Aldol additions simple diastereoselectivity

In a number of kinctically controlled aldol additions, simple diastereoselectivity is related to the geometry of the enolate (Z)-enolates furnish syn-aldols and (/f)-cnolatcs give //-aldols as the main products. 

Most aldol additions of preformed enolates are run under kinetic control. In some such kinetically controlled aldol reactions simple diastereoselectivity is related to the configuration of the enolate. The seminal investigations of Dubois [65], then intensive studies by the research groups of... 

If, on the other hand, the aldol addition is performed using either enolates with stereogenic units, which may be located in the a-substituent Y or in the ipso-substituent X, or using chiral aldehydes, the aldol products 4a, 5a and 6a arc diastcreomers with respect to 4b, 5b and 6b. Thus, both significant simple diastereoselectivity and induced stereoselectivity are highly desirable when ... 

A stereoconvergent reaction without any correlation between the geometry of the enolate and simple diastereoselectivity occurs when fluoride ions are used to induce an aldol addition of enolsilanes to aldehydes. For example, both a 99 1 and a 9 91 mixture of the following (Z)/( )-enolsilane lead predominantly to the formation of the. un-adduct in a highly selective manner, when the addition is mediated by tris(diethylamino)sulfonium difluorotrimethylsili-conate27,28. 

Ideal starting materials for the preparation of. svn-aldols are ketones that can be readily deprotonated to give (Z)-enolates which are known to give predominantly yyu-adducts. Thus, when (5,)-1-(4-methylphenyl)sulfonyl-2-(l-oxopropyl)pyrrolidine is treated with dibutylboryl triflate in the presence of diisopropylethylamine, predominant generation of the corresponding (Z)-boron enolate occurs. The addition of this unpurified enolate to 2-methylpropanal displays not only simple diastereoselectivity, as indicated by a synjanti ratio of 91 9, but also high induced stereoselectivity, since the ratio of syn- a/.vyn-lb is >97 3. 

Enolates also result from the deprotonation of ketones 4 by means of dieyclohcxylchloro-borane. As expected, the (A)-enolboranes 5 formed in this way lead to rw/Z-aldols. Remarkably simple induction of diastereoselectivity is achieved in aldol additions with isobutyraldehyde53d< ... 

In general, chiral propanoates providing simple diastereoselectivity (in favor of yyn-aldols), combined with a reasonable degree of auxiliary-induced stereoselectivity, are rare. Numerous terpenoid- and carbohydrate-derived propionates do not display satisfactory syn selectivity60. Similarly, the titanium(IV) chloride promoted aldol addition of the following JV-metbylephe-drine derived silylketene acetal leads to the formation of the. mi-adduct in the moderate diastereomeric ratio of 78 22 (syn-adduct sum of the other stereoisomers)61. 

The major difference, when compared with simple diastereoselection in aldol-type additions, is the E- and Z-geometrical isomers of the Michael acceptor. Model transition state G shows one of the orientations of the enantiofaces of an (A)-enolate with a (Z)-enone. These additions, again, result in the same. vyn/an/i-adducts, as in the case of an (A)-enone, but the substituent interactions will be different. 

Summary of the Relationship between Diastereoselectivity and the Transition Structure. In this section we considered simple diastereoselection in aldol reactions of ketone enolates. Numerous observations on the reactions of enolates of ketones and related compounds are consistent with the general concept of a chairlike TS.35 These reactions show a consistent E - anti Z - syn relationship. Noncyclic TSs have more variable diastereoselectivity. The prediction or interpretation of the specific ratio of syn and anti product from any given reaction requires assessment of several variables (1) What is the stereochemical composition of the enolate (2) Does the Lewis acid promote tight coordination with both the carbonyl and enolate oxygen atoms and thereby favor a cyclic TS (3) Does the TS have a chairlike conformation (4) Are there additional Lewis base coordination sites in either reactant that can lead to reaction through a chelated TS Another factor comes into play if either the aldehyde or the enolate, or both, are chiral. In that case, facial selectivity becomes an issue and this is considered in Section 2.1.5. 

The stereogenic centers may be integral parts of the reactants, but chiral auxiliaries can also be used to impart facial diastereoselectivity and permit eventual isolation of enantiomerically enriched product. Alternatively, use of chiral Lewis acids as catalysts can also achieve facial selectivity. Although the general principles of control of the stereochemistry of aldol addition reactions have been well developed for simple molecules, the application of the principles to more complex molecules and the... 

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. 

Catalysis with Bisoxazoline Complexes of Sn(II) and Cu(II). The bisoxazoline Cu(IT) and Sn(II) complexes 81-85 that have proven successful in the acetate additions with aldehydes 86,87, 88 also function as catalysts for the corresponding asymmetric propionate Mukaiyama aldol addition reactions (Scheme 8B2.8) [27]. It is worth noting that eithersyn or anti simple diastereoselectivity may be obtained by appropriate selection of either Sn(II) or Cu(II) complexes (Table 8B2.12). 

The simple diastereoselectivity of aldol reactions was first studied in detail for the Ivanov reaction (Figure 13.45). The Ivanov reaction consists of the addition of a carboxylate enolate to an aldehyde. In the example of Figure 13.45, the diastereomer of the /1-hydroxycarboxylic acid product that is referred to as the and-diastereomer is formed in a threefold excess in comparison to the. vy/j-diastereoisomer. Zimmerman and Traxler suggested a transition state model to explain this selectivity, and their transition state model now is referred to as the Zimmer-man-Traxler model (Figure 13.46). This model has been applied ever since with good success to explain the simple diastereoselectivities of a great variety of aldol reactions. 

The ketone enolate A of Figure 13.47 is generated in a Z-selective fashion (as we saw in Figure 13.15). The bulky and branched enolate substituent destabilizes the Zimmerman-Traxler transition state C by way of the discussed 1,3-diaxial interaction, while the transition state structure B is not affected. Hence, the aldol addition of enolate A occurs almost exclusively via transition state B, and the -configured aldol adducts D (Figure 13.47) are formed with a near-perfect simple diastereoselectivity. The acidic workup converts the initially formed trimethysilyloxy-substituted aldol adducts into the hydroxylated aldol adducts. 

M. Braun, Simple Diastereoselection and Transition State Models of Aldol Additions , in Stereoselective Synthesis (Houben-Weyl) 4th ed. 1996, (G. Helmchen, R. W. Hoffmann, J. Mulzer, E. Schaumann, Eds.), 1996, Vol. E 21 (Workbench Edition), 3, 1603—1666, Georg Thieme Verlag, Stuttgart. 

The problem of diastereoselective aldol addition has been largely solved48,108). Under kinetic control Z enolates favor erythro adducts and E enolates the threo diastereomers, although exceptions are known. This has been explained on the basis of a six-membered chair transition state in which the faces of the reaction partners are oriented so as to minimize 1,3 axial steric interactions 481108). This means that there is no simple way to prepare erythro aldols from cyclic ketones, since the enolates are geometrically fixed in the E geometry. 

Reetz, M. T., Kesseler, K., Jung, A. Aldol-additions to a- and p-alkoxy aldehydes the effect of chelation on simple diastereoselectivity. 

The same bisoxazoline Cu(II) and Sn(II) complexes have been utilized successfully in the corresponding propionate aldol addition reactions (Scheme 8-7). A remarkable feature of these catalytic processes is that either syn or anti simple dia-stereoselectivity may be accessed by appropriate selection of either Sn(II) or Cu(II) complexes. The addition of either - or Z-thiopropionate-derived silyl ke-tene acetals catalyzed by the Cu(II) complexes afford adducts 78, 80, and 82 displaying 86 14-97 3 syn anti) simple diastereoselectivity. The optical purity of the major syn diastereomer isolated from the additions of both Z- and i -enol silanes were excellent (85-99% ee). The stereochemical outcome of the aldol addition reactions mediated by Sn(Il) are complementary to the Cu(U)-catalyzed process and furnish the corresponding anp -stereoisomers 79, 81, and 83 as mixtures of 10 90-1 99 syn/anti diastereomers in 92-99% ee. 

Lewis Basic Phosphoramides. In a series of elegant investigations, Denmark has documented an aldol process that utilizes trichlorosilyl enolates such as 101 and 105 in catalytic, enantioselective addition reactions (Eqs. (8.28) and (8.29)) [45]. These unusual enoxysilanes are prepared by treatment of the corresponding tribu-tylstannyl enolates with SiCl4. Trichlorosilyl enolates are sufficiently reactive to add to aldehydes at -78 °C, but their addition can be substantially accelerated by the addition of Lewis basic phosphoramides. The use of catalytic amounts of chiral phosphoramides leads to the formation of optically active products. Thus, treatment of the cyclohexanone or propiophenone-derived trichloroenolsilanes 101 and 105 with a variety of aldehydes afforded adducts displaying high levels of simple diastereoselectivity and up to 96% ee. On the basis of the stereochemical outcome of the reaction, Denmark has postulated that the reaction proceeds through an or-... 

Myers et al. found that silyl enolates derived from amides undergo a facile non-catalyzed aldol addition to aldehydes at or below ambient temperature [90]. In particular, the use of cyclic silyl enolate 27, derived from (S)-prolinol propionamide, realizes high levels of diastereoface-selection and simple diastereoselection (anti selectivity) (Scheme 10.27). It has been proposed that this non-catalyzed highly stereoselective reaction proceeds via attack of an aldehyde on 27 to produce a trigonal bipyramidal intermediate 29 in which the aldehyde is apically bound 29 then turns to another isomer 30 by pseudorotation and 30 is then converted into 28 through a six-membered boat-like transition state (rate-determining step). 

Scheme 23 shows how four possible diastereomers can arise from the combination of two sp -carbon centers C-1 and C-2 in a donor component 23-1 and an acceptor component 23-2. Species 23-3 and 23-4 are two diastereomers and 23-5 and 23-6 are their enantiomers.The problem of simple diastereoselection is the control of the diastereomer ratio 23-3-1-23-5/23-4-1-23-6. The enantiocontrol of 23-3 vs 23-5 or of 23-4 vs 23-6 cannot be achieved by simple diastereoselection in this case an external source of chirality has to be applied, for instance a chiral catalyst or the incorporation of stereogenic units in one of the components. Simple diastereoselection can be exerted in terms of closed and open transition states, depending on the mutual interaction of the termini X and Do, respectively. If these termini are linked via a six-membered chelate, a closed ( Zimmerman-Traxler ) transition state 23-7 with synperiplanar olefinic units is formed. On the other hand, if the termini have a repulsive interaction an open transition state 23-8 with an antiperiplanar arrangement of the olefinic units is adopted. Efficient stereocontrol via Zimmerman-Traxler transition states 24-1 to 24-4 is observed in aldol-type and allylborane carbonyl additions (Scheme 24). The crucial stereo differentiating interaction is the diaxial repulsion between Rax and R, which must be kept as low as possible. Only small substituents (nor-...

The most intensely studied aldol addition mechanisms are those beUeved to proceed through closed transition structures, which are best understood within the Zimmerman-Traxler paradigm (Fig. 5) [Id]. Superposition of this construct on the Felkin-Ahn model for carbonyl addition reactions allows for the construction of transition-state models impressive in their abiUty to account for many of the stereochemical features of aldol additions [50a, 50b, 50c, 51]. Moreover, consideration of dipole effects along with remote non-bonding interactions in the transition-state have imparted additional sophistication to the analysis of this reaction and provide a bedrock of information that may be integrated into the further development and refinement of the corresponding catalytic processes [52a, 52b]. One of the most powerful features of the Zimmerman-Traxler model in its application to diastereoselective additions of chiral enolates to aldehydes is the correlation of enolate geometry (Z- versus E-) with simple di-astereoselectivity in the products syn versus anti). Consequently, the analyses of catalytic, enantioselective variants that display such stereospecificity often invoke closed, cyclic structures. Further studies of these systems are warranted, since it is not clear to what extent such models, which have evolved in the context of diastereoselective aldol additions via chiral auxiliary control, are applicable in the Lewis acid-catalyzed addition of enol silanes and aldehydes. 

Dicarbonyl compounds may be converted into dianions, which react with electrophiles at the more basic site. Huckin and Weiler found that 3-keto ester dianions undergo aldol addition reactions at the more basic methyl position (equation 32). The lithium/sodium dianion shows surprisingly weak reactivity, giving the aldol in only 11% yield after 1 h at -78 °C In contrast, the lithium enolates of simple ketones and esters, which should be much less basic than the 3-keto ester dianion, react with aldehydes to give nearly quantitative yields of aldols in THF in seconds at -78 °C. ° Seebach and Meyer also studied this reaction, and obtained the oxolactone (equation 33). Simple diastereoselection in the reaction of 3-keto ester dianions has also been studied (vide infra). 

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