Lithium enolates aldol reactions

Asymmetric Aldol Reactions. Lithium enolates, derived from an ester, and LDA react with aldehydes enantioselectively in the presence of the chiral amide 2 (eq 3). When benzaldehyde is employed, the major diastereomer is the anrt-aldol with 94% ee, while the minor yn-aldol is only 43% ee. In this reaction, the lithium amide 2 coordinates to an additional lithium atom. There are four additional examples of aldehydes with the same ester enolate. 

Aldol reactions. Lithium enolates of BINOL esters react with carbonyl compounds in an anfi-selective fashion. One method for the preparation of such BINOL esters is by reaction of the dibutyltin BINOLate with acid chlorides. ... 

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. 

Introduction and stereochemical control syn,anti and E,Z Relationship between enolate geometry and aldol stereochemistry The Zimmerman-Traxler transition state Anti-selective aldols of lithium enolates of hindered aryl esters Syn-selective aldols of boron enolates of PhS-esters Stereochemistry of aldols from enols and enolates of ketones Silyl enol ethers and the open transition state Syn selective aldols with zirconium enolates The synthesis of enones E,Z selectivity in enone formation from aldols Recent developments in stereoselective aldol reactions Stereoselectivity outside the Aldol Relationship A Synthesis ofJuvabione A Note on Stereochemical Nomenclature... 

Aldol reaction. Zirconium enolates are employed in conducting aldol reactions of amides derived from (+)-pseudoephedrine. These species are prepared from the corresponding lithium enolates on addition of CpaZrCla. 

Example 4.3 This example demonstrates a notable difference in stereoselectivity between alkylation and aldol reactions of enolates derived from chiral oxazolidi-nones. Lithium enolates of oxazolines 27 and 28 proved exceptionally efiicient in the control of the stereoselectivity of alkylation (Sect. 3.7.3, Schemes 3.12 and 3.13 ) but react with low stereoselectivity in aldol reactions. Instead, high stereochemical control of aldol reactions is achieved with boronic enolates of chiral oxazolidinones 9-13 (Scheme 4.11). 

Stereoselectivities of 99% are also obtained by Mukaiyama type aldol reactions (cf. p. 58) of the titanium enolate of Masamune s chired a-silyloxy ketone with aldehydes. An excess of titanium reagent (s 2 mol) must be used to prevent interference by the lithium salt formed, when the titanium enolate is generated via the lithium enolate (C. Siegel, 1989). The mechanism and the stereochemistry are the same as with the boron enolate. 

In contrast, fluorinated ketones have been used as both nucleophilic and electrophilic reaction constituents The (Z)-lithium enolate of 1 fluoro 3,3-di-methylbutanone can be selectively prepared and undergoes highly diastereoselec-tive aldol condensations with aldehydes [7] (equation 8) (Table 4)... 

Table 4. Directed Aldol Reaction of Lithium Enolate of l-Fluoro-3,3-dimethylbutanone [7]...

In general the reaction of an aldehyde with a ketone is synthetically useful. Even if both reactants can form an enol, the a-carbon of the ketone usually adds to the carbonyl group of the aldehyde. The opposite case—the addition of the a-carbon of an aldehyde to the carbonyl group of a ketone—can be achieved by the directed aldol reaction The general procedure is to convert one reactant into a preformed enol derivative or a related species, prior to the intended aldol reaction. For instance, an aldehyde may be converted into an aldimine 7, which can be deprotonated by lithium diisopropylamide (EDA) and then add to the carbonyl group of a ketone ... 

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... 

Transmetalation of lithium enolate 1 a (M = Li ) by treatment with tin(II) chloride at — 42 °C generates the tin enolate that reacts with prostereogenic aldehydes at — 78 °C to preferentially produce the opposite aldol diastereomer 3. Diastereoselectivities of this process may be as high as 97 3. This reaction appears to require less exacting conditions since similar results are obtained if one or two equivalents of tin(ll) chloride arc used. The somewhat less reactive tin enolate requires a temperature of —42 C for the reaction to proceed at an acceptable rate. The steric requirements of the tin chloride counterion are probably less than those of the diethyla-luminum ion (vide supra), which has led to the suggestion26 44 that the chair-like transition state I is preferentially adopted26 44. This is consistent with the observed diastereoselective production of aldol product 3, which is of opposite configuration at the / -carbon to the major product obtained from aluminum enolates. 

A powerful variation of the iron acetyl enolate aldol reaction utilizes the cnolate of complex 8 which bears a (pentafluorophenyl)diphenylphosphane ligand in place of the more usual triphenylphosphane47. The enolate species 9. prepared by treatment of 8 with lithium diiso-propylamide, reacts at — 78 °C with benzaldehyde to produce the aldol adduct 10 with a d.r. of 98.5 1.5. 

The lithium enolate 2a (M = Li ) prepared from the iron propanoyl complex 1 reacts with symmetrical ketones to produce the diastercomers 3 and 4 with moderate selectivity for diastereomer 3. The yields of the aldol adducts are poor deprotonation of the substrate ketone is reported to be the dominant reaction pathway45. However, transmetalation of the lithium enolate 2a by treatment with one equivalent of copper cyanide at —40 C generates the copper enolate 2b (M = Cu ) which reacts with symmetrical ketones at — 78 °C to selectively produce diastereomer 3 in good yield. Diastereomeric ratios in excess of 92 8 are reported with efficient stereoselection requiring the addition of exactly one equivalent of copper cyanide at the transmetalation step45. Small amounts of triphcnylphosphane, a common trace impurity remaining from the preparation of these iron-acyl complexes, appear to suppress formation of the copper enolate. Thus, the starting iron complex must be carefully purified. 

Conducting the aldol reaction at temperatures below —78 "C increases the diastereoselectivity, but at the cost of reduced yields45. Transmetalation of the lithium enolate 2 a by treatment with diethylaluminum chloride generated an enolate species that provided high yields of aldol products, however, the diastereoselectivity was as low as that of the lithium species45. Pre treatment of the lithium enolate 2a with tin(II) chloride, zinc(II) chloride, or boron trifluoridc suppressed the aldol reaction and the starting iron-acyl complex was recovered. 

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 diastereoselectivity of this reaction contrasts dramatically with the generally low selectiv-ities observed for aldol reactions of lithium enolates of iron acyls. It has been suggested thal this enolate exists as a chelated species48 the major diastereomer produced is consistent with the transition state E which embodies the usual antiperiplanar enolate geometry. 

In contrast, transmetalation of the lithium enolate at —40 C by treatment with one equivalent of copper cyanide generated a species 10b (M = Cu ) that reacted with acetaldehyde to selectively provide a 25 75 mixture of diastereomers 11 and 12 (R = CH3) which are separable by chromatography on alumina. Other diastereomers were not observed. Similar transmetalation of 10a (M = Li0) with excess diethylaluminum chloride, followed by reaction with acetaldehyde, produced a mixture of the same two diastereomers, but with a reversed ratio (80 20). Similar results were obtained upon aldol additions to other aldehydes (see the following table)49. 

Another example of a [4S+1C] cycloaddition process is found in the reaction of alkenylcarbene complexes and lithium enolates derived from alkynyl methyl ketones. In Sect. 2.6.4.9 it was described how, in general, lithium enolates react with alkenylcarbene complexes to produce [3C+2S] cycloadducts. However, when the reaction is performed using lithium enolates derived from alkynyl methyl ketones and the temperature is raised to 65 °C, a new formal [4s+lcj cy-clopentenone derivative is formed [79] (Scheme 38). The mechanism proposed for this transformation supposes the formation of the [3C+2S] cycloadducts as depicted in Scheme 32 (see Sect. 2.6.4.9). This intermediate evolves through a retro-aldol-type reaction followed by an intramolecular Michael addition of the allyllithium to the ynone moiety to give the final cyclopentenone derivatives after hydrolysis. The role of the pentacarbonyltungsten fragment seems to be crucial for the outcome of this reaction, as experiments carried out with isolated intermediates in the absence of tungsten complexes do not afford the [4S+1C] cycloadducts (Scheme 38). 

Alternatively, Cushman has devised a facile route to pyrroles by the reaction of Boc-a-amino aldehydes or ketones 14 with the lithium enolates of ketones 15 to afford aldol intermediates 16 which cyclize to pyrroles 17 under mild acidic conditions <96JOC4999>. This method offers several advantages over the Knorr since it employs readily available Boc-a-amino aldehydes or ketones and utilizes simple ketones instead of the p-diketo compounds or p-keto esters normally used in the Knorr. 

Aldol Reactions of Lithium Enolates. Entries 1 to 4 in Scheme 2.1 represent cases in which the nucleophilic component is a lithium enolate formed by kinetically controlled deprotonation, as discussed in Section 1.1. Lithium enolates are usually highly reactive toward aldehydes and addition occurs rapidly when the aldehyde is added, even at low temperature. The low temperature ensures kinetic control and enhances selectivity. When the addition step is complete, the reaction is stopped by neutralization and the product is isolated. 

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. 

Aldol Reactions of Boron Enolates. The matter of increasing stereoselectivity in the addition step can be addressed by using other reactants. One important version of the aldol reaction involves the use of boron enolates.15 A cyclic TS similar to that for lithium enolates is involved, and the same relationship exists between enolate configuration and product stereochemistry. In general, the stereoselectivity is higher than for lithium enolates. The O-B bond distances are shorter than for lithium enolates, and this leads to a more compact structure for the TS and magnifies the steric interactions that control stereoselectivity. 

Titanium enolates can be prepared from lithium enolates by reaction withatrialkoxy-titanium(IV)chloride,suchasfra-(isopropoxy)titaniumchloride.21 Titanium enolates are usually prepared directly from ketones by reaction with TiCl4 and a tertiary amine.22 Under these conditions, the Z-enolate is formed and the aldol adducts have syn stereochemistry. The addition step proceeds through a cyclic TS assembled around titanium. 

Zirconium enolates can also prepared by reaction of lithium enolates with (Cp)2ZrCl2, and they act as nucleophiles in aldol addition reactions.34... 

The enolates of other carbonyl compounds can be used in mixed aldol reactions. Extensive use has been made of the enolates of esters, thiol esters, amides, and imides, including several that serve as chiral auxiliaries. The methods for formation of these enolates are similar to those for ketones. Lithium, boron, titanium, and tin derivatives have all been widely used. The silyl ethers of ester enolates, which are called silyl ketene acetals, show reactivity that is analogous to silyl enol ethers and are covalent equivalents of ester enolates. The silyl thioketene acetal derivatives of thiol esters are also useful. The reactions of these enolate equivalents are discussed in Section 2.1.4. 

In Step D another thiazoline chiral auxiliary, also derived from cysteine, was used to achieve double stereodifferentiation in an aldol addition. A tin enolate was used. The stereoselectivity of this reaction parallels that of aldol reactions carried out with lithium or boron enolates. After the configuration of all the centers was established, the synthesis proceeded to P-D lactone by functional group modifications. 

In the presence of zinc chloride, stereoselective aldol reactions can be carried out. The aldol reaction with the lithium enolate of /-butyl malonate and various a-alkoxy aldehydes gave anti-l,2-diols in high yields, and 2-trityloxypropanal yielded the syn-l,2-diol under the same conditions.633 Stoichiometric amounts of zinc chloride contribute to the formation of aminoni-tropyridines by direct amination of nitropyridines with methoxyamine under basic conditions.634 Zinc chloride can also be used as a radical initiator.635... 

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