Enol derivatives, stereoselective reactions

The Michael reaction is of central importance here. This reaction is a vinylogous aldol addition, and most facts, which have been discussed in section 1.10, also apply here the reaction is catalyzed by acids and by bases, and it may be made regioselective by the choice of appropriate enol derivatives. Stereoselectivity is also observed in reactions with cyclic educts. An important difference to the aldol addition is, that the Michael addition is usually less prone to sterical hindrance. This is evidenced by the two examples given below, in which cyclic 1,3-diketones add to o, -unsaturated carbonyl compounds (K. Hiroi, 1975 H, Smith, 1964). 

When an enolate is forced to take the E configuration, e.g, the enolate derived from cyclohexanone, predominant formation of the anti-aldol might be expected. Surprisingly, early experiments gave more or less stereorandom results in that the reaction with benzaldehyde gave a ratio of. vvtt/ant/ -aldols of 48 521B 23, Contrarily, recent investigations24 reveal a substantial anti selectivity (16 84), which is lowered in a dramatic manner (50 50) by the presence of lithium salts. Thus, the low stereoselectivity in the early experiments may be attributed to impurities of lithium salts or lithium hydroxide. 

The reactions with preformed enol derivatives provide a way to control the stereoselectivity of the aldol reaction. As with the Michael reaction (15-16), the aldol reaction creates two new chiral centers, and, in the most general case, there are four stereoisomers of the aldol product, which can be represented as... 

Among the preformed enol derivatives used in this way have been enolates of magnesium, lithium, titanium, zirconium, and tin, ° silyl enol ethers, enol borinates,and enol borates, R CH=CR"—OB(OR)2. The nucleophilicity of silyl enol ethers has been examined. In general, metallic Z enolates give the syn (or erythro) pair, and this reaction is highly useful for the diastereoselective synthesis of these products. The ( ) isomers generally react nonstereoselectively. However, anti (or threo) stereoselectivity has been achieved in a number of cases, with titanium enolates, with magnesium enolates, with certain enol bor-inates, and with lithium enolates at — 78°C. ... 

Among the most useful carbonyl derivatives are (V-acyloxazolidinones, and as we shall see in Section 2.3.4, they provide facial selectivity in aldol addition reactions. l,3-Thiazoline-2-thiones constitute another useful type of chiral auxiliary, and they can be used in conjunction with Bu2B03SCF3,44 Sn(03SCF3)2,45 or TiCl446 for generation of enolates. The stereoselectivity of the reactions is consistent with formation of a Z-enolate and reaction through a cyclic TS. 

A very short and efficient synthesis based on the desymmetrization principle is shown in Scheme 13.39. mc.vo-2,4-Dimethylglularaldchyde reacted selectively with the diethylboron enolate derived from a bornanesultam chiral auxiliary. This reaction established the stereochemistry at the C(2) and C(3) centers. The dominant aldol product results from an anti-Felkin stereoselectivity with respect to the C(4) center. 

Table 2-5 summarizes the results of the asymmetric alkylation (Scheme 2-17) of the lithium enolates derived from 22 or 23.28 When chiral auxiliary 22 or 23 is involved in the alkylation reactions, the substituent at C-4 of the oxazolidine ring determines the stereoselectivity and therefore controls the stereogenic outcome of the alkylation reaction. 

The general trend then is that boron enolates parallel lithium enolates in their stereoselectivity but show enhanced stereoselectivity. They also have the advantage of providing access to both stereoisomeric enol derivatives. Table 2.3 gives a compilation of some of the data on stereoselectivity of aldol reactions with boron enolates. 

The synthesis in Scheme 13.30 uses stereoselective aldol condensation methodology. Both the lithium enolate and the boron enolate method were employed. The enol derivatives were used in enantiomerically pure form, so the condensations are examples of double stereodifferentiation (Section 2.1.3). The stereoselectivity observed in the reactions is that predicted for a cyclic transition state for the aldol condensations. 

Recently, Nakamura and coworkers described a related reaction of the zinc enolates derived from /3-aminocrotonamides of type 395256. In the presence of a stoichiometric amount of Et2Zn, the latter underwent smooth addition to terminal alkynes upon heating in hexane and afforded the corresponding tetrasubstituted 2-alkylidene acetoacetamides 396 (after acidic hydrolysis of the imine) with high (Z)-stereoselectivity (equation 173). 

A mechanism for this reaction was tentatively proposed by the authors based on deuterium labeling experiments. The carbometallation reaction could also be performed, albeit with decreased stereoselectivity ((E)/(Z) = 1/1), using the combination of a stoichiometric amount of Zn(OTf)2 or In(OTf)3 and triethylamine, but no addition was observed for the lithium or magnesium enolates derived from 395. 

The addition of acetate-derived, achiral lithium enolates to monoprotected a-amino aldehydes is controlled by chelation, and leads to a modest stereochemical preference in favor of the 3,4-syn configuration (Table 1, entry a). 18 The formation of the 3, A-syn-product is enhanced by the use of acetate-derived silyl ketene acetals and the addition of titanium(IV) chloride or tin(IV) chloride to the reaction mixture (Table 1, entries b and c). 22-23 The same enolates add stereoselectively to A2 A-dibenzyl a-amino aldehydes but with diastereomeric ratios in favor of the Felkin-Ahn 3,4-anti-product (Table 1, compare entries a and d, and b and f). 22-24 Reverse stereocontrol is observed in the presence of a Lewis acid such as tita-nium(IV) chloride, but the yield is low (Table 1, entry e). 24 ... 

Highly stereoselective aldol reactions of lithium ester enolates (LiCR1 R2CC>2R3) with (/0-2-(/ -tolylsulfiny I (cyclohexanone have been attributed to intermediacy of tricoordinate lithium species which involve the enolate and the sulfinyl and carbonyl oxygens of the substrates.43 The O-metallated /<-hydroxyalkanoatcs formed by aldol-type reaction of carbonyl compounds with enolates derived from esters of alkanoic acids undergo spontaneous intramolecular cyclization to /1-lactones if phenyl rather than alkyl esters are used the reaction has also been found to occur with other activated derivatives of carboxylic acids.44... 

If the boron enolate derived from (/ )-mandelic acid is used in Equation B5.6 then a reversal of selectivity to 2R,3S 2S,3R — 1 28 is anticipated. Thus, on combination of the (/ )-boron enolate with (-)-dimethylglutaric hemialdehyde, the stereochemical preferences of the two reagents work against each other (they are said to be mismatched ) and relatively low stereoselectivity is observed. The stereochemistry of the major diastereoisomer is that produced by the partner with the strongest control over the reaction (Equation B5.8). 

A number of methods have been developed for accomplishing aldol addition reactions in a stereoselective manner. The preformed lithium enolates of alkyl esters normally react with aldehydes to give mixtures of the two diastereomeric g-hydroxy esters (eq 1). However, the enolates derived from... 

E -Enolates often react with lower stereoselectivity than those of the corresponding Z-enolates. A classic example to illustrate this point is a study carried out by Heathcock et al.6 (Scheme 2.IV). When the carbonyl compounds 1 were deprotonated with lithium diisopropylamide (LDA) and the resulting enolates were subsequently treated with benzaldehyde at -72° C, the aldol products desired (2) were obtained in 83 to 99% yield. The Z-enolates derived from t -butyl and 1-adamantyl ethyl ketones afforded syn -products in excellent levels of diastereoselectivity. The fact that the syn/anti ratios directly reflect the isomeric purity of the reacting enolates hints that the Z-enolates in these cases undergo aldol reaction through a chairlike six-membered transition state (Scheme 2.III,... 

The stereochemical course of several Co2(CO)6-mediated reactions has been studied. For example, although alkynyl aldehydes undergo crossed aldol condensation with trimethylsilyl enol ethers with little stereoselectivity, their hexacarbonyldicobalt derivatives react with moderate to excellent syn diastereoselectivity.96 101 The mechanism behind this selectivity has not been fully elucidated and is complicated by the lluxional nature of the intermediate cations. This stereoselective reaction has been successfully applied to the synthesis of /3-lactam antibiotics.100... 

Intermediate samarium enolates derived from ketones 1522 or 1525 could stereoselectively be trapped with allyl halides, leading to tricycles 1524 and 1526. The intramolecular alkylation by the chloroalkyl terminus of compound 1527 led to tetracyclic compound 1528 with satisfactory efficiency. These cascade reactions selectively generate three continuous stereogenic centers, including a quaternary carbon atom at the 3-position of the dihydroindole moiety, a structural motif of many indole alkaloids. 

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 same research group has recently reported that the oxidative homocoupling of chiral aroylacetic acid derivatives proceeds stereoselectively when the sodium enolate derived from 38 is oxidized with bromine (equation 21). Good stereoselectivity was also observed in the oxidative homo- and heterocoupUng reactions of the lithium eno-lates of chiral 3-phenylpropionamides with iodine, copper(II) pentanoate and ferrocenium hexafluorophosphate. ... 

In recent organic synthesis, stereoselective aldol condensations has been performed under two different conditions. Under the influence of acid, stabilized enol derivatives, enolsilanes (M = SiMe3), can condense with aldehydes or acetals in a stereoselective fashion [Eq. (12)]. In this reaction the role of the acid is to activate aldehydes or acetals. Alternatively, under basic conditions, the same process can be carried out directly with aldehydes and reactive, preformed metal enolates (M = Li, MgL, ZnL, AIL2, BL2, etc.) of defined geometry. 

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