KR of Secondary alcohols a DIEA = N,N-diisopropylethylamine, Bn = benzyl, DMAP = 4dimethylaminopyridine, TESCl = triethylsilyl chloride.

Gratifyingly, in the presence of 70% aqueous tBuOOH (TBHP), the new vanadium/BHA catalyst could promote epoxidation of almost all types of allylic alcohols, including diand trisubstituted trans-allylic alcohols, cis-allylic alcohols and small allylic alcohols in excellent yield and enantioselectivity (Scheme 10). As hypothesized, it was found that the high reactivity and selectivity of the reaction was not altered even if the ratio of ligand/vanadium was increased to more than 3:1. Further, the vanadium/BHA catalyst system was applied to kinetic resolution (KR) of secondary allylic alcohols. Both the starting allylic alcohol and the epoxy alcohol were obtained in high enantiopurity (Scheme 11). The postulated model for the epoxidation of allylic alcohol has been depicted in Figure 3. Inside the catalyst scaffold, the bulky carboxylate substituents direct the carbonyl oxygen away from the metal center. In the transition state (TS), the allylic alcohol coordinates with the vanadium center through its oxygen atom from the top, the oxygen atom of TBHP is spiro overlapped with the olefin and attacks it from the bottom (Figure 3). Recently Noji and co-workers have developed an axially chiral C2-symmetric binaphthyl derived bishydroxamic acid ligand (BBHA).21 The vanadium complex of the new ligand catalyzes the AE of allylic alcohols in the presence of aqueous tert-butyl hydroperoxide (Scheme 12). Good to high enantioselectivity has been attained. Interestingly, the absolute stereochemistry of the resultant epoxy alcohols was determined as (2R)- in all cases when (S)-26 was used as the epoxidation catalyst.

Figure 3. Postulated TS for the VO(OiPr)3/BHA-catalyzed AE of allylic alcohols.

Scheme 12. AE of Allylic Alcohol Using Axially Chiral BHALigand

A central desire in synthetic chemistry is the achievement of environmental sustainability. In this context, the development of asymmetric oxidation using hydrogen peroxide, which is an atom-efficient and green oxidant, is a priority focus in oxidation chemistry. Katsuki et al. reported the first AE of allylic alcohol with hydrogen peroxide using urea−hydrogen peroxide complex (UHP) as the oxidant by means of a dimeric C2-symmetric 3395


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Nb(salen) complex.22 The catalyst Nb(salen) complex was presynthesized by mixing Nb(OiPr)5 and a salen ligand to give a monomeric Nb(salen) complex that slowly transforms into the more stable μ-oxo dimeric species upon standing in air. Good to high enantioselectivities were obtained in the Nb-catalyzed AE reaction (Scheme 13).

Scheme 14. Nb(salen)-Catalyzed AE of Allylic Alcohols Using 30% aq H2O2

Scheme 13. Nb(salen)-Catalyzed AE of Allylic Alcohols with UHP

tuning of the existing metal−ligand complexes or possibly from a completely new catalyst system. 2.1.2. Asymmetric Epoxidation of Longer Hydroxy Olefins. In contrast to hydroxy 2,3-olefins (allylic alcohols), hydroxy 3,4-olefins (homoallylic alcohols) and longer hydroxy olefins are challenging substrate classes for AE due to the following reasons: (1) the olefin reaction center resides at a longer distance from the hydroxy directing group; (2) from the study of angle strain of small cycloalkanes, it is apparent that the required energy for a 6-membered ring (0.1 kcal/mol) differs significantly from that for the 7−11-membered rings (6.2−12.6 kcal/mol). In general, a 6-membered TS is involved in a successful AE of allylic alcohol while a 7- or 8-membered TS is required for homo- and bis-homoallylic alcohols, respectively. This makes the substrate-controlled epoxidation of homoallylic and bis-homoallylic alcohols more challenging compared to simple allylic alcohols. Thus, a new strategy is required for these challenging substrate classes. Group IV metals in combination with chiral tartrate ester (or tartramide)-based catalyst systems as described by Sharpless25 and others26,27 do not exhibit satisfactory results in terms of both reactivity and stereoselectivity. Thus, it was a long-standing problem in organic synthesis. Based on the known ability of vanadium-catalyzed stereoselective epoxidation of allylic and homoallylic alcohols,9,28 in 2003 Yamamoto et al. extended the application of a vanadium/α-amino acid-derived hydroxamic acid system toward the enantioselective epoxidation of homoallylic alcohols.29 The hydroxamic acid ligand was screened in a similar fashion as in the epoxidation of allylic alcohols. Hence, VO(OiPr)3 in combination with the ligand 32 constitutes a catalyst system that promotes the AE of homoallylic alcohols in moderate to satisfactory enantioselectivities, using cumene hydroperoxide as the oxidant (Scheme 15). It was observed that a substituent in the 3-position of the homoallylic alcohol showed a positive influence on the stereoselectivity, while substituents in the 4-position provided a slightly negative effect.

In order to accomplish the AE of allylic alcohols in aqueous medium using 30% aq H2O2 solution, the Nb-based catalyst system was modified. In contrast to the μ-oxo-Nb(salen) complex 27 that readily decomposes into monomeric species in the presence of water or H2O2, a pretreated in situ generated Nb(salen) complex was found to serve as a better catalyst for the purpose.23 In addition, the latter minimizes the tedious purification steps as required for the previous preparation of Nb(salen) complex 27 and allows simple tailored ligand tuning. Hence, Nb(OiPr)5 in combination with a salen ligand 29 or 30 promotes the AE of allylic alcohols using 30% aqueous H2O2 solution as the terminal oxidant (Scheme 14). Although the AE of various allylic alcohols with diverse substitution patterns is primarily based on homogeneous catalytic systems, use of a heterogeneous catalyst system would be advantageous in terms of catalyst recovery and separation of the epoxide products. Xia et al. has published a review on the recent developments in this topic.24 Despite significant improvements that have been made in various ligand developments for metal catalyzed substratedirected AE of allylic alcohols, a completely general approach to AE remains elusive. This has encouraged the progress of alternative, indirect methods for the preparation of enantioenriched 2,3-epoxy alkanols, including kinetic resolution of racemic 2,3-epoxy alkanols and asymmetric reduction of α,β-epoxy carbonyl compounds. Although some of these methods display a high level of practicality, there is no doubt that the direct AE of allylic alcohols constitutes the most attractive approach. It remains to be demonstrated whether the next breakthrough toward a general AE of allylic alcohols will arise from further 3396


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Furthermore, the KR of primary homoallylic alcohols with preexisting stereogenic centers was also successfully carried out under the optimized reaction conditions (Scheme 18). Gratifyingly, both the starting homoallylic alcohols and epoxy alcohols were obtained in virtually enantiopure form.

Scheme 15. Vanadium/BHA-Catalyzed AE of Homoallylic Alcohols

Scheme 18. Vanadium/BHA-Catalyzed KR of 2,4Disubstituted Primary Homoallylic Alcohols

Subsequently, in 2007, the same research group reported an improved and practically useful protocol for the enantioselective epoxidation of cis- and trans-substituted homoallylic alcohols.30 In order to achieve outstanding enantioselectivities extremely bulky substituents were introduced into a C2-symmetric bishydroxamic acid ligand 35 that effectively binds with VO(OiPr)3 to catalyze the title reaction (Scheme 16). It is noteworthy that the reaction proceeds for a variety of cis- and trans-homoallylic alcohols at room temperature with only 1 mol % of vanadium loading (Scheme 17).

The desymmetrization of meso-secondary alkenyl alcohols that shares the same principle of facial discrimination of olefins with kinetic resolution should theoretically give 100% yield of the epoxide product as all of the starting material can be converted into products. Thus, this approach is more competent than kinetic resolution in providing enantiopure epoxy alcohols bearing at least two stereocenters. Owing to the remarkable kinetic resolution activity of the vanadium/BHA-system, Yamamoto and co-workers further utilized this catalyst system toward the enantioselective desymmetrization of meso-secondary alkenyl alcohols.31 Excellent diastereoselectivity and enantioselectivity were observed for a variety of allylic and homoallylic alcohols (Scheme 19). This approach provides the first direct

Scheme 16. Ligand Screening in V-Catalyzed AE of Homoallylic Alcohols

Scheme 19. Desymmetrization of meso-Secondary Allylic and Homoallylic Alcohols

Scheme 17. Substrate Scope of Vanadium/BHA-Catalyzed AE of Homoallylic Alcohols

a

a

2 mol % of VO(OiPr)3 and 4 mol % of 35 were used.

access to an extensively studied intermediate of atorvastatin (Lipitor) in 51% yield, 92:8 desired diastereomeric ratio, and 97% enantiomeric excess. After numerous successful applications of the vanadium/BHAcatalyst system in a variety of AE processes, Yamamoto et al. realized that further modification of the bulky BHA ligand is a rather challenging task to expand the substrate scope. They hypothesized that using a larger metal center would generate more space around its periphery, so that a smaller ligand could organize in an appropriate manner for the stereoselective

The cis-alcohol was used as the starting material.

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recognition of the longer alkenol substrate and oxidant molecules more simply.32 In the first attempt, zirconium(IV) was chosen as the candidate metal ion, based on the fact that a Zr−tartrate (or tartramide) complex could catalyze the AE of homoallylic alcohols.27 Afterward, an identical hafnium catalyst had been found to perform the desired reaction more efficiently. The TS of the Zr/Hf(OtBu)4 catalyzed reaction differs significantly from that previously proposed for V-catalysts: in zirconium- and hafnium-catalyzed reactions, the transition state should be a mononuclear pentacoordinated complex, while the vanadium-catalyzed reactions involved hexacoordinated vanadium complexes (Figure 4).

Scheme 21. Hf(OtBu)4/BHA-Catalyzed AE of Bishomoallylic Alcohols

homoallylic alcohols for the first time in high yields and enantioselectivities.33 The large Hf ion, with long metal−oxygen bonds creates less steric interaction between the bulky tertiary olefinic alcohol substrates and the metal complex. Using MgO as an additive, two BHA ligands, 22a and 22b, were found to be operational; 22b with an extra methylene group at the Cα position allowed for higher stereoselectivity for tert-allylic alcohols, while 22a showed better selectivity for tert-homoallylic alcohols. Selected examples of the Hf(OtBu)4/BHA-catalyzed AE of tert-allylic and homoallylic alcohols have been shown in Scheme 22. Further synthetic applications of this catalyst system include KR of aromatic tertiary olefinic alcohols and desymmetrization of meso-tertiary allylic and bis-homoallylic alcohols, which provided high diastereo- and enantioenriched products.32

Figure 4. Comparison of TS in V-, Zr-, and Hf-catalyzed epoxidation.

In fact, an initial screening experiment demonstrated that Zr(OtBu)4−22a serves as a better catalyst system than the corresponding V-catalyst. It is noteworthy that the ligand 22a has a smaller size than 35, the optimal ligand for vanadium-catalyzed epoxidation of homoallylic alcohols. Meanwhile, it was found that Hf(OtBu)4 compared to Zr(OtBu)4 gives a slightly better result with respect to reactivity and stereoselectivity. Employing a polar aprotic additive, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)pyrimidinone (DMPU), and rigorously anhydrous conditions by the use of molecular sieves made further improvement in the reaction outcome. Thus, under the optimized conditions, homoallylic alcohols were epoxidized in high yields and excellent enantioselectivities (Scheme 20). Furthermore, when the Hf-

Scheme 22. Hf(OtBu)4/BHA Catalyzed AE of tert-Allylic and Homoallylic Alcohols

Scheme 20. Zr/Hf(OtBu)4/BHA-Catalyzed AE of Homoallylic Alcohols

based system was applied to epoxidize 4-substituted bishomoallylic alcohols, the corresponding epoxides were formed in good yields and satisfactory enantioselectivities. In general, the epoxy alcohol products did not cyclize to tetrahydrofuran derivatives under the reaction conditions except for two cases (Scheme 21). However, bis-homoallylic alcohols with other substitution patterns gave poor results. The Hf(OtBu)4/BHA-based system was further utilized to promote the AE of notoriously unreactive tertiary allylic and 3398


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In 2014, Yamamoto et al. developed the first tungstencatalyzed AE of primary, secondary, and tertiary allylic alcohols and homoallylic alcohols using aqueous H2O2 as the atomeconomic and environmentally benign oxidant.34 A new BHA ligand, 48, with modified arms in the presence of WO2(acac)2 was shown to provide the best result in terms of both yields and enantioselectivities. NaCl was used as an additive to improve the selectivity of the catalytic reaction (Scheme 23).

Scheme 24. Regioselective Epoxidation of Farnesol Derivatives

Scheme 23. WO2(acac)2/BHA-Catalyzed AE of Allylic and Homoallylic Alcohols

The resulting chiral epoxide was produced in 91:9 enantiomeric ratios and was subsequently converted into the desired bicyclic epimeric products via several reaction steps (Scheme 25). Scheme 25. Application of Yamamoto’s AE Method for the Total Synthesis of Obtusallenes

a

Albeit the reported epoxidation systems exhibit broad reactivity and high selectivity toward numerous substrate classes, various classes of alkenols remain that cannot be epoxidized in high yields and enantioselectivities. In order to obtain a more general reaction system, recently Bhadra and Yamamoto have introduced a new bimetallic catalytic approach.36 They postulated that the AE of a longer chain alkenol could be achieved by means of a bimetallic Ti catalyst, in which if the two titanium centers reside at an appropriate distance, one metal center would bind to the hydroxy function of the alkenol substrate, while the other metal center delivers the oxidant to the reactive olefin site enantioselectively (Figure 5). Hence, both metal centers act as a Lewis acid for the hydroxy substrate as well as for the electrophilic oxidant. Owing to the rigidity and excellent binding ability of 8hydroxyquinoline with various metal ions, the authors reasoned to use this molecule as the metal template.37 The required ligand

b

Using 5 mol % WO2(acac)2 and 5.5 mol % 48 for 24 h. Using 1.0 equiv NaCl for 8 h at 0 °C.

In order to apply the W-based system to the late stage oxidation of complex molecules, the influence of the anchoring OH groups, as well as that of the geometry of the olefins on the reactivity of the substrates, was examined. The reactivity trend of the different substrates was found as follows: (a) primary alcohols ≫ tertiary alcohols and phenyl-substituted secondary alcohols; (b) cis- or trans-disubstituted olefins ≈ trisubstituted olefins > geminal disubstituted olefins. Finally based on this result, two farnesol derivatives, 46 and 48, containing three olefins and two alcohol moieties were successfully converted to their corresponding epoxides in almost complete regioselectivities, high yields, and enantiomeric excess (Scheme 24). Recently, Braddock et al. have successfully applied one of Yamamoto’s vanadium-BHA catalyst systems for the AE of a homoallylic alcohol during the total synthesis of two bicyclic 12membered ring ethers as the putative precursors (54 and 55) of obtusallene II and obtusallene IV, complex marine natural products isolated from Laurencia species.35 The V-based catalyst system consisting of VO(OiPr)3 and BHA-ligand 34 was used to epoxidize a homoallyl alcohol, 56 regio- and enantioselectively in the presence of cumene hydroperoxide (CHP) as the oxidant.

Figure 5. Working hypothesis of the new binuclear Ti-catalysis. 3399


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Scheme 26. Preparation of the New Ligand 58

whereas cinnamyl alcohol reacts at a much slower rate with moderate stereoselectivity, and bis-homocinnamyl alcohol remains unreactive. This suggests that the TS of the reaction considerably differs from that previously proposed for single metal or cooperative dual metal catalysts, as in those cases epoxidation only with allylic alcohols would provide high stereoselectivities. Subsequently, this catalyst system was applied to the KR of secondary homoallylic alcohols (Scheme 28). Both the starting homoallylic alcohol 60 and the epoxy alcohol 61 were formed in high enantiopurity. The scope of the new epoxidation method was further expanded toward 2-allylic phenol in which the reactive olefin is located three carbons away from the directing hydroxy substituent (Scheme 29). It was observed that the desired

58 was simply prepared in two steps: (1) Suzuki cross-coupling of (S)-2,2′-dimethoxy-1,1′-binaphthyl-3,3′-diyldiboronic acid with 2-bromo-7-tert-butyl-8-methoxyquinoline and (2) demethylation of the resulting tetramethoxy compound (Scheme 26). As postulated, soon it turned out that in the presence of 70% aqueous tBuOOH, a mixture of Ti(OiPr)4 and ligand 58 in 2:1 ratio in DCM constitutes a reaction system that allows for the AE of numerous homoallylic alcohols with diverse substitution pattern in good yields and high enantioselectivities (Scheme 27). The same catalyst system was also used to accomplish the regioand enantioselective monoepoxidation of conjugated homoallylic alcohols at the proximal double bond. Scheme 27. Substrate Scope of AE with the Binuclear TiCatalyst

Scheme 29. Ti-Catalyzed AE of 2-Allylic Phenols

a

epoxides were formed in high yields and significant enantioselectivities. This method provides the first practical access to optically active epoxides of 2-allylic phenol substrates. 2.1.3. Hydroxy-Directed Asymmetric S- and N-Oxidations. 2.1.3.1. Asymmetric Sulfoxidation. After the successful implementation of the reaction concept of the bimetallic Ti catalyst toward AE of various hydroxy olefin substrates, Bhadra

b

The ee of the benzoyl derivative. With 3.5 equiv of 70% aq TBHP and for 48 h. cTwenty-four hours. dAt 0 °C.

Control experiments revealed that the Ti-based system allows AE of homocinnamyl alcohol in excellent enantioselectivities,

Scheme 28. Kinetic Resolution of Secondary Homoallylic Alcohols

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Scheme 31. Ti-Catalyzed Asymmetric N-Oxidation of γAmino Alcohols

and Yamamoto became interested in extending the synthetic utility of the catalytic system for other asymmetric oxidation processes, for example, asymmetric oxidation of hydroxycontaining sulfides.36 It soon turned out that the presence of the sulfide functionality at the γ-position with respect to the hydroxy-directing group is the key to achieving excellent enantioselectivity, as the sulfoxidation of simple propyl phenyl sulfide and β-hydroxyethyl phenyl sulfide proceeded with diminished yields and enantioselectivities. A diverse range of γhydroxypropyl sulfides were converted into their sulfoxides in high yields and excellent enantioselectivities (Scheme 30). Scheme 30. Asymmetric Sulfoxidation of γ-Hydroxysulfides Catalyzed by Binuclear Ti-Complex

alcohols of opposite absolute configuration through various reduction methods. Although Bhadra and Yamamoto have demonstrated the syntheses of optically active sulfides and N-chiral amine oxides via substrate directed approaches, these are only preliminary results. The substrate directed sulfoxidation and N-oxidation processes require further advancement in the future. 2.2. Asymmetric Halogenation of Hydroxy Olefins

2.1.3.2. Asymmetric N-Oxidation. Recently, the synthesis of optically active amine oxides has received profound interest, owing to their increasing use as chiral ligands in asymmetric synthesis of complex molecules. However, the synthesis of Nchiral amine oxides has not been satisfactorily developed. The potential drawback of the direct asymmetric oxidation of amines to N-chiral amine oxides originates from the fact that the starting tertiary amine enantiomers remain in equilibrium as a result of a rapid pyramidal inversion on the stereogenic nitrogen atom. Bhadra and Yamamoto postulated that the required N-oxidation via dynamic kinetic resolution of the trivalent amine substrate could be accomplished by means of the new binuclear titanium catalyst if a hydroxy group were positioned at an appropriate distance from the N-center.38 An intensive investigation with various amino alcohol substrate classes indicated that the presence of a γ-hydroxy substituent with respect to the amine is the key to a successful asymmetric N-oxidation process since the N-oxidation was not effective for other substrate classes, including β-hydroxy amines, δ-amino alcohols, hydroxymethylaniline, and aminophenols. Subsequently, a range of N-chiral amine oxides were prepared from the corresponding (N,N-benzylalkyl)amino alcohols in satisfactory yields and with moderate to good enantioselectivities (Scheme 31). It was observed that a bulky substituent at the Nstereocenter facilitated enantioselectivity at much higher level in products, whereas the enantioselectivity drops in the presence of a less bulky substituent or a simple alkyl side chain instead of the benzyl group at the N-center. This N-oxidation strategy was finally applied to the kinetic resolution (KR) of racemic γ-amino alcohols that contain a preexisting stereogenic center, a transformation that has eluded success through the Sharpless method (Table 1).39,40 The primary and secondary γ-amino alcohols were obtained in virtually enantiopure form, while the corresponding N-oxides were formed in high enantioselectivity. The N-oxides thus formed can be transformed into the corresponding γ-amino

Despite the enormous success of asymmetric epoxidation since the 1980s, the asymmetric halogenation of hydroxy olefins has emerged only recently.41 Nicolaou and co-workers described the first direct dichlorination reaction of allylic alcohols in 2011.42 The reaction was accomplished by means of a dimeric cinchona alkaloid derivative (DHQ)2PHAL (72). While an array of transallylic alcohols was converted to the corresponding dichlorides in moderate to good enantioselectivities, cis-allylic alcohols showed inferior results (Scheme 32). Furthermore, the presence of a free hydroxy group in the allylic alcohol proved to be essential, since masking of this moiety with a triethylsilyl (TES) group provided diminished enantioselectivity. Mechanistically, the dichlorination proceeds through the H-bonded substrate control of allylic alcohols with one of the two nitrogen atoms of the phthalazine moiety in the catalyst 72, followed by an electrophilic chlorination with p-PhC6H4ICl2 giving a chloronium species (Figure 6), and a consequent regio- and facial-selective chlorenium delivery in an analogous fashion as proposed by Corey and Noe for the Sharpless asymmetric dihydroxylation.43,44 Subsequently, in 2013, Burns and co-workers developed a new strategy for the asymmetric dibromination of allylic alcohols.45 Since dibromination of alkenes by molecular bromine primarily proceeds with very fast background bromination leading to poor stereoselectivity, the authors reasoned that formally separating Br2 into electrophilic and nucleophilic partners that remain unreactive on their own, albeit in combination would form an active dibrominating species, would improve selectivity. Soon it turned out that in the presence of a TADDOL-based ligand, dibromomalonate served as the optimized electrophilic bromonium source, whereas bromotitanium triisopropoxide acted as nucleophilic brominating agent as well as the metal catalyst to allylic alcohols. It was observed that the reaction was operational in the presence of both 100% (stoichiometric) and 20% (catalytic) loading of the diol ligand, though giving a slightly diminished yield and enantioselectivity in the latter case. Thus, 3401


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Table 1. Kinetic Resolution of γ-Amino Alcohols

a

Conversion, C = eeS/(eeS + eeP). bThe selectivity factor s was calculated as s = ln[(1 − C)(1 − eeS)]/ln[(1 − C)(1 + eeS)].

atoms, the two products of the regioselective ring opening are enantiomers, while in the case of different electrophilic and nucleophilic halogen atoms, four distinct products can be formed. Considering this fact, the authors designed a new system in which chlorotitanium triisopropoxide plays a dual role: it binds with the allylic alcohol substrate and supplies the nucleophilic chloride ion, while N-bromosuccinimide (NBS) acts as the electrophilic bromonium source. It was found that a tridentate Schiff base ligand 82 and nonpolar solvent such as hexane are decisive components for the reaction outcome leading to C2selective anti-Markovnikov chloride adduct as the major product with satisfactory enantioselectivity (one constitutional isomer). Consequently, asymmetric bromochlorination of a range of allylic alcohols was performed under the optimized reaction conditions (Scheme 34). Furthermore, in order to show synthetic utility of the bromochlorination method, a concise chemo-, regio-, and enantioselective synthesis of (+)-bromochloromyrcene (87) was achieved for the first time (Scheme 35). Burns next successfully applied the bromochlorination strategy to the first stereoselective total synthesis of three interhalogenated naturally occurring compounds: (1) (−)-plocamenone and (2) (−)-isoplocamenone isolated from marine

numerous cinnamyl alcohols underwent dibromination under the optimized reaction condition (Scheme 33). Control experiments revealed the following facts: (1) the free hydroxy of allylic alcohol binds with the titanium center; (2) bromide is involved in the selectivity-determining step; (3) excess free alcohol, not alkene, interrupts the selectivity, possibly due to disruption of the coordination chemistry that is crucial for selectivity; (4) the role of diethyl dibromomalonate was found to be the bromonium source and that of titanium halide was the bromide ion source. Based on these observations, the authors proposed a catalytic cycle in which the reaction proceeds via the formation of a coordinatively saturated titanium complex obtained from titanium bromide, dibromo malonate, TADDOL ligand, and allylic alcohol (Figure 7). Consecutive metalpromoted intramolecular bromonium delivery and an intramolecular bromide transfer via the hypothetical TS 81 led to the dibrominated product. Burns further developed an efficient protocol for the enantioselective bromochlorination of allylic alcohols.46 Asymmetric dihalogenation of alkene occurs through the formation of a cyclic halonium intermediate, each enantiomer of which can be opened by halide ion to form two possible constitutional isomers. In the case of identical nucleophilic and electrophilic halogen 3402


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Scheme 32. Asymmetric Dichlorination of Allylic Alcohols

Figure 7. Proposed catalytic cycle for the dibromination of allylic alcohols.

Scheme 34. Asymmetric Bromochlorination of Allylic Alcoholsa a

PhICl2 was used in place of PhC6H4ICl2.

Figure 6. Proposed stereoinduction model.

Scheme 33. Asymmetric Dibromination of Allylic Alcohols

a

cr = constitutional isomer ratio.

Scheme 35. First Concise Synthesis of (+)-Bromochloromyrcene

chlorination as the key step using (S,R)-Schiff base 82 as the chiral catalyst starting from the allylic alcohol 88 (Scheme 36). The resulting alcohol 89 was then subjected to Dess−Martin periodinane (DMP) oxidation followed by Horner−Wadsworth−Emmons olefination with 90 to give ketone 91 in a 13:1 ratio of double-bond isomers. Treatment of 91 with Eschenmoser’s chloride salt 92 and successive activation with iodomethane afforded (Z)-isoplocamenone 93 and (E)plocamenone 94 as a separable 2:1 mixture. Finally, (E)plocamenone was obtained as the major component (in 3:1 ratio) by photoirradiation of (Z)-isoplocamenone with a flood lamp for 5 days.

red algae source Plocamium and (3) (+)-halomon, a preclinical anticancer natural product.47 The syntheses of plocamenone and isoplocamenone were thus accomplished using Burns bromo3403


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condition that allows for the bromochlorination of cinnamyl alcohols in good yield and moderate to excellent enantioselectivities.48 The authors screened a series of related multifunctional Schiff base ligands and demonstrated that ligands (S,R)102 and (S,R)-82 were optimal (Scheme 38).

Scheme 36. Total Synthesis of Plocamenone and Isoplocamenone

Scheme 38. Bromochlorination of Cinnamyl Alcohols

Recently, the stereoselective synthesis of polychlorinated sulfolipid natural products has received considerable attention. In contrast to Nicolau’s protocol,42 the dichlorination developed by Burns allows for the asymmetric dichlorination of nonstyrenyl allylic alcohols in satisfactory enantioselectivity. Subsequently, the authors described the strategic application of the stereoselective dichlorination method to furnish targeted synthetic intermediates during the concise enantioselective syntheses of two chlorosulfolipids: ent-(−)-deschloromytilipin and ent-(−)-danicalipin A.49 The asymmetric dichlorination had been shown to be functional for an array of aryl, as well as alkyl, group substituted allylic alcohols (Scheme 39).49 In this reaction, tert-butylhypo-

The first total synthesis of halomon in a scalable quantity was achieved starting from a known allylic alcohol 95 (Scheme 37). Scheme 37. Total Synthesis of (+)-Halomon

Scheme 39. Asymmetric Dichlorination of Allylic Alcohols with tBuOCl

The Burns halogenation conditions had been utilized two times in the entire reaction sequence. Thus, the alcohol 96, obtained via bromochlorination of 95 in the presence of (R,S)-82, was deoxygenated to give myrcene derivative 97. Consequently, 97 was converted to the bromohydrin 98, which was subjected to the dichlorination under Burns catalytic conditions. The alcohol 100 was formed in >20:1 diastereomeric ratio. Subsequent dehydration of 100 resulted in the formation of desired compound (+)-halomon 101 in good yield. The protocol thus developed provided 400 mg of pure (+)-101 starting from 3.4 g of 95. Despite the remarkable success of the Burns method, bromochlorination of certain substrate classes, such as arylsubstituted trans-allylic alcohols (trans-cinnamyl alcohols), was not addressed. Xu et al. described a complementary reaction

chlorite (tBuOCl) acts as the chloronium source, and ClTi(OiPr)3, in the presence of a Schiff base catalyst (S,R)-82, acts as oxophilic chiral Lewis acid to tBuOCl in addition to acting as the chloride source and metal activator to allylic alcohols. The first total synthesis of (−)-deschloromytilipin has been achieved in 10 steps starting from an enantioenriched dichloro alcohol 104b obtained via asymmetric dichlorination of crotyl alcohol (Scheme 40).49 This synthesis constitutes the first use of an asymmetric dihalogenation during the synthesis of a chlorosulfolipid. 3404


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Scheme 40. Synthesis of (−)-Deschloromytilipin

Scheme 42. Asymmetric Bromochlorination of Homoallylic Alcohol

Burns further described the total synthesis of (−)-danicalipin A by the use of a dichloroalcohol (−)-104c prepared according to their dichlorination method (Scheme 41).49 The alcohol Scheme 43. Enantioselective Bromohydroxylation of Allylic Alcohols

Scheme 41. Synthesis of (−)-Danicalipin A

(−)-104c was further oxidized to the corresponding aldehyde 107, which was subjected to allylation with a chloroallyl boronic ester 108. It turned out that the desired allylated chlorohydrin 109 could be obtained as a single enantiomer and diastereomer in gram scale by first activating the boronic ester 108 in situ as the corresponding borinate at low temperature. A formal hydrochlorination of 109 via a bromochlorination−chemoselective radical debromination sequence followed by a sulfation finally led to the desired compound (−)-danicalipin A. After demonstrating the tremendous potential of the bromochlorination method for allylic alcohols, Burns expanded the strategy toward homoallylic alcohols.50 It appeared that slight modification of the existing reaction conditions for allylic alcohols allowed for the bromochlorination of a homoallylic alcohol 111 in a practically useful level (Scheme 42). Addition of 20 mol % Ti(OiPr)4 was found to be crucial to achieve higher yield and enantioselectivity of the desired constitutional isomer. The synthetic utility of the bromochlorinated product 112 was demonstrated by the first total synthesis of an antibacterial polyhalogenated monoterpene, (−)-anverene 113. In 2013 Xie, Lai, Ma, and co-workers described an asymmetric bromohydroxylation of 2-aryl-substituted allylic alcohols by means of a quinine alkaloid catalyst, 114 (Scheme 43).51 The regioselectivity of the reaction was controlled via the formation of an in situ generated boronate ester from phenylboronic acid and allylic alcohols. The bifunctional quinine catalyst activates the boronate ester as well as NBS to accomplish the bromohydroxylation enantioselectively. Chiral bromohydrins,

which serve as useful synthetic intermediates, were produced in moderate to excellent enantioselectivity via a two-step reaction sequence. The secondary anchoring effect of a hydroxyl-substituent has also been realized in a few asymmetric halogenation strategies during the total synthesis of complex natural products. This includes Snyder’s enantioselective total synthesis of (−)-napyradiomycin A1 relying on an enantioselective chlorination as the key step.52 2.3. Asymmetric Cyclopropanation of Hydroxy Olefins

Enantioselective construction of cyclopropane rings constitutes a reaction of fundamental importance, given the abundance of the cyclopropane subunit in various natural and unnatural products possessing biological activities.53−55 Since the seminal studies by Simmons and Smith, numerous research groups have documented the use of various Zn-based and other complementary reagents for the cyclopropanation of olefins. These cyclopropanation reactions may proceed in the presence or absence of a directing group in a diastereoselective or enantioselective fashion or both. Charette,56 Walsh,57 and Jubault58 have independently reviewed developments of various cyclopropanation reactions, up to 2012. In this review we will highlight the advancement of hydroxy-controlled cyclopropanation reactions of allylic alcohols and allylic ethers since 2012. After the pioneering discovery of chiral dioxaborolane promoted enantioselective cyclopropanation of allylic alcohols in 1994,59 Charette and his co-workers have employed this 3405


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system to synthesize various diversely substituted cyclopropyl alcohols. However, the direct asymmetric halocyclopropanation of allylic alcohols remained elusive until the authors published preliminary results of the first enantioselective Simmons−Smith iodocyclopropanation reaction in 2009.60 Subsequently, in 2012, the same group reported a detailed study on the iodocyclopropanation, and expanded the reaction scope to chlorocyclopropanation.61 The reactions rely on the use of halo-substituted zinc carbenoid, generated in situ from a halogen source and Et2Zn, and dioxaborolane for the enantio- and diastereoselective preparation of halocyclopropyl alcohols. In the case of iodocyclopropanation, the reaction proceeds via the formation of a zinc carbenoid EtZnCHI2 by mixing Et2Zn and CHI3 in 1:2 ratio. A chiral dioxaborolane ligand 120 binds with the allylic alcohol 121 to form an ate complex 123, thus providing asymmetric induction at the cyclopropanation step with EtZnCHI2. An array of enantioenriched iodocyclopropyl alcohols was obtained under the optimized reaction conditions (Scheme 44).

Scheme 45. Synthesis of Functionalized 1,2,3-Substituted Cyclopropanes

Scheme 44. Asymmetric Iodocyclopropanation of Allylic Alcohols

Scheme 46. Asymmetric Chlorocyclopropanation of Allylic Alcohols

Whereas numerous Simmons−Smith type monohalocyclopropanation reactions had been reported, scant progress toward accomplishing an asymmetric monofluorocyclopropanation reaction had appeared in the literature.56 This is due to the lack of a suitable fluorocyclopropanating agent. Based on the previous findings on Simmons−Smith monohalocyclopropanation reactions it was evident that a halogen scrambling takes place in the dihalomethylzinc halide species during the course of the reaction.61 Thus, Charette et al. reasoned that they might prepare the active fluoromethyl zinc carbenoid species in situ starting from ethylzinc iodide and ICHF2.62 In fact the presence of FZnFCHI (128) was confirmed by the formation of bromofluoroiodomethane upon quenching IZnCHF2 (128) with Br2 (Scheme 47). The fluorocyclopropanation reaction with in situ generated zinc carbenoid species 128 exhibited practically useful yield, good to high diastereoselectivities, and excellent enantioselectivities for a range of allylic alcohols with a diverse substitution pattern, including trans-3-aryl/alkyl allylic alcohols, trisubstituted allylic alcohols, and cis-cinnamyl alcohol (Scheme 48).

In order to access highly enantioenriched 1,2,3-trisubstituted cyclopropanes, the unprotected or the O-benzyl-protected iodocyclopropanation products were subjected to either a lithium−halogen exchange reaction and a subsequent addition of a variety of electrophiles or a Negishi cross-coupling with a variety of aryl iodides (Scheme 45). During the chlorocyclopropanation of allylic alcohol, the required zinc carbenoid was prepared in situ from Et2Zn and ClCHI2 at −40 to −78 °C. Interestingly, control experiments revealed that the chloro-substituted zinc carbenoid is more reactive than the corresponding iodo-substituted analogue. Thus, 3-aryl- or alkyl-substituted allylic alcohols underwent chlorocyclopropanation in synthetically useful yields and enantioselectivities (Scheme 46).

Scheme 47. Preparation of Fluorohalomethylzinc Reagents

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Scheme 48. Asymmetric Fluorocyclopropanation of Allylic Alcohols

Scheme 50. Asymmetric Bromocyclopropanation of Allylic Alcohols

Charette and co-workers successively applied their fluorocyclopropanation strategy toward the diastereoselective synthesis of cyclopropyl alcohols starting from secondary allylic alcohols.63 The reaction provides access to chiral, nonracemic cyclopropyl alcohols with four stereocenters, by employing a chiral allylic alcohol prepared in situ using Walsh’s protocol (Scheme 49).64,65 Numerous allylic alcohols underwent the asymmetric bromocyclopropanation reaction providing the trans-diastereomer as the major product in satisfactory yields, high diastereoselectivities, and excellent enantioselectivities. Among further recent catalyst developments toward successful asymmetric cyclopropanation of allylic alcohol, Rachwalski, Kiełbasinski, and co-workers have reported that a chiral heteroorganic aziridinyl ligand 137 can be also useful in combination with Et2AlCl.67 The reaction system displayed reactivity and selectivity comparable with previously reported Albased systems.68 Good to high enantioselectivities were obtained for Simmons−Smith cyclopropanation of (E)-allylic alcohols (Scheme 51).

Scheme 49. Stereoselective Fluorocyclopropanation of Secondary Allylic Alcohols

Scheme 51. Simmons−Smith Cyclopropanation Catalyzed by Al-Aziridinyl Complex

Despite their stability as well as having the possibility of simple further functionalization of bromocyclopropane derivatives, a direct asymmetric bromocyclopropanation starting from achiral allylic alcohols was missing in the list of reported halocyclopropanation reactions. Being interested, Charette et al. initially submitted cinnamyl alcohol to zinc carbenoid-mediated Simmons−Smith type bromocyclopropanation with CHBrI2, which however resulted in a mixture of bromo- and iodocyclopropanes.61 Control experiments and careful mechanistic considerations revealed that the exclusive preparation of the actual brominated zinc carbenoid species from CHBr3 and Et2Zn is rather complicated and involves the formation of EtZnBr (Scheme 50).66 Thus, the active zinc carbenoid 135 was synthesized in situ via the formation of EtZnBr using a 1:1 ratio of Br2 and ZnEt2, and a subsequent addition of 1 equiv of CHBr3.

Another remarkable advancement in the catalyst development includes the use of a novel fluorous disulfonamide 139 as a chiral ligand (Scheme 52).69 In addition, 139 was shown to be recovered via simple solid-phase extraction using fluorous silica gel after reaction. The recovered fluorous ligand was reused without further purification or significant loss of catalytic efficiency. 2.4. Stereoselective Ring Opening of Epoxy Alcohols

Regio- and stereoselective ring opening of epoxy alcohols reliably furnishes optically active compounds that are frequently found as key intermediates in total synthesis of complex natural products.70−73 Another route to access those optically active intermediates involves the regioselective and enantiospecific ring 3407


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enantiomeric excesses were obtained, when cis-internal, β,βdisubstituted, and terminal 2,3-epoxy alcohols were employed as substrates (Scheme 54). It was found that the recovered epoxy alcohols were also obtained in high enantioselectivity after the KR process.

Scheme 52. Reusable Fluorous Ligand for Asymmetric Cyclopropanation Reaction

Scheme 54. Asymmetric Ring-Opening of 2,3-Epoxy Alcohols with Aminesa

opening of readily available enantioenriched epoxy alcohols.74 In general, the ring opening of epoxy alcohols is promoted by a metal catalyst, which simultaneously binds with the hydroxy group as well as with the epoxy oxygen of the substrate, thus allowing the incoming nucleophilic attack at the oxirane ring from the distal selective position with respect to the hydroxy group (Scheme 53). Scheme 53. Hydroxy-Controlled Ring Opening of Epoxides

a

Yields are based on the respective amines.

In order to achieve highly enantioenriched ring-opening products from epoxy alcohols, two routes can be considered81 (Scheme 55): (1) enantioselective epoxidation followed by

Since the landmark discoveries of a Ti-mediated regioselective ring opening of 2,3-epoxy alcohols as early as the 1980s by Sharpless and Caron75 and the kinetic resolution of mesoepoxides through enantioselective ring-opening reactions by Nugent76 and Jacobsen,77,78 regio- and enantioselective ring opening of epoxides using various nucleophiles has been intensively studied. However, prior to Yamamoto’s research work, a catalytic variant of hydroxy-directed highly regio- and enantioselective ring opening of the oxirane ring of an epoxy alcohol remained elusive. In 2014, Yamamoto et al. developed the first regioselective and stereospecific C3-selective ring opening of 2,3-epoxy alcohols with various amine nucleophiles. The reaction was accomplished by means of an achiral tungsten catalyst providing an important class of 3-amino-1,2-diols.79 To achieve the enantioselective variant of this reaction, a kinetic resolution of racemic 2,3-epoxy alcohols was developed through the oxirane ring opening with various primary and secondary amines.80 It turned out that W(OEt)6 in the presence of BHA-ligand 48 efficiently promotes the desired transformation. A ratio of 1:2.3 for the two reactants, amine and 2,3-epoxyalcohol, was shown to give the best result in the kinetic resolution. Furthermore, H2O2 was proven to be the key additive to attain excellent enantioselectivity, as it forms a Wperoxo complex, which has higher solubility in THF and mediates the ring-opening reaction with better facial selectivity.74 In the case of trans-2,3-epoxy alcohols, the reactions proceeded with complete regioselectivity in favor of the formation of the C3 regioisomers and with high enantioselectivities. However, lower

Scheme 55. Synthetic Routes to Enantioenriched and Enantiopure Amino Alcohols

regioselective and enantiospecific ring-opening and (2) simple epoxidation followed by kinetic resolution of racemic epoxides. However, both methods failed to produce virtually enantiopure compounds. As a possible solution to this challenge, Yamamoto and co-workers74 envisioned that an integrated route consisting of enantioselective epoxidation and kinetic resolution of the 3408


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resulting enantioenriched epoxides would furnish the products in nearly enantiopure form. Subsequently, based on their previous finding that the identical W/BHA-system catalyzes the AE of allylic alcohols, Yamamoto et al.80 aimed at combining the AE and the kinetic resolution of the resultant epoxides via ring-opening reaction in a one-pot fashion. Interestingly, to prepare enantiopure compounds, opposite enantiomers of the chiral BHA-ligands were found to be effective for the W-catalyzed AE and the W-catalyzed enantioselective ring-opening reactions. Nonetheless, this combined protocol constitutes a new entry to otherwise inaccessible virtually enantiopure building blocks (up to >99.8% ee) (Scheme 56).

Scheme 58. Synthesis of Enantiopure Amino Alcohols via a Two-fold Kinetic Resolution Strategya

Scheme 56. Synthesis of Enantiopure Amino Alcohols via Combined Asymmetric Routea

a

Yields are calculated over two steps.

processes in conjunction with the W-catalyzed aminolysis were investigated, and Sharpless epoxidation conditions turned out to provide the best results in most cases. The regio- and enantioselective ring opening of 3,4-epoxy alcohols is much more challenging compared to that of 2,3-epoxy alcohols.83 This is attributed to the fact that a relatively remotely located OH-directing group facilitates the control of the site preference of the nucleophilic attack. Nevertheless, a direct C4selective aminolysis of 3,4-epoxy alcohols in enantioselective fashion would provide easy access to optically active γ-hydroxy δamino alcohols that display certain pharmaceutical activities. Recently, Yamamoto’s research group has developed the first C4selective epoxide ring opening of 3,4-epoxy alcohols with diverse amine nucleophiles by means of a Ni catalyst.84 The reaction was found to proceed stereospecifically; for example, the epoxide ring opened product of enantioenriched trans-3,4-epoxy hexane-1-ol (98% ee) was formed with identical enantioselectivity (98% ee) as that of its epoxide precursor (Scheme 59).

a

Yields are calculated over two steps. b(S,S)-48 was used for the AE, while (R,R)-48 for the KR.

To demonstrate the synthetic utility of this method, three biologically active compounds were prepared in virtually enantiopure form via further derivatization of the ring-opening products (Scheme 57). In addition, a combination of two kinetic resolutions comprising an enantioselective epoxidation of secondary allylic alcohols and a subsequent enantioselective aminolysis delivered access to virtually enantiopure 3-amino-1,2-diols 159 bearing three consecutive stereocenters (Scheme 58).82 A variety of AE

Scheme 59. Stereospecific C4-Selective Ring Opening of 3,4Epoxy Alcohols

Scheme 57. Synthesis of Optically Pure Biologically Relevant Compounds

However, the epoxidation of homoallylic alcohols generally employs tailored ligands that require onerous and multistep preparation methods.11 Thus, a kinetic resolution of racemic 3,4epoxy alcohols utilizing a simple ligand system is highly desirable. In order to address this challenge Yamamoto et al. discovered that among a large number of privileged ligands a mono-Nalkylated 2,2′-bis(diphenylphosphinoamino)-1,1′-binaphthyl (BINAM) ligand in the presence of Ni(ClO4)2·6H2O enables the kinetic resolution of 3,4-epoxy alcohols through enantioselective ring opening by various amine derivatives.84 Gratifyingly, the kinetic resolution of aromatic epoxy alcohols with aniline derivatives proceeded with high enantioselectivities (Scheme 3409


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60). It is noteworthy that the epoxy tertiary alcohols, which are difficult to access in enantiopure form via AE, also served as a

Scheme 62. Enantioselective Epoxide Ring of Allylic Alcohols with Phenols

Scheme 60. Enantioselective Aminolysis of 3,4-Epoxy Alcoholsa

Yields are based on amines. bAt 55 °C using 20 mol % Ni(ClO4)2· 6H2O and 22 mol % (S)-53. a

suitable substrate class in this KR process. However, aliphatic epoxides, when serving as precursors, provided diminished enantioselectivities. Furthermore, a combined asymmetric route consisting of a Wcatalyzed asymmetric epoxidation34 and a subsequent Nicatalyzed enantioselective oxirane ring opening (kinetic resolution)84 was performed to prepare a virtually enantiopure amino diol compound (Scheme 61).

Although systematic studies on metal catalyzed ring-opening reactions of epoxy alcohols successfully implement the possibility of synthesizing various enantioenriched and enantiopure compounds, the reactions have been shown to be applicable only to amine and a few phenol nucleophiles. Thus, the scopes of S-, F-, and P-based nucleophiles are yet to be developed in the future.

Scheme 61. Synthesis of a Virtually Enantiopure Compound from 3,4-Epoxy Alcohol

2.5. Asymmetric Direct Aldol and Mannich Reactions

Hydroxy-directed asymmetric aldol87,88 and Mannich89 reactions have appeared as an essential tool for the synthesis of optically active syn- or anti-1,2-diol and 1,2-amino alcohol compounds, respectively. Numerous research groups have reported their extensive studies on the catalytic enantioselective approaches for hydroxy-directed aldol and Mannich reactions. The presence of a hydroxy group in the α-position with respect to the carbonyl group in the substrate can dictate the outcome of the reaction by producing up to two new stereogenic centers in the chiral product.90,91 Alternatively, the hydroxy group of the substrate may simply bind with the chiral catalyst to facilitate the enantioselective C−C bond forming step. In 2001, Trost and co-workers developed a direct asymmetric aldol reaction involving α-hydroxyketones and aldehydes by means of a bimetallic zinc catalyst.92,93 A proline-based chiral azacrown ligand, ProPhenol 174, in the presence of 2 equiv of diethyl zinc forms the binuclear metal catalyst via direct deprotonation of the three hydroxy groups. The formation of the binuclear zinc complex 175 was identified by gas titration experiments and ESI-MS analyses.92 A diverse range of αhydroxy aromatic ketones underwent aldol reaction with aliphatic aldehydes to give the corresponding syn-diol products in excellent enantioselectivities (Scheme 63). Mechanistically, the enolate of the hydroxyketone was believed to act as a bidentate ligand to bridge the two zinc centers of the catalyst.

Unlike the KR of epoxy alcohols through ring opening by amines, the same transformation by phenols or alcohols, is much less studied. Aral and Karakaplan developed an epoxide ring opening strategy for 2,3-epoxy alcohols using phenol as nucleophile.85 A chiral β-amino alcohol-based organocatalyst enables the desired epoxide ring opening with phenols in moderate to high yields and enantioselectivities (Scheme 62). By examining various β-amino primary and secondary alcohols as the organocatalyst, pyridine derived secondary C2-symmetric βamino alcohols were found to exhibit better reactivities and stereoselectivities.86 However, the reaction was applied to a limited number of substrates. 3410


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Scheme 63. Aldol Reaction with α-Hydroxyketone Donors Catalyzed by Bimetallic Zinc Complex

Scheme 64. Aldol Reaction en Route to the Stereoselective Synthesis of (+)-Boronolide

Scheme 65. Identification of the Suitable Ester Equivalent Donor for the Aldol Reaction

Subsequently, the aldehyde coordinates to a zinc center of the catalyst scaffold leading to the syn-1,2-diol as the major product (Figure 8).

equiv of the aldehyde is necessary to achieve excellent enantioselectivities. Furthermore, a new ProPhenol derivative, 187, was found to provide better yield and stereoselectivity. A broad range of aliphatic and aromatic aldehydes with diverse substitution pattern were functional in this aldol reaction to afford corresponding syn-diol (Scheme 66). The synthetic utility of a resulting N-acyl product 188a was realized by converting it into an ester or amide within a single step (Scheme 67). Further, Trost applied their hydroxyacetate equivalent aldol reaction to synthesize a key intermediate with satisfactory Scheme 66. Substrate Scope of the Hydroxyacetate Equivalent Aldol Reaction

Figure 8. Proposed bidentate coordination of α-hydroxyketone donor.

Next, Trost et al. applied their bimetallic zinc catalyst toward the syn-selective aldol reaction of α-hydroxyketones during the concise stereoselective synthesis of (+)-boronolide 183, a C12 lactone with a polyhydroxylated side chain that displays certain medicinal activities (Scheme 64). 94 The synthesis was accomplished in 12 steps starting from hydroxyacetylfuran and commercially available valeraldehyde. Compared to hydroxy ketones, ester enolate equivalents have proven much less reactive as aldol donors. In 2011, Trost developed a simplified approach that employs unprotected activated ester donors to produce syn-1,2-diols in synthetically useful yields and diastereo- and enantioselectivities.95 To identify a suitable activated ester equivalent, a series of those compounds were subjected to aldol reaction with the dinuclear Zn complex of 174. The use of an N-acylpyrrole donor exhibited the optimal result in terms of both reactivity and selectivity (Scheme 65). Thorough optimization of the reaction conditions revealed that 2 3411


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Scheme 67. Conversion of the Ester Equivalent to the Ester

Scheme 69. Zn-ProPhenol-Catalyzed Asymmetric Mannich Reaction of Hydroxyketones

diastereoselectivity during the formal total synthesis of laulimalide, a 20-membered marine macrolide (Scheme 68).96 Scheme 68. Synthesis of an Intermediate in the Total Synthesis of Laulimalide

a

The enantioselective Mannich reaction using α-hydroxy ketone donors is an excellent tool for the synthesis of chiral αhydroxy-β-amino carbonyl compounds. Trost et al. disclosed a protocol for the asymmetric Mannich reaction with a range of αhydroxy acetophenones and imines.97 The reaction was accomplished in excellent yields and diastereo- and enantioselectivities using their bimetallic Zn-catalyst obtained from diethyl zinc and ProPhenol ligand. An increased level of diastereo- and enantioselectivity was achieved when the reaction was carried out with bulky ProPhenol ligands 195 and 196. The reaction showed broad synthetic applicability toward various α-hydroxy acetophenones and aldimines (Scheme 69). In addition an imine aldol adduct, 198b, was successfully converted into an α-hydroxy-βamino acid derivative 199 (Scheme 70). Subsequently, Trost and co-workers demonstrated that the Zn-ProPhenol system also enables the Mannich reaction of hydroxyketones with more challenging enolizable aliphatic imines bearing labile N-protecting groups, such as diphenylphosphinoyl (DPP) and Boc.98 Gratifyingly, the Mannich reaction of bulky DPP-protected imine proceeded with the selective formation of the anti-1,2-amino alcohol (Scheme 71), while that of the Boc-protected imine led to the preferential formation of the corresponding syn-diastereomer (Scheme 72). In both cases, the absolute configuration at the α-position is identical, whereas the stereoselectivity differs at the β-position of the amino alcohol derivatives. Concurrently with Trost, Shibasaki and co-workers independently developed an aldol reaction of 2-hydroxyacetophenone with various aldehydes by means of two different kinds of chiral bimetallic catalysts. Interestingly, in the presence of a La−Libased heterobimetallic catalyst, originally developed for the direct aldol reaction of simple ketones and aldehydes,99,100 the aldol reaction provided anti-1,2-diols as the predominating diastereomers, whereas in the presence of a Zn−Zn linked chiral catalyst the reaction led to syn-1,2-diol products as the major diastereomer (Scheme 73).101 Albeit in most cases moderate diastereoselectivities were achieved, the observed stereoselectiv-

(2.5 mol % ligand +5 mol % Et2Zn) was added.

Scheme 70. Synthesis of α-Hydroxy-β-Amino Acid Derivative

Scheme 71. anti-Selective Mannich Reaction with DPPProtected Imines

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Scheme 72. syn-Selective Mannich Reaction with BocProtected Imines

Scheme 74. Aldol Reaction with 2-Hydroxy-2′methoxypropiophenone Donor

Scheme 73. anti- and syn-Selective Asymmetric Aldol Reaction Catalyzed by Shibasaki’s Bimetallic Catalysts

a

Yields and ee were determined after conversion to the corresponding acetonide derivatives. bee of free diol. Figure 9. Stereochemical interaction of the aldol reaction with 2hydroxy-2′-methoxypropiophenone.

ities can be attributed to the formation of a chelate complex between catalyst 204 or 205 and the enolate of hydroxyacetophenone, thereby shielding the si-face of the enolate from the attack of aldehydes. Hence anti- and syn-products were formed with an identical configuration at the α-position. An improved level of diastereo- as well as enantioselectivity in the Zn-catalyzed syn-selective aldol reaction was obtained by changing the aldol donor with 2-hydroxy-2′-methoxypropiophenone (Scheme 74).102 Mechanistic investigations reveal that the treatment of O-linked 1,1′-bi-2-naphthol (BINOL) 213 with Et2Zn in 2:1 ratio produces a trinuclear Zn complex 208 as a precatalyst. The Zn-complex facilitates the formation of Znenolate from 2-hydroxy-2′-methoxypropiophenone leading to the syn-adduct favorably as depicted in Figure 9. The positive effects of the ortho-methoxy-group on the observed stereoselectivity is presumably due to the coordination to one of the Zn

centers in the oligomeric complex. Enhanced syn-selectivity is justified by the steric interference of the aromatic ring in the enolate against aldehydes (Figure 9). Systematic mechanistic investigations, led to a modified catalyst system comprised of a ratio of Et2Zn to (S,S)-linkedBINOL 213 = 4:1 in combination with 3 Å molecular sieves. The modified system exhibited excellent performance even at very low catalyst loading. Thus, 0.1 mol % of (S,S)-linked-BINOL 213 and 0.4 mol % of Et2Zn promoted the direct aldol reaction efficiently, using only 1.1 equiv of the donor (substrate/ligand = 1000). Moreover, the new 4:1-system enables the direct catalytic asymmetric aldol reaction of 2-hydroxy-2′-methoxypropiophenone, with the formation of a chiral all-carbon-quaternary center 3413


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(tert-alcohol) in satisfactory yield (up to 97%) and ee (up to 97%); however low syn-selectivity was observed (Scheme 75).

Scheme 77. Transformation of Mannich Adduct

Scheme 75. Formation of All-Carbon-Quaternary Center in the Aldol Reaction

The anti-selectivity of the Mannich reaction was attributed to the sterically bulky Dpp group on the imine nitrogen. To minimize the steric interaction, the Mannich-type reaction occurs through the transition state as illustrated in Figure 10.

Figure 10. Proposed TS model for the Mannich-type reaction.

In 1997, Kobayashi et al. first presented a new concept for the catalytic enantioselective Mannich-type reaction of an aldimine and ketene silyl acetal, based on a hydroxy-governed bidentate chelation of an aldimine to a chiral Lewis acid catalyst.104 The aldimine was prepared from an aldehyde and 2-amino phenol. The reaction was accomplished by means of a chiral Zr(IV) catalyst. The required catalyst 220 was prepared in situ by mixing a 1:2 ratio of Zr(OtBu)4 and 5,5′-dibromo-BINOL. In this reaction, the hydroxyaldimine is proposed to bind with the Zr catalyst in a bidentate fashion. Subsequent silylenolate attack to the aldimine generates the trimethylsilylated adduct, which upon acidic workup furnishes the desired product (Figure 11). The presence of N-methyl imidazole (NMI) in catalytic amount was necessary as an additive to improve the enantioselectivity of the reaction. Good to high levels of ee’s were achieved for an array of

Shibasaki et al. further applied the 4:1 Zn/(S,S)-linked BINOL 213 system for a catalytic asymmetric Mannich-type reaction of 2-hydroxy-2′-methoxypropiophenone (Scheme 76).103 It was Scheme 76. anti-Selective Mannich-Type Reaction of 2Hydroxy-2′-methoxypropiophenone

found that a bulky, removable N-protecting group, for example, N-diphenylphosphinoyl (Dpp), at the imine nitrogen facilitates the reaction to give exclusively anti-amino alcohol products in outstanding diastereo- and enantioselectivities (up to >98:2 dr, up to >99.5% ee). The reaction proceeds successfully even with 0.25 to 1 mol % catalyst loading. Relying on the facile deprotection of the N-Dpp group, the Mannich adduct was converted to a synthetically useful cyclic carbamate without further epimerization (Scheme 77).

Figure 11. Proposed reaction cycle for the hydoxy-directed Mannich reaction. 3414


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Scheme 80. Zr-Catalyzed syn- and anti-Selective Mannich Reaction

aldimines and silyl ketene acetals (Scheme 78). The N-protecting group could be removed simply from the Mannich adduct (Scheme 79). Scheme 78. Zr(IV)-Catalyzed Mannich-Type Reaction

Scheme 79. Removal of the N-Protecting Group from the Mannich Adduct

Table 2. Effect of Electron-Withdrawing BINOL-Ligands on the Zr-Catalyzed Mannich Reaction The Zr-based catalyst system was further exploited to obtain both syn- and anti-β-amino alcohols in high yields and diastereoand enantioselectivities.105 It appeared that both syn- and anti-βamino alcohols were obtained in high selectivities by simply choosing the protective groups of the R-alkoxy parts and of the R2 (ester) part of the enolates, accompanied by formation of new carbon−carbon bonds. The tert-butyldimethylsilyl (TBS)protecting group as the α-O-substituent of ketene silyl acetals in toluene delivers the syn-Mannich adduct in excellent diastereoselectivities, whereas R-benzyloxy-ketene silyl acetals in DCM produce the anti-Mannich adduct predominantly. Interestingly, 1,2-dimethylimidazole (DMI), instead of NMI, improved the enantioselectivity of the reaction considerably (Scheme 80). Upon treatment with molecular sieves, the air and moisture sensitive Zr catalyst was further converted into a stable, storable, and reusable catalyst. The Zr catalyst with molecular sieves thus prepared was found to exhibit similar reactivity and stereoselectivity even after three months to the freshly prepared one.106,107 Subsequently, Kobayashi et al. demonstrated that the replacement of the Br substituent with a more electronwithdrawing substituent at the 6,6′-positions of BINOL derivatives increases not only the Lewis acidity of the Zr catalyst but also the stereoselectivities (Table 2).108,109 Thus, the Zr complex of 6,6′-pentafluoroethyl (C2F5)-substituted BINOL ligand 233 acts as a more effective catalyst to promote the Mannich reaction in high yields and excellent diastereo- and enantioselectivities.

entry

catalyst

temp (°C)

yield (%)

dr (syn/anti)

ee (anti)

1 2 3 4

229 229 233 233

−45 −78 −45 −78

94 52 92 96

9:91 13:87 7:93 4:96

47 66 84 95

The catalyst system was further applied to the total synthesis of a cytotoxic marine depsipeptide onchidine by a one-pot Mannich reaction starting from an aldehyde, o-aminophenol, and ketene silyl acetal (Scheme 81).110 A Hf variant of the Zr catalyst was reported to facilitate the hydroxy-directed Mannich reaction with comparable selectivity.111 Notably, an iron catalyst obtained from 3,3′-di-iodo-BINOL 237 in combination with FeCl2 promoted the Mannich reaction in moderate yields and selectivities as compared to the analogous zirconium system (Scheme 82).112 3415


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Scheme 81. Three-Component Mannich Reaction during the Synthesis of Onchidine

Scheme 83. Nb(V)-Catalyzed Mannich-type Reaction

Scheme 82. Iron-Catalyzed Mannich Reaction

Kobayashi et al. further developed a binuclear niobium(IV) catalyst, 241, from Nb(OMe)5 and 239. The Nb catalyst enables hydroxy-directed Mukaiyama−Mannich reaction between imines and a variety of silicon enolates in high yields and excellent enantioselectivities (Scheme 83).113,114 The structure of the binuclear niobium complex as determined by X-ray crystallographic analysis shows significant difference from that of the assumed structure of the complex. The basic characteristics of the complex are (1) a Nb-(μ2-O)-Nb component and (2) that BINOL is attached in a bidentate fashion to one niobium atom whereas the phenol-substituent is bonded to the other niobium atom. Consequently, in the following years several metal complexes were reported to accomplish the Mukaiyama−Mannich reaction, including a Zr−2,2′-diphenyl-(4-biphenanthrol) (VAPOL) complex described by Wulff115 and N,N′-dioxide scandium(III) triflate (2:1) complex described by Feng.116 In the latter case, the Mannich-type reaction proceeds in a three-component fashion directly starting from 2-aminophenol, an aldehyde, and ketene silyl acetal. Thus, the prior synthesis of the aldimine was avoided (Scheme 84). The hydroxy-directed Mannich reactions were reported not only with chiral Lewis acid catalysts but also with chiral Brønsted acid catalysts. In 2004, Akiyama first developed a sterically hindered chiral phosphoric acid-catalyzed Mannich reaction of hydroxy-aldimine and ketene silyl acetal.117 3,3′-(4-Nitrophenyl)-BINOL-derived phosphoric acid 246 furnished the best results. A variety of aldimines prepared from 2-aminophenol and aromatic aldehydes provided the syn-selective Mannich adducts in excellent diastereo- and enantioselectivities (Scheme 85). The reaction proceeds via the formation of an iminium salt, generated from the aldimine and the phosphoric acid. It was proposed that bulky 3,3′-diaryl groups, being non-coplanar with

Scheme 84. Sc-Catalyzed Three-Component Mannich-Type Reaction

the naphthyl groups effectively shielded the phosphate moiety to give an efficient asymmetric induction (Figure 12). Moreover, the Mannich reaction could be performed efficiently in gram scale with identical enantioselectivity.118,119 The N-protecting group can be removed readily to deliver free amino acid ester in 47% yield (Scheme 86).118 Akiyama further developed several other Brønsted acid catalysts for the hydroxy-assisted Mukaiyama−Mannich reaction (Figure 13).120,121 However, moderate to good stereoselectivities were obtained in these cases. In search of a more efficient and general Brønsted acid catalyst for asymmetric Mukaiyama−Mannich reaction, Zhou and Yanamoto recently developed a new BINOL-derived phosphoric acid catalyst.122 Owing to the beneficial effect of nitro substituents on Brønsted acid catalysts, various nitro-containing phosphoric acid catalysts were screened for the Mukaiyama− Mannich reaction.117 The authors predicted replacing the hydrogen atom in the para-position of the 3,5-dinitrophenyl 3416


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Scheme 85. Chiral Phosphoric Acid-Catalyzed Mannich Reaction

Figure 13. Different chiral phosphoric acid catalysts employed by Akiyama in Mukaiyama−Mannich reaction.

Scheme 87. Identification of More Efficient Brønsted Acid Catalysts

Figure 12. Proposed reaction pathway.

Scheme 86. Gram-Scale Synthesis of β-Amino Acid Ester

Figure 14. TS for the Mukaiyama−Mannich Reaction Catalyzed by Stronger Brønsted Acids.

triflyl phosphoramide group, free rotation of the triflyl group hinders the formation of the cyclic transition state. Thus, diminished enantioselectivity was obtained in the latter case. An array of hydroxy-aldimines derived from aromatic, heterocyclic, and aliphatic aldehydes afforded the corresponding Mannich adduct in satisfactory yields and excellent enantioselectivities (92 to >99% ee) (Scheme 88). Next, monosubstituted ketene silyl acetals were subjected to the Mukaiyama−Mannich reaction, leading to the corresponding adducts in high yields with excellent diastereo- and enantioselectivities (Scheme 89). Employing more challenging ketene silyl acetal substrates, bearing two different substituents on the vinyl carbon, further expanded the scope of the reaction. The latter reaction type allows for the simultaneous construction of vicinal tertiary and quaternary stereogenic centers in the product (Scheme 90). The relative and absolute configurations of the

ring with an alkyl group would force the nitro group out of the plane of the phenyl ring bringing the oxygen atoms of the nitro groups closer to the sphere of the phosphoric acids, leading to improved asymmetric induction. In fact, in the presence of 2,4,6trimethyl-3,5-dinitrophenyl substituents at the 3,3′-position of BINOL-derived phosphoric acid the desired reaction furnished the adduct in high yield with outstanding stereoselectivity (98%, >99% ee) (Scheme 87). The reaction has been considered to proceed via a dualactivation pathway through the formation of a cyclic transition state between the phosphoric acid and the hydroxy-aldimine (Figure 14). However, in the case of more acidic and larger N3417


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(PCCP) as the Brønsted acid core. The conjugate base of PCCP is further stabilized by σ-delocalization through electronegative ester groups and π-delocalization by conjugated functionality (Figure 15). The chiral derivative was obtained by

Scheme 88. Scope of the Asymmetric Mukaiyama−Mannich Reaction

Figure 15. Design of a new carbon acid for catalysis.

converting into the penta-ester of naturally occurring (−)-menthol. The required catalyst 259 was synthesized in two steps using commercially available inexpensive starting materials (Scheme 91).

Scheme 89. Scope of the Stereoselective Mukaiyama− Mannich Reaction

Scheme 91. Synthesis of Menthol-Derived PCCP Catalyst

a

At −40 °C for 48 h.

Scheme 90. Construction of Vicinal Tertiary and Quaternary Centers Catalyst 259 efficiently promotes the Mukaiyama−Mannich reaction of hydroxy-aldimine and ketene silyl acetal in synthetically useful yield and satisfactory enantioselectivity (Scheme 92A). Furthermore, the potential of the chiral PCCP catalyst was investigated via the enantioselective addition of ketene silyl acetal Scheme 92. Substrate Scope for the Mannich Reaction (A) and Oxocarbenium Aldol Reaction (B)

a

At −78 °C for 48 h.

major isomer of compounds as illustrated in Scheme 90 were determined as (2R, 3S) by analogy to the X-ray crystallographic analysis of 257a. Very recently, Lambert and co-workers introduced an entirely new concept in Brønsted acid catalysis.123 They envisioned that cyclopentadiene functionalized with electron-withdrawing groups would serve as a strong Brønsted acid, given the high stability of the conjugate base of cyclopentadiene relying on the aromatic nature of the cyclopentadienyl anion.124,125 Thus, they decided to employ 1,2,3,4,5-pentacarboxycyclopentadiene 3418


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to a notoriously difficult system including oxocarbenium ions. Thus, a hydroxy-controlled enantioselective addition to oxocarbenium ions generated in situ from the dimethyl acetal of salicylaldehyde, namely, oxocarbenium aldol reaction, proceeded smoothly with high yield and enantioselectivity (Scheme 92B). A stereochemical justification for this chemistry has been depicted in Figure 16A. For the Mannich reaction, the possible

Scheme 93. ADA Reaction via LACASA-DA Mechanism

Figure 16. Stereochemical rationale for the Mannich reaction (A) and oxocarbenium aldol reaction (B) catalyzed by 259.

TS involves interplay between the protonated imine and one of the carbonyl oxygens of the catalyst via two hydrogen bonds. This interaction requires substantial torquing of the carboxyl substituent, thereby holding the iminium in the vicinity of the neighboring carboxymenthyl substituent. Blocking of the re-face of the iminium then explains the observed stereochemistry. A similar model was proposed for the oxocarbenium addition; albeit in this case only one hydrogen bonding substituent is present (Figure 16B). In this case, π-facial blocking led to reaction via the si-face giving the observed stereoselectivity for the R-enantiomer.

was also equally active, although the catalyst turn over was very poor. However, combination of other metal sources and chiral catalysts provided inferior results (Table 3). Table 3. Optimization of LACASA-DA Reaction of Conjugated Allylic Alcohol and Methyl Acrylate no. LA1 (equiv) 1 2 3 4 5 6

2.6. Asymmetric Diels−Alder Reaction

The asymmetric Diels−Alder (ADA) reaction generates two new σ-bonds and up to four new stereogenic centers within a single reaction step during the construction of optically active functionalized cyclohexene rings.126,127 Since the 1980s, developments and applications of various ADA reactions have become ubiquitous to prepare numerous chiral cyclohexane derivatives that serve as key intermediates of complex natural products. Nevertheless, the stereocontrol by a substrate’s hydroxy group during the construction of a cyclohexene ring has not been developed drastically. In 2005, Ward and Souweha disclosed the first highly enantioselective DA reaction between a conjugated allylic alcohol (diene) and an acrylate (dienophile) by means of a heterobimetallic Lewis acid catalyst of Zn(II) and Mg(II) with BINOL.128 The new strategy to control the ADA reaction involves a Lewis acid-catalyzed reaction of a “self-assembled” complex (LACASA-DA). In this approach, enhanced reactivity as well as regio-, and stereoselectivity were accomplished by simultaneous activation of the hydroxy-bearing diene and the dienophile substrates to the chiral Lewis acid template (265). After careful screening of various Lewis acid sources and chiral ligands, it turned out that a combination of Zn(II) and Mg(II) species with optically active BINOL constitutes a heterobimetallic system that led to the best result in terms of both reactivity and enantioselectivity. As demonstrated, in a typical procedure, the conjugated allylic alcohol (diene) was treated with an equimolar quantity of Me2Zn (LA1) and BINOL was treated with an equimolar quantity of MeMgBr (LA2) separately. Subsequently, the two mixtures were combined and the acrylate was added (Scheme 93). The catalytic variant of the bimetallic system

Me3Al (1) Me3Al (1) Me2Zn (1) Me2Zn (1) Me2Zn (1) Me2Zn (0.3)

LA2 (equiv) Et2AlCl (1) MeMgBr (1) Et2AlCl (1) MeMgBr (1) MeMgBr (0.25)

BINOL (equiv)

time (d)

yield (%)

ee (%)

1 1 0 1 1 0.25

1 3 1 3 1 14

60 54 0 69 95 95

90 50 70 93 96

Thus, under the optimized reaction conditions, the conjugated allylic alcohol underwent the ADA reaction giving high yield and enantioselectivity. However, the conjugated homoallylic alcohol, when subjected to the ADA reaction under identical conditions, provided modest yield and enantioselectivity (55%, 33% ee). Nonetheless, the performance of this substrate was improved (60%, 82% ee) in the presence of the putative mononuclear catalyst prepared from BINOL and Me3Al (1 equiv) (Scheme 94). Nicolau and co-workers applied the LACASA-DA mechanism for the construction of the oxabicyclo[2.2.2]octane core 271 during the total synthesis of abyssomicin C.129,130 The required chiral hydroxy diene was prepared from the amido diene as depicted in Scheme 95. The DA reaction between the hydroxy diene 273 and methyl acrylate in the presence of MeMgBr and an aminophenol derivative provided the bicyclic compound 275, which upon several reaction steps afforded the oxabicyclo[2.2.2]octane core 271. Further, the group of Roush took advantage of the LACASADA mechanism to obtain a primary cyclohexene intermediate during the stereoselective synthesis of the common tricyclic core of hirsutellones, a natural polyketide that displays potent antitubercular activity.131 In fact, the synthesis of the common hirsutellone intermediate 276 began with the enantioselective 3419


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a siloxacyclopentene-constrained dienophile, which upon intramolecular DA reaction afforded 276. Jin et al. demonstrated the use of Ward’s LACASA-DA mechanism during the total synthesis of a simplified analogue of the marine macrolide, superstolide A.132 In this case, the starting lactone was prepared enantioselectively in 73% yield and 95% ee via Ward’s DA reaction (Scheme 97).

Scheme 94. ADA Reactions of Conjugated Allylic and Homoallylic Alcohols

Scheme 97. Application of LACASA-DA in Total Synthesis of Superstolide A

Scheme 95. Synthesis of a Fragment of Abyssomicin C

Although Ward’s hydroxy-governed LACASA-DA mechanism has found numerous applications in the total synthesis of complex natural products, it employs the chiral BINOL-derived bimetallic complex in stoichiometric quantity to achieve practical conversion.128 In 2015, Ishihara et al. first reported the catalytic variant of the protocol. The key to success was the use of bimetallic complex generated from (R)-5,5′,6,6′,7,7′,8,8′-octahydro-1,1′-bi-2-naphthol, Me2Zn, and MeMgBr in place of the BINOL-derived complex (Scheme 98).133 Thus, it was found Scheme 98. Catalytic Variant of Ward’s LACASA-DA Reaction

DA reaction of commercially available (E,E)-hexa-2,4-dien-1-ol 263 with methyl acrylate 264 in the presence of the bimetallic Zn,Mg complex of (R)-BINOL as described by Ward. The reaction produced the lactone in 95% yield with 96% ee (Scheme 96). Subsequent reaction steps allowed for the conversion of the resulting lactone to the ring opened triene aldehyde, followed by Scheme 96. Stereoselective Synthesis of the Common Tricyclic Core of Hirsutellones that 20 mol % of the bimetallic catalyst was sufficient to efficiently promote high asymmetric induction. A series of hydroxy dienes and acrylates underwent DA reaction to give the corresponding adduct in high yields and ee. Besides chiral Lewis acid-catalyzed protocols, a few organocatalyzed hydroxy-assisted ADA reactions were likewise reported. Nakatani et al. first demonstrated that a chiral base catalyst could promote the ADA reaction using 3-hydroxy 2pyrones 283 as dienes and N-methylmaleimide 284 as dienophiles.134 Preliminary investigations revealed that natural cinchona alkaloids (286a and 287b) could be used as the chiral 3420


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simple α′-aliphatic α,β-unsaturated ketones.136 Based on the fact that chiral primary and secondary amines can activate α,βunsaturated aldehydes and ketones, respectively, for enantioselective DA reactions with electron-rich dienes,137−140 they decided to use 9-NH2-cinchona alkaloid 290 as a catalyst for the ADA reaction. Indeed it was observed that 290 enables the desired reaction to afford the exo-adducts as the predominant product in high yields and amazingly high enantioselectivities (Scheme 101). In this reaction, the role of trifluoroacetic acid (TFA) as an additive was found to be crucial as its use led to excellent stereoselectivities.

base source giving the endo-product as the major diastereomer. However, modest enantioselectivity was achieved (Scheme 99). Scheme 99. Chiral Base Catalyzed ADA Reaction

Scheme 101. 9-NH2-Cinchona Catalyzed ADA Reaction

Deng et al. modified the natural cinchona alkaloids to give an efficient acid−base bifunctional catalyst for a DA reaction.135 Thus, the modified cinchona catalyst 287 can act as the hydrogen bond donor and acceptor in different spatial relationships, providing complementary diastereoselective adducts. The new catalyst allows for the ADA reaction of functionalized 3-hydroxy2-pyrones and various α,β-unsaturated carbonyl compounds in excellent yields and diastereo- and enantioselectivities. In this case exo-diastereomers were obtained as the predominant adduct (Scheme 100). Subsequently, Deng’s group discovered that amine-based, readily available cinchona catalyst 290, instead of 287, could promote a more challenging DA reaction between 2-pyrones and Scheme 100. ADA Reaction by Cinchona-Based Bifunctional Catalyst

2.7. Asymmetric Hydrogenation

The well advanced asymmetric hydrogenation of olefinic alcohols has become an indispensible tool in academia as well as in industry for the asymmetric construction of customized alcohols in virtually enantiopure form.141−147 The hydroxy substituent of alkenol substrates can act as a “classical” coordinating functional group to anchor the substrate to a metal catalyst that successively promotes the hydrogenation in enantioselective fashion. In a seminal work, Noyori et al. disclosed that a chiral Ru−2,2′-bis(diphenylphosphino)-1,1′binaphthyl (BINAP) complex efficiently allows for the hydroxyldirected asymmetric hydrogenation of allylic and homoallylic alcohols in satisfactory yields and outstanding enantioselectivities.148 Within the past three decades, numerous catalysts primarily based on Ru, Rh, and Ir complexes of various phosphine ligands have been developed for the asymmetric hydrogenation of olefinic alcohols, and 2-methyl cinnamyl alcohol appeared to be the standard substrate for the evaluation of these catalysts.149−154 In this section, we will focus on the recent progress of the asymmetric hydrogenation of olefinic alcohols that are directed by the hydroxy functionality of the substrate. 3421


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In 2014, Chen et al. developed a protocol that enables the asymmetric hydrogenation of otherwise challenging 2-substituted-alkenol substrates by means of a Rh−phosphine complex.155 It was hypothesized that a hydrogen-bonding interaction between the hydroxy substrate and the chiral catalyst would enable the asymmetric hydrogenation of 2-substituted 2alkenols in highly enantioselective manner (Scheme 104). Experimentally, the reaction gave superior results in terms of yields and enantioselectivities when carried out in polar chlorinated solvents including dichloromethane (DCM) and dichloroethane (DCE). It was suggested that in contrast to polar protic solvents (MeOH, EtOH, iPrOH) and polar aprotic solvents (THF, EtOAc), DCM and DCE do not have any Hbonding donor or receptor sites and thus do not interfere in the substrate−catalyst H-bonding interplay providing high asymmetric induction. A series of 2-substituted 2-alkenols were hydrogenated in satisfactory yields and outstanding enantioselectivities using Rh-ChenPhos complex as the catalyst and dichloromethane as the solvent (Scheme 102).

Scheme 103. Ir-Catalyzed Asymmetric Hydrogenation of 3,3Disubstituted Allylic and Homoallylic Alcohols

Scheme 102. Rh-Catalyzed Hydroxy-Directed Asymmetric Hydrogenation

a

1 mol % Ir-Catalyst was used.

Scheme 104. Possible Reaction Pathways for the Asymmetric Hydrogenation

Pflaltz et al. discovered that Ir-phosphinomethyl-oxazoline complexes constitute an effective catalyst system that promotes the direct asymmetric hydrogenation of sterically demanding 3,3′-disubstituted allylic alcohols and related homoallylic alcohols in excellent enantioselectivities.156 In contrast to the general finding that coordinating solvents cause significant loss of activity for iridium catalysts, the best outcome in this Ir-catalyzed hydrogenation was attained by carrying out the reaction in ethereal solvents, such as THF and 2-methyltetrahydrofuran. The iridium catalyst thus enables the asymmetric hydrogenation of a wide variety of 3,3-disubstituted allylic alcohols and analogous homoallylic alcohols (Scheme 103). To understand the actual reaction pathway, a 3,3′-disubstituted allylic alcohol was subjected to hydrogenation in the presence of 50 bar of D2 and it was found that deuterium enrichment took place exclusively at C2 and C3-positions with no deuterium incorporation at C1. This indicates that although there is no clear evidence for strong coordination between the hydroxyl and the Ir-center, the allylic alcohol underwent hydrogenation directly at the CC double bond and rules out the possibility of a pathway consisting of asymmetric isomerization and subsequent aldehyde reduction steps (Scheme 104).157 The synthetic utility of the method was demonstrated via the concise synthesis of a highly enantioenriched intermediate 297 that can be further converted to several bisabolane sesquiterpenes (Scheme 105). It has been established by Stork and co-workers that alkenes bearing Lewis basic substituents such as hydroxyl group can

Scheme 105. Utilization of a Hydrogenation Product

coordinate to Crabtree’s iridium catalyst [(PCy3)(Py)Ir(cod)]PF6 to facilitate the highly diastereoselective hydrogenation of both allylic and homoallylic alcohols.158 However, no clear evidence for this type of coordination was reported if the monodentate phosphine (PCy) and pyridine (Py) ligands had been replaced by a bidentate chiral N,P-ligand. Recently, Burgess and co-workers have demonstrated by a computational study 3422


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the reaction was further extended toward the synthesis of chiral geminal halofluoro compounds (Scheme 107).

that a 2-substituted allylic alcohol did not coordinate to Ir catalyst during the hydrogenation.159 In addition, recent investigations by Pfaltz indicated no clear evidence for strong coordination between the hydroxyl group and the Ir catalyst.156,160 Thus, the vast majority of Ru-, Rh-, and Ir-catalyst-based hydrogenations of olefinic alcohols proceed via simple coordination of the alkene to the metal center.161,162 As a consequence, these examples are not categorized as substrate-controlled reactions and are beyond the scope of this review.

Scheme 107. Synthesis of Geminal Fluorohalo Compounds

3. AMIDE-DIRECTED ASYMMETRIC REACTIONS Amides are versatile functional groups in organic synthesis.163−165 Since amides are composed of an electronwithdrawing carbonyl group as well as an electron-rich NR2substituent, they are anticipated to behave as bifunctional directing groups in substrate controlled reactions. In contrast to amines, the electron-donating nature of the NR2-function in amide is somewhat hindered as the lone pair of electrons on nitrogen is delocalized to the adjacent carbonyl group.166 Nevertheless, amides can coordinate to metal catalysts or organocatalysts that enable numerous catalytic asymmetric processes in unexpectedly high yields and stereoselectivities.

The authors speculated that due to the bifunctional nature of BINOL-derived phosphoric acid catalysts, the chiral phosphate anion generates an ion pair with the Selectfluor reagent through one of its oxygen atoms, while concurrently triggering the enamide activation through hydrogen bonding with the second. The proposed transition state model as depicted in Figure 17 clearly explains the observed stereoselectivity.

3.1. Asymmetric Fluorination

The asymmetric synthesis of fluorinated molecules is a fascinating theme of organofluorine chemistry, given their increasing use in pharmaceuticals and medicines.167 In the substrate-controlled approach, the substrate’s directing group, in the presence of either an electrophilic or a nucleophilic fluorinating agent, governs the fluorination of an organic compound. Thus, various directing groups have been explored. However, examples of amide-directed asymmetric fluorination methods are rather limited. Toste and co-workers described the only example of an enantioselective fluorination of enamides using Selectfluor as the electrophilic fluorinating reagent by means of a BINOL-derived phosphate as a chiral anionic phase-transfer catalyst.168 The reaction provided a wide variety of stable and synthetically useful α-(fluoro)benzoylimines as the product in high enantioselectivity (Scheme 106). It was found that an N-benzoyl group was necessary to achieve excellent enantioselectivity. The scope of

Figure 17. Preferred stereochemical model for the fluorination.

3.2. Asymmetric C−H Functionalization

Selective installation of a functional group onto a substrate via C−H bond activation provides the most straightforward and step economic access to a more complicated target molecule.169,170 The field of C−H functionalization has witnessed enormous growth within the last two decades, although it still remains as a central challenge in catalysis. Notably, stereoselective functionalization of alkyl C(sp3)−H bonds represents both a fundamental and a practical challenge to chemists due to (1) notoriously inert nature of C(sp3)−H bonds, (2) selective activation and functionalization of a particular C(sp3)−H bond in the presence of other similar C−H bonds, and (3) lack of suitable directing groups and catalysts.171 Typically, the regio- and stereoselectivity of a C−H functionalization process is controlled by the substrate’s directing group that coordinates with metal catalysts effectively. Amides, being coordinating directing groups, can facilitate many C−H functionalization processes in high yields and satisfactory stereoselectivities. In the current section of this review we will primarily focus on the amide-directed enantioselective C(sp3)−H functionalization processes. In 2011, Yu et al. first reported the amide directed enantioselective C−H functionalization of a cyclopropane ring.172 Inspired by their previous studies, they installed an electron deficient N-arylamide functional group onto the cyclopropyl ring as a weakly coordinating directing group.173 Initial investigation revealed that a Pd-based catalyst system allows for the arylation or alkylation of the cyclopropane ring with aryl or alkyl boronic acid pinacol ester, respectively, leading

Scheme 106. Amide-Directed Enantioselective Fluorination

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properties of the ligand might improve the product stereoselectivity. Relying on the beneficial effect of an O-methylhydroxamic acid group on facilitating Pd(II)-catalyzed C−H bond activation reactions,175−180 the authors decided to introduce this moiety with more Lewis basic character to replace the anionic carboxylate part of the MPAA ligand. Thus, after a heavy ligandscreening by varying different N-protecting groups and amino acid side chain substituents, a chiral mono-N-protected α-aminoO-methylhydroxamic acid (MPAHA) ligand 306 was found to give the best result. A wide range of cyclobutane carboxamides were functionalized at the α-position using the new strategy in good yields and high enantioselectivities (Scheme 110).

to a mixture of mono and bis arylated or alkylated cyclopropanes in good yield (Scheme 108). Scheme 108. Racemic C−H Functionalization of Cyclopropane Ring

Scheme 110. Asymmetric C−H Functionalization of Cyclobutane Amides

The asymmetric variant of this reaction was achieved by designing an optically active amino acid ligand for the Pd catalyst (Scheme 109). After screening several amino acid ligands by Scheme 109. Asymmetric C−H Functionalization of Cyclopropane Derivatives

Subsequently, the amide auxiliary had been shown to be removed at the end of the C−H functionalization process to give the corresponding carboxylic acid without loss of enantioselectivity (Scheme 111). The C−H activation strategy was further Scheme 111. Removal of the Amide Auxiliary varying several N-protecting groups and amino acid side chains, it was established that the mono-N-protected phenylalanine derivative 305 gave the best result in terms of both yields and enantioselectivities. The optimized reaction conditions allow for the asymmetric C−H borylation of an array of cyclopropanes by boronic acid pinacol esters with high levels of ee. It turned out that the addition of reagents in two subsequent batches to the cyclopropane derivative gave a consistent result compared to that in a single batch. After the successful demonstration of amide-directed asymmetric functionalization of reactive cyclopropyl C(sp3)−H bonds, Yu and co-workers become interested in functionalizing relatively inert C(sp3)−H bonds. An analogous enantioselective coupling of cyclobutanes with arylboron reagents was therefore developed by Pd catalysis.174 Preliminary investigation indicated that the mono-N-protected amino acid ligand (MPAA) 305, which furnished the best result for cyclopropanes, was no longer effective for the desired C−H functionalization reaction of cyclobutanes. The authors envisaged that altering the electronic

applied to acyclic substrates for a desymmetrization of prochiral methyl groups, albeit modest enantioselectivities were achieved (Scheme 112). Recently, Yu et al. described the enantioselective β-C(sp3)−H borylation of cycloalkane carboxylic acid derived amides by Pd(II) catalysis using acetyl-protected aminomethyl oxazoline (APAO) ligands. Selective choice of oxazoline ligands allows for the enantioselective borylation of an array of weakly coordinating cycloalkane amides, including cyclopropanes, cyclobutanes, and cyclohexanes with high levels of enantioselectivity.181 For 3424


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Scheme 112. Desymmetrization of Prochiral Methyl Groups

Figure 18. Proposed stereochemical model for the borylation of cyclobutanes.

Scheme 114. C(sp3)−H Borylation of Cyclopropane and Cyclohexane Rings

example, the Pd-catalyzed borylation of the cyclobutane ring proceeds smoothly in the presence of an (S,R)-oxazoline ligand 313 giving high yield and enantioselectivity (Scheme 113); Scheme 113. Asymmetric C(sp3)−H Borylation of Cyclobutane Amides

Having evidence for the C(sp3)−H bond activations of cyclopropyl, cyclobutyl, and cyclohexyl systems, Yu et al. developed a new class of ligand, which in combination with a Pd catalyst enables the β-C(sp3)−H activation of simple acyclic amide systems.182 This method serves as an attractive alternative to the preparation of β-functionalized carbonyl compounds via the conjugate addition of the corresponding α,β-unsaturated amide. The new ligand 324 bearing quinoline and acetylprotected amino coordinating substituents forms six-membered bis-chelating rings with palladium that significantly accelerate methylene C−H activation by controlling the stereoselectivity. Ligand screening experiments revealed that the ethyl group located at the benzylic position with respect to the quinoline ring and adjacent to the amino group is not only crucial to achieve excellent enantioselectivity, but also dictates the stereoselection of the C−H functionalization process. Gratifyingly, the new protocol was compatible with a diverse range of functional groups and efficiently promotes the asymmetric C(sp3)−H functionalization of a variety of amides with iodobenzenes in practically good yields and excellent enantioselectivities (Scheme 115). In addition, a Pd-catalyzed enantioselective β-C−H functionalization of isobutyric acid-derived substrates was developed as a resourceful technique for building synthetically valuable structures with enantioenriched α-chiral centers.183 Generally, those molecules are synthesized via enzymatic catalysis. The β-

however the yield and ee of the reaction drastically dropped when the other diastereomer (S,S) of the optimal ligand (S,R) was used. The observed stereoselectivity of the reaction is in accordance with the transition state model as depicted in Figure 18. The substituents on both stereocenters of the ligand backbone possess a synergistic effect in favoring five-membered palladacycle intermediate 316 over 317. The borylation of cyclopropane and cyclohexane derivatives was accomplished using 318 and 319 as optimal ligands with reasonably good selectivity.181 The borylated cyclohexanes were further converted to the corresponding alcohols through oxidation in high diastereo- and enantioselectivities (Scheme 114). 3425


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Scheme 115. Amide-Directed β-C(sp3)−H Functionalization of Acyclic Aliphatic Compounds

achieved for the arylation and heteroarylation of isobutyric acid amides and 2-amino isobutyric acid amide-derivatives (Scheme 116). Similar enantioselective β-C−H akenylation and alkynyScheme 116. Enantioselective β-C−H Arylation of Isobutyric Acid Amides

C−H arylation of isobutyric acid amide via desymmetrization of the isopropyl group is considerably challenging compared to a straight-chain aliphatic amide. This is because in β-methylene C−H activation of a straight-chain aliphatic amide (Figure 19A),

lation strategies using vinyl or alkynyl iodides led to remarkably high ee in the resulting C−H functionalized products (Scheme 117). Furthermore, Yu et al. discovered that a quinolone-based ligand enabled the Pd-catalyzed β-C−H fluorination of α-amino acid amides in the presence of Selectfluor as the fluorinating agent.184 Thus, an array of unnatural enantiopure fluorinated αamino acids were prepared via successive β-C(sp3)−H arylation and stereoselective fluorination reactions starting from readily available L-alanine (Scheme 118). The reaction occurs through a Pd(II)/Pd(IV) catalytic cycle providing the fluorinated compounds in excellent diastereoselectivities. In 2015, Gaunt and co-workers reported a copper catalyzed enantioselective C−H activation of allylic amide substrates that allows for the regiodivergent formation of two different types of products depending on the electronic nature of the incoming electrophiles, namely, diaryliodonium salts.185 The chiral copper(II) bisoxazoline catalyst 338 induces high enantioselectivity in an oxy-arylation step in which if the arylation takes place at the olefinic position close to the amide directing group, 1,3-oxazine rings 341 are formed; whereas β,β′-diaryl enamides 342 result when the arylation occurs at the other end of the alkene with a subsequent alkene reordering (Scheme 119). The arylation was controlled by the fine-tuning of the diaryliodonium salt, for instance, 1,3-oxazines 341 can be obtained by using electron-rich aryl(mesityl)diaryliodonium

Figure 19. Challenges in chiral differentiation.

steric differentiation takes place between a sterically demanding alkyl substituent and a methylene C−H bond, whereas the desymmetrization of an isopropyl group proceeds by the steric differentiation between the α hydrogen atom and a relatively small α-methyl substituent located at a distal position with respect to the transition metal (Figure 19B). The difficulty of desymmetrizing the gem-dimethyl groups in isobutyric acid amide substrates has been overcome by employing sterically hindered mono-N-protected aminomethyl oxazoline ligands 333 with an appropriate Pd catalyst.183 The reaction was believed to proceed through the transition state as shown in Figure 19C. Excellent enantioselectivities were 3426


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Scheme 117. Enantioselective C(sp3)−H Alkenylation and Alkynylation

Scheme 119. Cu-Catalyzed Amide-Directed Regiodivergent Enantioselective Arylation

Scheme 118. Diastereoselective Fluorination of Optically Pure Alanine Derivatives

for amines and thus can be interconverted to other functionalities after the desired transformation. 4.1. Asymmetric Epoxidation

In 2012, Yamamoto and co-workers demonstrated that a sulfonamide moiety, as a protected form of amine, could serve as an excellent directing group in catalytic enantioselective epoxidation reactions.187 The resulting chiral epoxide-bearing amine products are potentially very useful building blocks for the synthesis of enantioenriched complex molecules. Nevertheless, in contrast to hydroxy-directed AE, a catalytic approach for amine/sulfonamide-directed AE remained a long-standing challenge.11 Yamamoto et al. previously found that a Zr and Hf complex of C2-symmetric bis-hydroxamic acid ligand with stereochemically larger catalytic space can promote hydroxydirected AE of allylic and homoallylic alcohols.31 It was anticipated that these catalysts would be also effective for sulfonamide-directed AE. Indeed, the Hf(IV)-complex of the bishydroxamic acid ligand 22a enables the AE of various allylic sulfonamides with diverse substitution pattern in useful enantioselectivities. Careful optimization of the reaction conditions indicated that the electron-rich sulfonamides gave better results than the electron-deficient ones. MgO powder, as an additive, enhanced the catalytic activity (Scheme 120). It turned out from control experiments that replacing the NHgroup of allylic sulfonamide by O or CH2 does not alter the enantioselectivity of the epoxidation process remarkably (Scheme 121). This implies that the substrate anchors with the catalyst via one of its sulfonyl oxygens. This new activation mode has not been studied significantly, and it might constitute a new stage for Lewis acid catalysis.

reagents, while β,β′-diaryl enamide 342 can be prepared by using electron-deficient aryl(mesityl)diaryliodonium reagents. Jointly, this constitutes a stage for an electronically controllable regiodivergent enantioselective alkene arylation leading to synthetically versatile optically active products from a single starting material. The reaction is believed to proceed via the formation of arylcopper(III) intermediate, and the excellent enantioselectivity can be attributed to the use of PF6 as the counteranion for iodonium salts.186

4. SULFONAMIDE-DIRECTED ASYMMETRIC REACTIONS Sulfonamides can act as efficient directing groups in various metal-catalyzed reactions. Being weakly coordinating in nature, sulfonamide facilitates the metalation and subsequent demetalation steps during the course of a metal-promoted catalytic cycle. Furthermore, sulfonamides serve as a cleavable protecting group 3427


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using cumene hydroperoxide (CHP) as the terminal oxidant.188 To achieve excellent enantioselectivities, K2CO3 was proven to be optimal as an additive for this catalytic reaction. Alkenes with diverse substitution patterns were equally reactive; however an electron-withdrawing N-protecting group, compared to an electron-donating one, showed deleterious effect in the reaction outcome (Scheme 123). The reaction was successfully scaled up to multigram level with good yield and high enantioselectivity.

Scheme 120. Sulfonamide-Directed Asymmetric Epoxidation

Scheme 123. Ti-Catalyzed Asymmetric Epoxidation of NAlkenyl Sulfonamides

Scheme 121. Effect of the Sulfonyl-Based Directing Groups According to the plausible TS-model 352 for the epoxidation reaction (Figure 20), the hexacoordinated Ti-center holds the

Knowing the directing influence of the sulfonyl group, other substrates containing this functional group, for example, N-tosyl imines, were subjected to Hf−BHA catalyzed AE.187 Chiral oxaziridines were thus produced from the corresponding N-tosyl imines in very high yield and enantioselectivity (Scheme 122). This further indicates that the imine substrate binds through its sulfonyl oxygen with the Hf catalyst. Recently, He et al. have reported a catalytic enantioselective epoxidation of N-alkenyl sulfonamides. Ti(OiPr)4 in the presence of a cinchona alkaloid-derived Schiff base promoted the epoxidation in high yields with excellent enantioselectivities,

Figure 20. Proposed TS for the Ti-catalyzed epoxidation of N-alkenyl sulfonamide.

sulfonamide substrate, to which the oxygen nucleophile attacks from the re-face. The observed stereoselectivities of products were thus justified. 4.2. Stereoselective Ring Opening of Epoxy Sulfonamides

The combined route consisting of AE and regioselective aminolysis of enantioenriched amino epoxides provides easy access to optically active 1,3-diaminoalkan-2-ols, an important building block found in numerous naturally occurring compounds.74 However, catalytic regio- and stereoselective ring opening of internal amino epoxides remained elusive until Yamamoto’s discovery of a W-based catalyst system that enables the regioselective ring opening of 2,3-epoxy sulfonamide with various amines in excellent yield with complete C3-selectivity (Scheme 124).79 Thus, the regioselective aminolysis of enantioenriched 2,3-epoxy sulfonamides, prepared by using the Hf−BHA system,187 can be conducted in the presence of W(OEt) 6 as the Lewis acid catalyst. The W catalyst

Scheme 122. Asymmetric Oxidation of N-Tosyl Imines

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Scheme 124. W-Catalyzed C3−Selective Aminolysis of 2,3Epoxy Sulfonamides

Scheme 126. Catalyst Effect for the Enantioselective RingOpening of trans-2,3-Epoxy Cinnamyl Sulfonamide with Anilinea

a

Combined yield of the C3 and C2-regioisomers. bPhCF3 was used as solvent.

simultaneously coordinates to the epoxy oxygen and the sulfonamide-directing group of 2,3-epoxy sulfonamides thereby facilitating the nucleophile attack exclusively at the C3-position. Subsequently, the scope of this W-catalyzed ring-opening reaction of 2,3-epoxy sulfonamides was expanded with various Onucleophiles including phenols and aliphatic alcohols (Scheme 125). However, in the place of W(OEt)6, WO2 Cl2 in combination with AgOTf had to be used as the optimal catalyst system. Scheme 125. Regioselective Epoxide Ring Opening by ONucleophiles

a

a

Yields are based on aniline.

Thus, under the optimized conditions Gd-N,N′-dioxide promoted the ring opening of aromatic trans-2,3-epoxy sulfonamides by both aliphatic and aromatic amines furnishing the products in high yields, complete regioselectivities, and excellent enantioselectivities (Scheme 127). However, cis-, terminal, and aliphatic trans-2,3-epoxy sulfonamides provided the ring-opened products all with low enantioselectivities. Notably in the case of cis-epoxy sulfonamides, the regioselectivity of the reaction almost disappeared. Furthermore, the two different enantiomers of α-methylbenzylamine reacted favorably with the same enantiomer of the epoxide leading to both products (360e and 360f) in high diastereomeric ratios. To understand the anchoring effect of the sulfonamide moiety, several substrates such as unfunctionalized trans-1-phenyl propylene oxide, epoxy sulfone, Boc-protected epoxy amine, and Boc-protected epoxy sulfonamide were subjected to Gdcatalyzed epoxide ring-opening reactions (Scheme 128). Based on the outcome of these reactions, it turned out that the NHsulfonyl moiety plays a significant role in anchoring the substrate with the Gd catalyst, thereby promoting the ring-opening reaction enantioselectively.

Combined yields of the C3 and C2-regioisomers.

While regioselective aminolysis of optically active epoxy sulfonamides provides access to chiral 1,3-diaminoalkan-2-ols, 3phenyl-substituted 1,3-diaminoalkan-2-ols could not be obtained through this strategy, because the known method permitted the AE of only terminal and 3-alkyl-substituted N-alkenyl sulfonamides.187 Thus, the enantioselective aminolysis of 3-aryl 2,3-epoxy sulfonamides appeared as highly desirable. To attain the latter transformation, numerous catalyst systems were studied including Yamamoto’s W−BHA and Ni−BINAM complexes that served as the best catalyst systems for enantioselective ring opening of various epoxy alkanols.80,84 Finally, a gadolinium complex of N,N′-dioxide ligand was found to be the best catalyst for this reaction (Scheme 126).189

4.3. Asymmetric C−H Functionalization

Pioneering work by DuBois and co-workers brilliantly demonstrated that reactions of a series of sulfamate esters (-OSO2NH2) with PhI(OAc)2 in the presence of a dirhodium 3429


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Scheme 127. Gd-Catalyzed Enantioselective Ring-Opening of Epoxy Sulfonamides

Figure 21. Rh-dimer complex catalyzed intramolecular C−H amination.

the intramolecular C−N bond formation accordingly. Thus, a secondary N-phthalimide group or replacing the N−H with a methyl group in the α-amino moiety showed drastically deleterious effect (Scheme 129). Scheme 129. Effect of Various Rh2 Complexes on the Intramolecular C−H Activation Reaction a

Using 20 mol % Gd(OTf)3 and 24 mol % 359.

Scheme 128. Enantioselective Epoxidation of trans-2,3-Epoxy Cinnamyl Sulfonamide and Its Analogues

The intramolecular C−H amination of 3-aryl-substituted propylsulfamates led to the cyclic sulfamates in good yields and high enantioselectivities (Scheme 130A). However, the Rh2(Snap)4-catalyzed C−H bond insertion was found to be sluggish in the case of allylic substrates (up to 48% yields, and 84% ee) (Scheme 130B).194 Che et al. developed a similar enantioselective C−H amidation of sulfamates catalyzed by a chiral ruthenium−porphyrin complex 372.195 The C−H oxidation was accomplished with PhI(OAc)2 in the presence of Al2O3 as a basic additive. The C−N coupled products were formed with virtually complete diastereoselectivity and moderate to good yields and enantioselectivities (Scheme 131). The authors suggested that the reaction proceeds via the formation of the bis(imido) species [Ru(por*)(NSO2(OR))2] generated in situ from the Ru complex, sulfamate substrate, and PhI(OAc)2. Recently Yu et al. have developed a sulfonamide-directed enantioselective C−H iodination reaction based on a desymmetrization strategy of N-triflyl diarylmethyl amines.196 The resulting optically active diarylmethyl amine derivatives are frequently found as building blocks in bioactive compounds and in potential drug candidates such as cetirizine hydrochloride and SNC-80. In the presence of N-benzoyl leucine (Bz-Leu-OH) as the ligand, Pd(OAc)2 enables the desired C−H iodination of Ntriflyl diarylmethyl amines with molecular iodine preferably in a monoselective fashion. In this reaction, the use of mixed bases CsOAc and Na2CO3, and DMSO as an additive was particularly beneficial in terms of both the yield and enantioselectivity. Operational simplicity including tolerance of air and low reaction

complex afford cyclic sulfamidates with high regioselectivity and good to excellent diastereoselectivity.190 The reaction initiates with the formation of iminoiodinane R′OSO2NIPh, which subsequently adds to the dirhodium complex leading to an active nitrenoid intermediate.191 C−N bond formation then takes place via C−H oxidation to generate the heterocyclic ring (Figure 21). Du Bois and co-workers found that these intramolecular amidation reactions are stereospecific, permitting the synthesis of enantiomerically pure amidation products from enantiomerically pure sulfamates.192 In order to establish the enantioselective variant of this reaction, du Bois investigated the catalysis by various carboxamide-based dirhodium complexes.193 After screening several of those Rh2 complexes, Rh2(S-nap)4 was proven to be the most effective and unique catalyst for allowing the required C−H oxidation with PhIO, as most of the other amide-based Rh2 complexes were prone to degradation under the oxidative conditions. A hydrogen bond interaction between the N−H bond and the carbonyl oxygen inside the Rh2(S-nap)4 scaffold plays an important role for its stabilization, thereby promoting 3430


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Scheme 130. Substrate Scope for the C−N Bond Formation

Scheme 132. Sulfonamide-Directed C−H Iodination

Figure 22. Proposed intermediate for the C−H iodination.

5. MISCELLANEOUS EXAMPLES While hydroxy, amide, and sulfonamide functionalities play the key role of directing groups in the mainstream substrate-directed asymmetric reactions, other directing groups may also facilitate these reactions effectively in either an asymmetric or a nonasymmetric manner. In this section, we place primary emphasis on recent examples of attention-grabbing substratedirected reactions that have expected future applications.

Scheme 131. Ru−Porphyrin Complex Catalyzed C−N Bond Formation

5.1. Atroposelective Biaryl Synthesis

Structurally diverse molecules containing a rotationally hindered biaryl axis are ubiquitous in chiral catalysts, drug molecules, and natural products.197−200 Thus, the stereoselective construction of chiral biaryl axes is a synthetic transformation of fundamental importance. Three essentially different strategies have been recognized for the atroposelective synthesis of axially chiral biaryl compounds. In the classical approach, C−C coupling is realized with simultaneous asymmetric induction, leading to the biaryl formation in a single step. The second approach, by contrast, relies on the atroposelective (dynamic) kinetic resolution of an existing biaryl system. The third method is based on a few reports in which a C−C bond between an arene and a non-aryl substituent is transformed into a chiral biaryl axis via an aromatic ring construction.201,202 Among these, very few protocols rely on a substrate-controlled approach and are described herein. In 2013, Stoltz and Virgil presented a palladium-catalyzed, atroposelective C−P cross-coupling process that has been developed for the asymmetric synthesis of QUINAP and its derivatives in high enantiomeric excess.203 The C−P crosscoupling involves study of palladium-catalyzed atroposelective reactions between the bromide (Br), 4-methanesulfonylbenzenesulfonate or sosylate (OSs), and triflate (OTf) substrates with diphenylphosphine (Ph2PH) through a novel kinetic resolution (KR) process. Thus, the bromide substrates when subjected to phosphination with Ph2PH in the presence of Pd[P(o-Tol)3]2 and a chiral bidentate ligand, (S,S)-377, both the recovered bromide and QUINAP were obtained in high enantiopurity. The KR was scaled up to gram level to obtain the optically active

temperature (30 °C), as well as the use of inexpensive molecular iodine makes this process potentially useful for a large-scale production of enantiopure diarylmethyl amines. The reaction gave consistently high yield and excellent enantioselectivity for ortho-substituted diaryl amines; however for meta- and parasubstituted substrates, a mixture of mono- and di-iodinated compounds was obtained (Scheme 132). The coordinating effect of the triflamide-directing group was also discussed. The directing group binds with the Pd(II) as a neutral σ-donor, forming a weakly coordinating sulfonamine structure in the C−H activation step (Figure 22). The observed absolute configuration of 376a was determined as R by X-ray and is in accordance with the proposed transition state. 3431


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phosphination of triflate substrates in a similar manner as described by Fernández and Lassaletta in the dynamic kinetic cross-coupling strategy for the enantioselective construction of axially chiral heterobiaryls.204 They postulated that if the triflate substrate could undergo racemization upon optimized reaction conditions, while one of the enantiomers selectively underwent phosphination, asymmetric synthesis of QUINAP would be accomplished by means of dynamic kinetic resolution (DKR). The racemization rate of the triflate substrate appeared to be very slow, while a dramatically accelerated isomerization occurred during the lifetime of the arylpalladium intermediate under the reaction conditions (Scheme 135). This led to a successful DKR

QUINAP in virtually enantiopure form (>99.5% ee) (Scheme 133). Scheme 133. Atroposelective Synthesis of QUINAP by Kinetic Resolution

Scheme 135. DKR via Isomerization of Arylpalladium Intermediate

The KR of bromides was believed to be operational via an atroposelective oxidative addition of the aryl bromide to the C2symmetric bis(phosphine)−Pd(0) complex. With the use of (S,S)-377, the (S)-atropisomer of QUINAP would be formed preferably as depicted in Figure 23. After the KR, the (R)-

strategy to produce selectively one enantiomer of QUINAP. The overall effectiveness of the DKR was greatly improved by allowing more time for the isomerization of the palladium intermediate to proceed before its subsequent reaction with diphenylphosphine. This was attained by the slow addition of diphenylphosphine over 4 h to the triflate substrate to give 86% yield with 90% ee of (S)-QUINAP (Scheme 136).203

Figure 23. Proposed intermediate for the kinetic resolution process.

Scheme 136. Atroposelective QUINAP Synthesis via DKR bromide substrate was recovered in virtually enantiopure form. This (R)-bromide was further made to react with Ph2PH under reaction conditions identical to those of the racemic bromide to produce enantioenriched (R)-atropisomers of QUINAP derivatives, however (R,R)-377 had to be used as the catalyst. The sosylate compound 381 was also kinetically resolved under similar reaction conditions to obtain the (R)-QUINAP, and enantioenriched starting sosylate (S)-381 in useful ee (Scheme 134). In order to synthesize optically active QUINAP via dynamic kinetic resolution (DKR) process, the authors realized the Scheme 134. Synthesis of QUINAP via KR of Sosylate

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Encouraged by the seminal work of Stoltz and Virgil on the Pd0-catalyzed C−P cross-coupling via DKR of prefunctionalized (naphthyl)quinoline derivatives, Wencel-Delord and Colobert established a highly stereoselective, sulfoxide-directed acetoxylation and iodination of biaryls relying on a mild DKR-based C− H functionalization strategy.205 The working hypothesis was established on the fact that a configurationally stable racemic biaryl substrate containing a coordinating group would lead to a metallacyclic intermediate via directed C−H bond cleavage. The formation of such an intermediate should allow for lowering the rotational barrier, thereby accelerating an isomerization step. Thus, the desired functionalized Ar−Ar frameworks can be obtained in an atroposelective fashion by means of a DKR strategy. Optimization of the reaction conditions indicates that the acetoxylation of chiral p-tolyl sulfoxide-functionalized biaryls proceeds smoothly at ambient temperature with AcOH using Pd(OAc)2 as the catalyst and (NH4)2S2O8 as the stoichiometric oxidant. An array of acetoxylated biaryls was prepared in excellent diastereoselectivities utilizing this methodology (Scheme 137).

Scheme 138. Proposed Mechanistic Pathway

Scheme 139. Atroposelective Iodination of Biaryls

Scheme 137. Diastereoselective Acetoxylation of Biaryls via DKR Strategy

Scheme 140. Transformation of the Sulfoxide Directing Group

Since the axial chirality of the substrates is unrestricted at 25 °C, it was proposed that the rotation around the biaryl axis might arise after the formation of the palladacycle.204 Thus, the acetoxylation was believed to proceed considering the following sequence: (1) both diastereomers of the substrate undergo rapid C−H activation, (2) a subsequent facile reductive elimination from Int-B takes place, and (3) an isomerization of Int-A into a presumably more stable Int-B occurs leading to a successful DKR strategy (Scheme 138). Further mechanistic study indicates that albeit reasonable kinetic isotope effect was observed, the C−H activation step is reversible exhibiting significant D/H scrambling. Moreover, the direct metalation is relatively rapid, not rate limiting, and consistent with the fact that the transformation is possibly governed by the kinetics of reductive elimination and isomerization. Simple replacement of the oxidant (NH4)2S2O8 with Niodosuccinimide (NIS) led to a complete alteration in the reactivity of the catalytic system that promotes mild and highly diastereoselective C−I coupling (Scheme 139).205 However, slightly lowered diastereoselectivities were obtained and longer reaction times were required to realize full conversions. Furthermore, the traceless nature of the chiral sulfoxidedirecting group was demonstrated by a sulfoxide/lithium exchange and subsequent electrophilic trapping reaction sequence (Scheme 140). Subsequently, the same research group reported atropodiastereoselective, chiral sulfoxide-directed oxidative Heck

olefination reaction.206,207 It was found that the optimal solvent 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) has a crucial and unique role in controlling the reaction outcome.207 The mechanistic studies indicate that the key feature of the catalytic system was the formation of a hydrogen-bonded complex between the substrate and the solvent accelerating the C−H activation step and improving the stereochemical outcome of this transformation. A range of biaryls underwent Pd-catalyzed chiral sulfoxide-directed oxidative Heck olefination with acrylates using 3433


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the two bulky arenes, thereby elevating the energy barrier of the reaction.208,209 You and co-workers made a remarkable breakthrough in this context and developed the first enantioselective dehydrogenative Heck coupling of N-donor functionalized sterically demanding biaryls with terminal alkenes.210 A Rh complex bearing a C2-symmetric chiral ligand originally developed by Cramer211,212 catalyzes the C−H functionalization in the presence of dibenzoylperoxide and Cu(OAc)2 as additives and Ag2CO3 as the oxidant giving good to high yields and enantioselectivities (Scheme 142). Furthermore, the resulting chiral biaryl compounds were proven to be efficient ligands in promoting rhodium-catalyzed conjugate addition of phenyl boronic acid to cyclohexenone (Scheme 143). In order to improve the overall enantioselectivity of this substrate-controlled dehydrogenative Heck reaction, You further designed a series of new rhodium complexes derived from 1,1′spirobiindane-based cyclopentadienyl (Cp) ligands (SCps).213 The required ligand was synthesized in several steps starting from known dicarboxylic acid 397 as shown in Scheme 144. The metalation was executed at the final step with [Rh(C2H4)2Cl]2 providing the chiral SCpRh(I) complex 398. With the use of the new chiral Rh complex 398 the enantioselectivity of the Heck olefination was improved by a much greater magnitude compared to that with use of 392. Various functionalized biaryls react efficiently at room temperature with numerous olefins, including electronically and sterically diverse styrenes, functionalized alkenes, for example, α,β-unsaturated esters, amides, phosphonate ester, or even simple ethylene, leading to the corresponding chiral biaryls in practical yields (up to 97%) with excellent er values (up to 98:2) (Scheme 145). Gu and You further developed a kinetic resolution that enables synthesis of enantioenriched biaryls in good yields.214 The reaction relies on a Pd-catalyzed iodination of N-oxide substrates 400 with N-iodosuccinimide (NIS) in the presence of an optically active α-amino acid ligand, 399 (Scheme 146). Albeit moderate to good enantioselectivities were obtained for both the N-oxide substrate and the iodo-biaryl product 401, the enantioenrichment of the iodo-biaryl compounds could be improved by recrystallization as exemplified for one example. Thus, a phenyl substituent was further installed into the

AgOAc as the terminal oxidant. The corresponding olefinic biaryl products were obtained in excellent diastereoselectivities (Scheme 141). Scheme 141. Atroposelective Oxidative Olefination of Biaryls

Based on the mechanistic studies and literature data, it was proposed that initially a biarylsulfoxide substrate interacts through hydrogen bonding with HFIP to generate an “activated substrate”.207 This substrate−solvent arrangement has been presumed to adjust both the coordination properties and steric nature of the chiral directing group. Subsequently, Pd-promoted C−H bond activation occurs at the rate-determining step to give atropisomeric palladacycle intermediates II and IIa. Subsequent carbopalladation to the olefin coupling partner and β-H elimination furnish functionalized biaryl products as a single atropisomer. The catalytic cycle is completed upon reoxidation of palladium(0) V by the silver salt (Figure 24). A serious hurdle in atroposelective biaryl synthesis via C−H functionalization for sterically hindered substrates arises from the fact that accessing the five-membered cyclometalated species during the C−H activation process requires the coplanarity of

Figure 24. Proposed catalytic cycle for the oxidative olefination. 3434


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The use of this easily accessible menthyl phenylphosphinate group as the directing group was further expanded toward acetoxylation and iodination reactions (Scheme 149). Recently, Shi et al. employed commercially available tertleucine as an inexpensive, catalytic, and transient directing group for the synthesis of axially chiral biaryls by a palladium-catalyzed C−H olefination/DKR sequence.216 This strategy obviates additional steps to install and remove the external directing groups. The strategy was developed based on the postulate that a chiral amino acid would reversibly bind with rac-407 to generate imines 408a and 408b, between which one diastereomer (408b), due to steric reasons, produces the stereoenriched biaryl palladacycle intermediate at a relatively faster rate via C−H bond cleavage. Thus, the C−H functionalization would occur in an asymmetric fashion to give enantioenriched products 411 (Figure 25). Subsequently, control experiments revealed that Ltert-leucine was optimal among the other amino acids and that no desired product was obtained either in the absence of free amino acid or by using N- or C-terminally protected tert-leucines. This suggested that the amino acid acts as a transient chiral auxiliary to promote the C−H activation and ruled out the possibility of the aldehyde acting as a weakly coordinating directing group. A wide range of racemic biaryl-2-aldehydes with diverse substitution patterns were reactive under the optimum conditions, giving the alkenylated biaryl products in exceptionally high enantioselectivities (Scheme 150). Miller and co-workers have made a decisive discovery in the field of atroposelective biaryl synthesis. They demonstrated that a tripeptide-derived small-molecule catalyst could enable the dynamic kinetic resolution of racemic biaryl substrates that underwent electrophilic aromatic bromination in an atroposelective fashion.217 In search of an appropriate substrate class, the authors identified that biaryls 414 containing both carboxylic acid and phenolic -OH groups can simply undergo electrophilic bromination at the phenol ring with N-bromophthalimide in the presence of a tripeptide catalyst. The catalyst was designed with the rationale that the chiral atmosphere of the peptide β turn could assist in atropisomer selection during the electrophilic aromatic substitution reaction.218 To facilitate the catalyst− substrate interaction, the tripeptide catalyst was customized by introducing an additional basic site, for example, β-N,Ndimethylamino alanine (Dmaa), at the N-terminal residue and a simplified N,N-dimethyl amide at the C-terminal residue. Thus, the lead catalyst 413 promotes tribromination for a series of tailored biaryl compounds at the ortho-, meta-, and para-positions to the phenolic -OH group (Scheme 151). The method was applied to the asymmetric synthesis of several biologically relevant natural product substructures. For example, the catechol derivative, found as a subunit in the stegnane natural products, was converted to its tribromo product with an er of 95:5 and was improved up to >98:2 er by a single recrystallization. The observed stereochemistry of the bromination products was explained by a possible docking model as shown in Figure 26. The docking of the substrate through salt bridge formation between the Dmaa tertiary amine and the substrate carboxylic acid governs a presumed O-bromonium ion to brominate the phenol ring. In particular, free rotation of partly brominated (either mono- or dibromonated) species may likely occur until both the positions ortho- to the phenolic -OH are substituted, giving a highly sterically congested molecule with high rotational barrier. Alternatively, hydrogen bonds between the phenolic -OH and the catalyst amide groups may preclude such bond rotation in the intermediate.

Scheme 142. Atroposelective Dehydrogenative Heck Coupling

Scheme 143. Asymmetric 1,4-Addition of Boronic Acid to Cyclohexenone

enantioenriched iodo-biaryl compound by Suzuki−Miyaura cross-coupling to obtain a chiral N-oxide ligand, which promotes the Hosomi−Sakurai-type allylation reaction in asymmetric fashion (Scheme 147). In 2015, Yang et al. presented the first examples of Pd(II)catalyzed asymmetric C−H alkenylation, acetoxylation, and iodination protocols via dynamic kinetic resolution by means of a menthol-derived phosphinate chiral auxiliary (Scheme 148).215 A combination of Cu(OAc)2 (20 mol %) and Ag2CO3 (1 equiv) was found to be essential for the Pd-catalyzed olefination of axially racemic (S)-(−)-menthyl phenylphosphinate derivatives 403 with various acrylates. Excellent diastereomeric ratios with moderate to good yields were obtained for a broad range of biaryl products. 3435


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Scheme 144. Synthesis of the SCp Ligand and Its RhI Complex

Scheme 145. Improved Heck Olefination with the Modified Rh Complex

Scheme 146. Kinetic Resolution of Biaryl-N-oxide Substrate

Smith et al. introduced a new approach for the highly enantioselective organocatalytic synthesis of atropisomeric biaryls by means of a cation-assisted O-alkylation. The authors demonstrated that upon treatment of racemic 1-aryl-2-tetralones with a base using enantiopure quinidine-based ammonium salt as chiral cation source and benzyl bromide as the alkylating agent, the atroposelective O-benzylation takes place exclusively, with the complete suppression of the parallel C-alkylation process.219 Subsequent oxidation of the resulting O-alkylated products with DDQ leads to C2-symmetric and nonsymmetric BINOL derivatives in excellent er (Scheme 152). An array of atropisomeric BINOL derivatives was obtained in satisfactory yields and excellent enantioselectivities. It was found that the presence of a 2′ oxygen substituent has positive influence in achieving high reactivity and enantioselectivity, and its replacement with a methyl group led to poor conversion and moderate enantioselectivity. Introducing functionalities on other positions of the aromatic rings gave uniform results in terms of both reactivity and selectivity. Possibly, the reaction proceeds via the deprotonation of the racemic 2-tetralone derivatives with basic K3PO4 producing axially chiral and racemic potassium enolates in a reversible fashion (Scheme 153). It was suggested that counterion metathesis with the chiral ammonium salt gives rise to soluble diastereoisomeric ion pairs, which are benzylated subsequently at different reaction rates giving one of the atropisomers as the major product with the observed enantioselectivity. The authors proposed that the stereodiscrimination takes place in the

atropisomeric enolates in the presence of the chiral ammonium counterion leading to the highly atroposelective O-alkylation via a dynamic kinetic resolution process. 5.2. Stereoselective Borocyclopropanation

Borocyclopropanation of olefins is a noteworthy transformation allowing for the one-step synthesis of borocyclopropanes, versatile building blocks that can be further converted into a variety of cyclopropyl-bearing complex frameworks through the Suzuki−Miyaura cross-coupling reaction. Very recently, Benoit and Charette have developed a diastereoselective Simmon− Smith-type direct borocyclopropanation of allylic ethers and styrenes using diiodomethylpinacol boronate 421 as the source 3436


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Scheme 147. Further Application of the Enantioenriched NOxide Product

Scheme 148. C−H Olefination/DKR Strategy Using P-Based Directing Group Figure 25. Working hypothesis on the atroposelective synthesis of biaryls by a transient directing group.

Scheme 150. Atroposelective C−H Olefination Using tertLeucine as a Transient Directing Group

Scheme 149. Further Use of the Phosphinate Directing Group for Acetoxylation and Iodination Reactions

remains in cis fashion with respect to the ether side chain in all borocyclopropane products.223 The scope of the reaction was further expanded to styrenes 424 (Scheme 155). However, trans-borocyclopropanes were formed as predominating products in moderate to good yields and diastereoselectivities. The observed diastereoselectivities of the borocyclopropyldevised ethers were in agreement with the transition state model as depicted in Figure 27. The minimization of steric crowding between the pinacolboron group and the R1 and R2 substituents plays a crucial role in determining the diastereoselectivity of the products (Figure 27, 426a vs 426b). Nonbonding interaction between the zinc center and the allylic ether oxygen takes place only in the case of benzylic ethers. This model also explains the observed lower diastereocontrol for 1,1-disubstituted allylic ethers and styrene derivatives. Furthermore, the synthetic utility of the borocyclopropane compounds was deliberately demonstrated by postfunctionaliz-

of the reactive boromethylzinc carbenoid species (Scheme 154).220 The more reactive diiodomethylpinacol boronate 421 was prepared successfully from its relatively less reactive dichloromethyl precursor 420 in multigram scale and was employed for the borocyclopropanation to generate the boromethylzinc carbenoid in situ in the presence of the alkene and the zinc source.221,222 Thus, numerous borocyclopropane derivatives 423 with diverse substitution pattern were obtained from the corresponding protected allylic alcohols in good yield and excellent diastereoselectivity. Notably, the Bpin group 3437


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Scheme 151. Tripeptide Catalyzed Atroposelective Bromination

Scheme 153. Plausible Reaction Pathway

Scheme 154. Diastereoselective Borocyclopropanation of Allylic Ethers

Scheme 155. Diastereoselective Borocyclopropanation of Styrenes

Figure 26. Proposed docking model.

Scheme 152. Chiral Cation-Directed Atroposelective Biaryl Synthesis

a

Yield measured by 1H NMR using triphenylmethane as internal standard. bCombined isolated yield of both isomers.

ing a few representative compounds to 1,2,3-trisubstituted cyclopropane derivatives (Scheme 156).

Figure 27. Proposed TS model for the borocyclopropanation of allylic ethers. 3438


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regard to β-hydroxycarboxylic acid esters includes a series of βmono- and β-disubstituted β-hydroxycarboxylic acid esters that were smoothly transformed into the corresponding β-hydroxyamides in moderate to high yields with excellent chemoselectivities (Scheme 158).

Scheme 156. Postfunctionalization of Borocyclopropane Derivatives

Scheme 158. Scope of β-Hydroxy Esters in the HydroxyDirected Amidation of Carboxylic Acid Esters

5.3. Amidation of Carboxylic Acid Esters

Amide moieties are omnipresent in natural products, pharmaceuticals, polymers, and proteins.224,225 Given their natural abundance, the development of efficient catalytic approaches toward the synthesis of amides avoiding the use of waste intensive peptide coupling reagents is highly desirable.226−228 Encouraged by the high activity of a hydroxy group in metal catalysis as a directing group, Tsuji and Yamamoto envisaged that a hydroxy group located at the β-position with respect to the carbonyl group would accelerate the metal-catalyzed activation of the carbonyl group and subsequent amidation reactions, thus promoting the efficient and chemoselective direct amidation of carboxylic acid esters with amines.229 Indeed, it turned out that when an equimolar mixture of phenyl β-hydroxypropanoate and phenyl propanoate was subjected to amidation with p-toluidine in the presence of Ta(OEt)5, phenyl β-hydroxypropanoate selectively provided the desired amidated product. Thus, a range of β-hydroxyamides were prepared in excellent chemoselectivities (>98:2) (Scheme 157). The scope of the reaction with

Further, the amidation of an ester having two methyl ester groups located at different distances from the hydroxy group was studied (442 and 444). Nevertheless the amidation took place exclusively at the β-ester group with respect to the hydroxy substituent. A phenolic hydroxy group also promoted the amidation reaction (444). In addition, the amidation can be applicable to the α-hydroxyester 446 providing α-hydroxyamide 448 in 85% yield with excellent chemoselectivity (Scheme 159). Finally, the hydroxy-directed amidation was applied to synthesize dipeptide derivatives without using enzymatic methods. Thus, the Ta-catalyzed peptide coupling proceeded successfully using either N-Boc-serine methyl ester 450a or N-

Scheme 157. Hydroxy-Directed Amidation of Carboxylic Acid Esters

Scheme 159. Effect of Different Hydroxy Groups in Controlling the Amidation Reaction

a

Using 1.2 equiv of amine. bMethyl butyrate was used. c436f/437f = >98:2. 3439


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Boc-threonine methyl ester 450b with various amino acid methyl esters 451 leading to the corresponding dipeptide derivatives virtually as a single diastereomer in 43−81% yields (Scheme 160). No epimerization of the amino acid due to the use of simple methyl ester was detected in any case.

transformations. In 2013, he joined the group of Professor Hisashi Yamamoto at Chubu University, Japan, as a JSPS postdoctoral fellow. His work in the Yamamoto group was to design new chiral catalysts for substrate-directed asymmetric reactions. In 2016, he returned to India and joined CSIR-Central Salt and Marine Chemicals Research Institute, Bhavnagar, to start his independent research career. His current research interests revolve around developing new methods for metal-promoted organic synthesis and asymmetric catalysis. He is the recipient of Green Talent Award (2010) and DST-INSPIRE Faculty Award (2016) among others.

Scheme 160. Catalytic Synthesis of Dipeptide Derivatives

Hisashi Yamamoto received his Bachelor’s degree from Kyoto University under the supervision of Professors H. Nozaki and R. Noyori and Ph. D. from Harvard University under the mentorship of Professor E. J. Corey. His first academic position was as Assistant Professor and lecturer at Kyoto University, and in 1977, he was appointed Associate Professor of Chemistry at the University of Hawaii. In 1980, he moved to Nagoya University where he became Professor in 1983. In 2002, he moved to the United States as Arthur Holly Compton Distinguished Service Professor at the University of Chicago. He moved again from Chicago to Nagoya in 2012, where he is Professor and Director of Molecular Catalyst Research Center at Chubu University. He opened a new area of designer Lewis acid catalysts and their use for substrate controlled reactions in organic synthesis. He has been honored to receive the Prelog Medal (1993), the Chemical Society of Japan Award (1995), the Max-Tishler Prize (1998), Le Grand Prix de la Fondation Maison de la Chimie (2002), National Prize of Purple Medal (Japan) (2002), Yamada Prize in 2004, Tetrahedron Prize (2006), The Karl-Ziegler Professorship (2006), The Japan Academy Prize (2007), Honorary Member of the Chemical Society of Japan (2008), ACS Award for Creative Work in Synthetic Organic Chemistry (2009), Grand Prize of Synthetic Organic Chemistry of Japan (2009), Member of American Academy of Arts and Sciences (2011), Noyori Prize (2011), Fujiwara Prize (2012), and Roger Adams Award (2017).

6. CONCLUSION AND FUTURE PROSPECTS In this review, we primarily focused on recent progress in the field of substrate-directed asymmetric transformations. As can be seen, these reactions have tremendous potential and thus have gradually emerged as an indispensible device for the preparation of complex molecules. We have demonstrated the directing effect of various commonly used functional groups including hydroxy, amide, and sulfonamide in assisting various asymmetric reactions. Design of various metal-based and organocatalysts to attain these reactions successfully has also been described elaborately. However, examples of substrate-directed reactions, in particular with C(sp2)−H functionalizations, that proceed in a diastereoselective or regioselective fashion were not included in this review due to their large volume. This topic should be covered as a separate review elsewhere. Despite substratedirected asymmetric reactions advancing significantly within the last three decades, further potential reactions that occur not only in asymmetric but also in nonasymmetric regioselective fashion will be uncovered in the future.230 We believe that substratedirected asymmetric reactions will rapidly become complementary to classical asymmetric reactions and will eventually be employed in industry to achieve complex target molecules in a simpler manner.

ACKNOWLEDGMENTS This work was supported by Grant-in-Aid for Scientific Research (No. 23225002 and No. 17H06142), JST ACT-C Grant Number JPMJCR12ZD, Japan, The Uehara Memorial Foundation, Nippon Pharmaceutical Chemicals Co. Ltd., Advance Electric Co. Inc., and Department of Science and Technology, India (DST). We also sincerely thank DST for the DST-INSPIRE Faculty Award to S.B. (Grant no. DST/INSPIRE/04/2015/ 002248). CSIR-CSMCRI communication number 113/2017.

AUTHOR INFORMATION Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected].

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ORCID

Sukalyan Bhadra: 0000-0003-1266-0930 Hisashi Yamamoto: 0000-0001-5384-9698 Notes

The authors declare no competing financial interest. Biographies Sukalyan Bhadra received both Bachelors and Masters degrees in chemistry from the University of Calcutta, India. In 2011, he was awarded a Ph.D. under the supervision of Prof. Brindaban C. Ranu at Indian Association for the Cultivation of Science, Kolkata, India, for the development of useful synthetic procedures by metal-mediated reactions. He then moved to TU Kaiserslautern, Germany, in the Group of Professor Lukas J. Gooßen for his postdoctoral research work on transition metal-catalyzed decarboxylative and dehydrogenative 3440


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