Ti- -BINOL catalyst

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). 

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... 

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. 

Mikami et al. reported the first examples of catalytic asymmetric intramolecular carbonyl-ene reactions of types (3,4) and (2,4), using the BINOL-derived titanium complex (1) [46,49], The catalytic 7-(2,4) carbonyl-ene cyclization gives the corresponding oxepane with high enantiopurity, and the gem-dimethyl groups are not required (Scheme 8C.I8). In a similar catalytic 6-(3,4) ene cyclization, tran.v-tetrahydropyran is preferentially obtained with high enantiopurity (Scheme 8C. 19), The sense of asymmetric induction is the same as that observed for the glyoxylate-ene reaction, that is, (R)-BINOL-Ti catalyst provides (R)-alcohol. Therefore, the... 

Chiral (acyloxy)borane (CAB) is known as an effective chiral Lewis acid catalyst for enantioselective allylation of aldehydes. Marshall applied the CAB complex 1 to the addition of crotylstannane to achiral aldehydes and found that the CAB catalyst gives higher syn/anti selectivity than BINOL/Ti catalysts in the reaction [4]. CAB complex 2 was utilized in asymmetric synthesis of chiral polymers using a combination of dialdehyde and bis(allylsilane) [5] or monomers possessing both formyl and allyltrimethylsilyl groups [6]. 

Thus the chiral BINOL-Ti catalyst effects efficient chiral recognition of the enantio-face of the aldehyde and discrimination between the diastereotopic protons of the ene component in a truly catalytic fashion. 

Basic research on the synthesis of analogs of the biologically active form of vitamin D3, la,25-dihydroxy vitamin D3 (la,25(OH)2D3) has led to the development of an important new field in medicinal chemistry [84]. We have also reported symmetry assisted enantiospecific synthesis of the A-ring of the vitamin D hybrid analogs, 19-nor-22-oxa-la,25(OH)2D3 (Sch. 29) [85], It should be noted here that extremely high 1,3-frans selectivity was achieved by combining the (f )-BINOL-Ti catalyst and the (i )-ene substrate without geminal disubstitution. 

The aldol reaction of a silyl enol ether proceeds in a double and two-directional fashion, upon addition of an excess amount of an aldehyde, to give the silyl enol ether in 77 % isolated yield and more than 99 % ee and 99 % de (Sch. 33) [92]. This asymmetric catalytic aldol reaction is characterized by kinetic amplification of product chirality on going from the one-directional aldol intermediate to the two-directional product. Further transformation of the pseudo C2 symmetric product still protected as the silyl enol ether leads to a potent analog of an HIV protease inhibitor. Kinetic resolution of racemic silyl enol ethers by the BINOL-Ti catalyst (1) has been reported by French chemists [93]. 

An aldol reaction with chiral /3-benzyloxy aldehyde provides a method for the stereodivergent synthesis of both syn and anti diastereomers [97] with high diastereo-selectivity dictated primarily by the chirality of the BINOL-Ti catalyst (1) rather than the /1-benzyloxy aldehyde (Sch. 37) [98]. The aldol products can be used as useful key intermediates for /1-lactone synthesis [99]. 

Interestingly, the chiral titanium complex derived from 6-Br-BINOL affords higher cis selectivity, enantioselectivity, and catalytic activity than the parent BINOL-Ti catalyst in the hetero Diels-Alder reactions of 1-methoxydienes with glyoxylate, but not with bromoacrolein (Sch. 49) [130]. 

In the Diels-Alder reaction of glyoxylates with the Danishefsky diene (Sch. 53), asymmetric activation of (f )-BINOL-Ti(OPr )2 (2) by (/ )-BINOL is essential if enantioselectivity is to be higher than that achieved by use of the enantio-pure BINOL-Ti catalyst (5 % ee) [78], Effects of the torsional angles of 2,2 -biaryldiol ligands have been examined in the asymmetric Diels-Alder reaction of acrylate catalyzed by titanium complexes [133]. 

In the addition reaction of cyanotrimethylsilane [147] to aliphatic aldehydes, another synthetic application of a BINOL-Ti catalyst was reported by Reetz [88]. In this instance, however, BINOL-TiCh was prepared by treatment of the lithium salt of BINOL with TiCU in ether (vide supra). The BINOL-TiCh thus obtained was used as a catalyst for the cyanosilylation reaction to give the cyanohydrins in up to 82 % ee (Sch. 62). 

Another noteworthy attempt to improve the catalytic asymmetric allylation was carried out employing a tin(II)-mediated Barbier-type reaction [22]. An al-lyltin reagent, generated in situ from allyl bromide, a Sn(II) compound, and a catalytic amount of CuCl, was allowed to react with aldehydes under the influence of the BINOL-Ti catalyst 6A to provide the product with up to 63% ee. 

Regarding the origin of the high level of asymmetric induction by CAB or BINOL-Ti catalyst, Corey and coworkers postulated that the C-H" 0 hydrogen bond occurring in the transition-state assembly seems to be a key factor in determining the absolute stereochemical course of the allylation reactions of alde-... 

Tagliavini and Umani-Ronchi found that chiral BINOL-Zr complex 9 as well as the BINOL-Ti complexes can catalyze the asymmetric allylation of aldehydes with allylic stannanes (Scheme 9) [27]. The chiral Zr catalyst 9 is prepared from (S)-BINOL and commercially available Zr(0 Pr)4 Pr0H. The reaction rate of the catalytic system is high in comparison with that of the BINOL-Ti catalyst 4, however, the Zr-catalyzed allylation reaction is sometimes accompanied by an undesired Meerwein-Ponndorf-Verley type reduction of aldehydes. The Zr complex 9 is appropriate for aromatic aldehydes to obtain high enantiomeric excess, while the Ti complex 4 is favored for aUphatic aldehydes. A chiral amplification phenomenon has, to a small extent, been observed for the chiral Zr complex-catalyzed allylation reaction of benzaldehyde. 

The BINOL-Ti catalyst can also be used for the carbonyl-ene reaction with formaldehyde or vinyl and alkynyl analogues of glyoxylates in an asymmetric catalytic desymmetrization (vide infra) approach to the asymmetric synthesis of isocarbacycline analogues (Scheme 7) [31a, 31b]. 

The BINOL-Ti-catalyzed aldol reaction of chiral P-benzyloxy aldehyde and silyl enol ether provides a facile route to the stereoselective synthesis of both syn and anti-diastereomers of p,S-dihydroxy thioesters, which can be used as the key intermediates for P-lactone synthesis [111] (Scheme 14.39). The high diastereoselectivity of this reaction was found to be dictated by the chirality of the BINOL-Ti catalyst rather than that of the chiral aldehyde substrate. A catalytic enantioselective resolution of secondary alcohol containing silylenol ether moiety has been realized by an aldol reaction catalyzed by BINOL-Ti Lewis acid [112]. 

BINOL-Ti catalyst has also been applied to the Mannich-type reaction by using nitrone as the nucleophile, affording the corresponding P-amino acid ester derivatives in up to 92% ee (Scheme 14.45). It was found that the addition of phenolic additive is essential for obtaining high enantioselectivity of the reaction [125]. 

Mikami found that the ene reaction of 1,1-di- and trisubstituted olefins with glyoxylate ester can be catalyzed by the titanium complexes prepared from BINOL and Ti(O Pr)2Cl2, Ti(O Pr)2Br2, or Ti(O Pr)4 [128]. The remarkable level of enan-tioselectivity and rate acceleration observed with these BINOL-Ti catalysts stems from the favorable infiuence of the inherent C2 symmetry and the higher acidity of BINOL ligands compared with aliphatic diols. The reaction is applicable to a variety of 1,1-disubstituted olefins and furnishes the ene products with excellent enantiomeric excesses (Scheme 14.48). However, no reaction occurs when mono-and 1,2-disubstituted olefins were adopted as the reactants. 

For the HDA reaction of aldehydes and other activated dienes with a structure analogous to that of Danishefsky s diene, BINOL-Ti catalysts were found to be highly efficient for enantiocontrol of the reaction, providing the corresponding dihy-dropyranone derivatives in moderate to excellent yields and high enantioselectivities [167] (Scheme 14.71). 

The use of amine as the nucleophile for desymmetrization of meso epoxides to provide optically active amino alcohols has been developed by Inaba using BINOL-Ti catalyst [236]. Excellent stereoselectivity and yields were observed... 

For the catalytic asymmetric FC reaction, the application of chiral titanium complexes of BINOL derivatives was first realized by Mikami and coworkers in the reaction of electron-rich aryl and vinyl ethers with fluoral [245]. For the FC reaction of anisole, it was found that the catalytic activity and enantioselectivity of BINOL-Ti catalysts were critically influenced by the substituents of BINOL derivatives. The electron-withdrawing bromo atoms at 6,6 -positions of BINOL turned out to be beneficial to the catalysis, the trifluoroethanol derivatives were obtained in high yield (89%) and up to 90% ee with a p o isomer ratio of 4 1. The FC reaction of vinyl ether with fluoral catalyzed by BINOL-TiCb (10 mol%) gave a mixture of allylic alcohols in which the major isomer was usually the Z-alkene. The increase of bulkiness of silyl group is favorable for the formation of FC products with very high enantiomeric excess (Scheme 14.105). 

The self-supported heterogeneous BINOL-Ti catalysts developed by Ding [280], using in situ assembly of bridged multitopic BINOL ligands and Ti(O Pr)4 in the presence of water, showed excellent enantioselectivities in the oxidation of sulfides and can be recycled eight times over a month without loss of activity or enantioselectivity [136b] (Scheme 14.118). 

The F-C reactions of aromatic compounds can provide a practical synthetic route for chiral a-trifluorobenzylalcohols of synthetic importance (Scheme 1). In previous asymmetric syntheses of a-trifluorobenzylalcohols, the asymmetric reductions of trifluoromethyl ketone were used as a key step 30-34). In this F-C reaction, the catalytic activity and enantioselectivity of BINOL-Ti catalysts (55-57) were found to be critically influenced by the substituents of BINOL derivatives (Table I). 1) (i )-6,6 -Br2-BINOL-Ti catalyst was the most effective catalyst. This F-C reaction did not proceed easily as compared with the carbonyl-ene reaction (7,8) or the Mukaiyama-aldol reaction (7) with fluoral. Therefore, the role of the electron-witiidrawing group at the 6,6 -position of BINOL is very important for increasing the Lewis acidity (runs 1 3). Relatively high enantio-... 

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