Oxidation of sulfides to chiral sulfoxides using Schiff base-vanadium (IV) complexes

A library of Schiff base ligands was synthesized from salicylaldehyde by reaction with various β -amino alcohols. These ligands were used with vanadium (IV) to screen for the enantioselective oxidation of sulfides to chiral sulfoxides


Introduction
2][3][4][5][6] Satoh and coworkers have reported the synthesis of chiral allenes by first coupling alkenyl aryl sulfoxides with aldehydes followed by alkyl anion induced elimination of the sulfur. 7Toru has reported the enantioselective addition of Grignard reagents to 1-(arylsulfinyl)-2naphthaldehyde, where a chiral sulfoxide conformer controls stereoselectivity of the addition. 8ptically active β-(trimethylsilyl)ethyl sulfoxides supported on Merrifield resin undergo enantioselective Michael addition to α,β-unsturated esters, followed by removal of the sulfoxide group via thermal elimination. 91][12][13] Yuste and Ellman have independently described the use of sulfoxides as chiral auxilaries in the asymmetric synthesis of β-amino alcohols which, in turn are synthetically-useful chiral building blocks.14a, b, c, 15a, b Toru has reported the elegant use of a chiral sulfoxide to synthesize an insecticidal chiral chrysanthamate.16a More recently, Colobert 16b and Bravo 16c have demonstrated the use of chiral sufoxides in the synthesis of myoinositol, pyrrolidine and tetrahydroisoquinoline alkaloids, respectively.These examples clearly demonstrate the versatility of chiral sulfoxides as chiral auxilaries in asymmetric synthesis.
A number of sulfoxides are also finding application in the pharmaceutical industry.The chiral sulfoxide quinolone 1 is known to inhibit platelet adhesion by interfering with the release of 12(S)-hydroxyeicosatetraenoic acid from platelets.17a, b, 18 Pyrazolotriazine 2 is a new drug developed to treat hyperuricemia and isochemic reperfusion injury.The drug inhibits the biosynthesis of uric acid by blocking xanthine oxidase. 19Unge and co-workers have reported the asymmetric synthesis of esomeprazole, a drug containing a chiral sulfoxide group known to inhibit gastric acid secretion.20a Padmanahan and co-workers from Cambridge Neuro Science have reported the asymmetric synthesis of a sulfoxide containing a guanidine portion that is an active N-methyl-D-aspartate ion-channel blocker.20b These few examples clearly illustrate the growing importance of chiral sulfoxides in the pharmaceutical industry.Since enantiomerically pure sulfoxides can play an important role as chiral auxilaries in organic synthesis, it is surprising that very few examples exist in which this ligand participates in homogeneous catalysis.Khiar used a Fe(III) complex of C 2 -symmetric bis-sulfoxide as a catalyst in the asymmetric Diels-Alder reaction. 21Shibasaki and Williams have independently used Pdsulfoxide complexes in asymmetric allylic substitution. 22,23 olm and Carreño have also attempted the use of chiral sulfoxides to catalyse the enantioselective addition of diethyl zinc to aromatic aldehydes; the products were obtained in moderate ee's. 24,25 ese results have prompted researchers over the past two decades to develop new methods leading to asymmetric oxidation of a sulfide to a chiral sulfoxide (Equation 1).Numerous methodologies have been reported for the transformation of a prochiral sulfide to a chiral sulfoxide.Most of them involve use of a chiral ligand with a transition metal, such as titanium, vanadium or manganese, in the presence of hydrogen peroxide or an hydrogen peroxide adduct as the oxygen source.The chiral ligands that have been successfully used include: bidentate diethyl tartrate 3, 26 diol 4, 27 BINOL 5, 28,29 tridentate Schiff base ligands 6 [30][31][32] and tetradentate Salen type ligands 7. [33][34][35][36]

Results and Discussion
As part of a wider study of asymmetric transformations, we proposed the preparation of a large library of chiral Schiff base ligands of the -O---N---O-type 6.Along with a transition metal ion, Ti(IV), V(IV), Cu(II) or Zn(II)), it would permit screening of the Schiff base ligands in various asymmetric chemical transformations.Recent application of this strategy in our laboratories to the addition of trimethylsilyl cyanide to benzaldehyde in the presence of Ti (IV) ion resulted in trimethylsilyl cyanohydrins in 40-85% enantioselectivity (Equation 2). 37,38 nadium (IV)-Schiff base complexes have been successfully used by Bolm, 31 Ellman 15 and Skarzewski 32 to oxidize different sulfide substrates to chiral sulfoxides.Based on these reports we have created a library of Schiff base ligands with subtle variations in the size of the substituents on the ligand.The library of ligands was derived from salicylaldehydes 8 and chiral β-amino alcohols 9 as shown in Equation 3. (3) The results of our screening are shown in Table 1.From our previous work with these ligands in the trimethylsilylcyanation of benzaldehyde catalyzed by Ti(IV)-Schiff base complexes, we discovered it was necessary to have a bulky substituent ortho to the phenol (R 1 ). 37A similar trend was also observed in the sulfide oxidation; when R 1 = H, OCH 3 or R 2 , R 3 = naphthyl, the observed ee's were low.Hence, we designed a number of Schiff bases with a bulky substituent at R 1 , and then varied the size of substituents on R 2 , R 4 and R 5 .Initially, we incorporated a conformationally-rigid five membered ring at R 4 and R 5 , derived from cis-1amino-2-indanol. Our assumption here was that the bulky indanol ring would increase the energy difference between two diastereomeric transition structure orientations, thereby enhancing the resulting enantioselectivity.When R 1 = tert-butyl or adamantyl, and R 4 , R 5 = cis-1-amino-2indanyl, reasonably good enantioselectivities were observed (ligand 10).However, when R 1 was replaced with 3,3-dimethyl propyl or 1,1-dimethylbenzyl, enantioselectivity was considerably lower (ligands 15 and 16).This lowering of enantioselectivity probably came from steric overcrowding around the metal, thereby inhibiting the sulfide-metal coordination.Interestingly, when the rigid five-membered ring was replaced with a conformationally more flexible β-amino alcohol fragment (R 4 ), enantioselectivity was considerably improved, (ligands 42, 43 and 44).However, when both R 4 and R 5 were substituted, the enantioselectivity once again decreased (ligands 28-32).Our results are in accordance with the recent report from Bergman and Ellman, 14a who have isolated the active intermediate in the Schiff base-vanadium catalyzed oxidation of sulfide to sulfoxide.The intermediate was found to be a 2:1 complex of Schiff base ligand to vanadium, which then reacts with hydrogen peroxide, eliminating one of the ligands to give a vanadium hydroperoxide complex, which then oxidizes the sulfide to sulfoxide.It is reasonable to assume that a certain amount of steric crowding around the metal in the transition state is essential in order to enhance the enantioselectivity of the sulfide oxidation.From our and previous works related to trimethylsilylcyanation of aldehyde and sulfide to sulfoxide oxidation using Schiff base ligands, it appears that a tert-butyl substituent provides the ideal steric size and gives good enantioselectivity in both types of reactions.
Having investigated the size of substituents on the Schiff base ligands and their effects on the enantioselectivity, we next turned our attention to studying the electronic effects of these substituents in the sulfide to sulfoxide oxidation.Skarzewski and coworkers have reported that with the electron withdrawing nitro group para to the phenolic OH in the Schiff base-V(IV) complex(system) gives high enantioselectivity in the sulfide to sulfoxide oxidation. 32However, in our hands R 2 = NO 2 and R 1 = tert-butyl led to low ee, which is also in agreement with Ellmann's observation. 14When the strong electron withdrawing nitro was replaced with a less electron attractive bromine atom, along with sterically bulky substituents R 1 , R 4 and R 5 on the Schiff base ligand, enantioselectivity was improved (ligand 18).A similar trend was also seen in the trimethylsilylcyanation of benzalaldehyde catalyzed by Schiff base-Ti(IV) complex. 39n conclusion, the steric requirements of the Schiff base-vanadium (IV) complex-catalyzed oxidation of a sulfide to a chiral sulfoxide parallels the Ti(IV)-Schiff base catalyzed trimethylsilyl cyanation reactions. 38Added to this, the presence of electron-withdrawing bromine at R 1 or R 2 along with appropriate bulky substituents on the ligand enhances the enantioselectivity in the sulfide to sulfoxide oxidation.Thus, in designing new chiral Schiff base ligand-vanadium complexes for the sulfide to sulfoxide oxidation, consideration has to be given to both steric and electronic factors.

Experimental Section
General procedure for the oxidation of methyl phenyl thio ether to sulfoxide The enantiomeric excesses were determined using a Hewlett-Packard liquid chromatograph (detecting UV diodes at 254 nm), with a (R,R)-WHELK-01 chiral column.