Zr[bis(salicylidene)ethylenediaminato]-mediated SPECIAL FEATURE Baeyer–Villiger oxidation: Stereospecific synthesis of abnormal and normal lactones

Akira Watanabe, Tatsuya Uchida, Ryo Irie, and Tsutomu Katsuki†

Department of Chemistry, Faculty of Science, Graduate School, Kyushu University 33, and Core Research for Evolutional Science and Technology, Japan Science and Technology, Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan

Edited by Barry M. Trost, Stanford University, Stanford, CA, and approved January 7, 2004 (received for review October 29, 2003)

Baeyer–Villiger oxidation of racemic bicyclic cyclobutanones with Zr[bis(salicylidene)ethylenediaminato] (salen) complex 1 as cata- lyst in the presence of a urea-hydrogen peroxide adduct was found to proceed enantiospecifically. The enantiotopos selection in the oxidation was governed primarily by the Zr(salen) catalyst, al- though migratory aptitude (methine > methylene > methyl) in Baeyer–Villiger oxidation affected the selection to a varied extent, depending on the substrate structures; one enantiomer of cyclobu- Fig. 1. The first coordination spheres of metallosalen complex and a sche- tanones gave exclusively a normal lactone expected from the matic diagram of substituted cis-␤-metallosalen complex chelated by the migratory aptitude, and the other enantiomer gave an abnormal Criegee intermediate. lactone preferentially, the formation of which is counter to the migratory aptitude. Furthermore, the rates of abnormal lactone formation were found to be faster than those of normal lactone that chiral copper and aluminum catalysts catalyze B-V oxida- CHEMISTRY formation in most of the oxidations examined. For example, the tion with moderate enantiospecificity and topos selectivity. enantiomer of racemic bicyclo[3.2.0]heptan-6-one giving an abnor- The superior catalytic performance of enzymes is attributed to mal lactone reacted 2.2 times faster than the other enantiomer their efficient chiral recognition of substrates and appropriate giving a normal lactone. To our knowledge, this example of control of the stereoelectronic requirement for migration of the Criegee intermediate in B-V oxidation; the stereoelectronic chemocatalytic Baeyer–Villiger oxidation giving an abnormal lac- requirement is satisfied by regulating the conformation of the tone in preference to a normal lactone has been previously unre- Criegee intermediate suitably through hydrogen bond formation ported. This unusual behavior is likely to be attributable to strict with the enzyme (3–9). Thus, we expected that highly enantio- control of stereoelectronic demand in Baeyer–Villiger oxidation selective B-V oxidation would be realized if the conformation of and chiral recognition by complex 1. the Criegee intermediate, a kind of bidentate ligand, is appro- priately controlled by its forming a chelate with a chiral molec- aeyer–Villiger (B-V) oxidation, oxidative transformation of ular catalyst (18–20). In agreement with this expectation, we Bcarbonyl to ester (or lactone), has high synthetic value and recently found that, although both cis-␤- and trans-Co[bis(sali- has been widely used in various organic syntheses. In particular, cylidene)ethylenediaminato] (salen) complexes catalyzed B-V asymmetric B-V oxidation of racemic or prochiral cyclic ketones oxidation (18, 19), only chiral cis-␤-Co(salen) complexes could is a useful tool for the synthesis of optically active lactones. induce asymmetry in B-V oxidation. On the other hand, it is Several enzymes, so-called Baeyer–Villigerase, are known to known that some metallosalen complexes are transformed to the catalyze highly enantiospecific B-V oxidations (regiodivergent corresponding cis-␤-complexes in the presence of a bidentate parallel kinetic resolution) (1, 2) of racemic cyclic ketones, ligand (21). Thus, we further expected that a metallosalen although the stereochemistry of the oxidations depends on the complex bearing an oxygenophilic metal center and readily enzyme used (3–9). Some of them promote B-V oxidation of only exchangeable apical ligands would make a complex with the one enantiomer, leaving the other enantiomer intact, whereas bidentate Criegee intermediate and, therefore, serve as a good some other enzymes promote B-V oxidation of both enanti- catalyst for asymmetric B-V oxidation (Scheme 1). Indeed, high omers in an enantiospecific and topos-selective manner; that is, enantioselectivity of 87% enantiomeric excess (ee) was observed one enantiomer is converted to a normal lactone (NL) and the in B-V oxidation of prochiral 3-phenylcyclobutanone with a other is converted to an abnormal lactone (AL). [A lactone Zr(salen) complex 1 and urea–hydrogen peroxide adduct (UHP) generated in accord with the migratory aptitude of the carbonyl system (20, 22). Aoki and Seebach (17) have also independently substituent in B-V oxidation (tertiary Ͼ secondary Ͼ primary) reported stereoelectronic control of the rearrangement of the is called a NL, and a lactone generated in contravention of the Criegee intermediate through hydrogen bond formation. aptitude is called an AL (8).] On the other hand, chemical Different from B-V oxidation of prochiral ketones, the ste- versions of B-V oxidation of racemic ketones are still limited in reochemistry of B-V oxidation of racemic ketones is affected not number and are inferior to biocatalyzed B-V oxidation in terms of enantiospecificity and topos selectivity. In 1994, Bolm et al. (10) reported copper-catalyzed asymmetric B-V oxidation. In This paper was submitted directly (Track II) to the PNAS office. Abbreviations: salen, bis(salicylidene)ethylenediaminato; B-V, Baeyer–Villiger; UHP, urea– the same year, Strukul and coworkers (11) reported platinum- hydrogen peroxide adduct; AL, abnormal lactone; NL, normal lactone; ent, enantiomeric; catalyzed asymmetric B-V oxidation. Since then, several cata- ee, enantiomeric excess; acen, N,NЈ-ethylenebis(acetylacetoneiminate).

lysts have been introduced for asymmetric B-V oxidation (12– Data deposition: Crystallographic data for the structure of 1⅐(CH2Cl2)2 have been deposited 16). Although stoichiometric enantiospecific B-V oxidation has in the Cambridge Structural Database, Cambridge Crystallographic Data Centre, Cam- recently been reported (17), molecular catalysts are still difficult bridge CB2 1EZ, United Kingdom (CSD reference no. 222736). to exert a highly sophisticated catalysis comparable with en- †To whom correspondence should be addressed. E-mail: [email protected]. zymes. It has been reported by Bolm and colleagues (10, 14–16) © 2004 by The National Academy of Sciences of the USA

www.pnas.org͞cgi͞doi͞10.1073͞pnas.0306992101 PNAS ͉ April 20, 2004 ͉ vol. 101 ͉ no. 16 ͉ 5737–5742 Downloaded by guest on September 30, 2021 Scheme 1.

only by stereoelectronic control but also by chiral recognition. dation of a series of racemic bicyclic cyclobutanones with Efficient stereoelectronic control and chiral recognition by complex 1 as the catalyst (Scheme 2). Baeyer–Villigerase enables regiodivergent parallel kinetic reso- lution of racemic ketones through B-V oxidation (see above). Materials and Methods The first coordination sphere of a cis-␤-metallosalen complex is 1H NMR spectra were recorded at 400 MHz on a JEOL chiral, and the cis-␤-complex is expected to provide a concave- JNM-AL-400 instrument. IR spectra were obtained with a type chiral reaction site when an appropriate substituent like a Shimadzu FTIR-8400 instrument. Optical rotations were mea- 2-phenylnaphthyl group is introduced at the C3(3Ј) position of sured with a P-1020 polarimeter (Jasco, Tokyo). High- resolution fast atom bombardment mass spectra were obtained the salen ligand (Fig. 1). An asymmetric reaction site of the ͞ concave type is known to be efficient for chiral recognition (23). from a JEOL JMX-SX SX 102A spectrometer with the m- nitrobenzyl alcohol matrix. Column chromatography was con- Thus, it was expected that the Zr(salen) complex 1 would also ␮ serve as an efficient catalyst for enantiospecific B-V oxidation of ducted on silica gel 60N (spherical, neutral), 63–210 m, racemic ketones. available from Kanto Chemical (Tokyo), and preparative TLC was performed on a 0.5 mm ϫ 20 cm ϫ 20 cm Merck silica gel Most biological reactions show strong substrate specificity, plate (60 F-254). Enantiomeric excesses were determined by referred to as the lock-and-key model, because of their strict HPLC analysis by using Shimadzu LC-10AT-VP or by GLC molecular recognition. The above-described biological B-V ox- analysis using Shimadzu GC-17A equipped with an appropri- idations also undergo substrate specificity to a considerable ate optically active column, as described in Table 1. Solvents extent (3–9). The whole mechanism of molecular recognition by were dried and distilled shortly before use. For spectral data molecular catalysts is not completely understood, but some of Zr(salen)Cl2 2, which is the synthetic precursor of complex factors participating in interaction between the substrate and the 1, the starting bicyclobutanones and the produced lactones, see catalyst have become obvious. For example, some attractive Supporting Text, which is published as supporting information ␲ interaction(s) such as the CH- interaction (24) between the on the PNAS web site. substrate and the catalyst participates in asymmetric induction by

the catalyst. The salen ligand possessing a binaphthyl unit has Zr(salen)(OPh)2 1. Complex 2 (333.8 mg, 0.338 mmol) was dissolved been revealed to interact attractively with organic compounds in THF (10 ml) under nitrogen. Then, a THF solution of lithium through CH-␲ interaction (25). Thus, the stereochemistry of phenoxide (1.0 M, 680 ␮l) was added to this solution and stirred B-V oxidation catalyzed by complex 1 bearing a concave reaction for 6 h. The solution was concentrated on a rotary evaporator, site was considered to be strongly affected by the substrate and the resulting residue was redissolved in toluene. The mixture structure. Based on this consideration, we examined B-V oxi- was filtered through a pad of Celite to remove lithium chloride.

Scheme 2.

5738 ͉ www.pnas.org͞cgi͞doi͞10.1073͞pnas.0306992101 Watanabe et al. Downloaded by guest on September 30, 2021 Table 1. B-V oxidation of racemic bicyclo [n.2.0]alkan-(n ؉ 2)-one with complex 1 as the catalyst SPECIAL FEATURE

Ketone NL ent-AL

Entry Substrate Conversion, % ee, %Time, h Yield, % ee, % Yield, % ee, %

1 3 54a 27a 2.0 21a 88a,b 31a 97a,c 2 3 61a 32a 2.3 24a 90a,b 34a 96a,c 3 3 73a 41a 2.7 30a 91a,b 40a 96a,c 4 3 90a 62a 3.7 41a 93a,b 45a 96a,c

5 4 54d 42e 2.3 15d 91f,g 34d 95f,h 6 4 63d 52e 3.0 20d 93f,g 40d 95f,h 7 4 74d 61e 3.3 27d 93f,g 44d 95f,h

8 5 50i 27i 2.0 18j 89k,l 31j Ͼ99k,m 9 5 62i 38i 2.8 23j 89k,l 36j Ͼ99k,m 10 5 67i 42i 3.0 23j 91k,l 38j 96k,m

11 6 71n 77n 2.0 48n 85n,o 21i Ͼ99n,p CHEMISTRY 12 6 76n 86n 2.5 54n 82n,o 22i Ͼ99n,p 13 6 83n 94n 3.0 55n 80n,o 25i Ͼ99n,p

14 7 57q 74q 2.0 10q 58q,r 47q 95q,h 15 7 59q 80q 2.3 11q 65q,r 47q 95q,h 16 7 63q 86q 2.7 11q 67q,r 50q 94q,h 17 7 68q 92q 3.0 14q 76q,r 54q 94q,h

18 8 49s 30s 2.0 16s 82s,h 29p Ͼ99s,h 19 8 66s 49s 2.7 24s 83s,h 39p Ͼ99s,h 20 8 75s 65s 3.3 30s 86s,h 44p Ͼ99s,h 21 8 85s 79s 3.7 35s 87s,h 47p Ͼ99s,h

22 9 60t 7u 2.5 36t 81v,h 24t 98v,h 23 9 96t 29u 4.5 57t 76v,h 39t 98v,h

aDetermined by GLC analysis with optically active column Supelco Beta-Dex-255 [initial column temperature, 115°C for 10 min, heating rate 3.0°C͞min (to 165°C)]. bAbsolute configuration was determined to be (1S,5S), based on comparison of optical rotation (31). cAbsolute configuration was determined to be (1R,5S), based on comparison of optical rotation (32). dConversion of racemic ketone and yields of lactones were determined by, 1H NMR (400 MHz) analysis. eDetermined by HPLC analysis with Daicel CHIRALCEL OJ-H (hexane͞2-propanol 98:2) (Chemical Industries, Osaka). fDetermined by GLC analysis with optically active column Supelco Beta-Dex-255 (column temperature 165°C for 70 min). gAbsolute configuration was determined to be (1S,5R), based on comparison of optical rotation (33). hAbsolute configuration has not been determined. iDetermined by GLC analysis with optically active column Supelco Beta-Dex-255 [initial column temperature, 115°C for 13 min, heating rate 5.0°C͞min (to 180°C)]. jYields of lactones were determined by 1H NMR (400 MHz) analysis. kDetermined by HPLC analysis with Daicel CHIRALCEL OJ-H (hexane͞2-propanol 95:5) lAbsolute configuration was determined to be (1R,5S), based on comparison of optical rotation (34). mAbsolute configuration was determined to be (1R,5S), based on comparison of optical rotation (35). nDetermined by GLC analysis with optically active column Supelco Beta-Dex-255 [initial column temperature, 125°C for 14 min, heating rate 40.0°C͞min (to 140°C) for 4 min. heating rate 40.0°C͞min (to 170°C)]. oAbsolute configuration was determined to be (1S,6S), based on comparison of optical rotation (36). pAbsolute configuration was determined to be (1S,6R), based on comparison of optical rotation (32). qDetermined by GLC analysis with optically active column Supelco Beta-Dex-255 [initial column temperature, 150°C for 40 min, heating rate 1.0°C͞min (to 170°C)]. rAbsolute configuration was determined to be (1S,6R), based on comparison of optical rotation (36). sDetermined by GLC analysis with optically active column Supelco Beta-Dex-255 [initial column temperature, 115°C for 31 min, heating rate 10.0°C͞min (to 170°C)]. tConversion of racemic ketone and yields of lactones were determined by 1H NMR (400 MHz) analysis. uDetermined by HPLC analysis with Daicel CHIRALCEL OD-H (hexane͞2-propanol 99.9:0.1). vDetermined by GLC analysis with optically active column Supelco Beta-Dex-255 (initial column temperature, 165°C for 168 min).

Watanabe et al. PNAS ͉ April 20, 2004 ͉ vol. 101 ͉ no. 16 ͉ 5739 Downloaded by guest on September 30, 2021 Toluene was evaporated and the residue was purified by recrys- The B-V oxidation of racemic 3 was found to be highly tallization from a mixture of dichloromethane and heptane (2:1). topos-selective (entries 1–4). The topos selection by Zr(salen) 1 Complex 1 was obtained as yellow crystals in 83% yield. 1H NMR overwhelmingly overrode the migratory aptitude in B-V oxida- (400 MHz): ␦ 8.53 (s, 2H), 7.92 (m, 4H), 7.84 (d, J ϭ 8.0 Hz, 2H), tion. It is noteworthy that the fast-reacting isomer gave the AL 7.68 (m, 2H), 7.53 (d, J ϭ 8.5 Hz, 2H), 7.42 (d, J ϭ 8.5 Hz, 2H), [enantiomeric (ent)-AL] preferentially in Ϸ27:1 ratio of ent-AL 7.18 (m, 2H), 7.13–6.95 (m, 12H), 6.87 (m, 4H), 6.74 (m, 2H), and ent-NL, despite the fact that topos selection and migratory 6.67–6.53 (m, 6H), 6.07 (dd, J ϭ 8.4, 1.0, 4H), 3.42 (br-d, 2H), aptitude were canceled. On the other hand, the slow-reacting 2.37 (br-d, 2H), 1.93 (br-d, 2H), 1.50–1.37 (m, 2H), 1.30–1.20 (m, isomer gave the NL exclusively in Ϸ40:1 ratio of NL and AL, 2H). IR (KBr): 3053, 2928, 1611, 1585, 1479, 1356, 1275, 1186, suggesting that topos selection and migratory aptitude acted Ϫ 1151, 1124, 1024, 957, 864, 760, 696, 609, 515 cm 1. Anal. calcd. synergetically to give the NL. The relative reaction ratio (26) of ⅐ for C72H54N2O4Zr 2H2O: C, 75.96, H, 5.14, N, 2.46. Found: C, the fast- to the slow-reacting isomers was Ϸ2.0. The stereochem- 76.14, H, 5.24, N, 2.37. istry of the oxidation of racemic 4 was similar to that of racemic 3, although the relative reaction ratio (Ϸ2.9) was somewhat General Procedure for B-V Oxidation of Racemic Bicyclic Cyclobu- improved (entries 5–7); the fast-reacting isomer gave ent-AL tanone Derivatives in the Presence of Zr(salen)(OPh)2 1 as a Catalyst. exclusively in an Ϸ51:1 ratio of ent-AL͞ent-NL, whereas the Racemic bicyclic cyclobutanone (0.1 mmol) was dissolved in slow-reacting isomer gave NL preferentially in Ϸ22:1 ratio of chlorobenzene (1 ml). To this solution, bicyclohexyl or 1-bro- NL͞AL. The stereochemistry of the oxidation of racemic 5 was monaphthalene was added as an internal standard where also similar to those of 3 and 4 (entries 8–10); the fast-reacting needed. Then, complex 1 (8.8 mg, 8 ␮mol) and UHP (11.3 mg, isomer gave ent-AL preferentially in an Ϸ35:1 ratio of ent-AL 0.12 mmol) were added successively, and the resulting mixture and ent-NL, whereas the slow-reacting isomer gave NL selec- was stirred for the time specified in Table 1. Yields and tively in a Ϸ40:1 ratio of NL and AL. The relative reaction ratio enantiomeric excesses of the unreacted substrate and the result- of the fast- to the slow-reacting isomers was Ϸ2.2. In these ing NLs and ALs were determined as described in Table 1. reactions, the ees of ALs were much better than the ees of the corresponding NLs, especially at the early stage of the reaction, Determination of the Relative Reaction Ratio of Enantiomers of since the enantiomers giving a NL showed high topos selection Racemic Ketones and the Ratio of Normal and Abnormal Lactones and reacted slower than the enantiomers giving an AL. Scheme from Each Enantiomer. The relative reaction ratio of the enanti- 3 explains this stereochemistry with the reaction of 3 as a typical omers of the starting racemic ketones was determined by using example; the supply of the ent-NL was faster than the supply of ϭ ͞ ϭ Ϫ Ϫ ͞ Ϫ Kagan’s equation [krel kfast kslow ln{(1 c)(1 ee) ln(1 the AL at the early stage because of the relative reaction ratio c)(1 ϩ ee)}], where c stands for the conversion of the starting and the topos selectivity. Scheme 3 also shows that the reaction ketone and ee stands for the ee of unreacted ketone (26). is almost a regiodivergent parallel kinetic resolution. The ees of Conversion of ketones was determined by using GLC or NMR the NLs improved and the ees of the ALs decreased gradually as analysis, and the ee was determined as described in Table 1. the reaction proceeded. This change in ees with time reflects the ϭ ϭ The ratio of NLs and ALs (RK FNL:FAL and ReK above-described NL͞AL ratio and the relative reaction ratio. FeNL:FeAL) from each enantiomer (K or eK) of the starting These results indicate that the transition state for the oxidation ketone was determined by GLC or HPLC analysis, where F, NL, of the fast-reacting isomer, leading to AL, is favored probably AL, eNL, and eAL stand for the amount of an enantiomer, NL, because of some attractive interaction between the salen ligand AL, enantiomeric NL, and enantiomeric AL, respectively (see and the fast-reacting isomer, or the transition state for the Scheme 2). Retention times of the enantiomers of NLs and ALs oxidation of the slow-reacting isomer is disfavored because of were confirmed by the analysis of racemic lactones that were some repulsive interaction between the salen ligand and the prepared by conventional methods. If no side reaction occurs, slow-reacting isomer. At this moment, however, our knowledge ϩ ϩ ϭ ϩ the following equation should be hold: FA FNL FAL FB about the transition state is too naive to determine which is the ϩ FeNL FeAL, where A and B stand for the enantiomers of the case. The presence of an olefin or aromatic ring affects stereo- unreacted ketone. We did not observe any reaction other than selectivity in the reactions of 3–5 to a small extent. To our B-V oxidation and the this equation was satisfied within a margin knowledge, this example of chemocatalytic B-V oxidation of error of 4%, when the observed F values were applied to the whereby a fast-reacting isomer gives AL stereospecifically is equation. previously unreported. The stereochemistry of the reaction of racemic bicyclo ⅐ X-Ray Crystallographic Data for 1 (CH2Cl2)2. Recrystallization from [4.2.0]octan-7-one 6 was different from that observed in the ϭ dichloromethane and heptane, C74H60N2O5Cl4Zr, M ortho- reactions of 3, 4, and 5 (entries 11–13); the reaction of the ϭ ϭ rhombic space group P212121, a 13.0741(2), b 18.6919(3), fast-reacting isomer gave NL exclusively, whereas topos selection c ϭ 25.9780(4), V ϭ 6348.5(2), T ϭϪ90°C, Z ϭ 4, Dc ϭ 1.35, Ϫ in the reaction of the slow-reacting isomer was moderate (ent- ␮(Mo-K␣) ϭ 3.95 cm 1, R ϭ 0.064 [I Ͼ 2␴(I)], Rw ϭ 0.152 (all AL͞ent-NL 5.1:1). The fast-reacting isomer was consumed about data) for 8,124 reflections and 812 variables, GOF ϭ 0.87, four times faster than the slow-reacting isomer. A part of this ͞Ϫ Ϫ3 residual electron density 0.53 0.53 eÅ ; programs, SIR97 (27), chemistry has been reported (20). The stereochemistry of the DIRDIF94 (28), and SHELXL-97 (29) linked to TEXSAN (30) crys- reaction of racemic 2,3-benzobicyclo[4.2.0]octan-7-one 7 tallographic software package. Experimental detail is summa- seemed similar to that of the reaction of 6 (entries 14–17). rized in Supporting Text. However, the sense of topos selection observed in the reaction Results and Discussion Bicyclo[3.2.0]heptan-6-one 3, 2,3-benzobicyclo[3.2.0]heptan-6- one 4, bicyclo[3.2.0]hept-2-en-6-one 5, bicyclo[4.2.0]octan-7-one 6, 2,3-benzobicyclo[4.2.0]octan-7-one 7, bicyclo[5.2.0]nonan-8- one 8, and 2,3-benzobicyclo[5.2.0]nonan-8-one 9 were chosen as substrates to explore the influence of substrate structure and olefinic or aromatic functionality on the stereochemistry of their B-V oxidation with complex 1. The results obtained are sum- marized in Table 1. Scheme 3.

5740 ͉ www.pnas.org͞cgi͞doi͞10.1073͞pnas.0306992101 Watanabe et al. Downloaded by guest on September 30, 2021 respectively, suggesting that the configuration of 1 in solution is ␤

not cis- . The B-V oxidation of 3 in the presence of stoichio- SPECIAL FEATURE metric 1 and UHP was traced by 1H NMR, but no change in the NMR spectra of 3 was observed during the reaction, although 3 was converted into the corresponding lactones. Thus, to see if complex 1 adopts cis-␤-configuration at the reaction tempera- ture in the presence of a bidentate ligand that can replace a phenoxide and an aqua ligand, a 1:1 mixture of 1 and 1,3- Scheme 4. THF, tetrahydrofuran. propanediol was analyzed by 1H NMR. The NMR spectra indicated that all the 1,3-propanediol added was coordinated to the zirconium ion, and the resulting solution contained two new of 7 was opposite to that observed in the reaction of 6; the complexes (C and D) in a ratio of 20:1. The spectrum of C was oxidation of the fast-reacting isomer gave AL preferentially in almost the same as that of 1 except for the signals of the Ϸ30:1 ratio of AL and NL, whereas the reaction of the slow- 1,3-propanediol moiety; the signals of two imino protons and two reacting isomer gave ent-NL preferentially in Ϸ9:1 ratio of ent-NL and ent-AL. The fast-reacting isomer was consumed methine protons at the carbons adjacent to the imino group approximately eight times faster than the slow-reacting isomer. appeared at 8.52 and 3.42 ppm, respectively. This finding sug- Different from the reactions of bicyclo[3.2.0]heptan-6-one de- gested that the 1,3-propanediol coordinated with the zirconium rivatives, the presence of a benzene ring in bicyclo[4.2.0]octan- ion at the equatorial or apical position as a monodentate ligand, 7-one derivatives had a strong influence on the topos-selection and the structure of complex C is similar to that of 1.In by 1. The relative reaction ratio between the enantiomers contrast, the spectrum of D showed the signals of two imino observed in the oxidation of 6 reflected the matching or mis- protons and two methine protons at the carbons adjacent to the imino group at 8.45 and 8.58 ppm and 3.90 and 4.40 ppm, matching of the migratory aptitude and the topos selection. ␤ Intrigued with these results, we further examined the oxida- respectively, indicating that complex D adopted a cis- - tion of bicyclo[5.2.0]nonan-8-one derivatives. Bicyclo[5.2.0]- structure. These spectroscopic and the experimental data nonan-8-one 8 behaved similarly to compounds 3-5 (entries above support our proposal that the B-V oxidation using 1 ␤ 18–21); the slow-reacting isomer gave NL selectively, whereas proceeds through a cis- -complex bearing the Criegee inter- the fast-reacting isomer gave ent-ALpreferentially in Ϸ22:1 ratio mediate as the bidentate ligand, and the concave-type reaction CHEMISTRY ␤ of ent-AL and ent-NL. The relative reaction ratio was Ϸ2.6. On site on the cis- -complex can recognize well the structure of the other hand, 2,3-benzobicyclo[5.2.0]nonan-8-one 9 behaved the substrate. The chelation of the Criegee intermediate to 1 similarly to 6; the fast-reacting isomer gave NL exclusively and should be easier than the chelation of externally added 1,3- the slow-reacting isomer gave AL in preference to NL (AL͞NL diol, because the hydroperoxy group is more nucleophilic than lactone ϭϷ6.5:1), albeit with small relative reaction ratio (1.2). the hydroxy group, and five-membered chelate formation Thus, bicyclo[5.2.0]nonan-8-one derivatives were found to be- is more favored than six-membered chelate formation have differently from both bicyclo[3.2.0]heptan-6-one deriva- (Scheme 5). tives and bicyclo[4.2.0]octan-7-one derivatives, but the sense of In conclusion, we have demonstrated that Zr(salen) complex the topos selection in the oxidation of bicyclo[5.2.0]nonan-8-one 1 exhibits asymmetric catalytic activity similar to the catalytic derivatives is unclear, because the absolute configuration of the performance of some Baeyer–Villigerases. In B-V oxidation of products obtained from compounds 8 and 9 could not be racemic bicyclo[3.2.0]alkan-5-ones, one enantiomer led to a determined. Metallosalen complexes usually take octahedral configura- tion, but Zr- and Hf(salen) complexes have been reported to adopt unique pentagonal bipyramidal configuration (37). Struc- turally, related Zr- and Hf-N,NЈ-ethylenebis(acetylacetoneimi- nate) (acen) complexes have also been reported to adopt pen- tagonal bipyramidal configuration (Scheme 4). These Zr- and Hf-complexes are equatorially coordinated by a solvent. Fur- thermore, these pentagonal bipyramidal Zr- and Hf(acen) com- plexes have been reported to change into octahedral cis-␤-Zr- and Hf(acen) complexes, respectively, with loss of the solvent ligand, when they were heated in toluene. This study indicates that octahedral Zr- and Hf(acen) complexes and probably also octahedral Zr- and Hf(salen) complexes prefer cis-␤- configuration to trans-configuration. To see if complex 1 behaves similarly to the reported simple Zr(salen) and Zr(acen) com- plexes, we studied the x-ray structure of complex 1.Inaccord with the reported Zr(salen) complex, it was demonstrated that 1 also adopted pentagonal bipyramidal configuration, where the basal salen ligand takes an umbrella conformation and one water Fig. 2. An ORTEP diagram‡ for Zr–salen complex 1 with 30% probability. All molecule coordinated with the zirconium ion in its equatorial hydrogen atoms and the solvent molecules are omitted for clarity. Selected position (Fig. 2). The presence of the equatorial aqua ligand bond lengths and angles are as follows: ZrOO1 ϭ 2.081(4), ZrOO2 ϭ 2.011(4), should be of advantage for B-V reaction, because aqua and ZrOO3 ϭ 1.999(3), ZrOO4 ϭ 2.071(4), ZrOO5 ϭ 2.334(4), ZrON1 ϭ 2.348(5), alkoxide ligand exchange is usually fast. We next carried out 1H ZrON2 ϭ 2.372(4), ЄO1OZrOO5 ϭ 67.4(2), ЄO1OZrON1 ϭ 77.1(1), NMR studies of complex 1, a B-V reaction mixture, and the ЄO2OZrOO3 ϭ 169.7(1), ЄO4OZrOO5 ϭ 70.7(2), ЄO4OZr1ON2 ϭ 76.9(1), 1 and ЄN1OZr1ON2 ϭ 69.9(2). mixture of 1 and 1,3-propanediol in CDCl3. H NMR analysis of A 1 in CDCl3 showed the signals for two imino protons (CH N) and two methine protons at the carbons adjacent to the imino group (CHON) in the cyclohexane moiety at 8.53 and 3.42 ppm, ‡Farrugia, L. J. (1997) J. Appl. Crystallogr. 30, 565 (abstr.).

Watanabe et al. PNAS ͉ April 20, 2004 ͉ vol. 101 ͉ no. 16 ͉ 5741 Downloaded by guest on September 30, 2021 Scheme 5.

NL and the other enantiomer led to an AL. This unique supported that a bidentate ligand coordinates with 1 and forces catalytic performance of 1 may be explained by formation of it to adopt cis-␤-configuration. However, B-V oxidation with a cis-␤-Zr(salen) complex chelated by the Criegee intermedi- 1 showed unique substrate specificity, suggesting that a reac- ate, the conformation of which is regulated by the salen ligand tion site of the concave type recognizes well the substrate of concave structure to enable topos-selective ␴–␴* interaction structure and a structural change is reflected in the stereo- necessary for enantiospecific B-V oxidation. The NMR study chemistry of the reaction.

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