BINOL system aldol reaction

The reaction was studied in the absence, and presence, of (MeO)2AlMe as a model catalyst for the BINOL-AlMe system. The change in relative energy for the concerted hetero-Diels-Alder reaction, and formation of the hetero-Diels-Alder adduct 11 via a Mukaiyama aldol reaction, is shown in Fig. 8.13. The conclusion of the study was that in the absence of a catalyst the concerted reaction is the most... 

Reetz et al. reported that a chiral Ti complex prepared from TiCL). and the dilithium salt of (S)-BINOL promoted the aldol reaction of 3-mefhylbutanal with KSA 48 with only poor enantioselectivity (60%, 8% ee) [115 b]. After this pioneering work, the titanium-based catalyst system has been intensively improved to attain an efficient catalytic cycle and high stereoselectivity [147-155]. 

Table 11.1 Direct catalytic asymmetric aldol reaction with the first generation Et2Zn/ linked-BINOL = 2/1 system.

A chiral catalyst system for aldol reaction of conjugated thioketene silyl acetals (i.e., from thio esters) consists of Ti-BINOL and (MeO)3B. The teranuclear Ti complex is air-stable and its use in aldol reactions requires low loading. ... 

Catalytic, enantioselective Michael reactions of cyclopentenones have attracted particular attention in recent years. Ben L. Feringa, Albert S. C. Chan, Andreas Pfaltz and Amir H. Hoveyda described various hgand systems for stereoselective addition of organo-zinc reagents to cyclopentenones. With the aid of a phos-phoramidite derived from BINOL, Feringa developed an enantioselective, catalytic domino-Michael/aldol reaction for the preparation of (+)-PGEi methyl ester. [223]... 

Mikami reported that BINOL derived titanium complex efficiently catalyzed the aldol reaction of silyl enol ether with excellent control of both absolute and relative stereochemistry [106] (Scheme 14.37). The reaction was proposed to proceed via a prototropic ene reaction pathway that is different from that of Mukaiyama aldol condensation. A cyclic antiperiplanar transition-state model was proposed to explain the pref erential formation of the syn diastereomer from either (E)- or (Z)-silyl enol ethers [106]. Further modifications of the catalyst system include the use of perfluorophenols and other activating additives [107], or performing the reaction in supercritical fluids [108]. Furthermore, the nucleophile could be extended to enoxysilacyclobutane derivatives [109]. 

The catalytic version of this type of reaction was realized by using acetoacetate derived O-silyl dienolate as nucleophiles in the presence of Carreira s catalyst, giving acetoacetate y-adducts in high yields and enantiomeric excesses [119] (Scheme 14.42). The products are ubiquitous structural subunits in biologically active natural products such as the polyene macrolide antibiotic and medicinally important HMG-CoA reductase inhibitors. This aldol addition can also be catalyzed by BINOL-Ti complex in the presence of 4A MS with moderate to good enantioselectivity [120]. The same catalyst system was also efficient in the asymmetric aldol reaction between the aldehydes and Chan s diene [ 1,3-bis-(trimethylsilyloxy)-l-methoxy-buta-1,3-diene] and other related silyl enol ethers [121, 122] (Scheme 14.43) or the functionalized silyl enol ether such as 2-(trimethylsilyloxy)furan with good to excellent enantioselectivities [123]. 

In the aldol reaction of 2-trimethylsilyloxyfuran with aldehydes catalyzed by (BINOL)2Ti complex, a significant impact of the product on the enantioselectivity of the catalysis was observed [124]. As shown in Scheme 14.44, the addition of 5 mol% of the product (82% ee) in the catalyst can enhance the enantiomeric excess of the product from 70% to 96%. Therefore, an asymmetric autoinduction might be involved in the catalytic system. On the basis of this observation. 

A direct asymmetric aldol reaction of diazoester was catalyzed by the Zr-BINOL catalyst system (Equation 17) [22]. Although the enantioselectivity was moderate, it is worth noting that the Zr-BINOL complex realized the aldol reaction of nonactivated substrates under catalytic conditions in an enantioselective manner. 

In the approaches toward a direct asymmetric Mannich reaction by enolate formation with the metal of the catalyst also, the well-proved systems of the analogous aldol reactions were widely applied. Here, it is referred to some of these protocols wherein a metal enolate is involved, as least as assumed and plausible intermediate [183]. Shibasaki and coworkers used a dinuclear zinc complex derived from linked BINOL ligand 371 for catalyst in direct Mannich reactions of a-hydroxy ketones 370 with Af-diphenylphosphinoyl imines 369 to give ti-configured a-hydroxy-P-amino ketones 372 in high yield, diastereoselectivity, and enantioselectivity (Scheme 5.97) [184]. The authors postulate the metal to form a chelated zinc enolate by double deprotonation of the a-hydroxy ketone. This enolate approaches with its Si-face to the Si-face of the imine, as illustrated by the transition state model 373, in agreement with the observed stereochemical outcome. It is remarkable that opposite simple diastereoselectivity arises from the Mannich reaction (anti-selective) and the previously reported syn-selective aldol reaction [185], although the zinc enolates... 

Direct intermolecular aldol reaction leading to polypropionate building blocks was achieved by Mahrwald in 2(X)0. Also in this case the promoting system contains both, Lewis acidic and Brpnsted basic sites, and is used in stoichiometric amounts (Scheme 10.14). It is interesting to note that the best results were obtained when racemic BINOL-Ti(Oi-Bu)2 59 was combined with enantiomeri-cally pure (/f)-mandelic acid 60. 

SCHEME 10.14. Direct intermolecular aldol reaction promoted by the amphoteric BINOL-Ti(Ot-Bu)2-(R)-mandelic acid system. 

In 1993, Mikami and Matsukawa reported on an interesting reactivity while attempting enantioselective catalysis of the Mukaiyama aldol reaction using the 1, r-binaphthyl-2,2 -diol (BINOL) system (Scheme 10.21). ° The method used condensation of 3-pentanone-derived enoxysilane 91 with glyoxalate 92 in the presence of enantiomerically pure catalyst 93. Silyl enol ether 94 was obtained as an c/jc-type product with excellent diastereo- and enantioselectivity. 

A related Mukaiyama aldol catalyst system reported by Keck prescribes the use of a complex that is prepared in toluene from (R)- or (S)-BINOL and Ti(0 Pr)4 in the presence of 4 A molecular sieves. In work preceding the aldol addition reaction, Keck had studied this remarkable catalyst system and subsequently developed it into a practical method for enantioselective aldehyde allylation [95a, 95b, 95c, 96]. Because the performance of the Ti(IV) complex as an aldol catalyst was quite distinct from its performance as a catalyst for aldehyde allylation, a careful examination of the reaction conditions was conducted. This meticulous study describing the use of (BINOL)Ti(OiPr)2 as a catalyst for aldol additions is noteworthy since an extensive investigation of reaction parameters, such as temperature, solvent, and catalyst loading and their effect on the enantiomeric excess of the product was documented. For example, when the reaction of benzal-dehyde and tert-butyl thioacetate-derived enol silane was conducted in dichlo-romethane (10 mol % catalyst, -10 °C) the product was isolated in 45% yield and 62% ee by contrast, the use of toluene as solvent under otherwise identical conditions furnished product of higher optical purity (89% ee), albeit in 54% yield. For the reaction in toluene, increasing the amount of catalyst from 10 to 20 mol %... 

List documented another approach to effect catalytic enantioselective Pic-tet-Spengler reactions, using chiral phosphoric acids derived from BINOL [40-42, 133] (Equation 13) [134]. Treatment of substituted tryptamine 173 with aldehyde 174 in the presence of chiral Bronsted acid 175 afforded adduct 176 in 98% yield and 96% ee. List suggested that the operation of the Thorpe-lngold effect was critical for these systems. Thus, in the absence of geminal diester substitution (cf 177), aldol condensation to give 178 was observed exclusively. 

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