Asymmetric Catalysis with Chiral Bis(oxazolinyl)phenyl Transition-metal Complexes. Hisao Nishiyama

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1 o.172 esearch Article Asymmetric Catalysis with Chiral Bis(oxazolinyl)phenyl Transition-metal Complexes isao ishiyama Graduate School of Engineering, agoya University Furo-cho, Chikusa, agoya , Japan Abstract: The chiral ligands,,, and,c,-tridentate ligands {bis(oxazolinyl)pyridine [Pybox] and bis(oxazolinyl)phenyl [ebox]}, have been reviewed to show their high potential for asymmetric catalysis. The methods for preparation of their ligands and the corresponding complexes have been described. In addition, asymmetric catalytic reactions by use of ebox complexes are introduced concisely to show high enantioselectivities with relatively lower catalyst loading (1 mol% or lower). These tridentate and nitrogen-based ligands and their complexes are useful in modern catalytic organic synthesis. Keywords: Bis(oxazolinyl)pyridine, Pybox, Bis(oxazolinyl)phenyl, ebox, Transition-metal complex, Asymmetric catalytic reaction 1. Introduction Asymmetric catalysis is very important subject to provide optically active compounds, which are often applied to production of pharmaceutical and physically functional materials. Therefore, practical and environmentally benign methods have been desired for efficiently obtaining optically active compounds, especially by using transition-metal catalysts with chiral ligands. We have so far developed the optically active ligands,,, and,c,-tridentate ligands [bis(oxazolinyl)- pyridine, abbreviated as Pybox and bis(oxazolinyl)phenyl by ebox], which consist of two lateral chiral oxazolines and one central nitrogen atom or carbon atom, respectively (Figure 1). 1,2) The oxazoline rings of the Pybox and ebox ligands make the chiral reaction-site C 2 -symmetric to form metal intermediates stereoselectively giving high enantioselectivity. The ligands are modulated by substituents on the oxazoline skeletons and at the remote para-position (Y) in order to control the catalysis sterically and electronically. In this article, preparation of the ebox and Pybox ligands, preparation of the metal rhodium or ruthenium complexes, and development of asymmetric catalytic reactions are concisely described to show their potential for general use in organic synthesis. S S = : Pybox-ip-(S,S) Bis(oxazolinyl)pyridine S C S = : ebox-ip-(s,s) Bis(oxazolinyl)phenyl itrogen-based tridentate ligands Chiral environment with two oxazolines C 2 symmetry Diversity of substituents emote electronic control of substituents Y S Y X M chiral reaction site X =, C S chiral product reagent substrate Figure 1. Chiral bis(oxazolinyl)pyridine and bis(oxazolinyl)phenyl ligands: features of the nitrogen-based tridentate coordination and the chiral reaction site 2

2 o.172 h-pybox complexes catalyzed the hydrosilylation of ketones with diphenylsilane to give optically active secondary alcohols in high enantioselectivity up to 99% (Scheme 1). 3) Although h-pybox trichloride itself did not show the catalytic activity for the hydrosilylation, the complex was treated with silver ion to work efficiently giving the hydrosilylation products. ext, Pybox reacts with a u-cymene complex under an ethylene atmosphere (1 atm) to form the corresponding ethylene complex, which exhibits high catalytic activity for asymmetric cyclopropanation of terminal alkenes with diazoacetates. 4) Fortunately, the trans-isomer of the cyclopropane product was obtained in a high trans-cis ratio up to 97% with high enantioselectivity. The mechanism was clarified by isolation of the intermediate u-carbene complex. 4c) The cyclopropanation with u-pybox catalyst was later applied to the large scale production of pharmaceutical intermediates in industry (Scheme 2). 5) u-pybox catalysts have been applied to other synthetic reactions, for example, asymmetric transfer hydrogenation of ketones or asymmetric C amination. 6,7) Pybox ligands have been used for a number of asymmetric catalysts with a variety of metals to show high catalytic performance in enantioselective reactions. Pybox-ip and ph are now commercially available. h C 3 h-pybox-ip 1 mol% AgBF 4, 2 Si 2 Pybox-ip TF, 0 C, 2 h then 3 C 3 94% 95% ee C 3 3 C C 2 Et 87% 94% ee 73% 91% ee 92% 99% ee 91% 95% ee u 2 C C 2 u-pybox-ip 1 mol% 2 =CC 2 -l-menthyl C 2 C C 96% t:c 95:5 t 97% ee C 2 = Et 73% t:c 91:9 t 89% ee = t-bu 65% t:c 97:3 t 94% ee = l-ment 84% t:c 96:4 t 95% ee C 2 84% t:c 96:4 t 95% ee 3 C C 2 C 3 86% t:c 79:21 t 98% ee Scheme 1. Asymmetric hydrosilylation and cyclopropanation with Pybox catalysts u-pybox-ip 2 mol% 2 =CC 2 Et 1. a 2. 3 P 4 [Large scale 52 kg] toluene, 60 C C 2 Et 98% trans 91% 85% ee [Large scale 113 kg] 3. diastereo recrystalization C 2 total yield 65% >99.9% ee latonin agonist drug candidate C Ts C 2 C Ts Selective Serotonin euptake Inhibitor 2 Scheme 2. Large scale production in industry 3

3 o Preparation of Pybox and ebox, and their h and u complexes Preparation of Pybox starts from pyridine-2,6-dicarboxylic acid, which is treated with thionyl chloride giving the acid chloride followed by amide formation with valinol (Scheme 3). 3) Then, treatment of the amide-alcohol with thionyl chloride affords the corresponding amide-chloride, which is subsequently cyclized to form oxazoline rings by treatment with alkaline solution. Final product Pybox is purified by recrystallization to give white needles. The corresponding h and u complexes were prepared by the reaction with rhodium chloride and ruthenium-cymene complex, respectively. 3,4) Preparation of the ebox ligand precursor, [ebox], starts from isophtharoyl dichloride, which is treated with valinol followed by the reaction with Ms forming the sulfonate and subsequently oxazoline formation with base (Scheme 4). 8c) In order to prepare h-ebox-ip, a mixture of [ebox] and rhodium trichloride at 60 C gives the corresponding h- ebox dichloro complex, which is readily converted to the h- ebox 2 diacetate. 8a) Although the u-ebox complex could not be prepared with [ebox], the 3,5-dimethyl substituted ligand [dm-ebox] was found to be a good precursor for C bond formation. 9,10,11) The mixture of [dm- ebox] and ruthenium chloride in the presence of Zn and cycloocatadiene was heated at reflux temperature to give the corresponding u-ebox complex, which was proved to be a dimeric complex. Then, the complex was converted to a monomeric form by treatment with acetylacetonate, u-dm- ebox-ip-acac in good yield. 9,10,11) 2 C Pybox-ip C 2 1. S 2, reflux 2. S-Valinol 3. S 2 h 3 ( 2 ) 3 reflux in Et 77% 88% 68% h a - 2 h-pybox-ip range solids m.p. 279 C (dec) Pybox-ip White needles m.p C Pybox-ip 0.5 [u 2 (p-cymene)] 2 C 2 =C 2 (1 atm) C 2 2, r.t. 93% u 2 C C 2 u-pybox-ip C 2 4 Dark-red solids m.p C (dec) Scheme 3. Preparation of Pybox and their h and u complexes 1. S-Valinol Et 3 2. Ms 3. aq. K 2 C 3 C C C % [ebox-ip] Colorless solids m.p. 53 C [ebox-ip] h 3 ( 2 ) 3 a 2 C 3 in C, 5 h 56% h 2 h-ebox-ip dichloride Pale yellow solid m.p. 158 C (dec) AgAc r.t., C % h Ac Ac 2 h-ebox-ip diacetate Yellowish orange solid m.p. 235 C (dec) 3 5 [dm-ebox-ip] u Zn, CD Et reflux 65% u C 2 u-dm-ebox-ip-[(c)] 2 Yellow solid m.p C (dec) a(acac) toluene r.t. 90% u C u-ebox-ip-acac Yellow solid m.p C (dec) Scheme 4. Preparation of ebox and their h and u complexes 4

4 o Asymmetric ydrosilylation 3-1. Asymmetric ydrosilylation of Alkenes Asymmetric hydrosilylation of alkenes is a preparative method for optically active secondary alcohols via formation of silane-adducts with subsequent oxidation. h-ebox- diacetate complex (A and B, 1 mol%) works as a catalyst at 30 C in 1 h efficiently to give the corresponding silane-adducts in high yields and high enantioselectivity up to 99% (Scheme 5). β-thylstyrene was selectively converted to the α-hydroxy compound. 12) 3-2. Asymmetric Conjugate ydrosilylation h-tb-ebox-ip diacetate C was examined as an efficient catalyst for conjugate reduction of α,β-unsaturated aldehydes such as cinnamaldehyde to exclusively produce the corresponding conjugate reduction products in high yields (Scheme 6). 13) When chiral catalyst h-ebox-ip A was used, the 1,2-reduction product was obtained in ca % yield. β,β-disubstituted α,β-unsaturated ketones and esters were reduced with (Et) 2 Si and the acetate catalysts A and hdm-ebox-ip diacetate D to give the corresponding dihydro compounds in high yields and high enantioselectivities. 8a,14,15) h-ebox (1 mol%) hydrosilane (1.2 equiv) 2 2 C 3 toluene, 30 C, 1 h KC 3, KF #(Et) 2 Si (Et) 3 Si (Et) 3 Si Cat. A Cat. A Cat. B 97% 99% 99% α:β 63:37 78:22 75:25 α 95% ee 98% ee 99% ee h Ac Ac 2 C 3 as above # Si(Et) 2 C3 A: h-ebox-ip B: h-ebox-sb = = s-bu as above # 98% α:β = 95:5 α 98% ee Si(Et) 2 99% 100:0 91% ee Scheme 5. Asymmetric hydrosilylation of alkenes t-bu C h-ebox C (1 mol%) (Et) 2 Si (1.5 equiv) toluene, 60 C, h C 98% 0% h Ac Ac 2 as above Cat. A or D C: h-tb-ebox-ip Cat. A: Cat. D: = Et 98% 95% ee = 97% 92% ee = Et 99% 96% ee = 98% 97% ee = Et 90% 96% ee h Ac Ac 2 A: h-ebox-ip h Ac Ac 2 D: h-dm-ebox-ip Et C 2 Et Cat. A: 97% 98% ee Cat. A: 96% 92% ee Scheme 6. Asymmetric conjugate reduction of α,β-unsaturated carbonyl compounds 5

5 o.172 β,β-diarylacrylates (Ar 1 Ar 2 ) were reduced under the same conditions of the conjugate hydrosilylation to give optically active 3,3-diarylpropanoates, which are useful precursors for various pharmaceutical compounds (Scheme 7). 16) Although it is congested around the β-carbon, the reaction took place smoothly. The reaction on a gram scale was demonstrated. The starting β,β-diarylacrylates can be prepared by a stereospecific copper catalyzed coupling reaction with arylboronic acids and substituted phenylpropiolates according to Yamamoto s procedure. 17) The conjugate reduction with hydrosilane and the h- ebox catalyst can be applied to reductive desymmetrization of γ,γ-disubstituted cyclohexadienones (Scheme 8). 18) 4-Alkyl-4- aryl-cyclohexadienones were reduced to give the corresponding γ,γ-disubstituted cylcohexenone derivatives in high yields and up to 77% ee. Spiro-carbocyclic skeletons were subjected to the reduction giving higher ees up to 93%. The reaction with 2 SiD 2 clarified the direction of hydride attack on the β-carbon atom (Figure 2). A plausible model of the reduction and an optimized structure, which have the hydride in the equatorial position and attacks the e face of the double bond, was described. Ar 1 Ar 2 C 2 Et h-ebox-ip A (1 mol%) (Et) 2 Si (1.5 equiv) toluene, 60 C, 2 h then 3 Ar 1 Ar 2 C 2 Et A h Ac Ac 2 Et 2 C C 2 Et C 2 Et Et 2 C C 2 Et C 2 Et C 2 Et 97% 96% ee (S) Ar 1 = C 6 5, Ar 2 = p-c 6 4, 92% 97% ee () 90% 98% ee 95% 98% ee 96% 99% ee 99% 97% ee Scheme 7. Asymmetric conjugate reduction of β,β-diarylacrylates h-ebox-ip A (1 mol%) (Et) 2 Si (1.5 equiv) toluene 50 C, 1 h, then 3 91% 73% ee A h Ac Ac 2 p-c 6 4 p-c % 73% ee 92% 81% ee 95% 77% ee 89% 93% ee 88% 93.5% ee 95% 91% ee 89% 88% ee 91% 81% ee Scheme 8. Conjugate reduction of γ,γ-disubstituted cyclohexadienones Favored Disfavored C e 3 h SiX 3 h Si C 3 Figure 2. Plausible structure of asymmetric induction and catalytic cycle 6

6 o Asymmetric eductive Aldol eaction h-ebox diacetate complexes can work as catalysts for the conjugate reduction of α,β-unsaturated carbonyl compounds with hydrosilanes. n the basis of this fact, it was thought that the intermediate rhodium enolate species might be directly trapped with aldehyde to give the aldol coupling product. Into a mixture of benzaldehyde and acrylate, the catalyst h-ebox B and hydrosilane were added to start the reaction, which gave the aldol coupling product, propionate derivative, in high yields with high ees for the anti isomer and high anti-selectivity (Scheme 9). 19) 4-Substituted catalysts and 3,5-dimethyl catalyst D work as catalysts giving almost the same yields and up to 98% ee. 15,20) The conjugate reduction of cinnamates and successive aldol reaction with acetone gives the intermolecular aldol coupling products in high ee up to 98% (Scheme 10). 21) 2 Si is the best choice of hydrosilane. After the aldol reaction, subsequent dehydroxylation of the β-hydroxy group resulted in formation of α-chiral dihydrocinnamates in high yields and kept the enantioselectivity with 90% ee. 22a) As an extension of the reductive aldol reactions, there is the Felkin-Anh selectivity in the reaction of 2-phenylpropionaldehyde and unsaturated esters. 22b) h-ebox diacetate complex catalyzed the reductive Mannich-type coupling of acrylates and aldimines to form selectively the anti-product, but asymmetric induction could not be observed. 23) C h Ac Ac 2 A: h-ebox-ip B2: h-ebox-bn C 2 t-bu h-ebox-ip (A,B,C,D) 1 mol% (Et) 2 Si 2 toluene, 50 C, C 2 t-bu h then 3 3S anti 3 5 h Ac Ac 2 D: h-dm-ebox-ip Cat. A Cat. B2 Cat. D Cat. D1 Cat. D2 Cat. D3 2 3 C 2 t-bu syn 91% anti:syn 95:5 anti 91% ee 98% 98:2 94% ee 98% 95:5 92% ee 82% 96:4 93% ee 94% 95:5 92% ee 90% 94:6 94% ee X 4 h Ac Ac 2 D1: h- 2 -ebox-ip (X= 2 ) D2:h--ebox-ip (X= ) D3:h- 2 -ebox-bn (X= 2 ) C 2 t-bu Cat. A: 94% anti:syn 93:7 anti 94% ee C 2 t-bu Cat. A: 76% anti:syn 93:7 anti 92% ee C 2 t-bu Cat. A: 95% anti:syn 98:2 anti 95% ee Cat. D3: 99% anti:syn 98:2 anti 98% ee Scheme 9. Asymmetric reductive aldol reaction 2.7 equiv C 2 Et h-ebox-ip A 1 mol% 2 Si 2 toluene, 50 C, C 2 Et 0.5 h then 3 83% 97% ee C 2 - C 2 Et C 2 - C 2-82% 98% ee 81% 96% ee 82% 96% ee 90% dr 96:4 97/38% ee C C 2 - h-ebox-ip A 1 mol% 2 Si toluene, 50 C, 0.5 h then 3 Et 3 Si C 2 r.t., 50 C 87% 96% ee C 2 - Scheme 10. Asymmetric reductive aldol reaction of cinnamates and ketones (upper) and subsequent dehydroxylation (bottom). 7

7 o Asymmetric Boration 4-1. Asymmetric Diboration of Alkenes h-ebox diacetate complex A is capable of catalyzing the asymmetric diboration of terminal alkenes followed by oxidation to form the corresponding optically active 1,2-diols in high ee (Scheme 11). 24) The diboration reaction was accelerated by addition of a small amount of bases such as at-bu or Kt-Bu. The mixture of alkene and bis(pinacolato)- diboron (B 2 pin 2 ) was treated with 1 mol% of the catalyst to give the 1,2-diborated product, which was converted to 1,2-diol by oxidation with aqueous sodium perborate. A variety of terminal alkenes such as ethers, tert-amines, dienes can be subjected to the reaction. -Acyl protected allylamines also can be used as substrates to give the diols via the diboration reaction (Scheme 11, bottom). 25) The products are optically active 3-amino-1,2-diols, the skeletons of which are often included in many pharmaceutical compounds or synthetic intermediates Asymmetric Conjugate Boration of α,β- Unsaturated Carbonyl Compounds h-ebox-ip diacetate A can catalyze the conjugate boration of α,β-unsaturated carbonyl compounds to produce the β-boryl propanoates in high yields (Scheme 12). 26) Subsequent oxidation of the boryl products resulted in formation of β-hydroxy propanoates and related amides with high ee. h-ebox-ip A 1 mol%, at-bu B 2 pin 2 (0.6 mmol) 0.5 mmol TF, 60 C, 1 h then ab [g scale reaction: p-c 6 4 C=C g, 10 mmol/ 1,2-diol product 1.53 g, 8.9 mmol, 89% 98% ee] 94% 99% ee 83% 99% ee 83% 99% ee CF 3 86% 97% ee 78% 99% ee 71% 95% ee 78% 90% ee 82% 92% ee 80% 99% ee h-ebox-ip A 1 mol%, at-bu B 2 pin 2 (0.6 mmol) TF, 60 C, 1 h then ab 3 4 2, C 3 C 2 88% 96% ee 80% 99% ee Scheme 11. Asymmetric diboration of alkenes Et h-ebox-ip A, B 1 mol%, at-bu B 2 pin 2 (0.6 mmol) TF toluene, 80 C, 1 h Et ab Et Cat. A: Cat. B: 85% (Kt-Bu) 86% (at-bu) 95% ee 97% ee t-bu Et Et Et Et Cat. B: 89% 96% ee Cat. B: 95% 97% ee Cat. B: 75% 92% ee Cat. B: 75% 92% ee Et Cat. B: 90% 90% ee Cat. B: 79% 95% ee Cat. B: 91% 93% ee Scheme 12. Asymmetric conjugate boration of α,β-unsaturated esters and amides 8

8 o Asymmetric Alkynylation 5-1. Asymmetric Alkynylation of α-ketoesters hshima and Mashima et al. reported that various h- ebox diacetate complexes can be synthesized and catalyze asymmetric alkynylation of α-ketoesters and aryl-substituted or alkyl-substituted terminal alkynes to give functionalized propargylic alcohols in good yields with high ee up to 99% (Scheme 13). 27a) Morimoto and hshima extended the reaction using alkynyl complex I and found the highly reactive catalyst which was applied to alkynylation of ketiminoesters. 27b) 5-2. Cross-coupling of Alkynes The cross coupling reaction of terminal alkynes and dimethyl acetylenedicarboxylate proceeded with h-ebox catalyst D under hydrogen atmosphere (1 atm) at 100 C for 4 h to give the corresponding coupling product, the enyne derivatives, in high yield and high Z ratio (Scheme 14). 28) The acetylide complex was isolated and analyzed. C Bond activation by deprotonation from the terminal alkyne with acetate ligand as a base forms the corresponding acetylide complex followed by insertion of the alkyne and then elimination of the enyne product. C 2 Et h-ebox 3 mol% Et 2, 25 C, h C 2 Et Cat. A Cat. B2 Cat. F Cat. G 35% 88% ee 87% 83% ee 94% 91% ee 95% 91% ee h Ac Ac 2 A: h-ebox-ip B2: h-ebox-bn h Ac Ac 2 F : h-ebox-ind 2 4 h Ac Ac 2 G: h-ebox-ip,ind : h- 2 -ebox-ip,ind C 2 Et C C 2 Et C C 2 Et C Br C 2 Et Cat. F Cat. G 82% 95% ee 90% 94% ee Cat. F Cat. G Cat. 78% 80% ee 88% 90% ee 85% 99% ee Cat. F Cat. G 86% 94% ee 89% 95% ee Cat. G Cat. 85% 87% ee 93% 96% ee 2 h Cbz Et h-ebox I 0.5 mol% toluene, r.t., 6 h Cbz Et 97% 92% ee I: h-ebox-alkynyl = Si 3 Scheme 13. Asymmetric alkynylation of α-ketoesters X 2 C 1.5 equiv C 2 h Ac Ac 2 h-ebox D 1 mol% 2 (1 atm) toluene, 100 C, 4 h X Z C 2 C 2 X = 85% Z:E 98:2 X = Br 87% 97:3 X = CF 3 79% 98:2 X = 66% 99:1 D: h-dm-ebox-ip Scheme 14. Cross-coupling of alkynes 9

9 o ther C C Bond Formation eactions with h-ebox Catalysts h-ebox complexes also catalyzed several C C bond formation reactions as follows: asymmetric direct aldol reaction of benzaldehyde with cylcohexanone and cyclohexenone, respectively, 29,30) asymmetric allylation reaction of benzaldehyde with allyl- or methallyl-tributyltin, 31) asymmetric Michael addition of α-cyanopropionates to acrolein, 32) asymmetric aldol-type condensation of isocyanide group on h-eobx, 33) asymmetric hetero Diels Alder reaction of Danishefsky s dienes and glyoxylates. 34) The vacant site of h- ebox intermediate acts as a Lewis acid catalyst for those C C bond formation reactions. 7. Asymmetric Catalysis with u-ebox Complexes 7-1. Asymmetric ydrogenation of Ketones u-ebox complexes J and K act as catalysts for asymmetric hydrogenation of ketones to give optically active secondary alcohols (Scheme 15). 35) elatively bulky ketones were reduced with high enantioselectivities of up to 97% ee. Aryl-substituted acetophenones were reduced in the middle range of ee. 36) It was interesting in that using the catalyst, addition of optically active alcohols, such as additives I or II (10 mol%), enhanced ee over 90%. The bulky anthracenyl alcohol improves the selectivity due to coordination to the u atom Asymmetric Cyclopropanation Mono nuclear u-ebox complex M was prepared by C bond activation with magnesium as a reducing agent in ethanol (Scheme 16). 10) The complex M catalyzed the cyclopropanation of styrene derivatives to form the corresponding transcyclopropanes in high yields. Cat. J 1 mol% a IPA, 40 C, 24 h u C 99% 67% ee J: = K: = u-ebox-ip-acac u-ebox-ph-acac n-c 5 11 Cat. J 96% 85% ee Cat. K 99% 90% ee Cat. K 87% 96% ee Cat. K 94% 97% ee Cat. L 1 mol% a additive IPA, 40 C, 24 h CF 3 without additive 99% 56% ee with additive I 99% 93% ee with additive II 99% 93% ee u C 2 L: u-dm-ebox-ph-[(c)] 2 additive I (10 mol%) additive II (10 mol%) without additive with additive I 99% 49% ee 98% 92% ee without additive with additive I Scheme 15. Asymmetric hydrogenation of ketones with u-ebox catalysts (upper): enhancement of ee by alcohol additive (bottom) 96% 77% ee 98% 90% ee u cat. M (u 0.5 mol%) 2 CC 2 t-bu C C C 2 t-bu 87% t:c 92:8 t 99% ee u C 2 M: u-dm-ebox-ph 2 ( 2 ) C 2 t-bu C 2 t-bu C 2 t-bu 83% t:c 95:5 t 98% ee 86% t:c 92:8 t 98% ee 91% t:c 82:18 t 98% ee Scheme 16. Asymmetric cyclopropanation 10

10 o Asymmetric Alkynylation of Aldehydes u-ebox complexes catalyzed asymmetric alkynylation of aldehydes with terminal alkynes to produce optically active propargylic alcohols with high ee up to 93% (Scheme 17). 11) The acetate complex did not require base additives such as aac to give the alcohols in a similar yield and ee. As an acceptor, α,β-unsaturated carbonyl compounds were used to give Michael addition derivatives in high yields. 37) 8. Asymmetric Catalysis with Ir-ebox Complexes 8-1. C Activation on Ir-ebox Complexes A series of Ir-ebox dichloro complexes was prepared by the C bond activation reaction with [dm-ebox] or [4-tb- ebox] and iridium salts, followed by treatment with AgAc to give the corresponding acetates (Scheme 18). 15,37,38,39,40) The chiral Ir-ebox catalyzed asymmetric conjugate reduction and asymmetric reductive aldol reaction to attain high enantioselectivity. 15) ur group, the Goldberg group, and the Goldman group reported that the acetate complex P Ac reacts with benzene, n-octane, or mesitylene to form phenyl, octyl or mesityl complexes () by C activation on the iridium atom, respectively. 37,38,39) Boration of arenes was realized with B 2 pin 2 and Ir-ebox. 15) 8-2. Asymmetric C Insertion eaction Musaev, Davies, and Blakey group reported Ir-ebox complexes and S catalyzed the asymmetric C insertion reaction with cyclohexadienes and phenyldiazoacetate in high ee up to 99% (Scheme 19). 40) The products can be converted to optically active α,α-diarylacetates. They also proposed the reaction pathway and calculated the stereoisomer of the reactive carbene complexes. u-ebox (5 mol% u) aac IPA, 60 C, 96 h Cat. K Cat. J Cat. 75% 92% ee 74% 92% ee 74% 93% ee u C 2 : u-dm-ebox-ph-( 2 ) C CF 3 C CF 3 C aphthyl Cat. K (48 h) 94% 90% ee Cat. K (96 h) 70% 95% ee Cat. K (48 h) 82% 95% ee Cat. K (96 h) 53% 94% ee u-ebox J (5 mol%) aac TF, 60 C, 12 h = 92% = Et 99% = 2 94% Scheme 17. Asymmetric alkynylation of aldehydes and conjugate addition Ir 3 ( 2 ) 3 ac 3 50 C 3 5 Ir X X Ir X X Ir [dm-ebox-ip] : X = Ir-dm-ebox-ip dichloride Ac : X = Ac Ir-dm-ebox-ip diacetate P : X = Ir-dm-ebox-dm dichloride P Ac : X = Ac Ir-dm-ebox-dm diacetate Q1: = Q2: = n-c 8 17 Q3: = mesityl Scheme 18. Ir-ebox complexes and the related reactions 11

11 o ebox Complexes of ther tals ebox complexes of other metals, for examples, iron, 41) cobalt, 42) palladium, 43) and platinum, 44) were prepared by oxidative addition reactions of ebox-x (X = halogen) (Figure 3). owever, asymmetric catalysis with the complexes has not yet been explored extensively. Further applications are strongly expected. For other metal complexes, for examples, van Koten et al. reported synthesis of ebox-li and ebox-au complexes, which were successively used to prepare the corresponding Ti, V, Cr, Zr, f, b complexes. 45) Xu and Lu et al. reported ebox-lu complex, which was applied to the regioselective polymerization of isoprene. 46) 10. Summary Asymmetric catalysis with bis(oxazolinyl)phenyl ligands and their transition metal complexes, mainly rhodium and ruthenium complexes, has been developed to attain high enantioselectivities with relatively lower catalyst loading (1 mol% or lower). ebox ligands and their complexes are readily prepared and have high potential for organic reactions including asymmetric reactions and polymerizations. These tridentate and nitrogen-based ligands and the complexes are useful in modern catalytic organic synthesis. Procedures of Asymmetric Conjugate eduction and Asymmetric 1,2-Diol Synthesis Scheme 7. The preparation of (S)-ethyl 3-(naphthalen-1-yl)- 3-phenylpropanoate 16) Diethoxymethylsilane (202 mg, 1.5 mmol) was added at 60 C to a solution of (E)-ethyl 3-(naphthalen-1-yl)-3-phenylacrylate (302 mg, 1.0 mmol) and h-ebox-ip diacetate A (5.4 mg, mmol) in toluene (2.0 ml). The mixture was stirred for 2 h. At 0 C, TF (1 ml), (1 ml), and hydrochloric acid (1 ml, 1 ) were added, and the mixture was stirred for 1 h. The mixture was then extracted with ethyl acetate, and was washed with aq. sodium bicarbonate and saturated brine. The organic layer was dried over magnesium sulfate, and then concentrated to give a residual oil, which was purified by silica gel column chromatography with ethyl acetate/hexane to give the propanoate (293 mg, mmol, 96% yield) as a colorless oil: [α] D 24 = 16.8 (c 1.01, C 3 ); Chromatography: DAICEL CIALCEL D-, hexane/2-propanol (97:3, 1 ml/min), 27 C, retention time = 9.7 min for (minor) and 17.5 min (major) for S, 99% ee; MS-FAB (m/z, M = C ): found: [Ma], calcd: Scheme 11. The preparation of ()-1-(4-chlorophenyl)- ethane-1,2-diol from 4-chlorostyrene 24) h-ebox-ip diacetate A (2.7 mg, mmol), bis(pinacolato)diboron (152 mg, 0.60 mmol), and at-bu (2.5 mg, mmol), were placed in a flask. 4-Chlorostyrene (69.3 mg, 0.50 mmol) and TF (1.0 ml) were added under an argon atmosphere. The mixture was stirred at 60 C for 1 h. At room temperature, ab (385 mg, 2.5 mmol), TF (5 ml), and water (2.5 ml) were added to the reaction mixture, which was stirred for 1 h. The mixture was extracted with ethyl acetate (2 mlx5) and concentrated to give a crude product, which was purified by silica gel column chromatography with ethyl acetate/hexane as eluent. The diol was obtained in 94% yield (80.9 mg, mmol) as a white solid, m.p C: [α] D (c 1.0, C 3 ); Chromatography: DAICEL CIALCEL D-, hexane/2-propanol (98:2, 1.5 ml/min): retention time = 46.0 min (major), 52.8 min (minor), 99.5% ee; Elemental Anal: calcd. (%) for C : C 55.67; Found: C 55.94; u cat. (0.5 mol%) 4 Å MS, r.t., 24 h Cat. 1 Cat. 2 Cat. S1 Cat. S2 52% 94% ee 84% 98% ee 85% 98% ee >95% 97% ee 3 5 t-bu 4 Ir 2 Ir 2 1: Ir-dm-ebox-ph 2: Ir-dm-ebox-bn S1: Ir-tb-ebox-ph S2: Ir-tb-ebox-bn Cat. S2 86% 96% ee Cat. S2 88% 99% ee Cat. S2 97% 95% ee Scheme 19. Ir-ebox catalyzed asymmetric C insertion reaction Fe C Br C I Co I 2 Pd Pt Tf Fe-ebox-ip Co-ebox-ip Pd-ebox-ip Pd-ebox-ip Figure 3. ebox complexes of other metals 12

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14 o.172 TCI elated Products Ligands for Pybox and ebox B2217 (,)-2,6-Bis(4-isopropyl-2-oxazolin-2-yl)pyridine 250mg 1g 5g B2218 (S,S)-2,6-Bis(4-isopropyl-2-oxazolin-2-yl)pyridine 500mg 5g B4196 (S,S)-4,6-Bis(4-isopropyl-2-oxazolin-2-yl)-m-xylene 20mg h-ebox Complex B4195 Bis(acetato)aqua[(S,S)-4,6-bis(4-isopropyl-2-oxazolin-2-yl)-m-xylene]rhodium 10mg Major eagents for the Synthesis of Ligands and Complexes P0554 2,6-Pyridinedicarboxylic Acid 25g 100g 500g I0159 Isophthaloyl Chloride 25g 500g D4377 4,6-Dimethylisophthalic Acid 200mg 1g V0058 L-Valinol (S-Valinol in the article) 5g 25g D2751 Dichloro(p-cymene)ruthenium(II) Dimer 1g 5g Aldehydes C0352 trans-cinnamaldehyde 25mL 500mL B2379 Benzaldehyde 500g Alkoxysilanes D2403 Diethoxymethylsilane 25mL T1040 Triethoxysilane 25mL 100mL 500mL Alkynes A0090 Dimethyl Acetylenedicarboxylate 25mL 100mL 500mL B Bromo-4-ethynylbenzene 1g 5g E0196 Ethynylbenzene 25mL 100mL 500mL E Ethynyl-4-(trifluoromethyl)benzene 1g 5g E Ethynyltoluene 5g 25g Boron Compounds B1964 Bis(pinacolato)diboron (= B 2 pin 2 ) 1g 5g 25g 100g S0446 Silver Tetrafluoroborate 5g 25g Esters A1389 tert-butyl Acrylate (stabilized with MEQ) 25mL 500mL A0143 Ethyl Acrylate (stabilized with MEQ) 25mL 500mL C0359 Ethyl Cinnamate 25g 100g 500g T0432 Ethyl Trifluoroacetate 25g 100g 500g thers V Vinylbiphenyl 1g 5g C Chlorostyrene (stabilized with TBC) 10mL 25mL C0468 1,4-Cyclohexadiene (stabilized with BT) 10mL 25mL D1091,-Dimethylacrylamide (stabilized with MEQ) 25g 500g M0105 4'-thoxyacetophenone 25g 500g M0460 thyl Vinyl Ketone (stabilized with Q Ac) 25mL 100mL 500mL S0450 Sodium tert-butoxide 25g 100g 500g S0887 Sodium Perborate Tetrahydrate 25g 500g T1520 ()-(-)-2,2,2-Trifluoro-1-(9-anthryl)ethanol 100mg 1g T (Trifluoromethyl)styrene (stabilized with Q) 1g 5g 15