Asymmetric oxidation with chiral titanium complexes

Sharpless asymmetric epoxidation of allylic alcohols, asymmetric epoxidation of conjugated ketones, asymmetric sulfoxidations catalyzed, or mediated, by chiral titanium complexes, and allylic oxidations are the main classes of oxidation where asymmetric amplification effects have been discovered. The various references are listed in Table 4 with the maximum amplification index observed. 

Oxidation in the presence of chiral titanium tartrate (modified Sharpless method). Inspired by the Sharpless asymmetric epoxidation48 of allylic alcohols with hydroperoxides in the presence of chiral titanium complex [diethyl tartrate (DET) and Ti(0-i-Pr)4], Kagan and co-workers46 and Modena and co-workers47 developed almost at the same time two variations of this reaction leading to o.p. sulfoxides with high enantiomeric purity. 

Most applications of sulfide oxidations by alkyl hydroperoxides have involved titanium catalysis together with chiral ligands for enantioselective transformations. The groups of Kagan in Orsay [61] and Modena in Padova [62] reported independently on the use of chiral titanium complexes for the asymmetric sulfoxidation by the use of BuOOH as the oxidant. A modification of the Sharpless reagent with the use of Ti(0 Pr)4 and (J ,J )-diethyl tartrate (J ,J )-DET) afforded chiral sulfoxides with up to 90% ee (Eq. (8.17)). 

The asymmetric oxidation of sulphides to chiral sulphoxides with t-butyl hydroperoxide is catalysed very effectively by a titanium complex, produced in situ from a titanium alkoxide and a chiral binaphthol, with enantioselectivities up to 96%342. The Sharpless oxidation of aryl cinnamyl selenides 217 gave a chiral 1-phenyl-2-propen-l-ol (218) via an asymmetric [2,3] sigmatropic shift (Scheme 4)343. For other titanium-catalysed epoxidations, see Section V.D.l on vanadium catalysis. 

Thus, when cyclohexyl selenides 1, prepared from the corresponding 4-sub-stituted cyclohexanone via the selenoketals, were oxidized with various Davis and Sharpless oxidants, the chiral alkyl aryl 4-substituted cyclohexylidenemethyl ketones were obtained in excellent chemical yields with high enantiomeric excesses. Typical results are summarized in Table 4. In this asymmetric induction, of the substrate and the chiral oxidant employed were revealed to show a remarkable effect upon the enantioselectivity of the product. The use of a methyl moiety as instead of a phenyl moiety gave a higher ee value, probably due to the steric difference between the two groups bonded to the selenium atom of the substrate. The results indicate that the titanium complex of the Sharpless oxidant may promote the racemization of the chiral selenoxide intermediate by acting as a Lewis acid catalyst, whereas the racemization in the case of the Davis oxidant, which is aprotic in nature, is slow. 

K. Barry Sharpless (bom 1941) received his PhD in 1968 at Stanford University. Since 1990 he is W. M. Keck Professor of Chemistry at the Scripps Research Institute in La Jolla, USA. Among several other important discoveries. Sharpless developed catalysts for asymmetric oxidations. In 1980 he achieved the catalytic asymmetirc oxidation of allylic alcohols to chiral epoxides by utilizing titanium complexes with chiral ligands (e. g. Section 3.3.2). One of the many applications of chiral epoxides is the use of the epoxide (R)-glycidol for pharmaceutical production of beta-blockers. Sharpless received the Nobel prize for chemistry in 2001 together with Knowles and Noyori. 

Kagan has reported NLE as an indicator for distinction of closely related chiral catalysts (Eq. (7.6)) [20J. In asymmetric oxidation of sulfides with hydroperoxides promoted by chiral DET-Ti complexes, a wide diversity of titanium species is observed just by minor modifications of the catalyst preparation step. Stoichiometric use of a 1 4 mixture of Ti(Ot Pr)4 and DET exhibits (-)-NLE. An addition of /PrOH to this mixture, e.g. a 1 4 4 mixture of Ti(0/Pr)4, DET, and iPrOH, provides (-f)-NLE, while catalytic use of this ternary system leads to the disappearance of NLE. 

Previously, Pasini [27] and Colonna [28] had described the use chiral titani-um-Schiff base complexes in asymmetric sulfide oxidations, but only low selec-tivities were observed. Fujita then employed a related chiral salen-titanium complex and was more successful. Starting from titanium tetrachloride, reaction with the optically active C2-symmetrical salen 15 led to a (salen)titani-um(IV) dichloride complex which underwent partial hydrolysis to generate the t]-0x0-bridged bis[(salen)titanium(IV)] catalyst 16 whose structure was confirmed by X-ray analysis. Oxidation of phenyl methyl sulfide with trityl hydroperoxide in the presence of 4 mol % of 16 gave the corresponding sulfoxide with 53% ee [29]. 

In 1993, Shibuya and co-workers reported the stereoselective addition of DEHP to aldehydes to be catalysed by chiral complexes of titanium, specifically, dialkyl tartrate complexes of titanium that had been used previously with great success by Sharpless in the asymmetric oxidation of allylic alcohols (Scheme 9) [24]. Shibuya described moderate success in controlling enantioselectivities (<50% e.e.) with this extremely oxygen- and water-sensitive catalyst system. Rather large (10-20 mol %) catalyst loadings were required over a period of 15 h at 0 °C but the potential was definitely there. 

Self-supported titanium complexes with linked bis-BINOL ligands were used as an alternative approach for the immobilisation of catalysts, as shown in enantioselective sulfide oxidation (see Section 7.2.2). The same ligands were used with success in asymmetric carbonyl ene reactions. The chiral metal-bridged polymer 76, derived from ent-lOa, titanium tetraisopropoxide and water (Scheme 7.45), catalysed the ene reaction between 68b and 71, to give R)-72 in 88% yield and 88% enantiomeric excess. The catalyst can be reused at least five times without affecting its efficiency. 

For the diazoacetates, Mamoka and coworkers reported on the chiral titanium BINOLate-catalyzed highly enantioselective 1,3-dipolar cycloaddition reactions between diazoacetates and monodentate a-substituted acroleins, which give 2-pyrazolines with an asymmetric tetrasubstituted carbon center in 2006 (Table 7.6) [23], The titanium BINOLates, such as (5)-BlNOL/Ti(OPr )4 (2 1 molar ratio) complex (TB-b) and bis (5)-binaphthoxy)(isopropoxy)titanium oxide (TB-c), showed good results in terms of yields and enantiose-lectivities compared with simple (5)-BINOL/Ti(OPr )4 (1 1 molar ratio) complex (TB-a). The synthetic utility of the present reaction was further demonstrated by the total synthesis of a bromopyrrole alkaloid manzacidin A (Scheme 7.13), which was isolated firom the Okinawan sponge Hymeniacidon sp. [24],... 

In 1980, Sharpless and co-workers reported on the first practical asymmetric epoxidation of allylic alcohols using titanium-tartrate complexes in combination with ferf-butyl hydroperoxide (TBHP) as an oxidant." The procedure was later improved by the addition of 3-A or 4-A molecular sieves to the reaction mixmre, and under the optimal conditions the reaction can be performed with a catalytic amount of titanium catalysts prepared from Ti(0-f-Pr)4 and L or D-diethyltartrate (DET) or diisopropyltartrate (DIPT) to provide chiral epoxides in optical purities typically greater than 90% ee (Scheme 35.1). 

The first practical method for asymmetric epoxidation of primary and secondary allylic alcohols was developed by K.B. Sharpless in 1980 (T. Katsuki, 1980 K.B. Sharpless, 1983 A, B, 1986 see also D. Hoppe, 1982). Tartaric esters, e.g., DET and DIPT" ( = diethyl and diisopropyl ( + )- or (— )-tartrates), are applied as chiral auxiliaries, titanium tetrakis(2-pro-panolate) as a catalyst and tert-butyl hydroperoxide (= TBHP, Bu OOH) as the oxidant. If the reaction mixture is kept absolutely dry, catalytic amounts of the dialkyl tartrate-titanium(IV) complex are suflicient, which largely facilitates work-up procedures (Y. Gao, 1987). Depending on the tartrate enantiomer used, either one of the 2,3-epoxy alcohols may be obtained with high enantioselectivity. The titanium probably binds to the diol grouping of one tartrate molecule and to the hydroxy groups of the bulky hydroperoxide and of the allylic alcohol... 

Asymmetric epoxidation is another important area of activity, initially pioneered by Sharpless, using catalysts based on titanium tetraisoprop-oxide and either (+) or (—) dialkyl tartrate. The enantiomer formed depends on the tartrate used. Whilst this process has been widely used for the synthesis of complex carbohydrates it is limited to allylic alcohols, the hydroxyl group bonding the substrate to the catalyst. Jacobson catalysts (Formula 4.3) based on manganese complexes with chiral Shiff bases have been shown to be efficient in epoxidation of a wide range of alkenes. 

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