Aldehydes with lithium enolates

The potential for coordination depends on the oxy substituents.82 Alkoxy substituents are usually chelated, whereas highly hindered silyloxy groups usually do not chelate. Trimethylsiloxy groups are intermediate in chelating ability. The extent of chelation also depends on the Lewis acid. Studies with a-alkoxy and (3-alkoxy aldehydes with lithium enolates found only modest diastereoselectivity.83... 

Derivatives of Evans s oxazolidinones 1.116 and 1.117 have been broadly developed for use in aldol reactions [160, 167, 407, 408], The reactions of aldehydes with lithium enolates are usually poorly stereoselective, but remarkable results have been obtained from boron, tin(II) and titanium enolates. The boron... 

Lewis-acid-promoted alkylations of silylenol ethers and silyl ketene acetals [195] with Co-complexed acetylenic acetals [196] and acetylenic aldehydes [197,198] (Scheme 4-56) also proceed with fair to excellent syn diastereoselectivity, in contrast to the low selectivity reactions of the free acetylenic derivatives [199, 200]. Reactions of the complexed aldehydes with lithium enolates are stereospecific, with (Z)-enolates giving syn selectivity and ( )-enolates anti selectivity [201]. The complementary stereoselectivity of the crossed aldol reactions of free and cobalt-complexed propynals with silyl ketene 0,S-acetals has been elaborated by Hanoaka exclusive syn selectivity is exhibited by the complexes and high anti selectivity is found with pro-... 

Condensation of silylimine of (5)-lactic aldehyde with lithium enolate of t-butyl isovalerate affords the -lactam in 80% chemical yield and in a 97 3 diastereomeric ratio. The mixture was desilylated and treated with lead tetracetate to give, in one step, through a radical fragmentation reaction, the 4-acetoxy derivative as a 1 1 4(R) 4(S) imeric mixture. The lack oi stereospecificity is not easy to rationalize expecially if one considers that the analogous lead tetraacetate induced oxidative decarboxylation is completely trans stereoselective. Both reactions should have the same radical intermediate. However, this lack of stereospecificity is not important for the success of the synthesis since the mixture of diastereoisomers exclusively affords the trans 4-substituted azetidinone by the subsequent Merck procedure (Scheme 9). 

Murai and coworkers reported on operationally simple aldol reactions with lithium enolates generated from carbonylation of silylmethyl lithium species [57]. Upon 1,2-silicon shift, a-silyl acyllithium species can be stereo-selectively converted to (E) lithium enolates that undergo addition to aldehydes to give /3-hydroxy acylsilanes (Scheme 14). 

Diastereoface selection has been investigated in the addition of enolates to a-alkoxy aldehydes (93). In the absence of chelation phenomena, transition states A and B (Scheme 19), with the OR substituent aligned perpendicular to the carbonyl a plane (Rl = OR), are considered (Oc-or c-r transition state R2 Nu steric parameters dictate that predoniinant diastereoface selection from A will occur. In the presence of strongly chelating metals, the cyclic transition states C and D can be invoked (85), and the same R2 Nu control element predicts the opposite diastereoface selection via transition state D (98). The aldol diastereoface selection that has been observed for aldehydes 111 and 112 with lithium enolates 99, 100, and 101 (eqs. [81-84]) (93) can generally be rationalized by a consideration of the Felkin transition states A and B (88) illustrated in Scheme 19, where A is preferred on steric grounds. 

The synthesis of (-t-)-benzoylselenopederic acid (569) (477) (Scheme 71), the left-hand half of pederin (147), began with (-f-)-3-keto imide 570, which was subjected to the recently developed syn-directing Zn(BH4)2 reduction (482) to give 5yn-a-methyl-3-hydroxy acid derivative 571. Imide 571, after protection of the hydroxyl group as the THP ether, was reduced with DIBAH, and the resulting aldehyde was treated with lithium enolate of tm-butyl acetate to give the p-... 

Under conditions of kinetic control, the mixed Aldol Addition can be used to prepare adducts that are otherwise difficult to obtain selectively. This process begins with the irreversible generation of the kinetic enolate, e.g. by employing a sterically hindered lithium amide base such as LDA (lithium diisopropylamide). With an unsymmetrically substituted ketone, such a non-nucleophilic, sterically-demanding, strong base will abstract a proton from the least hindered side. Proton transfer is avoided with lithium enolates at low temperatures in ethereal solvents, so that addition of a second carbonyl partner (ketone or aldehyde) will produce the desired aldol... 

The (E) 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 borinates,and with lithium enolates at —78°C. ° Enolization accounts for syn-anti isomerization of aldols. ° In another variation, a (3-keto Weinreb amide (see 16-82) reacted with TiCLt and Hiinig s base ( Pr2NEt) and then an aldehyde to give the p-hydroxy ketone. ° ... 

Reminder of the problems with lithium enolates of aldehydes. 

Cerium enolates are generated by the reaction of lithium enolates with anhydrous cerium chloride in THF. The cerium enolates react readily with various aldehydes and ketones at -78 °C (Scheme 24). The yields are generally higher than in reactions of lithium enolates. This is presumably due tt> the relative stabilities of the adducts, that of the cerium reagent being greater by virtue of coordination to the more oxo lic cerium atom. The stereochemistry of the products is almost the same as in the case of lithium enolates, as shown in Table 4. The reaction is assiuned to proceed through a six-membeied chair-like transition state, as with lithium enolates. 

Oxoalkyl)benzothiazolines (prepared by the reaction of 3-methyl-2-phenylbenzothiazolim fluorosulfate with lithium enolates of ketones) act as enolate-transferring reagents in Lewis acid promoted cross aldol reactions of aldehydes with ketones (Equation (96)) <90BCJ497>. 

We shall discuss further aspects of the aldol reaction in the next two chapters where we shall see how to control the enolisation of unsymmetrical ketones, and how to control the stereochemistry of aldol products such as 121. We shall return to a more comprehensive survey of specific enol equivalents in chapter 10. In this chapter we are concerned to establish that chemoselective enolisation of esters, acids, aldehydes, and symmetrical ketones can be accomplished with lithium enolates, enamines, or silyl enol ethers, and we shall be using all these intermediates extensively in the rest of the book. 

In a recent study of asymmetric conjugate addition, Simon Woodward and co-workers8 required a series of enones 43. Some they made with lithium enolates 41 of ketones or esters 40 added to aldehydes to give the aldols 42 that were dehydrated to the enones 43 with concentrated HC1. 

Additions to chiral aldehydes in which the stereocenter ligands are H, methyl and alkoxy are also relatively common. With lithium enolates, these aldehydes show diastereofacial preferences that suggest that the major product does not involve addition to an intermediate chelate (vide supra). However, dia-stereomer ratios are often rather low. For example, in equation (112) the diastereofacial preference with reagent (27) is 65 35,and that with reagent (33) is 78 22. °... 

The use of lanthanide metal enolates in the aldol reaction has, to date, only been developed to a synthetically useful level in the case of cerium (Scheme S and Table 7). Stereoselectivities are no better than those of lithium enolates, but the cerium enolates of ketones woik well in crossed aldol additions to ketones (Table 7, entries 1-7) and sterically hindered aldehydes (Table 7, entries 9 and 10). Such crossed aldol reactions do not often work well with lithium enolates as enolate equilibration, retroaldolization and steric retardation of addition occur. Imamoto et al. have shown that cerium enolates (44), formed from anhydrous CeCb (1.2 equiv.) and the preformed lithium enolates of ketones in THF at -78 C, undergo such aldol reactions to give the corresponding p-hydroxy ketones (46), usually in high yield. The cerium suppresses the retroaldol reaction by efficient chelation of the aldolate (45). A similar effect is known for zinc halide mediated aldol reactions (Volume 2, (Chapter 1.8). The stereoselectivity of the... 

Scheme 2.8 Enantioselective aldol reaction of aldehydes with trimethoxysilyl enol ethers with the use of chiral lithium(i) binaphtholate.

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)... 

The lithium enolate of the 2(5//)-furanone 58 reacted with aldehydes to give a mixture of the y-adducts 154 and 155 together with the a-adduct 156, typically in a 1 1 6 ratio (Scheme 45) however, no significant selectivity was achieved (87TL985). 

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 ... 

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