Diastereoselectivity aldol reaction

The a-alkoxy iron-acyl complex 5 may be deprotonated to generate the lithium enolate 6, which undergoes a highly diastereoselective aldol reaction with acetone to generate the adduct 7 as the major product. Deprotonation of acetone by 6 is believed to be a competing reaction 30% of the starting complex 5 is found in the product mixture48 40. 

The boron enolates derived from (5)-4-silylated 2,2-dimethyl-l,3-dioxan-5-one undergo anti diastereoselective aldol reactions which provide access to protected oxopolyols of high stereochemical integrity <96SYN1095>. 

A jy -diastereoselective aldol reaction based on titanium enolates from (A)-l-benzyloxy-2-methyl-3-pentanone was developed by Solsona et al. (Equation (12)).64 The titanium enolate of this chiral ketone afforded the corresponding syn-syn aldol adducts in high yields and diastereomeric ratios with a broad range of aldehydes. 

Finally, several diastereoselective aldol reactions using titanium enolates and carbonyl electrophiles have also been applied to the total synthesis of natural products.69-72... 

TABLE 3-1. Diastereoselective Aldol Reaction Using Chiral Reagent 5... 

Scheme 4.37. Diastereoselective aldol reactions of an alkyl zirconocene.

Diastereoselective aldol reactions The boryl enolates of chiral crotonate imides (1) and (2) react with aldehydes to form adducts (3) and (4), respectively, with high diastereoselectivity and complete a-regioselectivity. The method of choice for reductive cleavage of the adducts is formulated for 3 hydrolysis can also be effected with LiOH and H202. 

Scheme 9 EGA-catalyzed diastereoselective aldol reaction of acetal with an enolether.

The oxazolidinones have been used as chiral auxiharies for enolate alkylation and aldol reactions in enantioselective and total syntheses The interest in these substrates is largely known for iyw-diastereoselective aldol reactions with chlorotitanium or diaUcylboron oxazilidinone enolates (equation 114). 

These highly diastereoselective aldol reactions have been used in a synthesis of 6-deoxyerythronolide B (5), which contains 10 asymmetric centers. Four aldol reactions, indicated by dotted lines, were used to construct the carhon framework with overall stereoselection of 85%.2... 

Other examples of the uses of enolate derivatives of thioesters highly diastereoselective aldol reactions were reported by Gennari [3 and Hanaoka et al. [374, 375]. The latter reported the reaction between chromium-complexed benzaldehyde (1) and the titanium enolate of thioester (2) as the first step of sequences directed towards the synthesis (+)-goniofufurone [374] and the taxol C13 side-chain [375]. They also u cobalt-complexed acetylenic aldehydes for the selective formation of sy aldols [376]. 

Acyl-l,3-oxazolidine-2-thiones, chiral (1). Nagao and co-workers1 have prepared the chiral 3-acetyl-l,3-oxazolidine-2-thiones (la and lb) and used them to effect diastereoselective aldol reactions. The two chiral auxiliaries show, as expected, opposite diastereoselectivities, but contrast with the diastereoselectivities observed with chiral 4-alkyl-2-oxazolidones (11, 379-381). This aldol reaction has been used to prepare the chiral azetidinone 4 (equation I) and (-I- )-Prelog-Djerassi lactone. 

Diastereoselective aldol reaction. Alkyl trityl ketones (2) are readily prepared by reaction of 1 with an aldehyde followed by Cr03 oxidation (50-70% overall yield). Because of steric effects these ketones undergo highly diastereoselective aldol condensation to give syn-adducts (95-99% syn). After protection of the hydroxyl group, the adduct is cleaved by lithium triethylborohydride.1... 

To address limitations in the use of glyceraldehyde acetonide (43) as a three-carbon chiral building block, butane-2,3-diacetal-protected glyceraldehyde (44, R1 = R2 = H) has been prepared. It undergoes diastereoselective aldol reactions with a range of carbonyl compounds esters, thioesters, and ketones. The work has been extended (g) to other derivatives such as the a-substituted aldehyde (44, R1 = Me, allyl) and the methyl ketone (44, R2 = Me).122a,b... 

Diastereoselective aldol reactions. Heathcock and Flippin6 have observed that BF3 etherate can improve syn-selectivity in the reaction of an enolate (1) of pinaco-lone with 2-phenylpropanal (equation I). Thus, the reaction of the t-butyldimethylsi-lyl enolate in the presence of BF3 etherate is more syn-selective than that of the... 

Amino-y-butyrolactones.5 The (dimethylamino)carbene 1 undergoes highly diastereoselective aldol reactions with aldehydes even in the absence of a Lewis acid to form syn-adducts 2, from which the metal unit can be removed by photolysis. 

P-Hydroxy carboxylic acids (12,3).2 This acetate on double deprotonation with LDA undergoes diastereoselective aldol reactions with aldehydes. The adducts are easily hydrolyzed to optically active P-hydroxycarboxylic acids with release of (R)-(+)-1,1,2-triphenyl-1,2-ethanediol, the precursor to 1. Optically pure acids can be obtained by crystallization of the salt with an optically active amine such as (S)-(—)-1 -pheny lethylamine. 

The diastereoselective aldol reaction of the tributyltin enolate of cyclohexanone with benzaldehyde in the presence of a catalytic amount of various metal triflates has been studied. The highest A-selectivity is observed with Pd(OTf)2, while Zn(OTf)2 in THF shows moderate yy -selectivity (Equation (68)).222 OSnBu3... 

The similar type of generation of tin(ll) enolate provides a diastereoselective aldol reaction for the asymmetric synthesis of a-substituted serines using Sn(OTf)2/A-ethylpiperizine.243... 

To achieve a stereoselective aldol reaction that does not depend on the structural type of the reacting carbonyl compounds, many efforts have been made to use boron enolates. Based on early studies by Mukaiyama et al.8a and Fenzl and K0ster,8b in 1979, Masamune and others reported a highly diastereoselective aldol reaction involving dialkylboron enolates (enol borinates)9... 

Having noticed certain limitations of chlorotitanium aldol reactions on Evans et al. s chiral auxiliary,21 in 1997 Crimmins and others developed a brilliant protocol to achieve a highly diastereoselective aldol reaction.22 Asymmetric aldol... 

In 1995, Boeckman et al. disclosed a highly diastereoselective aldol reaction using the ligand 79 derived from chiral bicyclic lactam28 (Scheme 2.1z). The imide 80, readily prepared from bicyclic lactam 79 and propionyl chloride, was converted to the boron Z-enolate, which was then treated with a representative series of aldehydes at -40° C for 48 hours. The levels of diastereoselectivity observed in reactions of boron enolate derived from 80 are comparable to those... 

Chiral acylthiazolidinethiones such as 26 can readily be prepared from commercially available amino acids in three steps12 (Scheme 2.2k). They have been employed as a synthetically useful auxiliary in diastereoselective aldol reactions.13 The magnesium-catalyzed aldol reaction of the thiazolidinethione 26.S with cin-namaldehyde afforded 27 as a major diastereomer in 87% yield. Interestingly, compound 27 is the opposite anti-aldol diastereomer to that seen with the oxa-zolidinone 23S. 

Two further syntheses of Lactacystin also deployed a diastereoselective aldol reaction to create a quaternary centre.250-251 Smith and co-workers,250 protected the 1,2-amino alcohol 129.1 [Scheme 3.129] by heating with trimethyl orthobenzoate to give the oxazoline 129 2 in 82% yield. The oxazoline served the dual puipose of protecting and activating group in the subsequent aldol reaction... 

Diastereoselective aldol reactions.2 The diastereoselectivity in the Lewis acid-catalyzed aldol reaction of chiral a-hydroxy aldehydes is independent of the geometry of the enol silyl ether. Also, the reaction does not involve prior Si—Ti or Si-Sn exchange. 

Acetals are a versatile alternative to aldehydes and ketones which have wide applicability in the titanium-mediated aldol reaction [51], Equation (10) shows the difference between an acetal and the parent aldehyde in the diastereoselective aldol reaction [52]. In this example the latter results in better diastereoselectivity than the former. The reactivity of an aldehyde and its acetal have been compared (Eq. 11) [53]. More examples of the directed aldol reaction starting from enol derivatives of aldehydes and ketones are summarized in Table 1. 

Akiyama, Y, Ishikawa, K, OzaM, S, Asymmetric synthesis of functionalized tertiary alcohols by diastereoselective aldol reaction of silyl enol ether and ketene silyl acetals with a-keto esters bearing an optically active cyclitol as a chiral auxihary, Synlett, 275-276, 1994. 

SCHEME 13.40 Diastereoselective aldol reaction with (/ )- HYTRA . 

The phenylalanine-derived oxazolidinone 108 undergoes a diastereoselective aldol reaction with crotonaldehyde to give the syn product 109. Formation of the Weinreb amide, followed by silylation of the crude secondary alcohol, provides 110. The chiral auxiliary is recovered at this stage. Product 110 is a potential precursor of all kinds of monosaccharides and analogs, including 1-deoxynojirimycin (Scheme 13.43) [85]. 

Another explanation takes into account that boat- and twist-shaped six-membered, closed transition states can successfully compete with the chair model. " Evans et al. pointed out that in a-unsubstituted enolate reactions, missing allyl strain interactions lead to lower selectivity in diastereoselective aldol reactions.Calculations indicate that a twist-boat can easily be formed from the U-configuration of a-unsubstituted enolates. The possible transition state in this case has a geometry like 34 and is favored by the chelating character of the complexation mode for the zinc cation and the outward-pointing substituents of the oxazolidinone moiety. This twist-boat transition state correctly predicts the stereochemical outcome of the reaction. 

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