Chirality chiral titanium complexes

Chiral Titanium Complexes. Chiral titanium complexes are useful for the enantioselective addition of nucleophiles to carbonyl groups ... 

The advantages of titanium complexes over other metallic complexes is high selectivity, which can be readily adjusted by proper selection of ligands. Moreover, they are relative iaert to redox processes. The most common synthesis of chiral titanium complexes iavolves displacement of chloride or alkoxide groups on titanium with a chiral ligand, L ... 

One of the most famous chiral titanium complexes is the Sharpless catalyst (16), based on a diisopropyl tartarate complex. Nmr studies suggest that the complex is dimeric ia nature (146). An excellent summary of chiral titanium complexes is available (147). 

A chiral titanium complex with 3-cinnamoyl-l,3-oxazolidin-2-one was isolated by Jagensen et al. from a mixture of TiCl 2(0-i-Pr)2 with (2R,31 )-2,3-0-isopropyli-dene-l,l,4,4-tetraphenyl-l,2,3,4-butanetetrol, which is an isopropylidene acetal analog of Narasaka s TADDOL [48]. The structure of this complex was determined by X-ray structure analysis. It has the isopropylidene diol and the cinnamoyloxazolidi-none in the equatorial plane, with the two chloride ligands in apical (trans) position as depicted in the structure A, It seems from this structure that a pseudo-axial phenyl group of the chiral ligand seems to block one face of the coordinated cinnamoyloxazolidinone. On the other hand, after an NMR study of the complex in solution, Di Mare et al, and Seebach et al, reported that the above trans di-chloro complex A is a major component in the solution but went on to propose another minor complex B, with the two chlorides cis to each other, as the most reactive intermediate in this chiral titanium-catalyzed reaction [41b, 49], It has not yet been clearly confirmed whether or not the trans and/or the cis complex are real reactive intermediates (Scheme 1.60). 

Table 8. 1-Substituted 3-Butenols from Enantiosclcctive Allylation of Aldehydes by Chiral Titanium Complexes...

Allyltrialkylsilanes add to aldehydes in the presence of a Lewis acid." The mechanism of this reaction has been examined." " When chiral titanium complexes are used in the reaction, allylic alcohols are produced with good asymmetric... 

The use of chiral titanium complexes as catalysts is also possible. As shown in Scheme 5-26, the Sharpless titanium catalyst gave ees up to 53% for the addition of diethyl phosphite to benzaldehyde. 

Titanium-mediated pinacol coupling reactions have been reviewed until 2000.80 81 Since then, various intermole-cular pinacol couplings have been reported with aldehydes, - ketones, a-ketoesters, and imines, as well as asymmetric versions thereof.101-104 Scheme 29 shows one example of an asymmetric pinacol coupling of aromatic aldehydes, promoted and catalyzed by the new chiral titanium complex (A)-75, that has been developed by Riant and co-workers.101 Yields for pinacol products 76 are generally high. Under catalytic conditions, ee is moderate (up to 63%), while stoichiometric conditions allow to obtain up to 91% ee. 

The proposed reaction mechanism is shown in Figure 2 8. First, a chiral titanium complex (/ )- 40 is formed by the exchange of two titanium alkoxides. 

Asymmetric epoxidation using a chiral titanium complex. 73... 

Binaphthol (BINOL), chiral titanium complexes of, 25 99 Binary alloys... 

Chiralsil-val, 6 96-97 Chiral smectic C liquid crystals, 15 106-107 Chiral stationary phases, 6 79-82 Chiral supramolecular clusters, 24 61 Chiral synthons, 11 5 Chiral titanium complexes, 25 98—99 Chirobiotic phases, for chiral separations, 6 90-91... 

Snapper and Hoveyda reported a catalytic enantioselective Strecker reaction of aldimines using peptide-based chiral titanium complex [Eq. (13.11)]. Rapid and combinatorial tuning of the catalyst structure is possible in their approach. Based on kinetic studies, bifunctional transition state model 24 was proposed, in which titanium acts as a Lewis acid to activate an imine and an amide carbonyl oxygen acts as a Bronsted base to deprotonate HCN. Related catalyst is also effective in an enantioselective epoxide opening by cyanide "... 

Chiral titanium complexes with a, a, a, a -tetraaryl-l,3-dioxolane-4,5-dimethanol (TADDOL) ligands are versatile auxiliaries in the Lewis acid catalyzed alcoholysis of racemic 4-(arylmethyl)-2-phenyl-5(477)-oxazolones 234, providing the corresponding enantiomerically enriched N-protected amino acid esters 235 (Scheme 7.73). The enantioselectivity of the reaction is dependent on the solvent, temperature, and chiral ligand. Selected examples of the alcoholysis of saturated 5(477)-oxazolones are shown in Table 7.21 (Fig. 7.23). 

A competing technology is the Sharpless asynunetric epoxidation, which uses chiral titanium complexes as the catalyst. Arco uses this for production of (K)-glycidol and other epoxy alcohols in commercial quantities. 

Oxidation of the enantiotopic electron pairs at sulfur, mediated by chiral titanium complexes, to yield chiral sulfoxides with high enantiomeric excess14. 

Mechanistic studies of asymmetric amplification using a chiral amino alcohol catalyst have continued to dale"1 151 155. In the case of the chiral titanium complex, the observed asymmetric amplification was influenced by the method of preparation of the catalyst153. Asymmetric amplification is also observed in the catalytic addition of diphenylzinc to ketones100. 

A full account5 describes the enantioselective carbonyl-ene reaction of glyoxylate esters catalyzed by a binaphthol-derived chiral titanium complex that is potentially useful for the asymmetric synthesis of a-hydroxy esters of biological and synthetic importance.6 The present procedure is applicable to a variety of 1,1-disubstituted olefins to provide ene products in extremely high enantiomeric purity by the judicious choice of the dichloro or dibromo chiral catalyst (see Table). In certain glyoxylate-ene reactions involving removal of a methyl hydrogen, the dichloro catalyst... 

Lewis acid-promoted asymmetric addition of dialkylzincs to aldehydes is also an acceptable procedure for the preparation of chiral secondary alcohol. Various chiral titanium complexes are highly enantioselective catalysts [4]. C2-Symmet-ric disulfonamide, chiral diol (TADDOL) derived from tartaric acid, and chiral thiophosphoramidate are efficient chiral ligands. C2-Symmetric chiral diol 10, readily prepared from 1-indene by Brown s asymmetric hydroboration, is also a good chiral source (Scheme 2) [17], Even a simple a-hydroxycarboxylic acid 11 can achieve a good enantioselectivity [18]. 

The Orsay group found serendipitously that methyl p-tolyl sulfide was oxidized to methyl p-toly 1 sulfoxide with high enantiomeric purity (80-90% ee) when the Sharpless reagent was modified by addition of 1 mole equiv. of water [16,17]. The story of this discovery was described in a review [19], Sharpless conditions gave racemic sulfoxide and sulfone. Careful optimization of the stoichiometry of the titanium complex in the oxidation of p-tolyl sulfide led to the selection of Ti(0iPr)4/(7 ,7 )-DET/H20 (1 2 1) combination as the standard system [ 17]. In the beginning of their investigations, the standard conditions implied a stoichiometric amount of the chiral titanium complex with respect to the prochiral sulfide [16,17,20-23]. Later, proper conditions were found, which decreased the amount of the titanium complex without too much alteration of the enantioselectivity [24,25],... 

Mikami reported a highly enantioselective carbonyl-ene reaction where a chiral titanium complex 11 prepared from enantiomerically pure binaphthol (BINOL) and Ti(0-i-Pr)2Br2 catalyzed a glyoxylate-ene reaction with a-methylstyrene to give chiral homoallyl alcohol 12 with 94.6% ee [22]. In this reaction, a remarkable asymmetric amplification was observed and almost the same enantioselectivity (94.4% ee) was achieved by using chiral catalyst prepared... 

Uemura reported a highly enantioselective oxidation of sulfides to sulfoxides using a chiral titanium complex prepared from chiral BINOL and Ti(0-i-Pr)4, and this reaction exhibits a remarkable asymmetric amplification (Scheme 9.15) [33]. 

The activation of a racemic catalyst by a chiral additive was achieved by Mikami in a chiral titanium complex-catalyzed asymmetric carbonyl-ene reaction (Scheme 9.21) [39], The racemic catalyst ( )-BINOL-Ti-(0-i-Pr)2 37 (10 mol %) is activated by adding (R)-BINOL (5 mol %), and the ene product 38 with 90% ee is obtained. (R)-BINOL is selectively associated with (/f)-BIN0L-Ti-(0-i-Pr)2 to give a dimeric catalyst whose activity is kinetically calculated to be 25.6 times greater than that of the remaining (S)-BIN0L-Ti-(0-i-Pr)2. 

Asymmetric ene and Diels-Alder reactions with methyl glyoxalate. The reaction of methyl glyoxalate with isoprene catalyzed by the BINOL-titanium complex (R)-l provides not only the expected ene product (2), but also the Diels-Alder product (3), both in 97% ee (equation I). This chiral titanium complex is also an... 

The solvent-free asymmetric Hetero-Diels-Alder reaction of 14 different aldehydes with Danishefsky s diene was carried out with 0.1-0.005 mol% of chiral titanium complexes to afford dihydropyrones with up to quantitative yields and 99.8% ee. A library of chiral metal complexes was generated by combining one or two different chiral diol ligands e.g. 5 (13 different diols were applied) with titanium isopropylate (Scheme 16) [46],... 

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. 

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