Titanium TADDOLate

It was our delight that the reactions catalyzed were activated even at -40 °C in the presence of a catalytic amount of achiral titanium catalysts (10 mol%) to afford the desilylacetylated 2-pyrazoline cycloadduct Na, l-acetyl-4-methyl-5-(2-oxo-3-oxazolidinylcarbonyl)-2-pyrazoline, in high yields as the far major product (Scheme 7.35). Although some chiral titanium TADDOlate catalysts were successfully applied to activate these reactions leading to the moderate enantioselectivities (up to 55% ee), the chemical yields were not satisfactory. 

Lewis acid-catalyzed additions can be carried out in the presence of other chiral ligands that induce enantioselectivity.156 Titanium TADDOL induces enantioselectivity in alkylzinc additions to aldehydes. A variety of aromatic, alkyl, and a, (3-unsaturated aldehydes give good results with primary alkylzinc reagents.157... 

TADDOL 104 and 126 afford 95-99% ee in the asymmetric addition of organozinc reagents to a variety of aldehydes. The best enantioselectivities are observed when a mixture of the chiral titanium TADDOL compound 127 and excess [Ti(OPr1)4] are employed (Scheme 2-49). The mechanism of the alkylzinc addition involves acceleration of the asymmetric catalytic process by the... 

The phosphino-oxazoline copper(II) complex (55) has also been found to be an effective catalyst[136] as have some titanium complexes, such as the extensively researched titanium-TADDOL system (56)[137]. A modified Ti(IV)-TADDOL compound is the catalyst of choice to promote Diels-Alder cycloaddition reactions between cyclopentadiene and alk-2-enyl phenylsulfonylmethyl ketones[138]. 

Narasaka et al. demonstrated the utility of titanium-ligand complexes in the resolution of chiral a-aryl esters [52]. Ti(Oi-Pr)4-ligand 56 complex resolves 2-pyridine thioesters with high selectivities (fcrei=26-42, see Scheme 13). Seebach and co-workers have examined titanium-TADDOLate complexes as reagents for the ring opening of meso anhydrides, dioxolanones, and azalactones [53]. Addition of an achiral isopropoxide source renders the desymmetrization of meso... 

On use as homogeneous catalysts in the asymmetric reductive alkylation of benzaldehyde with diethylzinc to form secondary alcohols, the corresponding dendritic titanium-TADDOL complexes having either chiral or achiral dendrons gave enantiomeric excesses (ee) of up to 98.5 1.5 at a conversion of 98.7% (for the catalyst with GO dendrons). With larger dendrons the reduction of the ee to 94.5 5.5 (G4) remained within reasonable limits, while the drop in conversion to 46.8% (G4) proved to be drastic. In comparison, the unsubstituted Ti-TAD-DOL complex gave an ee of 99 1 with complete conversion. This negative den-... 

Enantioselective addition of diethylzinc to benzaldehyde catalysed by titanium-TADDOLate (Structure 16)13... 

Titanium-TADDOL derived catalyst enantioselective cyclopropanation of cinnamyl alcohol37... 

These authors used titanium taddolate as a chiral catalyst, under heterogeneous conditions, giving partial precipitation of an inactive meso dimer. Titanium... 

It has been observed that enantioselective polymer-bound catalysts prepared by copolymerization produce in some cases better asymmetric inductions than systems prepared by grafting [175]. After much optimization, a monolithic polymer catalyst 51 suitable for a titanium-TADDOLate catalyzed Diels-Alder reaction was developed (Scheme 4.77). The monolith was applied in a flow system both under one pass and 24 h recirculation conditions, the latter producing the best yield (55%) and ee (23%) however, this contrasts poorly with the homogeneous batch reaction although the ee is comparable with the heterogeneous batch process. The reversal of topicity was also... 

Comparable selectivity can be obtained in the alkylation of ben-zaldehyde 3 with diethylzinc using the titanium TADDOL complex 20 (>99 1 er) or 3-exo-(dimethylamino)isoborneol, 21 (>99 1 er), although both methods employ higher catalyst loadings. While benzaldehyde is illustrative, the substrate scope is equally broad in the case of these two catalysts. 

This method is comparable to similar, catalytic Sim-mons-Smith-type methods employing the titanium TADDOL catalyst 20 (95 5 er) or the Ci-symmetric bis-sulfonamide catalyst 32 (93 7 er) for the cyclopropanation of the allylic alcohol 22 (eq 6). However, due to the preliminary nature of these earlier investigations, substrate scope and generality have not been extensively documented. All of the aforementioned methods are limited by their dependence on the allylic alcohol functionality. Only one method for Simmons-Smith-type cyclopropanation of other substrate classes has been developed. Use of a stoichiometric, chiral dioxaborolane [CAS 161344-85-0] additive allows for selective cyclopropanation of allylic ethers, homo-ally lie alcohols and allylic carbamates. ... 

Convergent dendrimers, with their versatile three-dimensional scaffold, may be tailored to mimic, perhaps crudely, some elements of enzymatic structures. Numerous catalytic moieties, including manganese porphyrins,253,254 bis(oxazoline) copper complexes,304 305 tertiary amines,306 binaphthol titanium complexes,285 307 titanium taddolates,292,308 thiazolio-cyclophanes,309 and fullerene-bound bisoxazoline copper complexes,310 have been incorporated at the core of dendritic molecules to determine the effect of dendritic encapsulation on their catalytic activity. 

Seebach s group demonstrated the utility of polymer-bound, chiral titanium TADDOLates in preparing chiral secondary alcohols (Figure 3.24).The polymeric catalyst 37 was contained inside a mesh tea bag, and was reused by simply charging fresh reagents and solvent. The ruggedness of the system was shown when the product enantioselectivity dropped from 96% (S) to only 92% (S) over 20 successive runs, and the average yield was 90% [50]. 

Scheme 2.95 Asymmetric electrophilic fluorination of j8-ketoesters, catalyzed by chiral titanium TADDOL complexes (Np = 1-naphthyl, R = Et, R = 2,4,6-(/Pr)3C6H2-CH2) pH].

For example, acid anhydride 219 is achiral and the molecule can be drawn above to highlight the mirror plane running through it. It has an R and an S chiral centre, one on either side of the mirror. The anhydride can be cleaved with Al(0i-Pr)3 in a reaction catalysed by a titanium TADDOLate 218. The resulting ester49 220 is formed in 88% yield and 88% ee. 

Seebach et al. have comprehensively examined the use of a chiral diol (TAD-DOL) derived from tartaric acid as a chiral ligand [22]. The titanium-TADDOL system also catalyzes the asymmetric addition of diethylzinc to various aldehydes (Scheme 8) [23,24]. This system is applicable to the alkylation of various... 

The combination of titanium-TADDOL 34 mediates the reaction of diethylzinc with nitroolefins to afford the products in relatively high ees (Scheme 18) [77]. 

The titanium-TADDOL system is notable for its breadth of reacting partners. Fumaroyl [104b] andacryloyl [107] imidedienophiles maybe employed with substituted and unsubstituted butadienes to afford cyclohexenes in high enantiomeric excess (Scheme 37). In the case of 2-thioethylbutadiene, the lower yield is accounted for by the intervention of a competing [2-1-2] cycloaddition pathway. 

Two examples of such processes are shown in Scheme 1.6. One is the titanium TADDOLate-catalyzed addition of diethylzinc to myrtenal (see Section 4.3, [52] the other is the Sharpless asymmetric epoxidation (see Section 8.2.2, [58,63]). In both cases, the diastereoselectivity for the reaction of the substrate with an achiral reagent is low (65-70% ds), while the catalysts have enantioselectivities of >95% with achiral substrates. In these cases of double asymmetric induction, the catalyst completely overwhelms the facial bias of the chiral substrate. 

Scheme 1.6. Matched and mismatched double asymmetric induction demonstrating Reagent-Based Stereocontrol (a) The diethylzinc addition catalyzed by titanium TADDOLates (Chapter 4, [52]). (b) The Sharpless asymmetric epoxidation (Chapter 8,...

Table 6.6. Asymmetric cycloadditions of crotyloxazolidinones and cyclopentadiene catalyzed by titanium TADDOLate complexes.

Figure 6.21. Titanium TADDOLate - crotyloxazolidinone complexes. The dioxolane ring of the chiral ligand (Figure 6.18h) is deleted for clarity, and the phenyl groups are labelled as axial (ax) or equatorial (eq). (a) Symmetrical complex found by NMR to be the predominant species in solution [237], and also characterized crystallographically [238]. (b) Complex judged to be most likely to be responsible for the asymmetic cycloaddition [228,237]. (c) This complex is probably less reactive, since approach of the dienophile is hindered by the axial phenyl [228].

This explanation is described as a mnemonic rule [228], which can only be taken as a first approximation of reality. The same rule can be used to rationalize the topicity of other asymmetric Diels-Alder reactions, such as those employing titanium BINOLate catalysts (Figure 6.18i, [230]), or iron bisoxazoline catalysts (Figure 6.18j,k [206,215]). Although the explanation seems reasonable, the picture is not complete, since it does not account for a number of observations, including the fact that the dioxolane substituents exert an extraordinary effect on catalyst efficiency (c/ Table 6.6, entries 2 and 5). Additionally, both titanium TADDOLate [228] and BINOLate [230] complexes show a nonlinear relationship between enantiomeric purity of the catalyst and that of the product, which suggests that some sort of dimerization phenomenon is involved. 

For titanium TADDOLATES Seebach D, Beck AK, Imwinkeiried R, Roggo S, Wonnacott A (1987) Helv Chim Acta 70 954... 

The titanium TADDOLATE complex was also used efficiently in the asymmetric addition of dimethyl zinc to 3-trimethylsilyl-2-propynal with and e.e. values over 90% (Schane 21.13). 

The field of catalytic metallodendrimers has seen many advances, particularly in enantioselective catalysis. " Thanks to the early work of Seebach and coworkers, the synthesis of core-functionalised TADDOL dendrimers 40 has been achieved by using four Frechet dendrons (Figure 7.2). These dendrimers were used as ligands in the synthesis of titanium TADDOLates, which were evaluated as catalysts in the asymmetric addition of diethylzinc to benzaldehyde. In a general manner, the good stereoselectivities (89-97% enantiomeric excesses) detected were found to be comparable to those observed with the monomeric TADDOL ligand (98% enantiomeric excess). No attempt to recycle the catalyst or the ligand was mentioned by the authors. 

The Simmons-Smith reaction is the conversion of olefins to cyclopropanes by the use of halomethylzinc halides or related agents. Charette et al. found that a catalytic amount of chiral titanium-TADDOLate complex 78 was able to induce an enantioselective cyclopropanation of allylic alcohols. After optimisation of the catalytic structure, good yields and enantioselec-tivities were obtained, especially when 3-aryl and 3-heteroaiyl substituted allylic alcohols were used (Scheme 7.47). However, the reaction required the use of a high catalyst loading (25 mol%). 

The widely used chiral auxiliaries, tetraaryl-l,3-dioxolane-4,5-dimethanols (TADDOLs), developed by Seebach and co-workers, have found applications in several fields of asymmetric synthesis (75). From their transition metal complexes, the titanium-containing ones (titanium-TADDOLates) are the most successful ones (see titanium complexes). 

Charette and co-workers reported a chiral Lewis acid-catalysed Simmons-Smith reaction, using a titanium TADDOL complex, although in general this system shows limited substrate scope compared to the Kobayashi system. ... 

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