Chiral N-salicylidene vanadyl carboxylate-catalyzedenantioselective aerobic oxidation of �-hydroxyesters and amidesShiue-Shien Weng, Mei-Wen Shen, Jun-Qi Kao, Yogesh S. Munot, and Chien-Tien Chen*

Department of Chemistry, National Taiwan Normal University, No. 88, Section 4, Ding-jou Road, Taipei 11650, Taiwan

Communicated by K. Barry Sharpless, The Scripps Research Institute, La Jolla, CA, January 4, 2006 (received for review November 6, 2005)

A series of chiral vanadyl carboxylates derived from N-salicylidene-L-�-amino acids and vanadyl sulfate has been developed. Theseconfigurationally well defined complexes were examined for thekinetic resolution of double- and mono-activated 2° alcohols. Thebest chiral templates involve the combination of L-tert-leucine and3,5-di-t-butyl-, 3,5-diphenyl-, or 3,4-dibromo-salicylaldehyde. Theresulting vanadyl(V)-methoxide complexes after recrystallizationfrom air-saturated methanol serve as highly enantioselective cat-alysts for asymmetric aerobic oxidation of �-hydroxyl-esters andamides with a diverse array of �-, O-, and N-substituents atambient temperature in toluene. The asymmetric inductions of theoxidation process are in the range of 10 to >100 in terms ofselectivity factors (krel) in most instances. The previously unde-scribed aerobic oxidation protocol is also applicable to the kineticresolution of C-13 taxol side chain with high selectivity factor(krel � 35). X-ray crystallographic analysis of an adduct between agiven vanadyl complex and N-benzyl-mandelamide allows forprobing the stereochemical origin of the nearly exclusive asym-metric control in the oxidation process.

alcohol oxidation � �-hydroxy acids � asymmetric catalysis �vanadyl(V) methoxides

The oxidation of alcohols normally requires stoichiometric useof DMSO-based reagents or metal oxides of high oxidation

state (1). Advances on their aerobic oxidations with catalyticmetal oxides [e.g., RuO2–H2O (2), V2O5–K2CO3 (3), andOsO4–Cu(O2CR)2 (4)], homogeneous metal complexes [e.g.,Co(OAc)2-N-hydroxyphthalimide (5), Ru(III)NOCl(salen) (6),RuCl2(PPh3)3-hydroquinone-K2CO3 (7), CuCl-Phen-DBADH2(8), RuCl2(PPh3)2-TEMPO (9)�CuCl-TEMPO (10), Pd(OAc)2-pyridine (11, 12), and Pd4Phen2(CO)(OAc)4 (13)], bimetallic com-plexes [e.g., RuCl3-Co(OAc)2-aldehyde (14) and MoO2(acac)2-CuNO3] (14, 15), or heterogeneous metal complexes [e.g., Ru(III)hydroxyapatite (16), polyaniline-supported MoO2(acac)2 (17), andPd(OAc)2-hydrotalcite-pyridine (18)] have been documented. No-tably, additives and�or bases are often needed to increase thecatalyst reactivity and�or to facilitate the turnover process. Inaddition, the targeted substrates are somewhat limited to primary,benzylic, allylic, and propargylic alcohols. Recently, the asymmetricvariants of the aerobic catalytic process have attracted a lot ofattention (19, 20). So far, Pd(II)-sparteine (21, 22), photoly acti-vated RuNOCl(salen) (23), and Mn(III)(salen)PF6 (24) have beendeveloped with fair to high enantioselectivity toward kinetic reso-lutions of 2° benzylic alcohols. In marked contrast, the asymmetricaerobic catalytic process with �-hydroxycarboxylic acid derivativesis relatively unexplored (25–31).

Optically pure �-hydroxycarboxylic acid and mandelic acid de-rivatives are important precursors toward enantioselective synthesis(ref. 32; for a leading application, see also ref. 33), drug develop-ment (34–38), and biologically active (e.g., antibacterial) com-pounds (39–42). Tremendous endeavors have been devoted toenzymatic kinetic resolutions of the racemic substrates by hydrolysis(43), acylation [including a dynamic process by (RuCp(CO)2)2H(44, 45)], and aerobic oxidation (46), albeit with limited substrate

scopes. Based on our experiences of using vanadyl and oxometallicspecies in catalyzing C–C and C–X bond forming (47–51), aerobicoxidative coupling (52, 53), and photoinitiated DNA cleavage (54)events, we thought to examine the feasibility of direct asymmetric,aerobic oxidation of �-hydroxy esters and amides at ambienttemperature by chiral vanadyl complexes (55, 56).

Results and DiscussionsEffects of Templates in Vanadyl Complexes. Methyl and benzylmandelates were first used as test substrates (for the biologicalactivity of mandelic acid, see ref. 57; see also refs. 58 and 59) for adiverse array of N-naphthalidene (1–6), N-salicylidene (7–14), andN-ketopinidene-based (15) vanadyl complexes bearing the optimalL-tert-leucine chiral template. So far, arenes and CCl4 are the bestsolvents of choice. Therefore, the test aerobic oxidations werecarried out in toluene under oxygen atmosphere at ambient tem-perature in the presence of 5 mol % of the individual catalysts 1–15(Fig. 1).

In general, the asymmetric oxidations of benzyl mandelate aremore selective than those of methyl mandelate (Table 1). It also wasfound that the enantiocontrol for the kinetic resolution of methyland benzyl mandelates (16a and 16d) highly depends on the stericsof the C-3 substituents in the catalyst templates. Within the sameN-naphthalidene family, the selectivity factors follow the order of4 (G � Ph2CH; krel � 26�94) � 5 (G � Ph2COH; krel � 12�28) �1 (G � 3,4-benzo; krel � 12�14) � 6 (G � OCH2Ph; krel � 5�10) �3 (G � 3,4-benzo-5,6-benzo; krel � 4�6) � 2 (G � H; krel � 1�1).An essentially similar trend (except in the oxidation of benzylmandelate by 13) was observed in the N-salicylidene family, wherethe selectivity factors follow the order of 8 (R1 � t-Bu; R2 � OMe;krel � 50�76), 10 (R1 � R2 � t-Bu; krel � 29��100), 9 (R1 � t-Bu,R2 � NO2; krel � 26��100), and 7 (R1 � t-Bu; R2 � H; krel �26�76) � 11 (R1 � adamantyl; R2 � CH3; krel � 20�32) � 13(R1 � R2 � Ph; krel � 36�8) � 12 (R1 � R2 � Br; krel � 10�15).

Notably, within the 3-tert-butyl N-salicylidene family, catalysts7–10 are the most selective ones, and the electronic effect of theC5 substituent (R2) plays a role on the reaction rate. Vanadylcomplex-8 bearing electron-donating C5-group (R2 � OMe)exhibits the slowest rates of oxidation (88–124 h) but with thebest enantioselectivities (krel � 50�76). On the contrary, vanadylcomplex-9 bearing electron-withdrawing C5-group (R2 � NO2)exerts the fastest rates of oxidation (14.5–22 h) but with slightlypoorer enantioselectivities (krel � 26��100). Finally, very poorenantioselectivities (krel � 1–2) were observed with 14 and 15 asthe catalysts.

N-benzyl-mandelamide was next examined with the more selec-tive vanadyl complexes 1 and 3–13 under the standard reactionconditions (Table 2). To our surprise, the enantiocontrols (krel �

Conflict of interest statement: No conflicts declared.

Freely available online through the PNAS open access option.

Abbreviation: ee, enantiomeric excess.

*To whom correspondence should be addressed. E-mail: chefv043@ntnu.edu.tw.

© 2006 by The National Academy of Sciences of the USA

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2–6) in the oxidation drop significantly by using the N-naphthalidene family 1 and 3–6 as the catalysts. Conversely, theselectivity factors (krel � 44 to �100) in the 3-tert-butyl N-salicylidene family 7–10 are generally higher than those from theaerobic oxidations of methyl and benzyl mandelates (krel � 26–50;76- �100). Similarly, the resultant enantioselectivity trend exertedby the electronic effect at C-5 group also was observed in the3-tert-butyl N-salicylidene family 7–10 (compare the results fromcatalysts 8 and 9). Notably, significant increase of asymmetricinductions was attained by the 3,5-dibromo- and 3,5-diphenyl-N-salicylidene-based vanadyl complexes 12 and 13. Both the selectivityfactors are �100. Based on the selectivity and reactivity profiles inthese three representative substrate studies with varying templatesin the chiral vanadyl complexes, 3-tert-butyl, 3,5-di-tert-butyl, 3,5-dibromo, and 3,5-diphenyl-N-salicylidene-based vanadyl complexes(7, 10, 12, and 13) were selected for subsequent substrate surveyregarding the effects of the pendant O- and N-alkyl (phenyl) groupsand �-substituents in the �-hydroxy esters and amides on theasymmetric oxidation. Ultimately, vanadyl complex 10 was pre-ferred for the oxidation of �-aryl-�-hydroxy esters and amides interms of selectivity concerns. Conversely, vanadyl complex 12 was

selected for the oxidation of �-alkyl-�-hydroxy esters and amides interms of faster reaction rate concerns.

Effects of the Pendant O- and N-Substituents. Vanadyl complex 10was chosen for the asymmetric oxidations of mandelates (16a–f)and mandelamides (17a–f) with varying O-alkyl, O-phenyl, N-alkyl,and N-phenyl appendages. The best enantioselectivities wereachieved by using substrates bearing O-�N-benzyl (krel � 100) and-diphenylmethyl (krel � 60 to �100) groups (Table 3). Conversely,there is no consistent selectivity trend by increasing the steric bulkof the pendant alkyl groups from methyl, ethyl, isopropyl totert-butyl. The worst scenarios go to substrates possessing N-tert-

Fig. 1. A list of chiral vanadyl(V) methoxides examined.

Table 1. Effects of catalysts on the asymmetric aerobic oxidationof racemic methyl and benzyl mandelates 16a and 16d

CatalystTime,

hConversion,*

%%ee,†

(yield,‡ %) krel§

1 43�36 55�53 83 (41)�80 (44) 12�142 63�58 48�52 2 (44)�7 (43) 1�13 87�130 51�53 48 (43)�61 (43) 4�64 9�13 52�50 87 (44)�93 (43) 26�945 13.5�15 52�50 75 (42)�83 (43) 12�286 75�90 52�52 56 (43)�72 (45) 5�107 22�14.5 52�52 87 (46)�97 (46) 26�768 88�124 54�52 98 (45)�97 (45) 50�769 22�14.5 52�50.5 87 (47)�97 (50) 26�167

10 23�19 54�50 93 (40)�98 (46) 29�45811 22�26 51�53 81 (44)�92 (45) 20�3212 14�12 55�56 78 (43)�87 (40) 10�1513 16�14 55�60 97 (44)�82 (37) 36�814 133�128 71�66 45 (26)�47 (29) 2�215 86�240 49�51 6 (44)�7 (46) 1�1

*Determined by 1H NMR analysis of the reaction mixture.†Determined by HPLC analysis on Chiralpak AD-H or AS column.‡Isolated, purified material for the alcohol by column chromatography.§krel � ln[(1 � C)(1 � ee)]�ln[(1 � C)(1 � ee)], where C � conversion and ee �enantiomeric excess.

Table 2. Effects of catalyst templates on the asymmetric aerobicoxidation of racemic N-benzyl mandelamide-17c

CatalystTime,

hConversion,*

%% ee,†

(yield,‡ %) krel§

1 168 52 58 (44) 63 254 51 28 (43) 24 264 46 21 (50) 25 240 47 41 (52) 46 192 52 56 (44) 57 20 50 98 (48) 4588 60 50 98 (50) 4589 13 52 93 (43) 44

10 25 50 99 (47) 1,05711 240 48 62 (48) 912 9 50 99 (46) 1,05713 8 51 97 (47) 119

Footnotes are the same as those in Table 1.

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butyl (krel � 1), O-ethyl (krel � 12), and O-�N-phenyl (krel � 10–13)groups. Reasonably high selectivity factors (krel � 29 and 66) wereobserved in the case of methyl and isopropyl mandelates-16a andc. However, very poor selectivity was resulted from N-isopropyl-mandelamide-17a (krel � 1). The results indicate that a delicatebalance among the steric, conformational (s-cis vs. s-trans), andelectronic (�–� interaction) factors in a given substrate is essentialduring asymmetric discrimination event in the incipient adductformed between the catalyst and the substrate (see below).

Effects of the �-Substituents in the Benzyl 2-Hydroxyesters. Based onthe screening of the pendant O-substituents above, a series of benzyl�-hydroxyesters bearing different �-aryl groups were further ex-amined under the optimal aerobic oxidation protocol catalyzed byvanadyl complex 10 (Table 4). For 4-substituted-phenyl (i.e., man-delate) derivatives, 18–21, the selectivity factors in the kineticresolution process range from 10 to 37. In general, substratesbearing electron-withdrawing para groups (e.g., 4-Cl and 4-Br) aremore reactive (15–24 h) and more enantioselective (krel 28–37) thanthose with electron-donating (e.g., 4-CH3; 95 h; krel � 14) and�orcoordinating (e.g., 4-CH3O; 57 h; krel � 10) groups. The electronicinfluence on enantiocontrol is even more pronounced for 2-sub-stituted-phenyl derivatives 22–24. The selectivity profiles follow theorder of 2-Cl (krel � 70) � 2-CH3 (krel � 21) � 2-NO2 (krel � 15).For naphthyl-containing benzyl mandelate analogs, 1-naphthyl (i.e.,2,3-�o,m-benzo-fused) system 25 (krel � 18) is more selective than2-naphthyl (i.e., 3,4�-m,p-benzo-fused) one-26 (krel � 9), indicatinga somewhat similar detrimental effect of the para-substituent on theenantiocontrol. For heteroaryl-containing systems, the enantiose-lectivity decreases dramatically with increasing coordination abilityof the heteroatom. By comparing 16d with 27 and 28, the selectivityfactors of the aerobic oxidations follow the order of 16d (krel �100) � 28 (for the biological activities of the acids from thecorresponding 28, see ref. 60) (krel � 43) � 27 (for the biologicalactivities of the acids from the corresponding 27, see ref. 57)(krel � 5).

The substrate class was further extended to benzyl �-hydroxyes-ters possessing �-alkenyl, �-alkynyl, and �-alkyl groups (Table 5). Ingeneral, the first two substrate classes as represented in 29 (R �trans-PhCHACH) and 30 (R � Ph–C'C) are more reactive thanthe corresponding �-aryl analogs 16d and 18–27. Their aerobicoxidations catalyzed by 10 can be completed at �50% conversionin 5.5–6 h. In addition, the asymmetric induction for 29 (krel � 27)

is a lot more enantioselective than that for 30 (krel � 7). Further-more, the conjugated alkene moiety in 29 remains intact withoutany intervening epoxidation. In marked contrast, substrates 31–35bearing �-alkyl groups are completely inert toward aerobic oxida-tion under the optimal catalytic conditions in the presence of 10.Nevertheless, the desired process can be effected by using the mostreactive 3,5-dibromo-N-salicylidene-based vanadyl complex 12, al-beit with prolonged reaction time (63–188 h). Notably, the selec-tivity factors of their oxidations catalyzed by 12 highly hinge on thesteric effects of the �-alkyl groups. In comparison, the substrate 35(61) bearing 2° �-cyclohexyl group (krel � 8) is more enantioselec-tive than that bearing 1° �-methyl group (i.e., lactate-31; krel � 2).Furthermore, the enantiocontrol increases with increasing sterichindrance of the �-branching units in 1° �-alkyl-substituted sub-

Table 4. Effects of �-aryl groups on the asymmetric aerobicoxidation of racemic benzyl mandelate derivatives 18–28 bycatalyst-10

ArTime,

hConversion,*

%% ee,†

(yield,‡ %) krel§

C6H5 (16d) 12 50 98 (46) 4584-CH3C6H4 (18) 95 58 90 (40) 144-CH3OC6H4 (19) 57 51 70 (49) 104-ClC6H4 (20) 23.5 50 86 (47) 374-BrC6H4 (21) 15 52 88 (43) 282-CH3C6H4 (22) 365 52 84 (46) 212-ClC6H4 (23) 63 51 94 (48) 702-NO2C6H4 (24) 50 53 81 (45) 151-Np (25) 73 51 80 (48) 182-Np (26) 24.5 59 81 (40) 9

(27) 58 51 55 (45) 5

(28) 4 53 95 (47) 43

Footnotes are the same as those in Table 1.

Table 5. Effects of �-alkenyl, alkenyl, and alkyl groups on theasymmetric aerobic oxidation of racemic 2-hydroxyesters 29–35by catalyst-10 and 12 (for R � alkyl only)

RTime,

hConversion,*

%% ee,†

(yield,‡ %) krel§

trans-PhCH � CH (29) 5.5 56 96 (40) 27

(30)� 6 50 (49)** 60 (46)�50 (50)** 7�5**

CH3 (31) 83 60 37 (36) 2(CH3)2CH (32) 63 49 71 (46) 14C6H5CH2 (33) 89 51 96 (46) 97syn-C6H5CHNHBz (34)¶ 112 57 99 (34) 35c-C6H11 (35) 188 49 60 (49) 8

Footnotes *, †, ‡, and § are the same as those in Table 1.¶Methyl esters were used.�Ethyl ester was used.**The data were obtained by using Toste’s best catalytic system.

Table 3. Effects of O-�N-substituents on the asymmetric aerobicoxidation of racemic mandelates 16a–f and mandelamides 17a–e

X–RTime,

hConversion,*

%% ee,†

(yield,‡ %) krel§

OCH3 (16a) 23 54 93 (40) 29OCH2CH3 (16b) 22.5 50 71 (48) 12OCH(CH3)2 (16c) 19 49 88 (49) 66OCH2Ph (16d) 19 50 98 (46) 458OCHPh2 (16e) 35 49 91 (50) 117OPh (16f) 14 53 79 (45) 13NHCH(CH3)2 (17a) 104 50 7 (44) 1NHCH2Ph (17b) 25 50 99 (47) 1057NHCHPh2 (17c) 52 51 93 (47) 60NH-t-Bu (17d) 119 49 8 (48) 1NHPh (17e) 82 51 70 (46) 10

Footnotes are the same as those in Table 1.

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strates 31–34. Namely, the selectivity factors follow the order ofbenzyl [33 (for the biological activity of 2-hydroxy-3-methylbu-tanoic and 3-phenylpropanoic acids derived from 32 and 33, see ref.62) and 34, krel � 97 and 35] � isopropyl [32 (32); krel � 14] �methyl [31; krel � 2). Notably, the kinetic resolution of N-benzoy-lated-3-phenylisoserine methyl ester-34 [i.e., the taxol C-13 sidechain (63)] at 57% conversion led to the recovery of the desirednatural fragment [33–35% yield, 99% enantiomeric excess (ee)]bearing (2R, 3S)-absolute stereochemistry. Unfortunately, the ox-idized product was further degraded into benzamide (56% yield)and benzaldehyde under the reaction conditions. To suppress theextensive oxidation of the resultant �-keto ester, other N-substi-tuted-3-phenylisoserine methyl esters would be required.

Effects of the �-Substituents in the N-Benzyl-2-Hydroxyamides. Inview of the screening results of the pendant N-substituents in Table3, a series of N-benzyl-�-hydroxy-amides bearing the same set of�-aryl groups (as in Table 4) were also examined under the optimalconditions catalyzed by vanadyl complex-10 (Table 6). In all casesexcept 4-methoxy-, 2-methoxy-, and 2-chloro-phenyl substitutedcases (37, 41, and 42), the selectivity factors of their aerobicoxidations are at least two times larger than those of the corre-sponding benzyl esters (compare Tables 4 and 6). In addition, onlythe 4-methoxy- and 2-methoxy-phenyl analogs-37 and 41 led tounsatisfactory result (krel � 7 and �3). Notably, the opposite(S)-enantiomer-41 was recovered in 34% ee. Presumably, thecompeting coordination of the 2-methoxyphenyl group to thevanadyl center with the amide carbonyl group during the chelationadduct formation event erodes and reverses the asymmetric differ-entiation (see below). Nevertheless, significant improvement wasachieved particularly in the case of 2-furanyl (krel � 24 for 45 vs. 5for 27).

Among all of the N-benzyl-�-hydroxy-amides examined, thereactivity profile again follows the order of �-alkenyl � �-aryl ���-alkyl (Tables 6 and 7). For the amides 47–51 possessing �-alkenyland �-alkyl groups, good to excellent kinetic resolutions (krel � 33to �100) remain attainable except in the methyl case (i.e., 48) where

poor selectivity factor (krel � 3) like that (krel � 2) for the analogousester-31 was observed.

During the x-ray structural identification of a catalyst–substrateadduct and the preparation of this work, a very recent elegant studyby Toste and coworkers (64) unraveled the use of in situ-generatedchiral vanadyl(V) isopropoxides by direct mixing of N-salicylidene-L-�-amino alcohols [i.e., Bolm’s ligands (65, 66)] with VO(OiPr)3

for asymmetric aerobic oxidations of �-hydroxyesters in acetonewith good enantiocontrols (krel � 13 to �50) except in the TMS-C'C �-substituted case (krel � 6). Notably, the corresponding�-hydroxyamides except N-t-butyl-mandelamide were not exam-ined, and the �-hydroxyesters they studied bear somewhat different�-substituents from ours. To probe whether their best system couldimprove the enantioselectivity of the worst substrate in our study,the aerobic oxidation of benzyl 4-phenyl-3-butynoate-30 was ex-amined by using their best catalyst under their optimal reactionconditions. It was found that the resultant selectivity factor (krel �5) is lower than that (krel � 7) carried out by our best system (entry2, Table 5). VO(Oi-Pr)3 is moisture sensitive. Anhydrous acetoneneeds to be used in Toste’s system. Therefore, our current chiralvanadyl(V) methoxide catalyst system represents a highly enantio-selective, complementary, and water-tolerant alternative particu-larly toward the asymmetric oxidations of �-hydroxyamide sub-strate class.

Structural Studies of a Catalyst-Substrate Adduct. To gain insightsinto the origin of enantiocontrol, we tried to get the single crystalof a stable vanadyl complex–substrate adduct. The slowest reacting,but highly enantioselective, catalyst 8 was combined with one equivof the racemic N-benzyl-mandelamide 17b in toluene under anaer-obic reaction condition (0.2 M), and the mixture was stirred atambient temperature in argon for 40 min followed by heating at100°C for 2 h. Some green precipitate was collected (14% yield) andrecrystallized from degassed and argon-purged toluene to give adiastereomeric crystalline adduct 52 of x-ray quality. The filtratecontains mainly the (R)-17b (37%) in essentially optically pure form(99% ee) along with some �-ketoamide (17b�, 40%). Based on thecrystallographic analysis of the adduct 52, the methoxide ligand inthe original catalyst 8 has been replaced by the 2-alkoxide unit ofthe N-benzyl-mandelamide with release of MeOH (i.e., protonexchange) (Fig. 2). In addition, the amide carbonyl group iscoordinated anti to the VAO unit. Remarkably, only the (2R)-enantiomer is chelated by which the �-phenyl group stays awayfrom the sterically congested 3-tert-butyl group in the template ofthe catalyst 8. In addition, the amide is in s-cis conformation, andthe phenyl group of the N-benzyl unit in the substrate is positionedunderneath the salicylidene template. More intriguingly, the phenyl

Table 6. Effects of �-aryl groups on the asymmetric aerobicoxidation of racemic N-benzyl mandelate derivatives 36–46by catalyst-10

ArTime,

hConversion,*

%% ee,†

(yield,‡ %) krel§

C6H5 (17b) 25 50 99 (47) 1,0574-CH3C6H4 (36) 130 60 99.6 (38) 244-CH3OC6H4 (37) 106 61 77 (38) 74-ClC6H4 (38) 70 50 97 (47) 2784-BrC6H4 (39) 24 53 �99 (45) �802-CH3C6H4 (40) 81 49 94 (45) 2112-CH3OC6H4 (41) 108 50 34 (44) �3¶

2-ClC6H4 (42) 18 50 92 (47) 791-Np (43) 130 53 99 (45) �802-Np (44) 114 64 �99 (32) 17

(45) 164 52 86 (43) 24

(46) 4 53 99 (42) 80

Footnotes *, †, ‡, and § are the same as those in Table 1.¶The (S)-enantiomer was obtained.

Table 7. Effects of �-alkenyl and alkyl groups on the asymmetricaerobic oxidation of racemic N-benzyl-2-hydroxyamides 47–51by catalyst-10 and 12 (for R � alkyl only)

RTime,

hConversion,*

%% ee,†

(yield,‡ %) krel§

trans-PhCH � CH (47) 9 51 �99 (47) �211CH3 (48) 92 50 33 (47) 3(CH3)2CH (49) 142 51 95 (46) 81C6H5CH2 (50) 102 52 95 (43) 56c-C6H11 (51) 182 52 90 (45) 33

Footnotes are the same as those in Table 1.

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group is sandwiched between the 3-tert-butyl and 5-methoxy groupsin the template in a perpendicular �–� staking fashion.

The oxygen-sensitive adduct 52 was then subjected to the oxi-dation in molecular oxygen in toluene again at normal concentra-tion (0.2 M). The oxidation went to completion in �1 h with ahalf-life (t1/2) of 20 min rather than 60 h as shown in Table 2, leadingto the �-ketoamide in quantitative yield. The results indicate thatone of the rate-limiting steps of the catalytic process is the depro-tonation of the substrate by the methoxide in the catalyst. Thethermodynamically more stable adduct 52 as shown in the x-rayanalysis is a slower-reacting diastereomeric species toward oxida-tion (Fig. 3). On the contrary, the sterically more encumbereddiastereomeric adduct 52� is faster reacting for subsequent �-protonelimination process leading to �-ketoamide 17b�.

The nearly exclusive enantiocontrol is further demonstrated bysubjecting each enantiomeric N-benzyl-mandelamide under thesame aerobic oxidation conditions catalyzed by 10. At 85% con-sumption of the (S)-enantiomer, the (R)-antipode-17b remainsintact.

Mechanistic Proposal. It was believed that the catalytic processproceeds through initial deprotonation of the substrate by chiralvanadyl(V) methoxide (e.g., 8 or 10) followed by ligand exchange,resulting in chelation of the substrate to the catalyst to give thediastereomeric adduct-52� with extrusion of methanol (i.e., 2 equiv)(Fig. 4). �-Proton elimination of the kinetically favored adduct 52�through a two-electron oxidation process with concomitant reduc-tion of the vanadyl(V) species to the corresponding vanadium(I-

II)OH would lead to the oxidized product (i.e., �-ketoamide-17b�)or the coupled adduct 53. The vanadium(III) hydroxide maydisproportionate with the starting vanadyl methoxide catalyst togive two vanadyl(IV) complexes with release of N-benzyl benzoyl-formamide and CH3OH (pathway I, Fig. 4). Alternatively, it may beoxidized by reaction with molecular oxygen to lead to a peroxo-dimer 54, which returns to the original catalyst but now with ahydroxide ligand instead of methoxide to complete the catalyticcycle (pathway II, Fig. 4).

In conclusion, we have documented a successful example of usingN-salicylidene-L-�-amino acid-based vanadyl(V) complexes forhighly enantioselective and chemoselective oxidations of racemic,functionalized �-hydroxy esters and amides under oxygen atmo-sphere at room temperature. Judicious selections of the C3,C5substituents and pendant chiral groups in the template and solventsallow us to access the optimal vanadyl complexes. Kinetic experi-ments and x-ray crystallographic analysis of the more stable diaste-reomeric adduct indicate the involvement of vanadyl(V)-�-alkoxyester�amide adduct responsible for subsequent two-electron oxi-dation event and clarify the origin of stereocontrol due to tightchelation of the substrate to the vanadyl catalyst. The currentprotocol works well for �-aryl-�-hydroxyesters and essentially allkinds of �-hydroxyamides and also can be applied to racemic taxolC-13 side-chain resolution, auguring well for its potential applica-tions in the pharmaceutical industry.

Materials and MethodsRepresentative Preparation Procedure and Analytical Data for Vana-dyl(V) Methoxide (or Hydroxide) Complexes 1–13. In a 50-ml, two-necked, round-bottom flask was placed L-tert-leucine (5 mmol) andNaOAc–5H2O (1.17 g, 10 mmol) in degassed water (10 ml). Afterhaving been stirred at 60°C for 10 min to effect their completedissolution, the reaction mixture was treated dropwise with asolution of respective 2-hydroxy-benzaldehyde derivatives (5 mmol)in degassed EtOH (12.5 ml). The reaction mixture became homo-geneous by heating at 80°C for 15 min and then gradually cooled toambient temperature for 2 h. To the resultant Schiff base was addeda solution of vanadyl(IV) sulfate trihydrate (1.08 g, 5 mmol) indegassed water (5 ml). Dark green complex started crashing out in15 min. The reaction mixture was stirred for 2 h and then concen-

Fig. 2. ORTEP (www.ornl.gov�sci�ortep�ortep.html) drawing (ellipsoids areshown at 20% probability level) for the x-ray crystal structure of the catalyst–substrate adduct 52.

Fig. 3. Reactivity difference for the diastereomeric adducts formed betweena vanadyl(V) methoxide and racemic mandelamide.

Fig. 4. Proposed mechanism.

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trated to half of the original solvent volume. The crude vanadyl(IV)complex collected by filtration was washed sequentially with water(5 � 25 ml) and cold ether (5 � 25 ml) and then dried in vacuo tofurnish pure vanadyl(IV) catalyst. The corresponding analyticallypure vanadyl(V) methoxide (or hydroxide) complexes were ob-tained by recrystallization from oxygen-saturated MeOH and wereused for asymmetric aerobic oxidation experiments.

Representative Procedure for the Asymmetric Aerobic Oxidation of�-Hydroxy-Esters and Amides. Into a 50-ml, two-necked, round-bottom flask was placed vanadyl catalyst-10 (0.05 mmol; 5 mol%)in oxygen-saturated toluene (3 ml) under oxygen atmosphere. Thereaction flask was vacuum-evacuated at 15 torr for 20 sec and thenfilled with an O2 balloon (150 ml). A solution of �-hydroxy-ester�amide (1 mmol) in oxygen-saturated toluene (2 ml) was added bycannula, and the resulting dark brown mixture was stirred atambient temperature. The reaction progress was monitored by 1HNMR spectroscopy for percent conversion (142 mg; i.e., 1 mmol of2-methyl-naphthalene was used as an internal standard). Theenantiomeric excess of the kinetically resolved product was deter-mined by chiral HPLC analysis after filtration of the reactionaliquot (100 �l) over a short plug of silica gel (Et2O or CH2Cl2 aseluent). Upon reaching optimal resolution of the asymmetricoxidation (50–64% conversion), the reaction was quenched byaddition of silica gel (150 mg), and the mixture was concentratedunder reduced pressure. The resulting residue was loaded directlyon top of an eluent-filled silica gel column and purified by flashcolumn chromatography. The enantiomeric excess of the pure,resolved �-hydroxy-ester�amide was analyzed again by chiralHPLC analysis.

Preperation of the Vanadyl(V) Complex-N-Benzyl-Mandelamide Ad-duct 52. To a reaction tube (15-mm outer diameter; 100-mm length)equipped with a magnetic stirring bar was placed vanadyl(V)

methoxide catalyst 8 (435 mg; 1 mmol) and racemic N-benzyl-mandelamide 17b (241 mg, 1 mmol) in freshly distillated argon-purged toluene (5 ml) under argon atmosphere. After it was stirredat ambient temperature for 40 min, the solution turned deep blue.The resulting deep blue solution then was heated at 100°C for 2 hunder argon atmosphere. The resulting mixture was graduallycooled to ambient temperature and concentrated in vacuo to givea green needle solid. The needle solid was redissolved in degassedCH2Cl2 (5 ml) and was reprecipitated by slow addition of degassedhexane (5 ml). Green precipitate of 52 was obtained from the mixedsolvents by slow decantation. The collected filtrate was loadeddirectly on top of an eluent-filled silica gel column and then purifiedby flash chromatography. The oxidized product N-benzyl-2-oxo-2-phenyl-acetamide-17b� was isolated in 40% yield (96 mg) along withthe resolved (R)-N-benzyl- mandelamide-17b in 37% yield (8 9 mg;99%ee).

The green precipitate again was redissolved in degassed CH2Cl2(3 ml), and argon-purged hexane (3 ml) was slowly diffused to thesolution under argon atmosphere at ambient temperature for 3days. The deep brown fine single crystals of 52 were collected in12% yield (73 mg). The absolute stereochemistry for 52 wasdetermined by x-ray crystallographic analysis.

Supporting Information. Spectral data and characterization for allthe vanadyl(V) methoxide complexes 1–15, kinetic resolutionproducts 16–51 and oxidation products 16�–51�, and selectedX-ray data of the adduct-52 are included as Appendices 1–5 andData Sets 1 and 2, which are published as supporting informationon the PNAS web site.

This work was supported by the National Science Council of Taiwan.

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