Lewis Acid Catalyzed Enantioselective Reactions Using Highly Coordinating Nucleophiles . Conjugate Additions of Thiols , Thiocarboxylic acids , and O-Benzylhydroxylamine

Studies of chiral Lewis acid catalyzed enantioselective reactions using strongly coordinating nucleophiles, as a rather unexplored categoly of catalyzed enantioselective reactions, are described. Selection of a proper chiral catalyst should be essential. The author has employed complexes of two chiral ligands, (R,R)-4,6-dibenzofurandiyl2,2'-bis(4-phenyloxazoline) and (R,R)-isopropylidene-2,2'-bis[4-(o-hydroxybenzyl)oxazoline)], designated R,RDBFOX/Ph and R,R-BOX/o-HOBn, respectively. The complex catalyst derived from R,R-DBFOX/Ph and Ni(ClO4)2 . 3H2O works as a powerful catalyst in the enantioselective thiol conjugate additions to 3-(2-alkenoyl)-2-oxazolines, and the complex derived from R,R-BOX/o-HOBn and Cu(OTf)2 catalyzes the reactions of O-benzylhydroxylamine to 1-alkyl-3-(2-alkenoyl)-2-imidazolidinones. Internal delivery of nucleophiles to the activated acceptors is proposed as a powerful principle for the development of the titled reactions. To the top of this index page


Introduction
Conjugate addition of heteronucleophiles to electron-deficient carbon-carbon double bonds is a fundamentally important reaction.*1*Lewis acid-catalyzed enantioselective conjugate additions of alpha,beta-unsaturated carbonyls are attractive as a direct access to enantiomers of beta-heterosubstituted carbonyl compounds.*2,3*Ready availability of the starting alpha,beta-unsaturated carbonyl acceptors is an advantage.However, a serious problem exists: Lewis acid catalysts should interact strongly with heteronucleophiles to inactivate the catalyst.Therefore, this promising enantioselective methodology is difficult to exploit in practice.Success depends upon the correct choice of chiral Lewis acid catalyst (Scheme 01).

Scheme 01
The cationic aqua complex*4* prepared between (R,R)-4,6-dibenzofuradiyl-2,2'-bis(4-phenyloxazoline) ligand (designated hereafter R,R-DBFOX/Ph) and nickel(II) perchlorate hexahydrate is an effective chiral Lewis acid catalyst in the Diels-Alder reactions of cyclopentadiene, even in the presence of a variety of coordinating reagents (Scheme 02).*4b*The high tolerance and catalytic activity observed depend upon the aqua complex structure, and we believe that the strongly coordinating reagents undergo rapid ligand exchange on the metallic center of the complex.Based on this high synthetic potential of the R,R-DBFOX/Ph -transition metal aqua complexes, enantioselective nitrone 1,3-dipolar cycloadditions*5* were already reported from this laboratory.The nickel(II) aqua complex R,R-DBFOX/Ph .Ni(ClO4)2 .3H2O was prepared in situ by treatment of equimolar amounts (10 mol%) of R,R-DBFOX/Ph ligand with nickel(II) perchlorate hexahydrate in tetrahydrofuran (THF) by stirring at room temperature for 30 min.Reaction of benzenethiol (1.1 equiv) with 3-crotonoyl-2-oxazolidinone (1 equiv) was quite slow and it took about 24 h at room temperature until the oxazolidinone acceptor was all consumed (checked by tlc).After aqueous workup, the mixture was purified through silica gel column chromatography to give the conjugate adduct, whose enantiopurity was determined by chiral hplc.*9*Based on the absolute configuration of adduct,*10* it was found that the thiol conjugate addition took place on the Si-face of the oxazolidinone acceptor (Scheme 05).Scheme 05 Among a variety of DBFOX/Ph complexes examined as chiral catalysts, the nickel(II) aqua complex was exceptionally effective (Scheme 06).Although the magnesium and zinc complexes prepared from R,R-DBFOX/Ph ligand by treatment with Mg(ClO4)2, Zn(ClO4)2 .6H2O, Zn(OTf)2, or ZnI2 showed satisfactory catalytic activity, the enantioselectivities observed in the catalyzed thiol conjugate additions were relatively poor.On the other hand, metal complexes prepared from the perchlorates of copper(II), iron(II), and manganese(II) ions showed only a low catalytic activity.

Scheme 06
Reactions of a variety of thiols were catalyzed by the nickel(II) aqua complex R,R-DBFOX/Ph .Ni(ClO4)2 .3H2O to give the corresponding adducts.Satisfactorily high enantioselectivities as well as high chemical yields were observed with some exceptions when the reactions were performed in THF at room temperature (Scheme 07).

Scheme 07
Enantioselectivities were found to change sharply depending upon the reaction conditions including catalyst structure, reaction temperature, solvent, and additives (Scheme 08).Some representative examples of such selectivity dependence are listed in the table for the reaction between benzenethiol and 3-crotonoyl-2oxazolidinone.The adduct was formed with 79% ee (81% yield) when the reaction was catalyzed by the nickel(II) aqua complex at room temperature in dichloromethane.However, reactions either by use of the anhydrous complex*11* or the aqua complex together with MS 4A gave racemic adduct, indicating that the aqua complex should be more favored than the anhydrous complex in thiol conjugate additions.Slow addition of the thiol to the dichloromethane solution of 3-crotonoyl-2-oxazolidinone was ineffective for enantioselectivity.Enantioselectivity was dramatically lowered and reversed to -17% ee in the reaction at -78 o C. A similar tendency was observed in the reactions in diethyl ether and THF.For example, a satisfactory enantioselectivity (80% ee) was observed in the reaction in THF at room temperature, while the selectivity almost disappeared (7% ee) at 0 o C.
To examine such high sensitivity of enantioselectivity to the reaction conditions, the reactions of benzenethiol with 3-crotonoyl-2-oxazolidinone were performed in dichloromethane at room temperature in the presence of a variety of additives.Although addition of methanol (CH2Cl2/MeOH = 10: 1 v/v) did not affect either the chemical yield or enantioselectivity of the adduct (quant, 82% ee), addition of acetonitrile or N,N-dimethylformamide (both 1:1 v/v ratios) slowed the reactions (13, 15% yields) and provided products with lower enantioselectivities (19, 30% ees).

Scheme 08
We suspected at the beginning of this work that thiol would strongly coordinate to the Lewis acid catalyst R,R-DBFOX/Ph .Ni(ClO4)2 .3H2O to poison its catalytic activity.We therefore examined the interaction between benzenethiol and the catalyst to learn about the catalytic activity of the thiol-coordinating complex (Scheme 09).
When the thiol was added to a solution of the catalyst in THF, the original pale blue color of the catalyst gradually faded to reddish brown.This color change was rapid in dichloromethane,*12* probably arising from the coordination of thiol to the catalyst.A brown colored solid was isolated as precipitate on treatment with a mixture of isopropyl alcohol and hexane,*13* and this showed sufficient catalytic activity in the reaction of benzenethiol with 3-crotonoyl-2-oxazolidinone in THF leading to a high enantioselectivity (97% yield, 70% ee).

Scheme 09
Accordingly, it is apparent that the thiol certainly binds with the catalyst, but the binding is not so strong that the thiol ligand may be easily replaced with the acceptor molecule in the reaction.This ligand exchange should be more favored in a coordinating media such as THF.However at the same time, THF competes with the acceptor molecule in coordination to the catalyst to deactive the reaction.In the presence of an amine base such as pyridine or triethylamine, a totally inert reddish brown complex immediately precipitated.*14*Since the resulting brown solid is totally insoluble in the reaction medium and free from perchlorate ions (according to analysis for chloride), we assume that the perchlorate counterions have been replaced with the highly nucleophilic thiolate ions.

Scheme 10
The time dependence of enantioselectivity in the reaction between benzenethiol with 3-crotonoyl-2-oxazolidinone catalyzed by R,R-DBFOX/Ph .Ni(ClO4)2 .3H2O at room temperature in THF is shown in Scheme 10.After 3 h, yield of the adduct is 70% with the enantioselectivity of 91% ee, but the enantioselectivity was 80% ee at the completion of reaction after 24 h (yield: 100%).Although the catalyst maintains a high catalytic activity, and hence a satisfactory enantioselectivity, at the early stage of reaction, the deterioration of catalyst cannot be neglected thereafter even under neutral conditions.However, to our delight, the reaction in a mixed solvent of CH2Cl2/THF = 10: 1 v/v (Scheme 11) catalyzed by the nickel(II) aqua complex at 0 o C in the presence of N,N,N',N'-tetramethyl-1,8-diaminonaphthalene (proton sponge, 10 mol%) gave the best result (84% yield, 94% ee, Scheme 12).Some other thiols provided excellent enantioselectivities under similar reaction conditions (condition B) with 97% ee for a bulky thiol such as oisopropylbenzenethiol.

Scheme 17
Importance of the o-hydroxyl group involved in the 4-benzyl shielding group of the complex catalyst was confirmed when enantioselectivities were compared among the following reactions.Thus, enantioselectivity observed in the reaction of O-benzylhydroxylamine with 1-crotonoyl-3-phenyl-2-imidazolidinone catalyzed by the R,R-BOX/o-HOBn .Cu(OTf)2 complex at room temperature was 85% ee, while the enantioselectivity was only 49% ee when the hydroxyl group is methylated (Scheme 18).Use of the catalyst having no hydroxyl group on the benzyl phenyl group provided 71% ee.The same absolute configurations were induced in these three reactions.We believe that the free hydroxyl groups of R,R-BOX/o-HOBn .Cu(OTf)2 weakly coordinate to the copper(II) ion to hinder to a certain extent the free rotation of the benzyl shielding substituent across the C(4) -CH2 bond.This conformational restriction either facilitates the coordination of the acceptor molecule to the metallic center of complex catalyst easy or increases the efficiency of chiral shielding.However, the catalytic activities of all three catalysts were about the same.

Scheme 18
Acceptors having N-alkyl-2-imidazolidinone chelating auxiliaries are more electron rich than those having Nphenyl-2-imidazolidinone and 2-oxazolidinone auxiliaries so that the N-alkyl acceptors should be less reactive under the uncatalyzed conditions than the later two, but coordination to the catalyst should be stronger.
Accordingly, the reaction rate difference between the catalyzed and uncatalyzed reactions should be greater for Nalkyl-2-imidazolidinone acceptors.Competitive coordination of the substrate O-benzylhydroxylamine and acceptors affects the total reaction rate in the Lewis acid-catalyzed reactions using coordinating nucleophiles so that N-alkyl-2-imidazolidinone acceptors are anticipated to be much more effective in reactivities and enantioselectivities (Scheme 19).

Scheme 20 Scheme 21
When the same reaction was diluted five-fold with dichloromethane (0.03 M), the reaction rate was not so fatally decreased as expected for the second-order reaction,*16* and the enantioselectivity (97% ee) was improved (0.15M: 93% ee at -40 o C).Accordingly the reactions using other acceptors were examined under dilute conditions (0.03 M) to find that the enantioselectivities were much improved regardless of the beta-substituents of the acceptors (Scheme 22).This probably indicates that both the acceptor and nucleophile are condensed on the copper catalyst and the nucleophile is delivered internally to the activated acceptor.This internal delivery mechanism should guarantee high enantioselectivity since the transition structure becomes much more rigid by coordination.Dilution should be favored for the inhibition of both competing external delivery of nucleophile and competing uncatalyzed background process.

Scheme 22
Dependence of enantioselectivities on reaction temperature was only small as shown in Schemes 17 and 20, while the reaction rates were highly temperature-dependent.This temperature insensitivity on the enenatioselectivity indicates that the transition structure has a rigid structure.Addition of O-benzylhydroxylamine to the bluish greencolored solution of R,R-BOX/o-HOBn .Cu(OTf)2 and 1-crotonoyl-3-isopropyl-2-imidazolidinone in dichloromethane induced the immediate color change to dark-green, indicating that coordination of amine to the catalyst is very rapid.The above observations are likely to support the internal delivery mechanism.

Scheme 23
In a preliminary experiment for the reaction between 1-crotonoyl-3-isopropyl-2-imidazolidinone and Obenzylhydroxylamine we have found that the enantioselectivity of the adduct changes depending upon the conversion of reaction; a low enantioselectivity results at the early stage of reaction and this is gradually recovered with the progress of reaction.Probably the intermolecular conjugate addition reaction providing a lower selectivity competes at the initial stage as mentioned above.The dilution method has offered an efficient solution.As an alternative, we tried to freeze the competing intermolecular reaction by applying "initial freeze procedure".The amine nucleophile was added to a 0.15 M solution of 1-crotonoyl-3-isopropyl-2-imidazolidinone and R,R-BOX/o-HOBn .Cu(OTf)2 at -78 o C and, after a while (20 min) at this temperature, the mixture was warmed up to the reaction temperature.By this "initial freeze procedure" the reaction was accelerated and the enantioselectivity was improved (Scheme 23).
We are happy to find that the neutral nickel(II) complex catalyst*17* derived from R,R-BOX/o-HOBn and nickel(II) acetate shows a high catalytic activity in the reaction of 1-crotonoyl-3-isopropyl-2-imidazolidinone with Obenzylhydroxylamine.With the catalytic loading of 10 mol% of the isolated catalyst, the reaction done at room temperature gave an enantioselectivity of 84% ee for the adduct (Scheme 24).

Scheme 24
To the top of this index page

Conclusion
We have succeeded in the establishment of highly effective enantioselective conjugate additions of thiols to 3-(2alkenoyl)-2-oxazolidinones in the presence of the nickel(II) aqua complex derived from R,R-DBFOX/Ph and Ni(ClO4)2 .6H2O, as well as the reactions of O-benzylhydroxylamine to 1-(2-alkenoyl)-3-isopropyl-2-imidazolidinones in the presence of the copper(II) complex catalyst prepared from R,R-BOX/o-HOBn and Cu(OTf)2.These reactions provide rare examples of "Lewis acid catalyzed enantioselective reactions using strongly coordinating nucleophiles".We believe these two reactions will pioneer a conceptually new methodology in the field of synthetic organic chemistry.
Use of tolerant chiral Lewis acid catalysts such as the complexes derived from R,R-DBFOX/Ph and R,R-BOX/o-HOBn ligands is no doubt highly responsible for the success.The author sincerely hopes the present lecture stimulates not only the field of synthetic organic chemistry but also the field of molecular catalyst chemistry.
To the top of this index page Scheme 02 Scheme 13