Kinetic resolution, of sulfoxides

Asymmetric oxidation of sulfides and kinetic resolution of sulfoxides... 

ASYMMETRIC OXIDATION OF SULFIDES AND KINETIC RESOLUTION OF SULFOXIDES... 

Uemura and coworkers utilized (R)-binaphthol 85 as chiral ligand in place of DET in association with Ti(IV)/TBHP, which not only mediated the oxidation of sulfides to (R)-configurated sulfoxides, but also promoted the kinetic resolution of sulfoxides (equation 50). In this latter process the two enantiomers of the sulfoxide are oxidized to sulfone by the chiral reagent at different rates, with decrease of the chemical yield, but increase of the ee values. Interestingly, the presence of ortho-nilro groups on the binaphthol ligand lead to the reversal of enantioselectivity with formation of the (5 )-configurated sulfoxide. Non-racemic amino triols and simple 1,2-diols have been successfully used as chiral mediators. 

The asymmetric oxidation of thioethers as well as kinetic resolution of sulfoxides with 30% H2O2 catalyzed by a stable, recyclable and commercially avialable solid WO3 catalyst provides a simple and effective procedure for the preparation of chiral sulfoxides in good enantimeric purity. The procedure is very easy to perform. 

Davis, F. A., Billmers, J. M. Chemistry of oxaziridines. 5. Kinetic resolution of sulfoxides using chiral 2-sulfonyloxaziridines. J. Org. Chem. 

Kinetic resolutions. A chiral alcohol is obtained on. selective removal of one enantiomer by acetylation using a chiral analog 1 of DMAP, or by oxidation based on hydrogen transfer to acetone mediated by a Ru complex 2. Benzylic secondary alcohols are resolved by selective pivaloylation with optically activeA-pivaloyl-4-t-butylthiazolidine-2-thione. A kinetic resolution of sulfoxides is based on asymmetric oxidation with (i-PrO)4Ti-cumyl hydroperoxide in the presence of a tartrate ester. Kinetic resolution of 1,3-diarylallenes is realized by selective oxidation with NaClO catalyzed by a chiral (salen)manganese(III) complex, whereas asymmetric hydrolysis of terminal epoxides with the aid of a chiral (salen)cobalt(II) catalyst solves the problem of their accessibility. 

Sulfides can usually be selectively oxidised to sulfoxides without (too much) over-oxidation to the corresponding sulfones. However, the conversion of sulfoxides into sulfones can be achieved under relatively mild catalytic conditions, if required. Uemura has demonstrated a kinetic resolution of sulfoxides by catalysed oxidation. For example, the oxidation of racemic phenyhnethylsulfoxide (5.152)... 

Bryliakov, K. and Talsi, E. (2008). Titanium-Salan-Catalyzed Asymmetric Oxidation of Sulfides and Kinetic Resolution of Sulfoxides with H2O2 as the Oxidant, Eur. J. Org. Chem., 19, pp. 3369-3376. 

The reaction of the enantiomerically pure sulfoxide anion (0.5 equiv) with a racemic bicyclic enone allows for the kinetic resolution of the enone15b. 

This type of asymmetric conjugate addition of allylic sulfinyl carbanions to cyclopen-tenones has been applied successfully to total synthesis of some natural products. For example, enantiomerically pure (+ )-hirsutene (29) is prepared (via 28) using as a key step conjugate addition of an allylic sulfinyl carbanion to 2-methyl-2-cyclopentenone (equation 28)65, and (+ )-pentalene (31) is prepared using as a key step kinetically controlled conjugate addition of racemic crotyl sulfinyl carbanion to enantiomerically pure cyclopentenone 30 (equation 29) this kinetic resolution of the crotyl sulfoxide is followed by several chemical transformations leading to (+ )-pentalene (31)68. 

Mikolajczyk and coworkers have summarized other methods which lead to the desired sulfmate esters These are asymmetric oxidation of sulfenamides, kinetic resolution of racemic sulfmates in transesterification with chiral alcohols, kinetic resolution of racemic sulfinates upon treatment with chiral Grignard reagents, optical resolution via cyclodextrin complexes, and esterification of sulfinyl chlorides with chiral alcohols in the presence of optically active amines. None of these methods is very satisfactory since the esters produced are of low enantiomeric purity. However, the reaction of dialkyl sulfites (33) with t-butylmagnesium chloride in the presence of quinine gave the corresponding methyl, ethyl, n-propyl, isopropyl and n-butyl 2,2-dimethylpropane-l-yl sulfinates (34) of 43 to 73% enantiomeric purity in 50 to 84% yield. This made available sulfinate esters for the synthesis of t-butyl sulfoxides (35). 

Kinetic resolution of racemic 4-bromophenyl methyl sulfoxide. Ill... 

KINETIC RESOLUTION OF RACEMIC 4-BROMOPHENYL METHYL SULFOXIDE... 

Table 8.2 Kinetic resolution of racemic sulfoxides (R-SO-Me) with 1.

Since in principle the reactions of enantiomeric sulfoxides with a chiral reagent are expected to proceed at unequal rates, a possibility exists for obtaining chiral sulfoxides, especially when the reacting racemic sulfoxide is used in excess in relation to the chiral reagent. A typical example of such a kinetic resolution of a racemic sulfoxide is its reaction with a deficiency of chiral peracid, affording a mixture of optically active sulfoxide and achiral sulfone (62,63). However,... 

Recently, Juge and Kagan (68) reported that a more efficient kinetic resolution of racemic sulfoxides takes place in the Pummerer-type reaction with optically active a-phenylbutyric acid chloride 38 in the presence of N,A-dimethylaniline. In contrast to the asym-... 

The kinetic resolution of /3-hydroxy sulfides mediated by CHMO provides an excellent result in the case of sulfide ( )-2 and moderate results with ( )-l and ( )-3. Indeed, the enzyme-catalysed oxidation to sulfoxide 2a showed remarkable enantio- and diastereo-selectivity with an enantiomeric ratio E of 299 and with an ee > 98 % (C = 47 %). 

In the sulfoxidation, small to appreciable amounts of over oxidation with formation of undesired sulfone were observed, a result that implies that kinetic resolution may be involved in influencing the overall stereochemical result 105). This was shown to be the case. Indeed, some of the mutants are also excellent catalysts in the kinetic resolution of racemic sulfoxides such as 25 105). Directed evolution was then applied successfully to eliminate undesired sulfone formation, specifically, by going through a second cycle of epPCR 105). This is significant because it shows for the first time that an undesired side reaction can be eliminated by directed evolution. 

Hoft reported about the kinetic resolution of THPO (16b) by acylation catalyzed by different lipases (equation 12) °. Using lipases from Pseudomonas fluorescens, only low ee values were obtained even at high conversions of the hydroperoxide (best result after 96 hours with lipase PS conversion of 83% and ee of 37%). Better results were achieved by the same authors using pancreatin as a catalyst. With this lipase an ee of 96% could be obtained but only at high conversions (85%), so that the enantiomerically enriched (5 )-16b was isolated in poor yields (<20%). Unfortunately, this procedure was limited to secondary hydroperoxides. With tertiary 1-methyl-1-phenylpropyl hydroperoxide (17a) or 1-cyclohexyl-1-phenylethyl hydroperoxide (17b) no reaction was observed. The kinetic resolution of racemic hydroperoxides can also be achieved by chloroperoxidase (CPO) or Coprinus peroxidase (CiP) catalyzed enantioselective sulfoxidation of prochiral sulfides 22 with a racemic mixmre of chiral hydroperoxides. In 1992, Wong and coworkers and later Hoft and coworkers in 1995 ° investigated the CPO-catalyzed sulfoxidation with several chiral racemic hydroperoxides while the CiP-catalyzed kinetic resolution of phenylethyl hydroperoxide 16a was reported by Adam and coworkers (equation 13). The results are summarized in Table 4. 

TABLE 4. Kinetic resolution of racemic hydroperoxides via CPO and CiP catalyzed enantioselec-tive sulfoxidation... 

With substrates 16b and 17a, Hoft and coworkers observed only low ee values of up to 4% for the hydroperoxides. On the other hand, phenyl ethyl hydroperoxide (16a) could be isolated in high enantiomeric excess of >99% from the CPO-catalyzed reaction. The observed enantioselectivities of the sulfoxides varied, depending on the conversion of the sulfide and the hydroperoxide used, being highest with 16a (92% ee). Unfortunately, the CPO-catalyzed resolution of chiral hydroperoxides is difficult on a preparative scale because of the high dilution necessary (0.5ttmolmL ). In the CiP-catalyzed kinetic resolution of 16a better results were obtained compared to the CPO-catalyzed reaction (see Table 5). 

Sulfides are generally oxidized much faster than alkenes, and in the presence of excess oxidant further oxidation to the sulfone occurs. In the cases where the reaction is conducted in an asymmetric way, the chiral catalytic system may react faster with one enantiomeric sulfoxide to form the sulfone than with the other, so that kinetic resolution of the primarily formed sulfoxide may occur. In general, the reaction is carried out with alkyl hydroperoxides like TBHP in the presence of a metal catalyst like Mo, W, Ti or V complexes. In some cases the sulfoxidation with hydroperoxides can take place without the need of a metal catalyst. Both examples will be discussed in the following. 

The catalytic sulfoxidation system developed by Uemura and coworkers in 1993381,386 consisted of Ti(OPr-i)4, (f )-BINOL, H2O and TBHP in different compositions. The best results (highest ee) were obtained with low amounts of catalyst 0.025 eq. Ti(OPr-i)4, 0.05 eq. (f )-BINOL, 0.5 eq. H2O and 2 eq. TBHP. With this method sulfoxides could be obtained with excellent enantioselectivities (ee 96%), although yields were low (28-44%) due to kinetic resolution of the formed sulfoxides to give the corresponding sulfones. More detailed investigations by Uemura and coworkers showed that an enantiomeric excess of 50% of the sulfoxides is obtained at the initial stage of the reaction and that an increase in ee results the longer the reaction takes place . So the Ti-(i )-BINOL complex catalyzes... 

A further catalytic method for asymmetric sulfoxidation of aryl alkyl sulfides was reported by Adam s group, who utilized secondary hydroperoxides 16a, 161 and 191b as oxidants and asymmetric inductors (Scheme 114) . This titanium-catalyzed oxidation reaction by (S)-l-phenylethyl hydroperoxide 16a at —20°C in CCI4 afforded good to high enantiomeric excesses for methyl phenyl and p-tolyl alkyl sulfides ee up to 80%). Detailed mechanistic studies showed that the enantioselectivity of the sulfide oxidation results from a combination of a rather low asymmetric induction in the sulfoxidation ee <20%) followed by a kinetic resolution of the sulfoxide by further oxidation to the sulfone... 

A solid-phase sulfur oxidation catalyst has been described in which the chiral ligand is structurally related to Schiff-base type compounds (see also below). A 72% ee was found using Ti(OPr-i)4, aqueous H2O2 and solid-supported hgand 91 . More recently, a heterogeneous catalytic system based on WO3, 30% H2O2 and cinchona alkaloids has been reported for the asymmetric oxidation of sulfides to sulfoxides and kinetic resolution of racemic sulfoxides. In this latter case 90% ee was obtained in the presence of 92 as chiral mediator. ... 

WO3-3O % H2O2-CINCHONA ALKALOIDS A NEW HETEROGENEOUS CATALYTIC SYSTEM FOR ASYMMETRIC OXIDATION OF SULFIDES AND KINETIC RESOLUTION OF RACEMIC SULFOXIDES... 

Chiral sulfoxides have emerged as versatile building blocks and chiral auxiliaries in the asymmetric synthesis of pharmaceutical products. The asymmetric oxidation of prochiral sulfides with chiral metal complexes has become one of the most effective routes to obtain these chiral sulfoxides.We have recently developed a new heterogeneous catalytic system (WO3-30% H2O2) which efficiently catalyzes both the asymmetric oxidation of a variety of thioethers (1) and the kinetic resolution of racemic sulfoxides (3), when used in the presence of cinchona alkaloids such as hydroquinidine 2,5-diphenyl-4,6-pyrimidinediyl diether [(DHQD)2-PYR], Optically active sulfoxides (2) are produced in high yields and with good enantioselectivities (Figure 9.3). ... 

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