Ti binol

The enantioselection depends greatly on the nature of the R2 group at the boron atom, and the ee values were as high as 97 %. High enantioselectivity was observed in the synthesis of 4-dihydropyranones, based on the Diels-Alder reactions of aldehydes 74 and Danishefsky s diene, catalyzed by a BINOL-Ti(0-i-Pr)4-derived catalyst [75] (Equation 3.23). 

The enantioselectivity of the BINOL-Ti(IV)-catalyzed reactions can be interpreted in terms of several fundamental structural principles.42 The aldehyde is coordinated to Ti through an apical position and there is also a 0-HC=0 hydrogen bond involving the formyl group. The most sterically favored approach of the alkene toward the complexed aldehyde then leads to the observed product. Figure 10.2 shows a representation of the complexed aldehyde and the TS structure for the reaction. 

Fig. 10.2. Structures of complexed aldehyde reagent (a) and transition structure (b) for enantios-elective catalysis of the carbonyl-ene reaction by BINOL-Ti(IV). Reproduced from Tetrahedron Lett., 38, 6513 (1997), by permission of Elsevier.

BINOL and related compounds have proved to be effective catalysts for a variety of reactions. Zhang et al.106a and Mori and Nakai106b used an (R)-BINOL-Ti(OPr )4 catalyst system in the enantioselective diethylzinc alkylation of aldehydes, and the corresponding secondary alcohols were obtained with high enantioselectivity. This catalytic system works well even for aliphatic aldehydes. Dialkylzinc addition promoted by TifOPr1 in the presence of (R)- or (A)-BINOL can give excellent results under very mild conditions. Both conversion of the aldehyde and the ee of the product can be over 90% in most cases. The results are summarized in Table 2-14. 

Preparation of the catalyst can be accomplished under mild conditions without stirring, heating, or cooling, and allyl addition can also be conducted more conveniently using 10 mol% of a 2 1 BINOL/Ti catalyst system at room temperature.91... 

The idea of enantioselective activation was first reported by Mikami and Matsukawa111 for carbonyl-ene reactions. Using an additional catalytic amount of (R)-BINOL or (/ )-5.5 -dichloro-4,4, 6,fi -tctramcthyl biphenyl as the chiral activator, (R)-ene products were obtained in high ee when a catalyst system consisting of rac-BINOL and Ti(OPri)4 was employed for the enantioselective carbonyl ene reaction of glyoxylate (Scheme 8-54). Amazingly, racemic BINOL can also be used in this system as an activator for the (R)-BINOL-Ti catalyst, affording an enhanced level of enantioselectivity (96% ee). 

Table 5 Aldol reactions using the (i )-BINOL-Ti(OzPr)2 catalyst...

Table 6 Reaction of Chan s diene with aldehydes under BINOL-Ti(OzPr)4 catalysis...

Vallee reported another example of a BINOL-based Lewis acid catalyst for the asymmetric Strecker reaction of ketoimines. While a traditional (BINOL)Ti(IV)-based system provided poor enantioselectivity [61], Sc(BINOL)2Li proved to be highly enantioselective for the cyanation of N-benzyl acetophenonimine (95% ee at 50% conversion, 91% ee at 80% conversion) [62], Unfortunately, results were provided only for a single ketoimine and a single aromatic aldimine, leaving the generality of the methodology in question. 

Mikami and Nakai et al. have developed a chiral titanium catalyst for the glyoxylate-ene reaction, which provides the corresponding a-hydroxy esters of biological and synthetic importance [7] in an enantioselective fashion (Scheme 8C.3) [8,9]. Various chiral titanium catalysts were screened [ 10]. The best result was obtained with the titanium catalyst (1) prepared in situ in the presence of MS 4A from diisopropoxytitanium dihalides (X2Ti(OPr,)2 X=Br [11] or Cl [12]) and enantiopure BINOL or 6-Br-BINOL [13], The remarkable levels of enantiose-lectivity and rate acceleration observed with these BINOL-Ti catalysts (1) [14] stem from the... 

Scheme 8C.3. Asymmetric carbonyl-ene reaction catalyzed by BINOL-Ti complex.

BINOL-Ti catalysis is also applicable to carbonyl-ene reaction with formaldehyde or vinylogous and alkynylogous analogs of glyoxylates in the catalytic desymmetrization (vide infra) approach to the asymmetric synthesis of isocarbacycline analogs (Scheme 8C.7) [24],... 

Dramatic changeover is observed not only in the ene/HDA product ratio, but also in the absolute stereochemistry upon changing the central metal from Ti to Al. Thus, Jprgensen et al. reported the HDA-selective reaction of ethyl glyoxylate with 2,3-dimethyl-1,3-butadiene catalyzed by a BINOL-derived Al complex [25], where the HAD product was obtained with up to 89% periselectivity and high enantiopurity (Scheme 8C.9). The absolute configuration was opposite to that observed by using BINOL-Ti catalyst. 

In an effort to develop new chiral BINOL-Ti complexes, chemical modifications of the chiral complex (f )-BINOL-Ti(OPr )2 (R-2) that can easily be prepared by simply mixing ( PrO)4Ti and (/ )-BINOL in the absence ofMS4A have been studied [37c-e]. A dimeric form has been reported for the single-crystal X-ray structure of complex R-2 [38], (I )-BINOL-Ti-p3-oxo complex, prepared via hydrolysis of complex R-2 has been shown to serve as an efficient and moisture-tolerable asymmetric catalyst [37d,e]. It is noteworthy that the (/ )-BINOL-Ti-)i3-oxo catalyst [37e] shows a remarkable level of (+)-NLE (asymmetric amplification), thereby attaining the maximum enantioselectivity for this system by using (/ )-BINOL with only 55-60% ee as the chiral source (consult Scheme 8C. 14). 

Catalysis of racemic BINOL-Ti(OPr )2 ( 2) in the glyoxylate-ene reaction with 2-phenyl-propene achieves extremely high enantioselectivity by adding another diol for enantiomer-selective activation (Scheme 8C.15, Table 8C.3) [42], For example, excellent enantioselectivity (90% ee, R) was achieved by adding just a half-molar equiv. (5 mol %) of (/ )-BINOL activator to racemic ( )-BINOL-Ti(OPr )2 complex ( 2) (10 mol %) in this reaction (Table 8C.3, entry 4). 

Scheme 8C.15. Enantiomer selective activation of racemic BINOL-Ti(OPr )2-...

For the same ene reaction, a possible activation of the enantiopure (R)-BINOL-Ti(OPr )2 [43] catalyst (R-2) by adding (R)-BINOL was investigated (Scheme 8C.16, Table 8C.4) [42a], In fact, the reaction in the presence of additional (R)-BINOL proceeded quite smoothly to provide the carbonyl-ene product in higher chemical yield (82%) and enantioselectivity (97% ee) than those without additional (R)-BINOL (20% yield, 95% ee). Based on the comparison of these results of enantiomer-selective activation of the racemic catalyst (90% ee, R) with those of the enantiopure catalyst with (97% ee, R) or without activator (95% ee, R), the reaction catalyzed by (R)-BINOL-Ti(OPr,)2/(/ )-BINOL complex (2 ) is calculated to be 27 times as fast as that catalyzed by (S)-BINOL-Ti(OPr )2 (S-2) in the reaction using racemic (+)-BINOL-Ti(OPr )2 ( 2) (Figure 8C.5a) [42a]. Indeed, kinetic studies indicated that the reaction catalyzed by the complex 2 is 26 times as fast as that catalyzed by the complex S-2 [42a], These results... 

The advantage of asymmetric activation of the racemic BINOL-Ti(OPr )2 complex ( 2) is highlighted in a catalytic version (Table 8C.3, entry 5) wherein high enantioselectivity (80.0% ee) is obtained by adding less than the stoichiometric amount (0.25 molar amount) of (R)-BI-NOL [42a], A similar phenomenon has been observed in the aldol [42c] and (hetero) Diels-Al-der [44] reactions catalyzed by the racemic BINOL-Ti(OPr )2 catalyst (+2). 

Another possibility has been explored by using racemic BINOL as an activator in the same ene reaction [42a]. Racemic BINOL was added to (/f)-BINOL-Ti(OPr )2 (/ -2), giving higher yield and enantioselectivity (69% yield 96% ee, R) than those (20% yield 95% ee, R) obtained... 

Figure 8C.5. Kinetic feature of asymmetric activation of BINOL-Ti (OPr >2-...

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