Asymmetric aldol reactions using chiral boron enolates

Asymmetric Aldol Reactions Using Chiral Boron Enolates... 

Evans et al. utilized the chiral oxazolidones to prepare optically pure 3-hydroxy-a-amino acids, - important constituents of peptides and 3-lactams. As shown in Scheme 31, an asymmetric aldol reaction using the boron enolate derived from the V-(a-haloacyl)oxazolidone (68) provides the jyn-3-hydroxy-ot-halocarbonyl derivative (69), which is converted to the ann-3-hydroxy-a-azidocarbonyl derivative (70)... 

Diastereoselective Aldol Reactions Using Chiral Enolates Although the approach that uses chiral auxiliaries or other elements of stoichiometric chiral information is not as elegant as asymmetric catalysis, it is highly practical. At present, the boron-mediated aldol reaction of enolates 112 and 115 with aldehydes giving the syn aldol products 113 and 116 constimtes one of the best C C bond forming methods (Scheme 10.26). ... 

Although in the recent years the stereochemical control of aldol condensations has reached a level of efficiency which allows enantioselective syntheses of very complex compounds containing many asymmetric centres, the situation is still far from what one would consider "ideal". In the first place, the requirement of a substituent at the a-position of the enolate in order to achieve good stereoselection is a limitation which, however, can be overcome by using temporary bulky groups (such as alkylthio ethers, for instance). On the other hand, the ( )-enolates, which are necessary for the preparation of 2,3-anti aldols, are not so easily prepared as the (Z)-enolates and furthermore, they do not show selectivities as good as in the case of the (Z)-enolates. Finally, although elements other than boron -such as zirconium [30] and titanium [31]- have been also used succesfully much work remains to be done in the area of catalysis. In this context, the work of Mukaiyama and Kobayashi [32a,b,c] on asymmetric aldol reactions of silyl enol ethers with aldehydes promoted by tributyltin fluoride and a chiral diamine coordinated to tin(II) triflate... 

Several methods for the anti-selective, asymmetric aldol reaction recorded in the literature include (i) the use of boron, titanium, or tin(ll) enolate carrying chiral ligands, (ii) Lewis acid-catalyzed aldol reactions of a metal enolate of chiral carbonyl compounds, and (iii) the use of the metal enolate derived from a chiral carbonyl compound. Although many of these methods provide anti-aldols with high enantioselectivities, these methods are not as convenient or widely applicable as the method reported here, because of problems associated with the availability of reagents, the generality of reactions, or the required reaction conditions. 

Asymmetric Aldol Reactions. Reaction of (1) with Boron Tribromide in CH2CI2 affords, after removal of solvent and HBr, a complex (5) useful for the preparation of chiral enolates (eq 5). Complex (5) is moisture sensitive and is generally prepared immediately before use. For propionate derivatives, either syn or, less selectively, anti aldol adducts may be obtained by selection of the appropriate ester derivative and conditions. Thus reaction of f-butyl propionate with (5) and triethylamine produces the corresponding E 0) enolate, leading to formation of anti aldol adducts upon addition to an aldehyde (eq 6). Selectivities may be enhanced by substitution of the t-butyl ester with the (+)-menthyl ester. Conversely, reaction of 5-phenyl thiopropionate with (5) and Diisopropylethylamine affords the corresponding Z(0) enolates and syn aldol products (eq 7). ... 

Silyl enol ethers react with aldehydes in the presence of chiral boranes or other additives " to give aldols with good asymmetric induction (see the Mukaiyama aldol reaction in 16-35). Chiral boron enolates have been used. Since both new stereogenic centers are formed enantioselectively, this kind of process is called double asymmetric synthesis Where both the enolate derivative and substrate were achiral, carrying out the reaction in the presence of an optically active boron compound ° or a diamine coordinated with a tin compound ° gives the aldol product with excellent enantioselectivity for one stereoisomer. Formation of the magnesium enolate anion of a chiral amide, adds to aldehydes to give the alcohol enantioselectively. 

In sharp contrast to the utility of chiral boron Lewis acids, chiral aluminum Lewis acids have been little used for asymmetric aldol reactions of silyl enolates since the first example reported by Reetz et al. [115]. Fujisawa et al. have reported that an equimolar amount of a chiral Lewis acid prepared from Et2AlCl and a bor-nane-2,3-diol promotes the aldol reaction of 48 in moderate yields with good enantioselectivity [127]. 

In recent years, catalytic asymmetric Mukaiyama aldol reactions have emerged as one of the most important C—C bond-forming reactions [35]. Among the various types of chiral Lewis acid catalysts used for the Mukaiyama aldol reactions, chirally modified boron derived from N-sulfonyl-fS)-tryptophan was effective for the reaction between aldehyde and silyl enol ether [36, 37]. By using polymer-supported N-sulfonyl-fS)-tryptophan synthesized by polymerization of the chiral monomer, the polymeric version of Yamamoto s oxazaborohdinone catalyst was prepared by treatment with 3,5-bis(trifluoromethyl)phenyl boron dichloride ]38]. The polymeric chiral Lewis acid catalyst 55 worked well in the asymmetric aldol reaction of benzaldehyde with silyl enol ether derived from acetophenone to give [i-hydroxyketone with up to 95% ee, as shown in Scheme 3.16. In addition to the Mukaiyama aldol reaction, a Mannich-type reaction and an allylation reaction of imine 58 were also asymmetrically catalyzed by the same polymeric catalyst ]38]. 

Other oxazolidinones have been used as chiral auxiliaries in asymmetric aldol reactions. Bomane derivatives 1.121 (X = O or S) and 1.122 are readily transformed into V-acyl derivatives. The reactions of their boron or titanium enolates with aldehydes give the same selectivities as Evans s reagents [426, 428, 429, 431, 436], iV-Acylimidazolidinones 1.131 and 1.132 [449, 1270] lead to similar results, but the selectivities observed are somewhat lower. 

Asymmetric Aldol Reactions. Reaction of (1) with boron tribromide in CH2CI2 affords, after removal of solvent and HBr, a complex (5) useful for the preparation of chiral enolates (eq 5). Complex (5) is moisture sensitive and is generally prepared immediately before use. For propionate derivatives, either syn or. 

Conventional asymmetric aldol reactions have been performed by using chiral enolates and achiral carbonyl compounds. A chiral boron enolate generated from a chiral oxazolidone derivative (26 and 28), dialkylboron tri-fiate, and diisopropylethylamine reacts stereoselectively with aldehydes to afford the corresponding syn aldol adducts (27 and 29) in good yields with excellent diastereoselectivity (Eqs. (8) and (9)) [12]. The opposite sense of asymmetric induction is achieved by changing the chiral auxiliary. Several other chiral auxiliaries have also been developed for highly diastereoselec-tive synthesis of syn aldol adducts (Eqs. (10)-(13)) [13]. 

After the first reports of the above-mentioned highly eflident catalytic enantioselective aldol reaction, some groups independently reported catalytic symmetric aldol reactions of silicon enolates vith aldehydes using chiral boron [72], titanium [73], zirconium [74], and copper Le vis acids [75], or by transmetalation to chiral Pd(II) enolates [44]. Chiral phosphoramide-promoted aldol reactions of trichlorosilyl enol ethers have been reported as Le vis base-catalyzed asymmetric aldol reactions [76]. 

A fundamentally different, albeit stoichiometric, concept that was successfully applied for asymmetric aldol reactions locates the chiral inductor into covalently bound residues or ligands at the enolate metal. This approach was mainly developed for boron enolates but also efficiently used in titanium enolates. The application of this concept has the advantage that the extra steps of introduction and cleavage of the auxiliary are not necessary. On the other hand, the possibility of the enrichment of the stereochemical purity by chromatographic purification or recrystallization of diastereomeric adducts ceases to exist. A further drawback is frequently the fact that the recovery of the chiral inductor is problematic or even impossible. 

The reactions of enolates with aldehydes (aldol reactions) or with imines have been widely developed since the 1970s. Asymmetric aldol-type reactions are very important in the multistep synthesis of complex molecules such as ionophores or p-lactam antibiotics. Chirality has been introduced either on the substituents of boron, on the metal ligands or on the carbon skeleton of the enolate. Aldol reactions are usually run at low temperatures, and when metal enolates are used, the reactions are sometimes easily reversible [160, 209],... 

---