Titanium catalysts chiral auxiliaries

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... 

The 4-thiazolidinyl phosphonates 143 (Scheme 44) are known for their therapeutical properties, in particular as anti-inflammatory agents [5,89]. Their asymmetric synthesis by hydrophosphonylation of 3-thiazolines has been described using various chiral auxiliaries chiral phosphites such as (2S,4i )-2H-2-oxo-5,5-dimethyl-4-phenyl-l,3,2-dioxaphosphorinane (de = 2-8%) [90] or BINOL-phos-phite (de = 65-90%) [91] and also chiral catalyst such as titanium or lanthanide chiral complexes (ee = 29-98%) [92]. Hydrophosphonylation of C2-chiral3-thi-azolines has also been performed (de = 32-38%) [93]. 

As is the case for aldol addition, chiral auxiliaries and catalysts can be used to control stereoselectivity in conjugate addition reactions. Oxazolidinone chiral auxiliaries have been used in both the nucleophilic and electrophilic components under Lewis acid-catalyzed conditions. (V-Acyloxazolidinones can be converted to nucleophilic titanium enolates with TiCl3(0-/-Pr).320... 

The proposed dinuclear transition-state model (1) has been supported by the observation of nonlinear relationship between enantiomeric excess (ee) of the epoxide and ee of DAT.33 The use of simple diol instead of tartrate vitiates stereoselectivity of the reaction.34,35 The ester group of DAT is indispensable for the construction of the desired catalyst. It is noteworthy that 1,2-di(o-methoxy-phenyl)ethylenediol is an efficient chiral auxiliary for titanium-mediated epoxidation, while 1,2-diphenylethylenediol is a poor one.36... 

Brimble and coworkers172 reported the asymmetric Diels-Alder reactions between quinones 265 bearing a menthol chiral auxiliary and cyclopentadiene (equation 73). When zinc dichloride or zinc dibromide was employed as the Lewis acid catalyst, the reaction proceeded with complete endo selectivity, but with only moderate diastereofacial selectivity affording 3 1 and 2 1 mixtures of 266 and 267 (dominant diastereomer unknown), respectively. The use of stronger Lewis acids, such as titanium tetrachloride, led to the formation of fragmentation products. Due to the inseparability of the two diastereomeric adducts, it proved impossible to determine which one had been formed in excess. 

The reaction of 3-crotonoyloxazolidone 15a and cyclopentadiene was examined in toluene in the presence of an equimolar amount of various chiral alkoxy titanium(IV) derivatives. It was found that the corresponding endo-adduct 18a was obtained in 55 ee when the chiral 2,3-0-isopropylidene-1,1,4,4-tetraphenylbutanetetraol 17a(15 ) was introduced as a chiral auxiliary. In this titanium catalyst, the conformation of... 

Enantioselective epoxidation of allylic alcohols using hydrogen peroxide and chiral catalysts was first reported for molybdenum 7B) and vanadium 79) complexe. In 1980, Sharpless 80) reported a titanium system. Using a tartaric acid derivative as chiral auxiliary it achieves almost total stereoselection in this reaction. 

The development of a large scale manufacturing route to Esomeprazole is described by Federsel and Larsson ° using the titanium catalyst originally described by Kagan and Luukas. Employment of a tartaric acid derived chiral auxiliary, with the addition of a base such as diisopropylethylamine to the reaction mixture, resulted in a full-scale catalytic process capable of delivering multi-ton quantities of product with optical yields well above 90 %, a figure which could be raised to 99.5 % ee by recrystallization from methyl isobutyl ketone. 

The known allylic alcohol 9 derived from protected dimethyl tartrate is exposed to Sharpless asymmetric epoxidation conditions with (-)-diethyl D-tartrate. The reaction yields exclusively the anti epoxide 10 in 77 % yield. In contrast to the above mentioned epoxidation of the ribose derived allylic alcohol, in this case epoxidation of 9 with MCPBA at 0 °C resulted in a 65 35 mixture of syn/anti diastereomers. The Sharpless epoxidation of primary and secondary allylic alcohols discovered in 1980 is a powerful reagent-controlled reaction.12 The use of titanium(IV) tetraisopropoxide as catalyst, tert-butylhydro-peroxide as oxidant, and an enantiopure dialkyl tartrate as chiral auxiliary accomplishes the epoxidation of allylic alcohols with excellent stereoselectivity. If the reaction is kept absolutely dry, catalytic amounts of the dialkyl tartrate(titanium)(IV) complex are sufficient. 

Practical and efficient asymmetric allylation of aldehydes is successfully promoted by Lewis acid catalysts bearing chiral auxiliaries to afford high levels of enantioselectivity.165 The effective catalysts for asymmetric allylation to benzaldehyde are shown below (Scheme j) 166-176 The catalytic asymmetric allylation of ketones has proved to be a more challenging transformation owing to the significantly low reactivity compared to aldehydes. In 2002, a catalyst based on titanium complex was developed (Equation (51)).A ... 

Chiral homoallylic alcohols. The chiral acetals 2 formed from an aldehyde and 1. undergo titanium-catalyzed coupling with allyltrimcthylsilane with marked stereoselectivity. Highest sterco.selectivity is usually obtained with the mixed catalyst TiClj-Ti(0-/-Pr)j (6 5). Cleavage of the chiral auxiliary, effected by oxidation to the ketone followed by -elimination, provides optically active alcohols (4) with —95% ee (equation I). ... 

Preliminary results for asymmetric epoxidations of ( )-cinnamyl alcohol and geraniol using (15,25)-l,2-di(2-methoxyphenyl)ethane-l,2-diol or (15,25)-l,2-di(4-methoxyphenyl)ethane-l,2-diol as chiral auxiliaries with titanium(IV) isopropoxide and TBHP have been described. High enantioselectivity (95% ee) is observed when the 2-methoxyphenyl compound is used, while somewhat lower enantioselectivity (64% ee) and opposite face selectivity is described for the catalyst comprised of the 4-methoxyphenyl analog.Further elaboration of the scope and generality of these observations will be of interest. 

Kobayashi et al. developed chiral Lewis acids derived from A -benzyldiphenylproli-nol and boron tribromide and used these successfully as catalysts in enantioselective Diels-Alder reactions [89]. The corresponding polymeric catalyst 71 was prepared and used for the Diels-Alder reaction of cyclopentadiene with methacrolein [90]. Different polymeric catalysts 72, 73, 74 were prepared from supported chiral amino alcohols and diols fimctionalized with boron, aluminum and titanium [88,90]. In these polymers copolymerization of styrene with a chiral auxiliary containing two polymerizable groups is a new approach to the preparation of crosslinked chiral polymeric ligands. This chiral monomer unit acts as chiral ligand and as a crosslink. 

Titanium complexes involving a chiral auxiliary derived from BINOL, are good catalysts for the glyoxylate ene-reaction (see example in Scheme 6). With these species very high (-l-)-NLEs have been observed [18,33,34,35]. 

The scope of kinetic resolution of this type is not limited to alcohol derivatives but can be extended to N-tosylamino derivatives when the titanium-tartrate catalyst modified with calcium hydride and silica gel is used. Resolution of AT-tosylamines 47 is effected with high efficiency but the configuration of the slow reacting isomer is opposite to that expected from the empirical rules for kinetic resolution (Scheme 11) The (R)-isomer of 47 is oxidized prior to the (S)-isomer when (-i-)-DIPT is used as a chiral auxiliary. Again, the A -piperidone 49 of high enantiopurity can be obtained by oxidation of the enantioenriched furylamines 48 with ra-CPBA [79]. 

The fundamental principles of asymmetric synthesis employed throughout also apply to ene reactions. Chiral additives, chiral auxiliaries, and the preparation of chirons all lead to good enantioselectivity when applied to the ene reactions. Most chiral ene reactions seem to involve addition of a chiral catalyst or the use of a chiral auxiliary. Oppolzer et al. utilized a chiral auxiliary in 713 to prepare 714 (90 % de) in a synthesis of (+)-a-allokainic acid.515 Yamamoto used the chiral aluminum catalyst 715 for the intermolecular ene reaction of 1,6-dichlorobenzaldehyde and 2-phenylthio-l-propene to give 716 in 96% yield (65 % ee).5i6 These catalysts are similar to those used in Section 11.9.B. A similar titanium catalyst (717) was used to couple methylenecyclohexane and methyl glyoxalate, giving 89% of 718 (98 % ee). The titanium catalyst... 

Although tremendous advances in the catalytic Pauson-Khand reaction have been made, the development of an asymmetric version did not share the same degree of success. Several asymmetric Pauson-Khand reactions were reported using chiral auxiliaries. However, those systems required stoichiometric amounts of cobalt as well as the chiral source. Attempts at using a catalytic amount of cobalt did not give satisfactory results. By contrast, the use of titanium chiral catalyst S,Sy (EBTHI)Ti(CO)2 (EBTHI = ethylene-l,2-bis(tiM,5,6,7-tetrahydro-l-indenyl)... 

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