Selective Asymmetric Aldol Reaction

An anti-selective diastereoselective aldol reaction [14] has been performed by using enantiomerically pure carboxylic esters derived from (-) or (+) norephedrine 30 [15], This method is applicable to a wide range of aldehydes with high selectivity (both syn/anti and diastereoselectivity of anti isomer). It is proposed that ( ) boron enolates 31 are formed by this procedure and aldol reaction proceeds via the six-membered transition state (Eq. (14)). The aldol products 32 are converted to the corresponding alcohols (LiAlH4 THF) or carboxylic acids (LiOH, THF-H2O) without loss of stereochemical integrity. 

It is also reported that addition of Lewis acids to the reaction of chiral boron enolates and aldehydes changes syn-selectivity to anti-selectivity (Eqs. 

boron enolates prepared under mild conditions enable aldol-type reactions essentially under neutral conditions. Stereocontrolled synthesis of acyclic molecules has been achieved by employing boron enolate-mediated aldol reactions this method has been extensively applied to the synthesis of natural products. 

Typical Procedure for syn-Selective Asymmetric Boron Aldol Reaction (Eq. (17)) [13] 

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See the procedure describing the anti-selective asymmetric aldol reaction of carboxylic esters, p. 116. 

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. 

The stereochemical course of the aldol reaction can be controlled by the judicious selection of the enolization reagents. Treatment of propionate esters with <7-Hex2BOTf and triethylamine produced anti-aldol products, and that of with Bu2BOTf and diisopropylethylamine selectively gave syn-aldol products after reaction with aldehydes (Equation (180)).684 685 Complementary anti- and yy/z-selective asymmetric aldol reactions were also demonstrated in structurally related chiral norephedrine-derived propionate esters (Equation (181)).686... 

The air stable and storable zirconium catalyst, formed from Zr(0 Bu)4, 3,3 -diiodo-l,l -binaphthalene-2,2 -diol (3,3 -l2-BINOL), -propanol and water, with the putative dimeric structure (7.33) also catalyses auft -selective asymmetric aldol reactions. While this process is beheved to proceed through an acyclic transition state, as depicted in Figure 7.2, it is postulated that the greatest steric interaction is now between the silyl enol ether substituent R3 and the bulky Lewis acid resulting in the formation of the fluft -diastereomer predominantly. 

Inoue, T., Liu, J., Buske, D.C., and Abiko, A.J. (2002) Boron-mediated aldol reaction of carboxylic esters complementary anti- and syn-selective asymmetric aldol reactions. J. Org. 

Yamashita Y, Ishitani H, Shimizu H, Kobayashi S. Highly anti-selective asymmetric aldol reactions using chiral zirconium catalysts. Improvement of activities, structure of the novel zirconium complexes, and effect of a small amount of water for the preparation of the catalysts. J. Am. Chem. Soc. 2002 124 3292-3302. 

We now tum our attention to the C21-C28 fragment 158. Our retrosynthetic analysis of 158 (see Scheme 42) identifies an expedient synthetic pathway that features the union of two chiral pool derived building blocks (161+162) through an Evans asymmetric aldol reaction. Aldehyde 162, the projected electrophile for the aldol reaction, can be crafted in enantiomerically pure form from commercially available 1,3,4,6-di-O-benzylidene-D-mannitol (183) (see Scheme 45). As anticipated, the two free hydroxyls in the latter substance are methylated smoothly upon exposure to several equivalents each of sodium hydride and methyl iodide. Tetraol 184 can then be revealed after hydrogenolysis of both benzylidene acetals. With four free hydroxyl groups, compound 184 could conceivably present differentiation problems nevertheless, it is possible to selectively protect the two primary hydroxyl groups in 184 in... 

TiX4 is employed as an effective promoter for asymmetric aldol reactions. A chiral aldehyde or a chiral enolate reacts to afford homochiral aldol adducts with high selectivity (Scheme 20).78 79... 

The gold(I) complex of a chiral ferrocenylphosphine complex promotes asymmetric aldol reactions of a-isocyanocarboxylates to form chiral oxazolines in high diastereo- and enantio-selectivities (Scheme 52).225,226 In these reactions, the analogous silver(I) ferrocenylphosphine complex also works well. 

Besides their application in asymmetric alkylation, sultams can also be used as good chiral auxiliaries for asymmetric aldol reactions, and a / -product can be obtained with good selectivity. As can be seen in Scheme 3-14, reaction of the propionates derived from chiral auxiliary R -OH with LICA in THF affords the lithium enolates. Subsequent reaction with TBSC1 furnishes the 0-silyl ketene acetals 31, 33, and 35 with good yields.31 Upon reaction with TiCU complexes of an aldehyde, product /i-hydroxy carboxylates 32, 34, and 36 are obtained with high diastereoselectivity and good yield. Products from direct aldol reaction of the lithium enolate without conversion to the corresponding silyl ethers show no stereoselectivity.32... 

Double asymmetric aldol reaction has been widely used for the efficient construction of the, sr -unit.10b 42 With above-described organoboron compounds (Section 3.3.1), antz -selectivity can be obtained. 

Bis(oxazoline)-type complexes, which have been found useful for asymmetric aldol reactions, Diels-Alder, and hetero Diels-Alder reactions can also be used for inducing 1,3-dipolar reactions. Chiral nickel complex 180, which can be prepared by reacting equimolar amounts of Ni(C10)4 6H20 and the corresponding (J ,J )-4,6-dibenzofurandiyl-2,2 -bis(4-phenyloxazoline) (DBFOX/Ph) in dichloromethane, can be used for highly endo-selective and enantioselective asymmetric nitrone cycloaddition. The presence of 4 A molecular sieves is essential to attain high selectivities.88 In the absence of molecular sieves, both the diastereoselectivity and enantioselectivity will be lower. Representative results are shown in Scheme 5-55. 

The catalytic asymmetric aldol reaction has been applied to the LASC system, which uses copper bis(-dodecyl sulfate) (4b) instead of CufOTf. 1261 An example is shown in Eq. 6. In this case, a Bronsted add, such as lauric add, is necessary to obtain a good yield and enantioseledivity. This example is the first one involving Lewis acid-catalyzed asymmetric aldol reactions in water without using organic solvents. Although the yield and the selectivity are still not yet optimized, it should be noted that this appredable enantioselectivity has been attained at ambient temperature in water. 

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... 

ANTI-SELECTIVE BORON-MEDIATED ASYMMETRIC ALDOL REACTION OF CARBOXYLIC ESTERS SYNTHESIS OF (2S, 3R)-2,4-DIMETHYL-1,3-PENTANEDIOL... 

ANTI-SELECTIVE BORON-MEDIATED ASYMMETRIC ALDOL REACTION OF 116... 

Anti-selective Boron-mediated Asymmetric Aldol Reaction of Carboxylic Esters. 

Aminocatalysis is a biomimetic strategy used by enzymes such as class I aldolases. Application of aminocatalysis in an asymmetric aldol reaction was reported in the early 1970s. Proline (19) efficiently promoted an intramolecular direct aldol reaction to afford Wieland-Miescher ketone in 93% ee [17,18]. More than 25 years later, in 2000, List, Barbas, and co-workers reported that proline (19) is also effective for intermolecular direct aldol reactions of acetone (le) and various aldehydes 3. Notably, the reaction proceeded smoothly in anhydrous DMSO at an ambient temperature to afford aldol adducts in good yield and in modest to excellent enantioselectivity (up to >99% ee, Scheme 9) [19-22]. The chemical yields and selectivity of proline catalysis are comparable to the best metallic catalysts, although high catalyst loading (30 mol %) is required. Proline (19)... 

The asymmetric aldol reaction can also be performed as an enantio- and diastereo-selective reaction forming molecules of type 50 with two stereogenic centers. The principle of this reaction is shown in Scheme 6.25. 

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