Stereoselectivity aldol addition

The classical aldol addition, which is usually run in protic solvents, is reversible. Most modern aldol methodologies, however, rely on highly reactive preformed metal enolates, whereby proton donors are rigorously excluded. As a consequence, the majority of recent stereoselective aldol additions are performed under kinetic control. Despite this, reversibility and, as a consequence, an equilibration of yrn-aldolates to a t/-aldolates by retro-aldol addition, should not be excluded a priori. 

In another approach, a glucose-derived titanium enolate is used in order to accomplish stereoselective aldol additions. Again the chiral information lies in the metallic portion of the enolate. Thus, the lithiated /m-butyl acetate is transmetalated with chloro(cyclopentadienyl)bis(l,2 5,6-di-0-isopropylidene- -D-glucofuranos-3-0-yl)titanium (see Section I.3.4.2.2.I. and 1.3.4.2.2.2.). The titanium enolate 5 is reacted in situ with aldehydes to provide, after hydrolysis, /i-hydroxy-carboxylic acids with 90 95% ee and the chiral auxiliary reagent can be recovered76. 

The requirement that an enolate have at least one bulky substituent restricts the types of compounds that give highly stereoselective aldol additions via the lithium enolate method. Furthermore, only the enolate formed by kinetic deprotonation is directly available. Whereas ketones with one tertiary alkyl substituent give mainly the Z-enolate, less highly substituted ketones usually give mixtures of E- and Z-enolates.7 (Review the data in Scheme 1.1.) Therefore efforts aimed at increasing the stereoselectivity of aldol additions have been directed at two facets of the problem (1) better control of enolate stereochemistry, and (2) enhancement of the degree of stereoselectivity in the addition step, which is discussed in Section 2.1.2.2. 

The syntheses in Schemes 13.45 and 13.46 illustrate the use of oxazolidinone chiral auxiliaries in enantioselective synthesis. Step A in Scheme 13.45 established the configuration at the carbon that becomes C(4) in the product. This is an enolate alkylation in which the steric effect of the oxazolidinone chiral auxiliary directs the approach of the alkylating group. Step C also used the oxazolidinone structure. In this case, the enol borinate is formed and condensed with an aldehyde intermediate. This stereoselective aldol addition established the configuration at C(2) and C(3). The configuration at the final stereocenter at C(6) was established by the hydroboration in Step D. The selectivity for the desired stereoisomer was 85 15. Stereoselectivity in the same sense has been observed for a number of other 2-methylalkenes in which the remainder of the alkene constitutes a relatively bulky group.28 A TS such as 45-A can rationalize this result. 

In the synthesis in Scheme 13.46, a stereoselective aldol addition was used to establish the configuration at C(2) and C(3) in Step A. The furan ring was then subjected to an electrophilic addition and solvolytic rearrangement in Step B. 

The addition of doubly deprotonated HYTRA to achiral4 5 as well as to enantiomerically pure aldehydes enables one to obtain non-racemic (3-hydroxycarboxylic acids. Thus, the method provides a practical solution for the stereoselective aldoi addition of a-unsubstituted enolates, a long-standing synthetic problem.7 As opposed to some other chiral acetate reagents,7 both enantiomers of HYTRA are readily available. Furthermore, the chiral auxiliary reagent, 1,1,2-triphenyl-1,2-ethanediol, can be recovered easily. Aldol additions of HYTRA have been used in syntheses of natural products and biological active compounds, and some of those applications are given in Table I. (The chiral center, introduced by a stereoselective aldol addition with HYTRA, is marked by an asterisk.)... 

Espelt, L., Parella, T., Bujons, J., Solans, C., Joglar, J., Delgado, A. and, Clapes, P., Stereoselective aldol additions catalyzed hy dihydroxyacetone phosphate-dependent aldolases in emulsion systems preparation and structural characterization of linear and cyclic iminopolyols from aminoaldehydes. Chem. Eur. J., 2003, 9, 4887. 

The second Nicolaou synthesis is shown in Scheme 13.49. Stereoselective aldol additions are used to construct the fragments which are brought together by esterification at step D. The synthesis uses an olefin metathesis reaction to construct the 16-membered ring (step E). 

The olefin metathesis reaction is also a key feature of the synthesis of epothilone A completed by a group at the Technical University in Braunschweig, Germany. This synthesis, shown in Scheme 13.50, employs a series of stereoselective additions to create the correct stereochemistry. Step A-l uses a stereoselective aldol addition to bring together the two starting materials and also create the stereocenters at C-6 and C-... 

The development of enantioselective methods remains challenging. In principle, any of the methods that are used for stereoselective aldol additions can also be tested in the Darzens Reaction, as the first step is an aldol addition. 

Methyl-2-trimethylsilyloxypentan-3-one (1) is the prototype member of a series of a-trimethyls1lyloxy ketones that are useful for stereoselective aldol addition reactions (eq l).2 6-Hydroxy ketones 2 may be converted into 6-hydroxy acids,2 g-hydroxy aldehydes, and other e-hydroxy ketones. ... 

The required diastereomerically pure allylic sulfides 364-366 were prepared by a combination of stereoselective aldol additions and 1,2-arylsulfanyl migrations [214]. Under carefully controlled conditions [211] they could be... 

The enantioselective total synthesis of the cytokine modulator (-)-cytoxazone using a syn-stereoselective aldol addition and a Curtius rearrangement as key steps was described by J.A. Marco et al. The key intermediate acid was treated with DPPA and triethylamine in toluene at reflux. This step furnished the oxazolidinone directly and in good yield through an in situ capture of the isocyanate group by the free secondary alcohol functionality. Removal of the protecting group led to the formation of the natural product. 

In addition to the acetate aldol problem, stereoselective aldol additions of substituted enolates to yield 1,2-anti- or f/treo-selective adducts has remained as a persistent gap in asymmetric aldol methodology. A number of innovative solutions have been documented recently that provide ready access to such products. The different successful approaches to anri-selective propionate aldol adducts stem from the design of novel auxiliaries coupled to the study of metal and base effects on the reaction stereochemistry. The newest class of auxiliaries are derived from A-arylsulfonyl amides prepared from readily available optically active vicinal amino alcohols, such as cw-l-aminoindan-2-ol and norephedrine. 

A series of innovative investigations by Kiyooka and co-workers have introduced the use of tandem reaction processes that commence with a stereoselective aldol addition reaction and are followed by C=0 reduction [13]. A chiral oxazaboroli-dine complex prepared from BH3-THF and A-/ -toluenesulfonyl (L)-valine controls the absolute stereochemical outcome of the aldol reaction. In a subsequent reaction, the /i-alkoxyboronate effects intramolecular reduction of the ester to furnish the corresponding /i-hydroxy aldehyde. 

Danishefsky has proposed that the unusual behavior of the unsaturated aldehyde as substrate is accounted for by an energetically stabilizing interaction between polarized aldehyde carbonyl and olefin Ti-electrons. The seemingly parallel behavior of similarly functionalized aldehydes Is consistent with this proposal. This type of electronic stabilization may prove general, offering innovative avenues for the future design of stereoselective aldol addition reactions. 

Fleming has generated enolates by conjugate addition of lithium bis(phenyldimethylsilyl)cuprate to a,p-unsaturated esters. The intermediate (Z)-enolates undergo stereoselective aldol addition, providing adducts having three contiguous stereocenters one example of this process is seen in equation (20). - ... 

For a thorough analysis of stereoselective aldol additions of achiral lithium and boron enolates to chiral aldehydes, see ref. [123]. 

The aldol addition reaction, and the related crotyl metal additions (section 5.1), have figured prominently in the total synthesis of a number of complex natural products (reviews [48,140-142]). Figure 5.8 illustrates those mentioned in the preceding discussion, along with others selected from the recent literature, with the stereocenters formed by stereoselective aldol addition indicated ( ). For the Prelog-Djerassi lactone and ionomycin, recall (Figure 3.8) that most of the other stereo-centers were formed by asymmetric enolate alkylation. 

Aldolases are a group of C—C bond forming enzymes with widespread applications. The stereoselective aldol addition reaction catalyzed by aldolases represents an attractive alternative to conventional chiral organic chemistry methods for chemical and pharmaceutical industries. Aldolases are classified according to both their proposed catalytic mechanism and the structure of the donor substrate, their sources and microbial production processes being presented in this chapter. To design appropriate bioreactors for aldol synthesis, the characteristics of aldolase biocatalysts obtained after purification procedures in free and immobilized form are discussed. 

For recent reviews on stereoselective aldol additions, see a) Nogradi M (1987) In Stereoselective synthesis, Berlin b) Evans DA (1982) Aldrichimica Acta 15 23 c) Seebach D (1988) Angew Chem Int Ed Engl 27 1624... 

Here we recount the latest research on chemoenzymatic multistep and cascade strategies for the synthesis of iminocyclitols, carbohydrates, and deoxysugars from N-protected ami noaldehydes, hydroxyaldehydes, and simple alkylaldehydes, respectively. The key step in all of them is the stereoselective aldol addition reaction of dihydroxyacetone phosphate (DHAP) and its unphosphorylated analogs to the acceptor aldehydes using DH AP-dependent and dihydroxyacetone- (DH A)-utilizing aldolases, respectively, as biocatalysts. 

Denmark SE, Pham SM (2003) Stereoselective aldol additions of achiral ethyl ketone-derived trichlorosilyl enolates. J Org Chem 68 5045-5055... 

The influence of further counter-ions like ammonium, magnesium and zinc on the reversibility has been studied [65, 71]. Another influence comes from the stability of the enolate. As a rule, the rate of the retroaldol reaction correlates vith the stability of the enolate. In stereoselective aldol addition, the reversibility is, in general, rather considered as a complication than a tool to obtain high selectivity. In particular, thermodynamically controlled aldol additions are usually not suitable to obtain non-racemic aldols. 

Stereoselective Aldol Addition of Lithium, Magnesium and Sodium Enolates... 

Remarkably high stereoselectivity is obtained by means of the sodium enolate of a-N,N-dibenzylamino-substituted ketone 51, a counter-ion not very frequently used in stereoselective aldol additions. In this instance, however, the sodium enolate turned out to be more efficient than the lithium analog. The predominant formation of the main diastereomeric product 52a rather than 52b is explained by an open transition state, assumed to be strongly favored over the cyclic transition state, when the more ionic sodium enolate is used rather than the corresponding lithium reagent (Eq. (24)) [103]. 

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