Chiral -hydroxy aldol reaction, stereoselectivity

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... 

Covalently bonded chiral auxiliaries readily induce high stereoselectivity for propionate enolates, while the case of acetate enolates has proved to be difficult. Alkylation of carbonyl compound with a novel cyclopentadienyl titanium carbohydrate complex has been found to give high stereoselectivity,44 and a variety of ft-hydroxyl carboxylic acids are accessible with 90-95% optical yields. This compound was also tested in enantioselective aldol reactions. Transmetalation of the relatively stable lithium enolate of t-butyl acetate with chloro(cyclopentadienyl)-bis(l,2 5,6-di-<9-isopropylidene-a-D-glucofuranose-3-0-yl)titanate provided the titanium enolate 66. Reaction of 66 with aldehydes gave -hydroxy esters in high ee (Scheme 3-23). 

Access to the corresponding enantiopure hydroxy esters 133 and 134 of smaller fragments 2 with R =Me employed a highly stereoselective (ds>95%) Evans aldol reaction of allenic aldehydes 113 and rac-114 with boron enolate 124 followed by silylation to arrive at the y-trimethylsilyloxy allene substrates 125 and 126, respectively, for the crucial oxymercuration/methoxycarbonylation process (Scheme 19). Again, this operation provided the desired tetrahydrofurans 127 and 128 with excellent diastereoselectivity (dr=95 5). Chemoselective hydrolytic cleavage of the chiral auxiliary, chemoselective carboxylic acid reduction, and subsequent diastereoselective chelation-controlled enoate reduction (133 dr of crude product=80 20, 134 dr of crude product=84 16) eventually provided the pure stereoisomers 133 and 134 after preparative HPLC. 

The group of Arai and Nishida investigated the catalytic asymmetric aldol reaction between tert-butyl diazoacetate and various aldehydes under phase-transfer conditions with chiral quaternary ammonium chloride 4c as a catalyst. The reactions were found to proceed smoothly in toluene, even at —40°C, when using 50% RbOH aqueous solution as a base, giving rise to the desired aldol adducts 23 with good enantioselectivities. The resulting 23 can be stereoselectively transformed into the corresponding syn- or anti-P-hydroxy-a-amino acid derivatives (Scheme 2.20) [42],... 

The gold(I) complex is prepared in situ by the reaction of (1) with bis(cyclohexyl isocyanide)gold(I) tetrafluoroborate (2), typically in anhydrous dichloromethane. The dihydrooxazolines obtained provide a ready access to enantiomerically pure p-hydroxy-a-amino acid derivatives. High diastereo- and enantios-electivity are generally maintained with a wide variety of substituted aldehydes, and a-isocyanoacetate esters. N,N-Dimethyl-a-isocyanoacetamides and a-keto esters have been substituted for the a-isocyanoacetate ester and aldehyde component, respectively, sometimes with improved stereoselectivity. The effect of both the central and planar chirality of (1) on the diastereo- and enantioselectivity of the gold(I)-catalyzed aldol reaction has been studied. The modification of the terminal di-alkylamino group of (1) can lead to improvements in the stereos-... 

Tin(n) triflate mediated cross aldol reactions between a-bromo ketone (124 Scheme 56) and aldehydes afford iyn-a-bromo-P-hydroxy ketones (125) with high stereoselectivity. The resulting halohydrins are converted to the corresponding (Z)-2,3-epoxy ketones (126). Chiral aldehyde (127) reacts with lithium alkynide (128) followed by mesylation and base treatment to give chirally pure ( )-epoxide (129). The initially formed alkoxide anion should be trapped in situ by mesylation, otherwise partial racemization takes place owing to benzoate scrambling (Scheme 56). ... 

A series of innovative investigations by Kiyooka and co-workers have introduced the use of tandem reaction processes that commence with a stereoselective aldol addition reaction and are followed by C=0 reduction [13]. A chiral oxazaboroli-dine complex prepared from BH3-THF and A-/ -toluenesulfonyl (L)-valine controls the absolute stereochemical outcome of the aldol reaction. In a subsequent reaction, the /i-alkoxyboronate effects intramolecular reduction of the ester to furnish the corresponding /i-hydroxy aldehyde. 

The Evans aldol reaction using chiral p-keto imide 23 as a dipropionate building block is also very effective for the construction of polypropionate segments in polyoxomacrolides (Scheme 2) [8]. The diastereoselective aldol reaction of 23 via different metal enolates (Ti, Sn, and B enolates) afforded three kind of aldols, syn-syn-24, anti-syn-25, and anti-anti-26, with high diastereoselectivity, respectively. The subsequent stereoselective reduction of the resulting p-hydroxy ketones 24-26 provides various types of dipropionate units. Based on this strategy, the... 

On the methodological front of these broadly based endeavors, we have exploited pericyclic processes such as the dipolar cycloadditions of nitrile oxides together with the aldol reaction and related constructions as tactical devices for the formation of new carbon-carbon bonds with high levels of stereochemical control Another important focus of these explorations has been upon the development of techniques for the manipulation and refunctionalization of hydropyrans, since this structural subunit is not only common to a variety of natural substances, but it may also be effectively exploited as a conformationally-biased template for the stereoselective construction of various skeletal arrays present in numerous natural products. In this context, we have devised a novel and highly effective strategy for the asymmetric syntheses of oxygenated natural products. The fundamental approach features the intermediacy of the hydro-3-pyranones 12, which may be accessed from the chiral furfuryl carbinols 10 via the hydroxy enediones 11 by well-established oxidative techniques (Scheme 1). A critical element of this overall planll is that the hydro-3-pyranones 12 are admirably endowed with differentiated functionality that is suitable for further elaboration by reaction with selected nucleophiles... 

The aldol reaction is an important carbon-carbon bond-forming method for constructing p-hydroxy carbonyl compounds in which new stereogenic centers are created. Especially, regio- and stereoselective aldol reactions are the most useful for organic synthesis of complex molecular skeletons [11-15]. From a viewpoint of atom economy, an aldol reaction via direct formation of an enolate with a catalytic amoimt of base is highly desired, and high Brpnsted basicity of the alkaline-earth metal compounds is suitable for this purpose. In recent researches on chiral alkaline-earth metal catalysis, direct-type asymmetric aldol and related reactions have been developed. 

Polypropionates possessing chiral chains compose a big group of natural products called polyketides. Polyketides are produced in nature by Claisen condensation and the subsequent reduction. However, people think that aldol reactions should be adequate to construct polypropionate skeletons because an aldol reaction constructs two stereo-genic centers at the a and 3 positions. For example, as shown in Scheme 8.1, erythromycin A would be synthesized by repetition of aldol reactions and manipulation of (3-hydroxy groups. Therefore, the stereoselective aldol reaction should be a key to the synthesis of polypropionates, and chemists have developed many types of aldol reactions. ... 

The stannous enolates of Evans (/ )- and (5)-4-benzyl-3-(isothiocyanoacetyl)oxazolidin-2-ones 223 (Figure 11.76) react with aliphatic and aromatic aldehydes to afford 5-substituted 2-thioxo-oxazolidine-4-carboxylates, which are readily hydrolyzed to give syn-(2S,3R)- and (2R,35)-/3-hydroxy-a-amino acids, respectively, in fairly good yields (50-70%) and excellent stereoselectivities (90-99% d.e.) . Although 223 is readily accessible from the respective chloroacetyl precursor through treatment with sodium azide and transformation of the resultant azide with PhsP and CS2, the less commonly used ethyl (lR,2R,5/ )-((2-hydroxypinan-3-ylene)amino)acetate 12241 and its (-l-)-antipode are the only linear chiral glycinate exploited so far in aldol reactions in isotope chemistry. ... 

A DFT study of the origins of stereoselectivity in the aldol reaction of bicyclic amino ketones (20) with aromatic aldehydes has been reported (Scheme 18). ° Base-catalysed direct aldolization of a-alkyl-a-hydroxy trialkyl phosphonoacetates with aldehydes proceeds via a fully substituted glycolate enolate intermediate formed by a [l,2]-phosphonate-phosphate rearrangement. High enantioselectivity can be achieved by the application of chiral iminophosphorane catalysts. 

Stereoselective aldol condensation. Heathcock and Buse have previously employed 2-methyl-2-trimethylsiloxy-3-pentanone (1) in a highly stereoselective route to 3-hydroxy-2-methylcarboxylic acids (8, 295). Aldol condensation of the lithium enolate derived from 1 with a chiral aldehyde yields ery//iro-aldols, which are cleaved with periodic acid to -hydroxy carboxylic acids. However, when 1 is condensed with a chiral aldehyde such as 2, two eryt/iro-products (3 and 4) are produced. Heathcock and co-workers now report that the 1,2-diastereoselectivity of these aldol condensations can be enhanced by use of the ketone 5. Reaction of racemic 5 with racemic aldehyde 2 furnishes a single (racemic) adduct 6. 

The reaction of a glycine Schiff base (159) with aldehydes can be catalyzed by cinchona-derived salts, though the stereoselectivity is rather low [171]. Maruoka reported that this reaction proceeded well with a C2-symmetric chiral quarternary ammonium salt (160) as a phase-transfer catalyst [172]. The reaction generated tz fi -(3-hydroxy-a-aminoacids with reasonable yields and stereoselectivities (Scheme 3.28). Further modifications of the catalyst structure led to a salt which provided predominantly jy -aldols [173]. 

Later, Yamamoto and coworkers developed the axially chiral ester 183 for asymmetric acetate aldol additions. After formation of the lithium enolate with LDA, the reaction with various aldehydes yielded P-hydroxy esters 184 in very high diastereoselectivity. It was shown, for two adducts, that a nearly quantitative saponification leads to P-hydroxy carboxylic acids 176 and liberates phenol 185 in nearly quantitative yield and undiminished optical purity (Scheme 4.40) [100]. The authors discuss a twist-boat as well as an open transition state for rationalizing the preferred Re-face attack to the aldehyde, observed with (R,R)-configured acetate 183. Yamamoto s procedure is impressive because of its stereoselectivity, but one has to be aware that the chiral auxiliary 185 is by far not as readily accessible as others also enabling the asymmetric acetate aldol addition. 

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