Enolates in aldol reactions

More impressive and more important is the performance of these lithium enolates in aldol reactions. Ester enolates are awkward things to use in reactions with enolisable aldehydes and ketones because of the very efficient self-condensation of the aldehydes and ketones. The traditional solutions involve such devices as Knoevenagel-style reactions with malonates.11 Lithium enolates of esters, e.g. 76, react cleanly with enolisable aldehydes and ketones to give high yields of aldols,12 e.g. 79 in a single step also involving a six-membered cyclic transition state 77. 

A "heterocyclic" strategy used an oxazolidone ring as a protected carboxyl (an amide) which also served as a chiral auxiliary. Treatment of 6.127 with a boron triflate, for example, gave boron enolate reagent 6.128 in situ, and it reacted with N-Boc leucinal to form 6.129. Boron enolates have been used in many syntheses as an alternative to lithium or sodium enolate in Aldol reactions.S7 Hydrogcnolysis of the methylthio moiety gave a methylene moiety and treatment of the amide auxiliary with base gave 6.95 (24% overall yield). 

Tin and Lead.—A series of papers by Mukaiyama and co-workers has appeared further describing the use of tin enolates in aldol reactions, in which a common feature is the ryMro-selectivity reported for the products. The enolates are prepared using either stannous triflate "" or activated metallic tin, - and in the stannous triflate example depicted in Scheme 21 high enantioselectivity is... 

Scheme 4.34 Selection of chiral ketones used as enolates in aldol reactions.

Chiral Metal Enolates in Aldol Reaction A general overview on common acetate aldol reaction using chiral metal enolates is given in Scheme 2.115. Both Masamune [18] and Corey [19] in their acetate aldol reaction use C2-symmetric boron complexes and as the acetate building block thio esters. Transformations with aldehydes usually provide enantiomeric ratios between 92 8 and 96 4 in good yields. More commonly used nowadays are Paterson s, Duthaler s, and Braun s acetate strategies. 

Still s synthesis of monensin (1) is based on the assembly and union of three advanced, optically active intermediates 2, 7, and 8. It was anticipated that substrate-stereocontrolled processes could secure vicinal stereochemical relationships and that the coupling of the above intermediates would establish remote stereorelationships. Scheme 3 describes Still s synthesis of the left wing of monensin, intermediate 2. This construction commences with an aldol reaction between the (Z) magnesium bromide enolate derived from 2-methyl-2-trimethylsilyloxy-3-pentanone (21) and benzyloxymethyl-protected (/ )-/ -hydroxyisobutyraldehyde (10).2° The use of intermediate 21 in aldol reactions was first reported by Heathcock21 and, in this particular application, a 5 1 mixture of syn aldol diastereoisomers is formed in favor of the desired aldol adduct 22 (85% yield). The action of lithium diisopropylamide (LDA) and magnesium(n) bromide on 21 affords a (Z) magnesium enolate that... 

From these and many related examples the following generalizations can be made about kinetic stereoselection in aldol additions of lithium enolates. (1) The chair TS model provides a basis for analyzing the stereoselectivity observed in aldol reactions of ketone enolates having one bulky substituent. The preference is Z-enolate syn aldol /(-enolate anti aldol. (2) When the enolate has no bulky substituent, stereoselectivity is low. (3) Z-Enolates are more stereoselective than /(-enolates. Table 2.1 gives some illustrative data. 

Tin enolates are also used in aldol reactions.27 Both the Sn(II) and Sn(IV) oxidation states are reactive. Tin(II) enolates can be generated from ketones and Sn(II)(03SCF3)2 in the presence of tertiary amines.28 The subsequent aldol addition is syn selective and independent of enolate configuration.29 This preference arises from avoidance of gauche interaction of the aldehyde group and the enolate P-substituent. The syn stereoselectivity indicates that reaction occurs through an open TS. 

Summary of the Relationship between Diastereoselectivity and the Transition Structure. In this section we considered simple diastereoselection in aldol reactions of ketone enolates. Numerous observations on the reactions of enolates of ketones and related compounds are consistent with the general concept of a chairlike TS.35 These reactions show a consistent E - anti Z - syn relationship. Noncyclic TSs have more variable diastereoselectivity. The prediction or interpretation of the specific ratio of syn and anti product from any given reaction requires assessment of several variables (1) What is the stereochemical composition of the enolate (2) Does the Lewis acid promote tight coordination with both the carbonyl and enolate oxygen atoms and thereby favor a cyclic TS (3) Does the TS have a chairlike conformation (4) Are there additional Lewis base coordination sites in either reactant that can lead to reaction through a chelated TS Another factor comes into play if either the aldehyde or the enolate, or both, are chiral. In that case, facial selectivity becomes an issue and this is considered in Section 2.1.5. 

Lewis-Acid Catalyzed. Recently, various Lewis acids have been examined as catalyst for the aldol reaction. In the presence of complexes of zinc with aminoesters or aminoalcohols, the dehydration can be avoided and the aldol addition becomes essentially quantitative (Eq. 8.97).245 A microporous coordination polymer obtained by treating anthracene- is (resorcinol) with La(0/Pr)3 possesses catalytic activity for ketone enolization and aldol reactions in pure water at neutral pH.246 The La network is stable against hydrolysis and maintains microporosity and reversible substrate binding that mimicked an enzyme. Zn complexes of proline, lysine, and arginine were found to be efficient catalysts for the aldol addition of p-nitrobenzaldehyde and acetone in an aqueous medium to give quantitative yields and the enantiomeric excesses were up to 56% with 5 mol% of the catalysts at room temperature.247... 

Sc(OTf)3 is an effective catalyst in aldol reactions of silyl enol ethers with aldehydes.49 Compared with other typical rare-earth-metal (Y, Yb) trifiates, Sc(OTf)3 has the strongest activity in the reaction of 1-trimethylsiloxycyclohexane with benzaldehyde in dichloromethane. Although the reaction scarcely proceeded at —78°C in the presence of Y(OTf)3 or Yb(OTf)3, the aldol adduct was obtained in 81% yield in the presence of Sc(OTf)3 (Scheme 9). 

Sc(OTf)3 is effective in aldol reactions in aqueous media (water-THF, Scheme 15).49 Direct treatment of aqueous solutions of water-soluble formaldehyde and chloroacetaldehyde with silyl enol ethers affords the corresponding aldol adducts in good yields. Water-sensitive silicon enolates can be used in aqueous solutions in the presence of a catalytic amount of Sc(OTf)3. 

In aldol reactions, especially Mukaiyama aldol reactions, TiIV compounds are widely employed as efficient promoters. The reactions of aldehydes or ketones with reactive enolates, such as silyl enol ethers derived from ketones, proceed smoothly to afford /3-hydroxycarbonyl compounds in the presence of a stoichiometric amount of TiCl4 (Scheme 17).6, 66 Many examples have been reported in addition to silyl enol ethers derived from ketones, ketene silyl acetals derived from ester derivatives and vinyl ethers can also serve as enolate components.67-69... 

In boron enolate-mediated aldol reactions, stoichiometric amounts of boron reagents are necessary. However, it has been reported that only a catalytic amount of a boron source is sufficient for boron enolate-mediated aldol reactions in water (Scheme 65).302 It should be noted that even water-sensitive boron enolates can be successfully employed in water. 

In order to gain more insight into this proposed mechanism, Montgomery and co-workers tried to isolate the intermediate metallacycle. This effort has also led to the development of a new [2 + 2 + 2]-reaction.226 It has been found that the presence of bipyridine (bpy) or tetramethylethylenediamine (TMEDA) makes the isolation of the desired metallacycles possible, and these metallacycles are characterized by X-ray analysis (Scheme 56).227 Besides important mechanistic implications for enyne isomerizations or intramolecular [4 + 2]-cycloadditions,228 the TMEDA-stabilized seven-membered nickel enolates 224 have been further trapped in aldol reactions, opening an access to complex polycyclic compounds and notably triquinanes. Thus, up to three rings can be generated in the intramolecular version of the reaction, for example, spirocycle 223 was obtained in 49% yield as a single diastereomer from dialdehyde 222 (Scheme 56).229... 

Titanium enolates54 are widely used in aldol reactions and this research area has been reviewed until 2003.55 Thus, examples described in this chapter cover the literature since 2003. Recently, Mikami and co-workers reported the direct generation of titanium enolate 68 of an a-trifluoromethyl ketone56 for a high-yielding and zz /z -diastereose-lective aldol reaction (Scheme 25).57 The aldol reaction proceeded more smoothly if titanium(rv) isopropoxide was added as Lewis acid. On the other hand, low yield and moderate //-selectivity were obtained if HMPA was used instead of the titanium(rv) Lewis acid. 

Double asymmetric induction (See section 1.5.3) can also be employed in aldol reactions. When chiral aldehyde 15 is treated with achiral boron-mediated enolate 14, a mixture of diastereomers is obtained in a ratio of 1.75 1. However, when the same aldehyde 15 is allowed to react with enolates derived from Evans auxiliary 8, a syn-aldol product 16 is obtained with very high stereo-... 

As with the above pyrrolidine, proline-type chiral auxiliaries also show different behaviors toward zirconium or lithium enolate mediated aldol reactions. Evans found that lithium enolates derived from prolinol amides exhibit excellent diastereofacial selectivities in alkylation reactions (see Section 2.2.32), while the lithium enolates of proline amides are unsuccessful in aldol condensations. Effective chiral reagents were zirconium enolates, which can be obtained from the corresponding lithium enolates via metal exchange with Cp2ZrCl2. For example, excellent levels of asymmetric induction in the aldol process with synj anti selectivity of 96-98% and diastereofacial selectivity of 50-200 116a can be achieved in the Zr-enolate-mediated aldol reaction (see Scheme 3-10). 

As the t-butyl group can readily be removed upon acidic or basic hydrolysis, this method can also be used for //-hydroxyl acid synthesis. In analogy with allylation reactions, the enolate added preferentially to the Re-face of the aldehydes in aldol reactions. Titanium enolate 66 tolerates elevated temperatures, while the enantioselectivity of the reaction is almost temperature independent. The reaction can be carried out even at room temperature without significant loss of stereoselectivity. We can thus conclude that this reaction has the following notable advantages High enantiomeric excess can be obtained (ee > 90%) the reaction can be carried out at relatively high temperature the chiral auxiliary is readily available and the chiral auxiliary can easily be recovered.44... 

Besides the silyl enolate-mediated aldol reactions, organotin(IY) enolates are also versatile nucleophiles toward various aldehydes in the absence or presence of Lewis acid.60 However, this reaction requires a stoichiometric amount of the toxic trialkyl tin compound, which may limit its application. Yanagisawa et al.61 found that in the presence of one equivalent of methanol, the aldol reaction of an aldehyde with a cyclohexenol trichloroacetate proceeds readily at 20°C, providing the aldol product with more than 70% yield. They thus carried out the asymmetric version of this reaction using a BINAP silver(I) complex as chiral catalyst (Scheme 3-34). As shown in Table 3-8, the Sn(IY)-mediated aldol reaction results in a good diastereoselectivity (,anti/syn ratio) and also high enantioselectivity for the major component. 

Lewis acids as water-stable catalysts have been developed. Metal salts, such as rare earth metal triflates, can be used in aldol reactions of aldehydes with silyl enolates in aqueous media. These salts can be recovered after the reactions and reused. Furthermore, surfactant-aided Lewis acid catalysis, which can be used for aldol reactions in water without using any organic solvents, has been also developed. These reaction systems have been applied successfully to catalytic asymmetric aldol reactions in aqueous media. In addition, the surfactant-aided Lewis acid catalysis for Mannich-type reactions in water has been disclosed. These investigations are expected to contribute to the decrease of the use of harmful organic solvents in chemical processes, leading to environmentally friendly green chemistry. 

On the other hand, Ln(OTf)3 compounds, which were found to be effective catalysts for the hydroxy-methylation in aqueous media, also activate aldehydes other than formaldehyde in aldol reactions with silyl enol ethers in aqueous solvents.1121 One feature of the present reactions is that water-soluble... 

The nonracemic 2/7-1,3-benzoxazin-4(3//)-one 202 was successfully applied as a chiral auxiliary in asymmetric transformations the titanium enolate-mediated aldol reactions of its A-acyl derivatives provided the products in high yields and with excellent diastereoselectivity <1996SL455, 1996TL5565>. 

The chelation between a Boc group and Mg(II) is often used to control the stereochemistry in aldol reactions. For instance, Donohoe and House have reported the diasteroselec-tive reductive aldol reactions of Boc-protected electron-deficient pyrroles. The key step of the synthesis is the preparation of an exocyclic magnesium enolate of Boc-protected 2-substituted pyrroles. ... 

Transfer of chirality in aldol reactions has been attempted using / -allenyl ester enolates. These ambident nucleophiles have an axis of chirality, and such compounds have been less utilized in stereoselective reactions. They are prepared by transmetallation of the... 

Conseqnently, the magnesinm chelate 71 can also react as a nucleophilic donor in aldol reactions. In the chemistry involving magnesium chelates, these two aspects model their mode of action as nucleophilic partners in aldol condensations. This is exemplified in aldol condensations of y-diketones . Thus, sodium hydroxyde catalyzed cyclization of diketone 73 to give a mixtnre of 3,5,5-trimethyl-cyclopent-2-enone 74 and 3,4,4-trimethyl-cyclopent-2-enone 75 in a 2.2/1 isomeric ratio (equation 100). When treated with magnesinm methanolate, the insertion of a a-methoxy carbonyl group as control element, as in 76, allows the formation of a chelated magnesium enolate 77, and the major prodnct is now mainly the aldol 78. This latter treated with aqueous NaOH provides the trimethylcyclopent-2-enones 74 and 75 in a 1/49 ratio. 

In contrast to titanium enolates of ketones, titanium enolates of aldehydes exhibit practically no stereoselectivity in aldol reactions. However, titanation of dimethylhy-drazones of aldehydes with 1 results in substrates (2) that show high eryt/iro-selecti v i ty in aldol-type reactions with aldehydes (equation I). Bromotitanium tris(diethylamide) can be used in place of 1, but is less efficient, as is Ti(IV) isopropoxide.6... 

Triethylgallium has been used as a non-nucleophilic base to generate enolates from ketones, both cyclic and acyclic, without forming carbonyl addition products.290 The gallium enolates can then be C-benzoylated, and can participate in aldol reactions. Unsymmetrical ketones preferentially enolized at the methylene, under kinetic control. 

Evidence for chair-like transition states in aldol reactions of methyl ketone lithium enolates has been obtained from deuterium-labelled enolates.121... 

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