Substrate-Directed Catalytic Selective Chemical Reactions

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Substrate-Directed Catalytic Selective Chemical Reactions Takahiro Sawano, and Hisashi Yamamoto J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b03180 • Publication Date (Web): 27 Feb 2018 Downloaded from http://pubs.acs.org on February 28, 2018

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The Journal of Organic Chemistry

Substrate-Directed Catalytic Selective Chemical Reactions

Takahiro Sawano,* and Hisashi Yamamoto* Molecular Catalyst Research Center, Chubu University, 1200, Matsumoto-cho, Kasugai, Aichi 4878501, Japan

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ACS Paragon Plus Environment

The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Abstract The development of highly efficient reactions at only the desired position is one of the most important subjects in organic chemistry. Most of the reactions in current organic chemistry are reagent- or catalyst-controlled reaction, and the regio- and stereoselectivity of the reactions is determined by the inherent nature of the reagent or catalyst. In sharp contrast, substrate-directed reaction determines the selectivity of the reactions by the functional group on the substrate and can strictly distinguish sterically and electronically similar multiple reaction sites in the substrate. In this perspective, three topics of substrate-directed reaction are mainly reviewed: (1) directing groupassisted epoxidation of alkenes, (2) ring-opening reactions of epoxides by various nucleophiles, and (3) catalytic peptide synthesis. Our newly developed synthetic methods with new ligands including hydroxamic acid-derived ligands realized not only highly efficient reactions but also pinpointed reactions at the expected position, demonstrating substrate-directed reaction as a powerful method to achieve the desired regio- and stereoselective functionalization of molecules from the different viewpoint from reagent- or catalyst-controlled reaction.

O

OH

OH n

n

Epoxidation Hf

V

W

Ti

OH

O

W

OH

Mo

Ce

Ni

Gd

Nu

OH

n

n

Ta

Ring-Opening Reaction

O

O RO

R1

OH

N

OH

R2 Amidation

2


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The control of all aspects of reaction selectivities such as stereoselectivity and regioselectivity is a long-standing and challenging problem in synthetic organic chemistry. In the selective reactions, the reaction controlled by the inherent nature of the reagent or catalyst is termed reagent- or catalyst-controlled reaction.

A standard metal/chiral ligand complex catalyzed

asymmetric reaction is one of the examples of reagent- or catalyst-controlled reaction, where the conformation of the chiral ligand of catalyst plays the important role for the absolute configuration of the product. On the other hand, when the selectivity of the reaction is determined by the inherent nature of the substrate, the reaction is called substrate-controlled reaction,1 which is further divided into two groups: (1) passive substrate-controlled reaction and (2) active substrate-controlled reaction or substrate-directed reaction as described by Mulzer1d and Breit1b,1c. During the course of passive substrate-controlled reaction, the selectivity of the reactions is determined by the steric repulsion between the substrate and the reagent or catalyst, where the reagent or catalyst approaches the reactive site of the more open side.

In contrast, substrate-directed reaction controls the

selectivity on the basis of the interaction between the functional group on the substrate and the catalyst or reagent, which can distinguish the multiple similar reactive sites. Substrate-directed reaction starts from the interaction of polar functional groups apart from the reaction site through hydrogen bonds, covalent bonds, coordinate bonds, Coulombic (cation-anion) interactions, or Lewis acid-base interactions, bringing the reagent or catalyst closer to the reaction sites. The reaction proceeds through intramolecular reaction fashion while maintaining the interaction between the functional group and the catalyst or reagent, which is a source of the reaction selectivity. In other words, the distance between the functional group and the reactive site is quite important for substrate-directed reaction. The reaction proceeds at the only reactive site bearing the proper position of a functional group. The choice of the functional group is also important key for the success of substrate-directed reaction. Considered by the facility of the preparation and the synthetic utility after the reaction, the common functional groups in nature such as alcohol and amine are desirable, which can react with a reagent or catalyst though the formation of covalent bond, coordinate bond, or hydrogen bond. Two important early examples of substrate-directed reaction are hydroxy group-directed epoxidations of allylic alcohols with a peroxide and Simmons-Smith cyclopropanations. In 1959, Henbest and Wilson reported stereoselective epoxidation of 2-cyclohexenol with a peroxide to form the cis-epoxide selectively (Scheme 1a).2 The epoxidation proceeds at the more sterically hindered face due to the formation of a hydrogen bond between the hydroxy group on the substrate and the peroxide. This unusual and unique selectivity demonstrates the utility of substrate-directed reaction. Two years later, Winstein and Sonnenberg reported a hydroxy group-directed SimmonsSmith cyclopropanation of 3-cyclopenten-1-ol to give a cis isomer as a single stereoisomer (Scheme 1b).3 The low activity of the cyclopropanation with cyclopentyl acetate, whose hydroxy group is 3



protected by an acetyl group, indicates the interaction between the free hydroxy group and the zinc reagent activates the reaction. Scheme 1. Early Works of Substrate-Directed Reaction

Catalytic substrate-directed reaction was first developed by Thompson and McPherson in 1974, and it was reported that rhodium-catalyzed cis-selective hydrogenation proceeded with the alkoxide on the substrate as a directing group (Scheme 2).4 Scheme 2. First Example of Substrate-Directed Reaction with a Metal Catalyst

One of the most successful and well-known examples of substrate-directed reaction is Sharpless Asymmetric Epoxidation.

Asymmetric epoxidation is one of the most important

transformations in organic synthesis for constructing diverse chiral epoxides, which are useful chiral building blocks for the synthesis of natural products and bioactive synthetic analogs.5 In 1980, Sharpless reported Ti(Oi-Pr)4/chiral dialkyl tartrate complex-catalyzed asymmetric epoxidation of allylic alcohols by use of tert-butyl hydroperoxide (TBHP) as an oxidant to provide chiral epoxides with high regioselectivity as well as high enantioselectivity (Scheme 3).6 Scheme 3. Sharpless Asymmetric Epoxidation

From the crystal structure of titanium-dialkyl tartrate, in Sharpless asymmetric epoxidation the formation of titanium alkoxide is thought to play an important role in delivering high regioselectivity.7 Formation of a titanium alkoxide from a titanium complex and a hydroxy group brings the peroxide closer to the olefin on the allylic alcohol, so that the epoxidation at the allylic position is accelerated (Figure 1). 4


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Figure 1. Reaction Model for Sharpless Asymmetric Epoxidation

As represented by the brilliant works by Sharpless, various substrate-directed reactions have been studied due to the attractive ability to distinguish sterically and electronically similar reactive sites on the basis of the interaction between the functional groups on the substrates and catalysts or reagents. Our laboratory has mainly developed the substrate-directed reactions based on the formation of covalent bond between the metal complex and alcohol. In this perspective, we primarily focus on two topics: (1) epoxidation of alkenes and (2) ring-opening reactions of epoxides by nucleophiles.8 Some of our interesting achievement are the substrate-directed reactions with the functional group apart from the reactive site, which are difficult reactions due to the nature of the substrate-directed reaction.

Through our effort on the development of catalytic systems, the

importance of the proper position of OH from the reactive site for the reactivity and selectivity will be demonstrated. 1. Metal-Catalyzed Asymmetric Epoxidation 1.1. Early Work Before the considerable development of Sharpless asymmetric epoxidation utilizing Ti/chiral tartrates, Sharpless clearly demonstrated the importance of an alcohol at an allylic or homoallylic position for the smooth reaction of V or Mo-catalyzed nonenantioselective epoxidations of alkenes (Scheme 4a).9 The reactivity of 2-cyclohexen-1-ol, bearing a hydroxy group at an allylic position, is significantly higher than cyclohexene, and the epoxidation proceeds in a cis selective fashion. V catalyst is specifically active for the epoxidation of allylic alcohols and applied for the regioselective epoxidation of geraniol and linalool, which have two alkenes in the structure.

Several years later, our group and the Sharpless group collaboratively achieved

stereoselective epoxidation of acyclic allylic alcohols by use of V and Mo catalysts (Scheme 4b).10 With this epoxidation as a key step, we synthesized dl-C18 Cecropia juvenile hormone from farnesol. Scheme 4. Stereoselective Epoxidation of Cyclic- and Acyclic Allylic Alcohols 5



An important advance for the chiral version of epoxidation of allylic alcohols was achieved by Sharpless with a vanadium complex and a chiral hydroxamic acid (HA) ligand (L1) (Scheme 5).11,12,13

Due to the strong coordination ability to metals, hydroxamic acids play

important roles in a wide range of fields from biochemistry to extraction of metals, and the utility as a chiral ligand was first reported in that study. Shortly after, a proline derived-hydroxamic acid ligand (L2) was also developed, showing high activity and enantioselectivity for epoxidation of allylic alcohols.10b Scheme 5. V/HA Complex-Catalyzed Asymmetric Epoxidation of Allylic Alcohols

Despite the promising initial results, V-catalyzed asymmetric epoxidation quickly lost the attention of scientists due to the ligand deceleration effect of V complexes.14 The preparation of the chiral V complex does not provide a single complex but forms a mixture of V complexes in equilibrium (Scheme 6).

One-to-one complex of metal and ligand (B) is the true active species for the

epoxidation. To suppress the background reaction from achiral complex (A), the addition of excess ligand is essential, but the percentage of more ligand coordinated unreactive complexes (C) and (D) is increased, decreasing the yield of oxidation. Scheme 6. Equilibrium between the Hydroxamic Acid-Derived Ligand and a Vanadium Complex

In contrast, a ligand acceleration effect was observed in Sharpless asymmetric epoxidation utilizing Ti/chiral tatrate. Addition of a tartrate ligand to a titanium alkoxide forms a more highly reactive 6


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chiral complex. Thus, compared with the rapid progress of asymmetric epoxidation with titanium catalysts,5b vanadium catalyzed asymmetric epoxidation has not received much attention from scientists. However, vanadium catalysts have several advantages over titanium catalysts: (1) low catalyst loading, (2) stability in water, (3) easy work-up, and (4) broad scope of substrates. These advantages of V catalysts have prompted us to pursue asymmetric epoxidation with V complexes.5d,13 1.2. Monodentate HA Ligand 1.2.1 Binap-derived ligand15 As mentioned above, the biggest problem of V-catalyzed asymmetric epoxidation are the ligand deceleration effect and ligand exchange.

To address these problems, we developed a

sterically hindered hydroxamic acid-derived ligand based on binaphthyl to prevent excess coordination of chiral ligands to V (Scheme7).

The new ligand (L3) has sterically hindered

substituents at both a carbonyl group and a hydroxyl amine. Binaphthyl is one of the most useful backbones for asymmetric catalysts, and its utility has been proven in an enormous number of asymmetric reactions. The epoxidation with triphenylmethyl hydroperoxide (THP) as an oxidant proceeds smoothly at low temperature to convert a variety of substituted allylic alcohols into the corresponding epoxides in high enantioselectivity. Scheme 7. Asymmetric Epoxidation by a Hydroxamic Acid-Derived Ligand Based on a Binaphthyl Group

The effect of the ratio of ligand and metal for the epoxidation was examined. Larger amounts of ligand lowered the yield, and the enantioselectivity was not improved by the addition of more than 1.2 equivalent of ligand. This result indicates higher concentration of ligand in the reaction mixture decreases the amount of highly active one-to-one complex. 1.2.2 Amino Acid-Derived Ligands16 7



Whereas the HA ligand based on the binaphthyl group was successful in the asymmetric epoxidation, relatively difficult modification of the ligand prevented the further development of asymmetric epoxidation. In this context, we designed a readily tunable and available chiral ligand. The ligand is constructed from three units: (1) L-amino acid derivative as chiral source, (2) dicarboxylimide as a protecting group of nitrogen, and (3) hydroxylamine (Scheme 8). Systematic screening of the ligands by free combination of three various units revealed L4 is the best ligand to obtain high enantioselectivity (Scheme 9). Only 0.1 mol% of catalyst loading is enough for the reaction while the enantioselectivity is slightly decreased (99% yield, 86% ee). Scheme 8. Readily Tunable HA Ligand Synthesized by Combination of Three Units

Scheme 9. Asymmetric Epoxidation of Allylic Alcohols with the New HA Ligand

The same screening method was also applied to finding an appropriate chiral ligand for the asymmetric epoxidation of homoallylic alcohols. The reaction site, alkene, is further away from the directing group. A new ligand (L5) results in the best enantioselectivity while both the yield and the enantioselectivity were moderate, and the substituent pattern of homoallylic alcohols is restricted (Scheme 10). With a V/L5, the total synthesis of (-)-α-bisabolol and (-)-8-epi-α-bisbolol were achieved with the asymmetric epoxidation as a key reaction.

8


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Scheme 10. Asymmetric Epoxidation of Homoallylic Alcohols

1.3 C2 Symmetric HA Ligands 1.3.1 Epoxidation of Allylic Alcohols17 Amino acid-derived HA ligands showed high reactivity and enantioselectivity for the asymmetric epoxidation. However, the ligand deceleration effect was still observed, and the desired one-to-one complex between metal and ligand was not selectively formed. To overcome the ligand deceleration effect, we designed and synthesized C2 symmetric bidentate bishydroxamic acid (BHA) ligands. The BHA ligand can strongly bind the metal due to the chelate effect. Furthermore, the steric hindrance of the substituents prevents the over coordination of ligands to the metal to form one-to-one complex exclusively. A series of differently steric hindered BHA ligands were synthesized and applied to the asymmetric epoxidation of allylic alcohols (Figure 2). Figure 2. BHA Ligands

In the presence of V/L6-8 complex, the asymmetric epoxidation with cumene hydroperoxide (CHP) or TBHP as oxidants gave high yield and enantioselectivity of a variety of allylic alcohols including relatively difficult small allylic alcohols (Scheme 11). Furthermore, V/BHA have several advantages over other catalysts: (1) the catalyst loading can be reduced to 0.2 mol%. (2) the reaction proceeds under air with aqueous TBHP as an oxidant. (3) the ligand deceleration effect was not observed even in the presence of 3 equivalents of ligand in the reaction mixture. (4) high enantioselectivity was achieved for Z olefins. Scheme 11. V/BHA-Catalyzed Asymmetric Epoxidation of Allylic Alcohols 9



V/BHA complex can be also applied to the kinetic resolution of secondary allylic alcohols, where both the epoxides and the recovered allylic alcohols after the reaction show high enantioselectivity (Scheme 12). Scheme 12. V/L6-Catalyzed Kinetic Resolution of Secondary Allylic Alcohols by Epoxidation

1.3.2. Epoxidation of Homoallylic Alcohols18 Newly designed V/BHA complex can be also applied to the asymmetric epoxidation of homoallylic alcohols. Compared with many examples of the efficient asymmetric epoxidation of allylic alcohols, the development of asymmetric epoxidation of homoallylic alcohols has been restricted due to the longer distance between the hydroxy group and the alkene. Furthermore, the epoxidation with HA ligand cannot achieve the highly enantioselective epoxidation of trans-, or cissubstituted homoallylic alcohols. To our delight, with more sterically hindered BHA ligand (L10), asymmetric epoxidation of E or Z-4-substituted homoallylic alcohols proceeded with high enantioselectivity under mild reaction conditions (Scheme 13). Scheme 13. Asymmetric Epoxidation of Homoallylic Alcohols with a V/L10 Complex

Furthermore, V/BHA complex is an effective catalyst for the kinetic resolution of 2,4disubstituted homoallylic alcohols, and the enantioselectivity of both the epoxides and the recovered starting materials was quite high (Scheme 14).

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Scheme 14. Kinetic Resolution of Homoallylic Alcohols by Asymmetric Epoxidation

1.3.3 Enantioselective Desymmetrization19 Kinetic resolution of secondary allylic alcohols by epoxidation is a superior method to obtain chiral epoxides with high enantioselectivity. However, the inherent problem of kinetic resolution is the maximum yield is theoretically 50%, and half of the substrate remains as a byproduct after the reaction.

In sharp contrast, desymmetrization of meso secondary allylic

alcohols, which requires the same face enantiodifferentiation of alkenes as kinetic resolution, does not have the limitation of the yield, and theoretically, 100% of the substrate can be used for the reaction. Thus, desymmetrization is more useful than kinetic resolution, yielding epoxy alcohols bearing more than two chiral centers.20 By V/BHA complex, kinetic resolution of both allylic alcohols and homoallylic alcohols by epoxidation proceeds in highly diastereo- and enantioselective manner (Scheme 15). Furthermore, kinetic resolution achieved a one-step synthesis of a synthetic intermediate of atorvastatin (Liptor), which was synthesized in six steps.21 Scheme 15. Desymmetrization of meso Secondary Allylic Alcohols and Homoallylic Alcohols

1.4 Hf/BHA catalyst 1.4.1 epoxidation of homoallylic alcohols22 In section 1.3, we developed asymmetric epoxidation of homoallylic alcohols by V/BHA complexes.

Our next target was lowering the catalyst loading and broadening the scope of

substrates. Since further modification of BHA ligand is difficult due to the restriction of the structure, we focused on the metal center. As represented by Sharples asymmetric epoxidation, titanium is an effective metal for the epoxidation, and Zr, which is in the same group on the periodic table, also has good catalytic activity.23 In this context, Group 4 elements such as Ti, Zr, and Hf 11



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were selected as candidates. With less sterically hindered L6, Hf(Ot-Bu)4 and Zr(Ot-Bu)4 exhibited higher activity and enantioselectivity than Ti(Oi-Pr)4, V(O)(acac)2, and Nb(OEt)5.24 In particular, Hf(Ot-Bu)4 showed slightly better results than Zr(Ot-Bu)4 (Scheme 16). Screening of the reaction conditions revealed the difference of the reaction system between V/BHA and Zr/BHA. (1) Although the addition of excess ligand is essential in V/BHAcatalyzed reactions to suppress the background reaction (Sections 1.3), the Zr/BHA reaction system required only an equimolar amount of the ligand to the metal. (2) The reaction with Zr/BHA was accelerated by the addition of highly polar aprotic additive. Coordination of the additive to the metal center would convert the oligomer or polymer structure to the monomer structure by the stabilization

of

the

mononuclear

complex.25

Among

the

tested

additives,

N,N'-

dimethylpropyleneurea (DMPU) was the best additive. (3) the reaction with Zr/BHA should be performed under inert atmosphere with molecular sieves as with the Sharpless asymmetric epoxidation.26 Under these conditions, the reactions with 3,4-disubstituted Z-homoallylic alcohols especially proceeded well to give high enantioselectivity. Scheme 16. Hf/L6-Catalyzed Asymmetric Epoxidation of Homoallylic Alcohols

With 10 mol% catalyst loading, the epoxidation with 4-aryl substituted bishomoallylic alcohols also proceed to give 4,5-epoxy alcohol.

It should be noted that, in most cases,

intramolecular cyclization did not proceed although 4,5-epoxy alcohols tend to be easily cyclized (Scheme 17). However, the scope of substrates is quite limited, and other substituent types of bishomoallylic alcohols resulted in quite low yield. To gain the insight of the reaction mechanism of the enantioselective epoxidation, the relationship between the ee of ligand and the ee of product was examined. The result of direct proportion between two ees indicates, in the reaction mixture, the expected one-to-one complex of the ligand and the metal is formed. Scheme 17. Hf/L6-catalyzed Asymmetric Epoxidation of Bishomoallylic Alcohols

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We predicted that the high enantioselectivity for the bishomoallylic alcohols and homoallylic alcohols bearing long alkyl chains is realized by larger space around the metal center, thus allylic alcohols and the peroxide can be aligned at the proper positions by the chiral ligand. The presence of the enough space around Hf/L6 system was supported by the following facts. (1) ionic radius of Zr4+ (0.72 Å) and Hf4+(0.71 Å) are obviously larger than Ti4+ (0.61 Å) and V5+ (0.54 Å).27 (2) Zr and Hf are pentacoordinated complexes in the transition state28 whereas V forms hexacoordinated complex.18 (3) The bond length between Zr and Hf, and oxygen atom is longer than Ti, providing a larger space around the metal center. (4) The best ligand, L6, for Hf-catalyzed epoxidation is smaller than L10 which is used for the V-catalyzed reaction. These facts indicate the presence of enough space around the metal center for success of the epoxidation of homoallylic alcohols bearing a long alkyl chain. 1.4.2. tertiary allylic alcohols29 The development of an efficient synthetic method for enantioenriched tertiary 2,3-epoxy alcohols is an important task, which provides useful chiral building blocks bearing a quaternary carbon.

Unfortunately, Sharpless asymmetric epoxidation, which is a leading reaction for

asymmetric epoxidation of allylic alcohols, is not an effective method for the synthesis of enantioenriched epoxy alcohols from the corresponding tertiary allylic alcohol. Two examples of asymmetric epoxidation of tertiary alcohols have been already reported,30 however, moderate yield and low enantioselectivity were obtained, and stoichiometric quantities of chiral ligand were essential. In this context, truly efficient and reliable asymmetric epoxidation is desired. The biggest problem is the poor reactivity of tertiary allyl alcohols originating from the steric hindrance around the hydroxy group, which prevents coordination to the metal center. As mentioned above, Hf/BHA complex has open space around the metal center. We predicted the sufficient space and absence of steric repulsion between Hf and the tertiary allylic alcohol would provide the desired epoxides.

Indeed, Hf/BHA complex showed both high reactivity and

enantioselectivity for the asymmetric epoxidation of tertiary allylic alcohols (Scheme 18). It should be noted that homoallylic alcohols are also applicable to the reaction (Scheme 19). 13



Scheme 18. Hf/BHA-Catalyzed Asymmetric Epoxidation of Tertiary Allylic Alcohols

Scheme 19. Hf/BHA-Catalyzed Asymmetric Epoxidation of Tertiary Homoallylic Alcohols

1.4.3. N-Allylic Sulfonamide31 In most substrate-directed epoxidations, the directing group is restricted to the hydroxy group. Toward the further development of substrate-directed reaction, amine has been used as the directing group for epoxidation. Screening appropriate protecting groups for the amines revealed that asymmetric epoxidation with sulfonamides such as Ts gave excellent enantioselectivity. As for the substituent on sulfonamide, electron-donating groups are better than electron-withdrawing groups, and MgO is used as an additive instead of DMPU. Under optimized reaction conditions, various alkenes and protecting groups on the amines can be applied for the epoxidation, and, in particular, the epoxidation with 3-Z substituted N-allylic sulfonamides provides high enantioselectivity (Scheme 20). Epoxidation with an easily removed substituent, TMS, proceeded without loss, demonstrating the mild reaction conditions. Scheme 20. Hf/BHA-Catalyzed Asymmetric Epoxidation of N-Allylic Sulfonamides

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Interesting results were obtained through a series of control experiments investigating the effect of amine as a directing group for epoxidation (Scheme 21). Replacement of an NH moiety with O or CH2 in the substrates, surprisingly, gave nearly similar enantioselectivity while the yields were decreased. These results indicate the amine moiety is not essential for the epoxidation, and the true directing group would be the sulfone group. Sulfone-directed reactions have not been well developed and could provide a new path for substrate-directed reaction.32 Scheme 21. Control Experiments for Revealing the True Directing Group

The discovery that the sulfonyl group is the true directing group for the epoxidation of Nallylic sulfonamides prompted us to develop the epoxidation of sulfonyl group-protected imines.33 Under the same conditions as the epoxidation of N-allylic sulfonamide, the asymmetric epoxidation of N-tosyl imine proceeded to give the corresponding oxaziridines in high yield with excellent enantioselectivity (Scheme 22). Scheme 22. Asymmetric Epoxidation of N-Tosyl Sulfonamide

1.4.4 H2O234 As shown in Sections 1.3 and 1.4, our efforts toward the development of a series of unique BHA ligands enabled numerous variations of efficient asymmetric epoxidation of allylic alcohols and homoallylic alcohols. However, in all reactions, toxic and non-atom economical alkyl peroxides such as TBHP and CHP were employed as oxidant. In terms of both atom economy and eco-compatibility, development of catalytic epoxidation with H2O2 aqueous solution as the oxidant has been expected.35 H2O2 is an ideal oxidant, which is safe, inexpensive, easily handled and forms only water as byproduct. Since the tungsten complexes display high oxygen transfer ability and 15



hardly disproportionate H2O2, W complexes were employed for the asymmetric epoxidation of allylic alcohols with H2O2. WO2(acac)2 and L6 and L7, which are effective ligands for V- and Hf-catalyzed epoxidation, were tested for asymmetric epoxidation of allylic alcohols with H2O2. However, neither yield nor enantioselectivity were sufficient. Modified BHA ligand (L9) was found to achieve high yield and excellent enantioselectivity. However, all reactions with L9 gave ringopened epoxides through nucleophilic attack by H2O2. Screening of various additives for further improvement of the yield revealed the addition of LiCl efficiently suppresses the formation of ringopened epoxides without the loss of enantioselectivity. With the developed method, a wide range of allylic alcohols and homoallylic alcohols can be applied to the asymmetric epoxidation to give high enantioselectivity in the products (Schemes 23 and 24). It should be noted that all reactions proceed under air with commercially available solvents without further drying, and precomplexation of W/BHA catalyst is unnecessary. Scheme 23. Asymmetric Epoxidation of Allylic Alcohols with H2O2 as an Oxidant

Scheme 24. Asymmetric Epoxidation of Homoallylic Alcohols with H2O2 as an Oxidant

The W/L9 reaction system is easily influenced by the electronic- and steric environment of the alkenes, which suggests the possibility of exclusive site-selective epoxidation of complex molecules bearing multiple alkenes. To our delight, the epoxidation of farnesol derivatives bearing three alkenes and two alcohols provided the corresponding epoxides in almost perfect regioselectivity, demonstrating the utility of substrate-directed reaction (Scheme 25). Scheme 25. Regioselective Asymmetric Epoxidation of Farnesol Derivative

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1.5. Binuclear Titanium Complex 1.5.1. Epoxidation and Sulfoxidation36 In sections 1.2-1.4, we describe a series of hydroxamic acid-derived chiral ligands we have developed and applied to various useful asymmetric epoxidations. However, several different asymmetric epoxidations of alkenyl alcohols still do not provide sufficient yield and enantioselectivity. To address this issue, we designed a new chiral ligand (L11) constructed from an 8-hydroxyquinoline unit and a binol unit. The ligand (L11) strongly binds two metals, so that a binuclear complex is formed (Scheme 26). One metal can interact with a hydroxy group of a homoallylic alcohol whereas the other metal can react with an oxidant to form a peroxio metal species. When the distance of the two metals on the ligand (L11) is adequate for the substrates, the epoxidation can proceed smoothly. In other words, L11 works as a dual catalyst in the reaction mixture. Scheme 26. Design of a Binuclear Metal Complex and its Application for Asymmetric Epoxidation

The titanium binuclear complex achieved highly enantioselective epoxidation of homoallylic alcohols (Scheme 27). It should be noted that the reaction system can be applied to conjugated homoallylic alcohols, whereas BHA complex gave low yield and enantioselectivity. Some experiments indicate binuclear titanium complex actually acts as a dual catalyst for the epoxidation. First, high-resolution mass spectrometry (HRMS) of the Ti complex shows the ratio of Ti and ligand is 2:1. Second, epoxidation of the terminal alkene, which does not have a hydroxy group, did not proceed, indicating the hydroxy group acts as a directing group during the course of the epoxidation.

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Scheme 27. Binuclear Titanium Complex-Catalyzed Asymmetric Epoxidation of Homoallylic Alcohols

The newly developed method can be also applied to the sulfoxidation of γ-hydroxy sulfide. Various kinds of sulfides can be converted to the corresponding sulfoxides with high enantioselectivity (Scheme 28).

In sharp contrast, enantioselectivity was quite low with the

sulfoxidation by BHA complex. The hydroxy group at the γ position to the sulfide is essential for achievement of high enantioselectivity. The sulfoxidation with simple propyl phenyl sulfide and βhydroxyethyl phenyl sulfide resulted in low yield and enantioselectivity. Scheme 28. Ti Binuclear Complex-Catalyzed Asymmetric Sulfoxidation of γ-Hydroxy Sulfide

1.5.2 N-chiral amine oxide37 Chiral sulfoxides, phosphine oxides, and amine oxides are useful classes of compounds, which can be found in biologically related compounds and used for chiral ligands in metal catalysis and organocatalysis.38 In this context, the development of synthetic methods for chiral sulfoxides, phosphine oxides, and amine oxides is quite valuable. Whereas synthetic methods for chiral sulfoxides and phosphine oxides have been well established, examples of synthesis of amine oxide have been quite limited except for relatively low enantioselective synthetic methods facilitated by enzymes. A direct synthetic method for chiral amine oxides is asymmetric oxidation of tertiary amines.

During the course of the reaction, stereo inversion through a pyramid shape easily

proceeds, so that two enantiomers are always in equilibrium, which might increase the difficulty of straightforward synthesis of N-chiral amine oxides from tertiary amines.

We expected the

cooperative activity of our binuclear titanium complex to realize the asymmetric oxidation of γhydroxy amine to give amine oxides in high enantioselectivity. As well as the binuclear titanium complex-catalyzed asymmetric epoxidation of homoallylic alcohols, one titanium would interact with a hydroxy group while the other titanium 18


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would oxidize the tertiary amine. Indeed, asymmetric oxidation of γ-hydroxy amine provided chiral amine oxides in highly enantioselective manner (Scheme 29). Under similar conditions, kinetic resolution of racemic secondary amino alcohols by asymmetric oxidation was also achieved to give chiral γ-amino alcohols with high enantioselectivity (Scheme 30).

Optically active γ-amino

alcohols can be found in bioactive natural products and pharmaceutical agents, and the application of chiral γ-amino alcohols for chiral ligands is increasing. Scheme 29. Binuclear Titanium Complex-Catalyzed Enantioselective Oxidation of γ-Hydroxy Amines

Scheme 30. Kinetic Resolution of γ-Amino Alcohols

2. Enantio- and Regioselective Ring-Opening Reactions of Epoxides with Various Nucleophiles 2.1. Introduction In synthetic organic chemistry, asymmetric epoxidation of alkenes is one of the most significant transformations to give a wide range of chiral epoxides, which have potential to be useful chiral building blocks for the synthesis of natural products and biologically active synthetic analogs.5 Regio- and enantiospecific ring-opening reactions of readily available chiral epoxides synthesized by well-established asymmetric epoxidation provide a direct route to useful highly functionalized molecules with multiple chiral centers.39

However, in most cases, highly

regioselective ring-opening reaction of epoxides is achieved only when two epoxide carbons can be sterically or electronically distinguishable.

In other words, the electronic nature and steric

hindrance of substituents on the epoxide play important roles for the regioselectivity of ringopening reactions, and high regioselectivity has been predominantly achieved with terminal and

19



aromatic epoxides. For epoxides bearing electronically and sterically similar carbons such as aliphatic internal epoxides, highly regioselective ring-opening reaction is quite difficult. Substrate-directed ring-opening reactions with functional groups such as a hydroxy group are elegant methods for achieving high regioselectivity (Scheme 31). By the formation of a metal alkoxide followed by the coordination of the epoxide oxygen to the metal center, two epoxide carbons can be electronically distinguished to achieve high regioselective ring-opening reactions. The favored position of the ring-opening reaction is determined by the relative position of the two epoxide carbons to the directing group regardless of the substituent pattern of the epoxide. The utility of the substrate-directed ring-opening reaction was first demonstrated by Sharpless and Caron in 1985, where regioselective ring-opening reaction of 2,3-epoxy alcohol with various nucleophiles proceeded with a stoichiometric amount of Ti complex (Scheme 32).40 However, all directing group-assisted ring-opening reactions required a stoichiometric amount of promoter, hence, catalytic reactions were strongly desired. Scheme 31. Regioselective Ring-Opening Reactions with Directing Groups

Scheme 32. Stoichiometric Amount of Ti Complex-Catalyzed Ring-Opening Reactions of Epoxides with a Directing Group

2.2. Regioselective Ring-Opening Reactions of 2,3-Epoxy Alcohols41 2.2.1 Amines As mentioned in Section 1.4.4, during the course of our research on W/BHA-catalyzed asymmetric epoxidation of allylic alcohols with H2O2 as oxidant, formation of ring-opened epoxides by nucleophilic attack of H2O2 was observed. Although the regioselectivity of the ringopening reactions is not sufficient, the formation of the ring-opened product indicates W salts can be effective catalyst for the regioselective ring-opening reactions of 2,3-epoxy alcohols. We first focused on the regioselective amination of 2,3-epoxy alcohol to give 3-amino-1,2-diol, which is a useful synthetic intermediate for biologically active compounds.42

20


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With a catalytic amount of W(OEt)6, amination of 2,3-epoxy alcohols proceeded for a broad scope of substrates to give 3-amino-1,2-diol in good to excellent yield and high regioselectivity (Scheme 33).

Nucleophilic attack selectively proceeded at the C3 position

regardless of the substituent pattern of epoxy alcohols. High regioselectivity is also obtained for challenging aliphatic internal alkanes, and, in particular, the trans isomer gave better regioselectivity than the cis isomer. Surprisingly, the reactivity of highly nucleophilic aliphatic amine is lower than aromatic amine for the amination, so that high catalyst loading was necessary to obtain sufficient yield. One explanation for the result is that higher basicity of aliphatic amines than aromatic amines results in lower Lewis acidity of W through the coordination due to the stronger electron-donating nature of aliphatic amines. Scheme 33. W(OEt)6-Catalyzed Amination of 2,3-Epoxy Alcohols

2.2.2 Alcohols We next focused on the ring-opening reactions of 2,3-epoxy alcohols with oxygen nucleophiles. Unfortunately, under the same reaction conditions as the amination, the yields of the ring-opening reactions with alcohols are miserable probably due to the lower nucleophilicity of oxygen nucleophile than amine nucleophile.

To address the problem, a strong Lewis acid,

WO2(OTf)2, was prepared in situ from WO2Cl2 and AgOTf to facilitate the attack of oxygen nucleophiles. Indeed, WO2(OTf)2 catalyzed the ring-opening reactions with phenols and alcohols in moderate yield and perfect regioselectivity (Scheme 34). Compared with the yields of amination, the yields of the ring-opening reaction with alcohols were relatively low, even if excess alcohol was added. A control experiment showed the epoxy alcohol was completely consumed in short time without the addition of oxygen nucleophile, indicating the decomposition of 3,4-epoxy alcohol by nucleophilic attack of the alcohol in another epoxy alcohol. Scheme 34. WO2(OTf)2-Catalyzed Ring-Opening Reaction of 2,3-Epoxy Alcohols with Alcohols

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Several control experiments by use of the epoxides without a hydroxy group demonstrated the role of hydroxy for the ring-opening reactions of epoxy alcohols (Table 1). The ring-opening reactions of trans-2,3-epoxy octane with an amine and alcohol did not exhibit regioselectivity at all (Table 1, entries 1 and 4). In contrast, the ring-opening reaction of styrene oxide with an alcohol with selectively proceeded at only the benzylic position probably due to the electronic effect of the phenyl group (Table 1, entry 2). For 1,2-epoxy-3-methylpropane, the more substituted carbon was favored, but the regioselectivity was moderate (Table 1, entry3). All results indicate the hydroxy group assists the regioselective W-catalyzed ring-opening reaction.

In

particular, as shown in entries 1 and 4, when two epoxide carbons are electronically and sterically similar, the presence of hydroxy group is crucial to obtain high regioselectivity. Table 1. Effect of Hydroxy Group for Regioselectivity

Entry

a

Epoxide

Nu

Condition A

yield (%) 71

1

PhNH2

2

r.r. 50:50

PhNH2

A

74

>99:1a

3

PhNH2

A

30

70:30a

4

n-PrOH

B

76

50:50

The more substituted site was favored.

Not only the presence of hydroxy group in the substrate but also the relative position of hydroxy group from the epoxide is important for the W-catalyzed ring-opening reactions (Scheme 35). Whereas W-catalyzed amination of 2,3-epoxy pentanol proceeded in high regioselectivity (Scheme 33), the amination of 3,4-epoxy butanol, which has a hydroxy group more distant from the epoxide, resulted in almost no regioselectivity.

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Scheme 35. W(OEt)6-Catalyzed Ring-Opening Reaction of 3,4-Epoxy Alcohol

2.2.3 Halogenation43 Regioselective ring-opening reactions of 2,3-epoxy alcohols with halogens have required a stoichiometric amount of promoter, and a catalytic version of these reactions has been highly desirable. In terms of the utility of reactions, we focused on the catalytic halogenations of 2,3epoxy alcohol with simple and commercially available lithium halides as nucleophile. According to the types of substrates, WO2Cl2, MoO2(acac)2, and CeX3 (X = Cl, Br, or I) were used for the regioselective halogenation, respectively (Scheme 36).

First, WO2Cl2 smoothly catalyzed

chlorination of 2,3-epoxy alcohols to provide ring-opening products with high regioselectivity. Next, during the halogenation with LiBr and LiI as halogen sources, the chlorination as well as the desired bromination and iodination proceeded due to the halogen exchange reactions between WO2Cl2 and lithium salts. Screening of chlorine-free W and Mo salts indicated MoO2(acac)2 is the best catalyst for the bromination and iodination. Finally, CeX3 was employed for the halogenation of aliphatic 2,3-disubstituted epoxy alcohols to achieve high regioselectivity due to the low regioselectivity by WO2Cl2 and MoO2(acac)2. Scheme 36. Halogenation of 2,3-Epoxy alcohols by W, Mo, and Ce Salts

To test the effect of the hydroxy group on the halogenation of epoxy alcohols, several epoxides bearing Ac-protected alcohol were applied to the ring-opening reaction (Scheme 37). Whereas low regioselectivity was observed with the trans-aromatic epoxide, the terminal epoxide provided perfect regioselectivity. These results indicate the effect of hydroxy as the directing group is important for the regioselectivity when the steric- and electronic differences between two epoxide carbons are small. 23



Scheme 37. Effect of the Hydroxy Group for Halogenation

To explain the C3 selective nucleophilic attack on 2,3-epoxy alcohols, we proposed model A in Figure 3, where 2,3-epoxy alcohol coordinates the W center in a bidentate fashion. The overlap between C3-O bond and the unoccupied d orbital of W is larger than that of C2-O bond. In this situation, C3-O bond can be cleaved more easily, resulting in regioselective ring-opening. In Figure 3B and 3C, the higher reactivity of trans isomer than cis isomer is explained. During the reaction with cis-epoxy alcohol, the substituent R at C3 position points to the W center, generating steric repulsion between W and the substituent R. In sharp contrast, the substituent R of transepoxy alcohol points to the opposite side of the W center. Less steric repulsion leads to stronger coordination of trans-epoxy alcohol to the W center and results in higher reactivity and regioselectivity for ring-opening reaction.

Figure 3. Reaction Models for Regioselective Ring-Opening Reaction 2.3. Kinetic Resolution of 2,3-Epoxy Alcohols by Enantioselective Amination44 Although the ring-opening reaction of chiral epoxides synthesized by well-established enantioselective epoxidation efficiently leads to highly functionalized molecules without the loss of enantioselectivity, kinetic resolution of readily available racemic epoxides with a simple ligand by enantioselective ring-opening reactions has remained quite attractive due to the following reasons. (1) Asymmetric epoxidation cannot be applied to several substitution patterns of substrates. (2) Preparation of some chiral ligands for asymmetric epoxidation requires several steps for synthesis from commercially available compounds.

(3) Combination of asymmetric epoxidation and 24


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asymmetric ring-opening reactions provides a route for synthesis of almost enantiopure compounds (Section 4). Since the important work by Nugent and Jacobsen for kinetic resolution of epoxides by ring-opening reactions, enantioselective ring-opening reactions with various nucleophiles has been studied.45

Whereas remarkable results with high enantioselectivity were reported, high

regioselectivity was only realized by unfunctionalized terminal epoxides or meso-epoxide. To address this issue, we developed a hydroxy group-directed highly regioselective kinetic resolution of 2,3-epoxy alcohols by ring-opening reactions. Based on the result of W/BHA-catalyzed highly enantioselective epoxidation of allylic alcohols (Section 1.4.4), BHA ligand was employed as a chiral ligand for kinetic resolution. For achieving high enantioselectivity, addition of a catalytic amount of H2O2 is crucial. Heterogeneous W(OEt)6 solution became clear after the addition of H2O2 probably due to the formation of easily soluble W-peroxo complex from the W complex and H2O2. Under the optimized reaction conditions, various 2,3-epoxy alcohols and amines were tested (Scheme 38).

All amination with trans-2,3-epoxy alcohols provided the ring-opening

products in almost perfect regioselectivity with high enantioselectivity. A variety of aryl amine can be applied to the amination while the reaction with aliphatic amine gave miserable results. Some of the obtained chiral epoxy alcohols can be converted to biologically active compounds. Scheme 38. W/BHA-Catalyzed Kinetic Resolution of Allylic Alcohols by Amination

2.4. Ni-Catalyzed Regioselective Amination of 3,4-Epoxy Alcohols46 Regio- and stereoselective ring-opening reaction of 3,4-epoxy alcohols with various nucleophiles is a straightforward method for the synthesis of a variety of chiral building blocks. For instance, various chiral γ-hydroxy δ-aminoalcohols can be synthesized by C4 selective amination of 3,4-epoxy alcohols. δ-aminoalcohol can be converted to important synthetic intermediates of γamino acids and has received attention from the perspective of pharmaceuticals.47 Thus, highly regio- and enantioselective ring-opening reactions of 3,4-epoxy alcohols are desired.

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In contrast to the well-studied regioselective ring-opening reactions of 2,3-epoxy alcohols over the last decades, the development of ring-opening reactions of 3,4-epoxy alcohol, bearing hydroxy group apart from the epoxide, are quite limited and challenging projects.48 As shown in Scheme 35, our W complex-catalyzed reaction system, which is effective for the amination of 2,3-epoxy alcohols, did not exhibit regioselectivity for the amination of 3,4-epoxy alcohols. To obtain sufficient regioselectivity, our group screened appropriate catalysts and ligands with aniline and racemic trans-3,4-epoxy hexane-1-ol. Since two epoxide carbons of trans-3,4epoxy hexane-1-ol are sterically and electronically similar, regioselective ring-opening reaction is quite difficult. The combination of Ni and chiral BINAM ligand provided promising regio- and enantioselectivity for the kinetic resolution. Screening of various BINAM derivatives revealed mono-N-naphthylmethylated BINAM showed high enantioselectivity.

Kinetic resolution with

aromatic epoxy alcohol and aniline derivatives yielded the ring-opening product in high diastereoselectivity whereas, unfortunately, relatively low enantioselectivity was obtained for aliphatic epoxides (Scheme 39). Scheme 39. Ni/L12-Catalyzed Kinetic Resolution of 3,4-Epoxy Alcohols by Amination

Control experiments demonstrate the role of the hydroxy group for the amination (Scheme 40). The results of kinetic resolution of trans-epoxy cinnamyl alcohol, OAc and OTBSprotected trans-epoxy homocinnamyl alcohol, and trans-epoxy bishomocinnamyl alcohol indicate the properly positioned free hydroxy group is essential for both the yield and regioselectivity. Scheme 40. Effect of the Hydroxy Group on the Amination

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2.5. Ring-Opening Reactions of 2,3-Epoxy Sulfonamide 2.5.1 Non-Asymmetric Reactions41,43 Regioselective amination of chiral 2,3-epoxy amines affords chiral 1,3-diaminoalkan-2ols, which are characteristic structures found in an enormous number of biologically active compounds. The starting material, chiral 2,3-epoxy amine, is available by our developed Hf/BHAcatalyzed asymmetric epoxidation of allylic sulfonamides (Section 1.4.3). However, to the best of our knowledge, regioselective and catalytic ring-opening reaction of internal epoxy amines by use of amine as a directing group has not been achieved yet. Based on the results of ring-opening reactions of 2,3-epoxy alcohols in Section 2.2, ring-opening reactions of 2,3-epoxy sulfonamide regioselectively proceeded with various nucleophiles including not only amines but also alcohols and halogens (Scheme 41). Scheme 41. Regioselective Ring-Opening Reaction of 2,3-Epoxy Sulfonamides with Various Nucleophiles

2.5.2. Gd-Catalyzed Kinetic Resolutions49 As mentioned above (Section 2.5.1), the combination of Hf/BHA-catalyzed asymmetric epoxidation of allylic sulfonamides and W-catalyzed regioselective ring-opening reaction is an efficient method to access 1,3-diaminoalkan-2-ols. However, the first-step reaction, Hf/BHAcatalyzed epoxidation, can be applied to only terminal- or aliphatic olefins.

3-Amino-3-

phenylpropan-2-olamines, which can be found in biologically active compounds and drug candidates, cannot be synthesized by this method. To overcome the limitation of the method, we developed a kinetic resolution of aromatic 2,3-epoxy sulfonamides by amination, which provides chiral 3-amino-3-phenylpropan-2-olamines. Screening of various catalysts including Ni/BINAM and W/BHA indicates Gd/N,N-oxide complex is appropriate for the amination.50 With Gd/N,N-dioxide complex, both aliphatic and aromatic amines reacted with aromatic trans-2,3-epoxy sulfonamides to provide the ring-opening 27



products in high yield and enantioselectivity, and perfect regioselectivity (Scheme 42). In contrast, unfortunately, the substitution pattern of epoxy sulfonamide is limited. The amination with cis-, terminal-, and aliphatic trans-2,3-epoxysulfonamide gave low enantioselectivity of ring-opened products. In particular, the regioselectivity was completely lost with cis-epoxy sulfonamide. Scheme 42. Enantioselective Ring-Opening Reactions of trans-2,3-Epoxy Sulfonamides by Amine Nucleophiles

Control experiments revealed the role of the sulfonamide group for the Gd-catalyzed ring-opening reaction (Table 2). Unfunctionalized trans-1-phenyl propylene oxide, epoxy sulfone, Boc-protected epoxy amine, and Boc-protected epoxy sulfonamide were employed for the ringopening reactions. As shown in Scheme 42, high yield and enantioselectivity of the ring-opening product is obtained with NHTs as a directing group (Table 2, entry 2). In contrast, the reaction with unfunctionalized trans-1-phenyl propylene oxide, epoxy sulfone, and Boc-protected epoxy amine results in low yield and poor enantioselectivity. (Table 2, entries 1, 3, and 4). The ring-opening reaction with Boc-protected epoxy sulfonamide did not give the desired product (Table 2, entry 5). All results indicate that not only sulfonyl moiety but also NH-sulfonyl group itself plays important role as directing group for Gd-catalyzed ring-opening reactions of epoxides, which is in contrast to the results of asymmetric epoxidation of allylic sulfonamide (Section 1.4.3). In the epoxidation, the coordination of the sulfonyl moiety played a central role in the reactions. Table 2. Control Experiments for Enantioselective Amination of Epoxides

entry 1 2 3 4 5

R Me NHTs Ts NHBoc BocNTs

n 0 1 2 1 1

T (°C) 55 r.t. 55 55 55

28

yield (%) 21 98 52 23 0


ee (%) 14 96 26 30 –

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2.6. Ni-catalyzed Regio-, Diastereo-, and Enantioselective Arylation of 3,4-Epoxyalcohols51 C4 selective ring-opening reaction of aryl substituted 3,4-epoxy alcohols with aryl reagents is a challenging reaction to directly give 4,4-diarylalkane, which can be found in various bioactive units and has been used in the pharmaceutical industry due to important roles in living organisms.52 To realize an efficient synthetic method, we have developed hydroxy group-directed Ni-catalyzed regio-, diastereo-, and enantioselective ring-opening reaction of 3,4-epoxy alcohols with aryl reagents. Ni/chiral bisoxazoline (L14) complex realized the arylation of chiral 3,4-epoxy alcohols with aryl iodine (Scheme 43). In most cases, the resioselectivity and diastereoselectivity of diaryl alkanes were quite high. Scheme 43. Regio-, Diastereo, and Enantioselective Arylation of 3,4-Epoxy Alcohols

To test the effect of the hydroxy group on the cross-coupling reactions, 2-methyl-3phenyloxirane and trans-2-(3-phenyl-oxiran-2-yl)ethanol were reacted under the same reaction conditions, respectively (Scheme 44).

The coupling reaction with trans-2-(3-phenyl-oxiran-2-

yl)ethanol, which has a hydroxy group at a β position, gave higher diastereoselectivity of coupling products (12:1 vs 4:1), suggesting the hydroxy group at the β position is essential for the high diastereoselectivity. Scheme 44. Effect of the Hydroxy Group on the Diastereoselectivity of Coupling Reaction

29



3. Synthesis of Almost Enantiopure Compounds44,53 As mentioned in Section 3, chiral ring-opened products of epoxides can be synthesized by the following two methods: (1) enantioselective epoxidation followed by regioselective ringopening reaction and (2) nonasymmetric epoxidation followed by kinetic resolution of racemic epoxides by nucleophilic attack. However, preparation of almost enantiopure compounds, which are important in pharmaceuticals, is difficult with these methods. For the synthesis of almost enantiopure compounds, we proposed a new method with the combination of asymmetric epoxidation and kinetic resolution of the generated epoxides, where the enantioselectivity can be improved in each step (Scheme 45).54 Scheme 45. Synthesis of Almost Enantiopure Compounds by Combination of Two Asymmetric Reactions

The combination of our developed W/BHA-catalyzed asymmetric epoxidation and enantioselective amination gave a wide range of almost enantiopure amino alcohols (Scheme 46). The key to achieve smooth reaction is the use of opposite absolute configuration of BHA ligand for each W-catalyzed epoxidation and ring-opening reaction.

30


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Scheme 46. Synthesis of Almost Enantiopure 3-Amino-1,2-Diol by Enantioselective Epoxidation of Allylic Alcohols Followed by Amination

Kinetic resolution of racemic secondary allylic alcohols by epoxidation followed by amination of the generated epoxides also leads to almost enantiopure 3-amino-1,2-diol bearing three continuous chiral centers. Among Sharpless asymmetric epoxidation and our developed VO(OiPr)3/BHA (Section 1.3.1), Hf(Ot-Bu)4/BHA (Section 1.4.1), and WO2(acac)2/BHA (Section 1.4.4), in most cases, Sharpless asymmetric epoxidation followed by W/BHA-catalyzed amination resulted in the best reactivity (Scheme47). Furthermore, enantioselective synthesis of three biologically active compounds was also achieved by this combined method. Scheme 47. Synthesis of Almost Enantiopure Compounds with Two Kinetic Resolutions

4. Amidation of Carboxylic Acid Esters with Directing Group55 As mentioned in section 1-3, we have developed two types of substrate-directed reactions: epoxidation of alkenes and ring-opening reactions of epoxides with various nucleophiles. Toward the further development of the substrate-directed reaction, we next focused on directing group-assisted amidation of β-hydroxy carboxylic acid esters. Amide is one of the most important functional groups, which can be found in natural products, pharmaceuticals, polymers, and proteins. Due to the utility of the amide group, efficient amidation without wasteful peptide coupling reagent is an important goal in current organic synthetic chemistry.56

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The development of synthetic methods for catalytic amidation has received the attention of a number of scientists, and brilliant methods have already been achieved.57 However, the development of chemoselective catalytic amidation has been limited although chemoselective amidation can be applied to pinpoint chemical ligation of peptides and the reaction for complex organic compounds. Our developed substrate-directed amidation with β-hydroxycarboxylic acid ester elegantly realized metal-catalyzed chemoselective amidation.

Metal catalyst can

chemoselectively activate the ester group of the β-hydroxycarboxylic acid ester due to the direction of the hydroxy group (Scheme 48). The activated carboxylic acid ester is selectively reacted with amines to give β-hydroxy amides. Scheme 48. Hydroxy Group at β Position Directing Amidation of Carboxylic Acid Esters

An equimolar amount of β-hydroxycarboxylic acid ester and carboxylic acid ester were reacted with amines in the presence of Ta(OEt)5 catalyst to test the chemoselectively. Ta(OEt)5 preferentially catalyzed the amidation of β-hydroxycarboxylic acid ester to provide β-hydroxy amides in high yield. The amidation chemoselectively proceeded with various combinations of βhydroxycarboxylic acid ester and amines. (Scheme 49). Scheme 49. Ta(OEt)5-Catalyzed Chemoselective Amidation of Carboxylic Acid Esters

The synthetic utility of hydroxy group-directed chemoselective amidation was demonstrated by application to the catalytic synthesis of dipeptide derivatives without enzyme, which is still a challenging reaction in modern organic chemistry.

To our delight, Ta(OEt)5

chemoselectively catalyzed amidation of N-Boc serine methyl ester with amino acid methyl esters to give the corresponding dipeptides (Scheme 50). Neither epimerization of the amino acid or

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amidation of the ester group of amino acid methyl ester inhibited the practicality of hydroxy groupdirected amidation. Scheme 50. Dipeptide Synthesis by Ta(OEt)5

In summary, our laboratory has mainly developed the metal complex-catalyzed substratedirected reactions with alcohols as the directing group and demonstrated the proper position of alcohol is important for the activity and selectivity for the reactions. First, we discussed the asymmetric epoxidation of alkenes with the chiral ligands based on hydroxamic acid. Modification of the ligands and the choice of metal complexes realized the challenging reactions such as asymmetric epoxidations of homoallyl alcohols and bishomoallyl alcohols. In some cases, we actually represented our methods can distinguish the sterically and electronically similar alkenes. Furthermore, a new chiral ligand bearing 8-hydroxyo quinoline unit was synthesized, which acts as cooperative catalyst after the metalation with Ti during the course of the asymmetric epoxidation of homoallyl alcohols.

Regioselective ring-opening reactions of epoxy alcohols with various

nucleophiles were also achieved by use of various metal catalysis, where the direction of alcohol results in the selectivity. Finally, we recently developed hydroxy group-directed chemoselective amidation of β-hydroxy carboxylic acid ester and applied the method for the peptide synthesis. As shown in this perspective, the substrate-directed reaction is attractive strategy to realize the selective modification of molecule bearing multiple sterically and electronically similar reactive sites through the interaction between the functional group and the catalyst or reagent from the different viewpoint from reagent- and catalyst-controlled reaction.

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AUTHOR INFORMATION Corresponding Author E-mail: [email protected] E-mail: [email protected] ORCID Takahiro Sawano: 0000-0001-6851-9579 Hisashi Yamamoto: 0000-0001-5384-9698 Notes The authors declare no competing financial interest. Biographies

Takahiro Sawano was born in Shizuoka (Japan) in 1986. He obtained his B.S. degree from Tohoku University in 2008 under the supervision of Professor Minoru Ueda and received his Ph.D from Kyoto University in 2013 under the supervision of Professor Tamio Hayashi.

He joined the

laboratory of Professor Wenbin Lin at the University of Chicago (USA) as a postdoctoral fellow. In 2017, he started working in the laboratory of Professor Hisashi Yamamoto as Research Assistant Professor.

Hisashi Yamamoto received his Bachelor degree from Kyoto University (Japan) and his Ph.D. from Harvard University. He became assistant professor at Kyoto University and in 1977 was appointed as associate professor at the University of Hawaii. In 1980, he moved to Nagoya University (Japan)

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as a full professor. In 2002, He moved to the University of Chicago as a professor. In 2012, he was appointed as professor and director of Homogeneous Catalyst Research Center at Chubu University (Japan). Acknowledgement 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, and Advance Electric Co., Inc.

We also thank

Hayanon's Science Manga Studio for the design of cover art.

References (1) (a) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. Rev. 1993, 93, 1307-1370. (b) Breit, B.; Scmidt, Y. Chem. Rev. 2008, 108, 2928-2951. (c) Rousseau, G.; Breit, B. Angew. Chem., Int. Ed. 2011, 50, 2450-2494. (d) Mulzer, J. Basic Principles of Asymmetric Synthesis. In Comprehensive

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Substrate-Directed Catalytic Selective Chemical Reactions

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