Stereoselectivity chiral enolates

Indeed, the combination of the aldehyde 1 with the (S)-enolate 2 delivers the diastereomers 3a and 3b in excellent selectivity (>100 1, matched pair ). On the other hand, a 1 30 ratio of 4 a/4 b is found in the corresponding reaction of the (2 )-enolate 2. Although the selectivity in the latter case ( mismatched pair ) is distinctly lower, the reliability of this chiral enolate 2 provides a degree of induced stereoselectivity which is sufficient for practical applications ( double diastereodifferentiation )29. The stereochemical outcome is largely determined by the chirality of the enolate in that the (S)-enolate 2 attacks the aldehyde almost exclusively from the Re-face whereas the (/ -enolate adds preferably to the Si-face of the carbonyl group in the aldehyde. 

Double stereodifferentiation This refers to the addition of a chiral enolate or allyl metal reagent to a chiral aldehyde. Enhanced stereoselectivity can be obtained when the aldehyde and reagent exhibit complementary facile preference (matched case). Conversely, diminished results might be observed when their facial preference is opposed (mismatched pair). 

With chiral enol species (/ )-silylketene acetal derived from (1 R,2S)-N-methyl ephedrine-O-propionate, both the aldehyde carbonyl and the ephedrine NMe2 group are expected to bind to TiCU, which usually chelates two electron-donating molecules to form ra-octahedral six-coordinated complexes.25 Conformational freedom is therefore reduced, and the C-C bond formation occurs on the six-coordinated metal in a highly stereoselective manner.18... 

Now, we examine the interaction of chiral aldehyde (-)-96 with chiral enolate (S )-lOOb. This aldol reaction gives 104 and 105 in a ratio of 104 105 > 100 1. Changing the chirality of the enolate reverses the result Compound 104 and 105 are synthesized in a ratio of 1 30 (Scheme 3-38).66 The two reactions (—)-96 + (S )-lOOb and (—)-96 + (7 )-100b are referred to as the matched and mismatched pairs, respectively. Even in the mismatched pair, stereoselectivity is still acceptable for synthetic purposes. Not only is the stereochemical course of the aldol reaction fully under control, but also the power of double asymmetric induction is clearly illustrated. 

If stoichiometric quantities of the chiral auxiliary are used (i.e., if the chiral auxiliary is covalently bonded to the molecule bearing the prochiral centres) there are in principle three possible ways of achieving stereoselection in an aldol adduct i) condensation of a chiral aldehyde with an achiral enolate ii) condensation of an achiral aldehyde with a chiral enolate, and iii) condensation of two chiral components. Whereas Evans [14] adopted the second solution, Masamune studied the "double asymmetric induction" approach [22aj. In this context, the relevant work of Heathcock on "relative stereoselective induction" and the "Cram s rule problem" must be also considered [23]. The use of catalytic amounts of an external chiral auxiliary in order to create a local chiral environment, will not be considered here. 

Diastereomer analysis on the unpurified aldol adduct 52b revealed that the total syn anti diastereoselection was 400 1 whereas enantioselective induction in the syn products was 660 1. On the other hand, Evans in some complementary studies also found that in the condensation of the chiral aldehyde 53 with an achiral enolate 56a only a slight preference was noted for the anti-Cram aldol diastereomer 58a (58a 57a = 64 36). In the analogous condensation of the chiral enolate 56b. however, the yn-stereoselection was approximately the same (57b 58b > 400 1) as that noted for enolate 49 but with the opposite sense of asymmetric induction (Scheme 9.17). Therefore, it can be concluded that enolate chirality transfer in these systems strongly dominates the condensation process with chiral aldehydes. 

Since ketone R)-16 was prepared in a non-selective way when an achiral imino enolate was alkylated, it was considered whether alkylation of chiral enolates, such as that of oxazoline 18, with benzyl bromide 14, would provide stereoselective access to the corresponding alkylation product 19 with R-configuration at C(8) (Scheme 4). Indeed, alkylation of 18 with 14 gave the biaryl 19 and its diastereoisomer almost quantitatively, in a 14 1 ratio. However, reductive hydrolysis using the sequence 1. MeOTf, 2. NaBH4, and 3. H30", afforded hydroxy aldehyde 20 in 25% yield at best. Furthermore, partial epimerization at C(8) occurred (dr 7.7 1). An alternative route, using chiral hydrazones, was even less successful. 

For stereoselective synthesis of a-aminocarbonyl compounds, a number of protocols have been reported using chiral enolates and A-(alkoxycarbonyl)-0-(arenesulfonyl) hydroxylamines. 

Rotation is hindered in the enolate. Thus, if the a-substituent R1 4= R2, the enolate can exist in two forms, the syn- and anti-forms (enolates 2 and 3, respectively, if R2 has higher priority than R1). Attack of an electrophile on either face of the enolates, 2 or 3, leads to a mixture of the alkylated amides, 4 and 5. If R1 and R2 and the A-substituents R3 and R4 are all achiral, the two alkylated amides will be mirror images and thus a racemate results. If, however, any of the R substituents are chiral, enolate 2 will give a certain ratio of alkylated amide 4/5, whereas enolate 3 will give a different, usually inverted, ratio. Thus, for the successful design of stereoselective alkylation reactions of chiral amide enolates it is of prime importance to control the formation of the enolate so that one of the possible syn- or anti-isomers is produced in large excess over the other,... 

S. Masamune, S. A. Ali, D. L. Snitman, and D. S. Garvey, Highly stereoselective aldol condensation using an enantioselective chiral enolate, Angew. Chem. Int. Ed. Engl. 79 557 (1980). 

Stereoselective syntheses of several unnatural amino acids were required to initiate this work. Evans group used asymmetric reactions of chiral enolates to generate these starting materials, as illustrated in the diagram shown below. In this particular example, an isothiocyanate functionality traps the alcohol of an aldol product giving a thiooxazolidinone that provides O- and N-protection in subsequent steps. 

Chiral enolates can be made from compounds with a stereogenic centre 3 to a carbonyl group. Once the carbonyl is deprotonated to form the enolate, the stereogenic centre is next to the double bond and in a position to control the stereoselectivity of its reactions, The scheme below shows stereoselectivity in the reactions of some chiral enolates with methyl iodide. 

In diastereoselective asymmetric oxygenation of chiral enolates the introduction of new stereo-genic centers (chiral a-hydroxy carbonyl structural units) are induced by covalently bonded chiral units that are i) incorporated into the target molecule (substrate-induced diastereosclec-tivity) or ii) removed after the stereoinduction step (auxiliary-induced stereoselectivity). 

The asymmetric hydroxylation of ester enolates with N-sulfonyloxaziridines has been less fully studied. Stereoselectivities are generally modest and less is known about the factors influencing the molecular recognition. For example, (/J)-methyl 2-hydroxy-3-phenylpropionate (10) is prepared in 85.5% ee by oxidizing the lithium enolate of methyl 3-phenylpropionate with (+)-( ) in the presence of HMPA (eq 13). Like esters, the hydroxylation of prochiral amide enolates with N-sulfonyloxaziridines affords the corresponding enantiomerically enriched a-hydroxy amides. Thus treatment of amide (11) with LDA followed by addition of (+)-( ) produces a-hydroxy amide (12) in 60% ee (eq 14). Improved stereoselectivities were achieved using double stereodifferentiation, e.g., the asymmetric oxidation of a chiral enolate. For example, oxidation of the lithium enolate of (13) with (—)-(1) (the matched pair) affords the a-hydroxy amide in 88-91% de (eq 15). (+)-(Camphorsulfonyl)oxaziridine (1) mediated hydroxylation of the enolate dianion of (/J)-(14) at —100 to —78 °C in the presence of 1.6 equiv of LiCl gave an 86 14 mixture of syn/anti-(15) (eq 16). The syn product is an intermediate for the C-13 side chain of taxol. 

Another example of this methodology has appeared recently from Masamune and coworkers in connection with a total synthesis of bryostatin (equation 67). The salient point here is the demonstrated utility of the thiol ester, prepared directly through stereoselective boron enolate aldol condensation. Notice Aat no further activation or removal of a chiral auxiliary is necessary for this transformation, unlike other related aldol methodology. 

Goodman, J. M., Kahn, S. D., Paterson, I. Theoretical studies of aldol stereoselectivity the development of a force field model for enol borinates and the investigation of chiral enolate -face selectivity. J. Org. Chem. 1990, 55, 3295-3303. 

Gennari, C. Rationally designed chiral enol borinates powerful reagents for the stereoselective synthesis of natural products. Pure Appl. Chem. 1997, 69, 507-512. 

Evans, D. A., Bartroli, J. Stereoselective reactions of chiral enolates. Application to the synthesis of (+)-Prelog-Djerassi lactonic acid. Tetrahedron Lett. 1982, 23, 807-810. 

Evans, D. A., Britton, T. C., Dellaria, J. F., Jr. The asymmetric synthesis of a-amino and a-hydrazino acid derivatives via the stereoselective amination of chiral enolates with azodicarboxylate esters. Tetrahedron 1988, 44, 5525-5540. 

New auxiliaries and reaction methods are now available for the stereoselective synthesis of all members of the stereochemical family of propionate aldol additions. These also include improvements on previously reported methods that by insightful modification of the original reaction conditions have led to considerable expansion of the versatility of the process. In addition to novel auxiliary-based systems, there continue to be unexpected observations in diastereoselective aldol addition reactions involving chiral aldehyde/achiral enolate, achiral aldehyde/chir-al enolate, and chiral aldehyde/chiral enolate reaction partners. These stereochemical surpri.ses underscore the underlying complexity of the reaction process and how much we have yet to understand. 

A discussion of approaches to the stereoselective synthesis of 3-(dichlorovinyl)-2,2-dirrethylcyclapraparie carboxylic acid through intramolecular alkylation of an enolate ion is presented. Principles for achieving good control of the relative stereochemistry about the cyclopropane ring will be described. The control of the absolute stereochemistry on the ring was accomplished through the use of a chiral enolate. 

We chose to explore the intramolecular alkylation of amide enolates as a potential stereoselective route to cis pyrethroid cyclopropane carboxylates. If the relationship between the stereoselection in enolate formation and ring closure is operable, amide enolates would be an excellent means of developing a stereoselective synthesis of cis products (8). Furthermore, recent progress in achieving enantioselection in the intermolecular alkylation of chiral amide enolates would provide a means of obtaining optically active pyrethroid acids (Figure 6) (9-13). 

The stereoselection in the cyclization of each diastereomer was examined independently. The stereochemical outcome of the cyclization should be predictable based on our assumption regarding the relationship between enolate stereochemistry and cyclopropane stereochemistry, the principles of asymmetric, intermolecular alkylation of optically active amides (9-13) and the assumption that the mechanism of cyclopropane formation involves a straightforward back-side, %2 reaction. In the case of the major diastereomer, the natural tendency of the enolate to produce the cis-cyclopropane will oppose the facial preference for the alkylation of the chiral enolate. Consequently, poorer stereochemical control would be ejected in the ring closure. In the minor diastereomer these two farces are working in tandem, and high degrees of stereocontrol should result. 

By incorporating a chiral auxiliary, (+ )-rrans-2-(a-cumyl)cyclohexyl (TCC), into pyridinium salt 688, Comins and co-workers were assured of excellent asymmetric induction in a divergent synthesis of three 5,8-disubstituted amphibian indolizidine alkaloids (Scheme 93) (467,499). Addition of but-3-enylmagnesium bromide to 688 yielded the dlhydropyridone 689 as a single diastereomer in 91% yield after recrystallization. After a series of functional group manipulations, the C-8 methyl group was introduced stereoselectively by enolate alkylation (690 -> 691),... 

Finally we ll have a quick look at how combinations of these methods have been applied. In the aldol reactions we have looked at so far there has been no chirality at the start. Both the aldehyde and the enolate have been achiral species that have reacted in a stereoselective way to give a particular diastereomer. With the aldol reaction there is a lot of opportunity to introduce aspects of chirality. The enolate could be chiral as could the aldehyde. In addition to this, the whole reaction could be mediated by a chiral catalyst. Although chiral enolates are most commonly associated with asymmetric methods (most famously the method of Evans in Chapter 27) it is important to remember that the components could just as easily be chiral and racemic. The diastereoselectivity that allows the Evans s chemistry to work with optically pure materials will operate whether the auxiliary is optically pure or not. 

The counterion of an enolate has a pronounced influence on competing transition states of enolate reactions. The effect is often the result of cation chelation by the carbonyl oxygen atom and one or more additional basic portions of the reactants. For example, alkylation of chiral enolates may lead to more or less diastereomerically pure products and selectivity often depends on the countercation. The importance of the countercation in controlling enolate reaction product distributions requires that the synthetic chemist has at hand stereoselective methods for the preparation of enolate anions with a wide variety of counterions. This chapter is divided into several sections. The 10 following sections describe important current methods for preparing Li, Mg, B, Al, Sn, Ti, Zr, Cu, Zn and other transition metal enolates. 

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