Lithium enolates directed aldol reaction

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 ... 

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... 

Asymmetric induction is another important aspect of the directed aldol reaction. The approach involves the use of a chiral aldehyde which influences the stereochemistry of the addition reaction. Reaction of a chiral phenylpropanaldehyde with a lithium enolate yields only two of the possible diastereoisomers in the ratio of 86 14 (equation 76).377... 

Triphenylsilyl ethers are similar in lability to TMS ethers toward basic hydrolysis but they are about 400 times more stable than TMS ethers towards acid hydrolysis. A triphenylsilyl ether group played an important strategic role in the finale of a synthesis of the polyether antibiotic Lonomycin A [Scheme 4.96],154 Model studies of the directed aldol reaction by which the lithium enolate 96.1... 

Table 2. Products of the Directed Aldol Reaction of the Lithium Enolate of Ethyl Fluoroacetate...

The chemistry of alkali enolates is subject of a number of extensive reviews [5-13]. The stereochemistry of directed aldol reactions with lithium enolates is discussed in the review of Mukaiyama [5]. 

A number of methods have been developed to bring about the directed aldol reaction between two different carbonyl compounds to give a mixed-aldol product. Most of them proceed from the preformed enolate or silyl enol ether of one of the components. With enolates, a number of metal counterions have been used and the best results have been obtained with lithium or boron enolates, although zinc or transition-metal enolates have found widespread use. For example, the aldol reaction of acetone with acetaldehyde under basic aqueous conditions is inefficient... 

One of the most effective and versatile ways to bring about a crossed aldol reaction is to use a lithium enolate obtained from a ketone as one component and an aldehyde or ketone as the other. An example of this approach, called a directed aldol reaction, is shown by the following mechanism. 

Directed Aldol Reactions via Lithium Enolates (Section 19.5B)... 

Crossed Aldol Condensations Using Strong Bases Lithium Enolates and Directed Aldol Reactions... 

Regioselectivity can be achieved when unsymmetrical ketones are used in directed aldol reactions by generating the kinetic enolate using lithium diisopropylamide (LDA). This ensures production of the enolate in which the proton has been removed from the less substituted a carbon. The following is an example ... 

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. 

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... 

More traditional carbon nucleophiles can also be used for an alkylative ring-opening strategy, as exemplified by the titanium tetrachloride promoted reaction of trimethylsilyl enol ethers (82) with ethylene oxide, a protocol which provides aldol products (84) in moderate to good yields <00TL763>. While typical lithium enolates of esters and ketones do not react directly with epoxides, aluminum ester enolates (e.g., 86) can be used quite effectively. This methodology is the subject of a recent review <00T1149>. 

Traditional models for diastereoface selectivity were first advanced by Cram and later by Felkin for predicting the stereochemical outcome of aldol reactions occurring between an enolate and a chiral aldehyde. [37] During our investigations directed toward a practical synthesis of dEpoB, we were pleased to discover an unanticipated bias in the relative diastereoface selectivity observed in the aldol condensation between the Z-lithium enolate B and aldehyde C, Scheme 2.6. The aldol reaction proceeds with the expected simple diastereoselectivity with the major product displaying the C6-C7 syn relationship shown in Scheme 2.7 (by ul addition) however, the C7-C8 relationship of the principal product was anti (by Ik addition). [38] Thus, the observed symanti relationship between C6-C7 C7-C8 in the aldol reaction between the Z-lithium enolate of 62 and aldehyde 63 was wholly unanticipated. These fortuitous results prompted us to investigate the cause for this unanticipated but fortunate occurrence. 

One difference between this method and the malonate method is that lithium enolates add direct to the carbonyl group of enals 76 while malonates do conjugate addition. Further, malonate adducts such as 62 normally dehydrate under the reaction conditions while lithium enolates normally give the aldol product 77 without dehydration. 

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