Felkin model aldol reaction

The issue of stereochemistry, on the other hand, is more ambiguous. A priori, an aldol condensation between compounds 3 and 4 could proceed with little or no selectivity for a particular aldol dia-stereoisomer. For the desired C-7 epimer (compound 2) to be produced preferentially, the crucial aldol condensation between compounds 3 and 4 would have to exhibit Cram-Felkin-Anh selectivity22 23 (see 3 + 4 - 2, Scheme 9). In light of observations made during the course of Kishi s lasalocid A synthesis,12 there was good reason to believe that the preferred stereochemical course for the projected aldol reaction between intermediates 3 and 4 would be consistent with a Cram-Felkin-Anh model. Thus, on the basis of the lasalocid A precedent, it was anticipated that compound 2 would emerge as the major product from an aldol coupling of intermediates 3 and 4. 

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. 

The asymmetric synthesis of (—)-denticulatin A (30) shows an interesting application of the boron aldol chemistry (Scheme 6) [23]. In a group-selective aldol reaction between the weso-aldehyde 27 and (5)-28, the hydroxyalde-hyde 29 was formed with > 90 % de, which spontaneously cyclized to the lactol 31. The configuration at the stereocenters of C-2 and C-3 in 29 is in accordance with the induction through the sultam auxiliary as well as with preference of an a-chiral aldehyde to react to the ant/-Felkin diastereomer in an aldol reaction which is controlled by the Zimmermann-Traxler model [24, 25]. 

As a Stereochemical Prohe in Nucleophilic Additions. Historically, the more synthetically available enantiomer, (4R)-2,2-dimethyl-l,3-dioxolane-4-carhoxaldehyde, has been the compound of choice to probe stereochemistry in nucleophilic additions. Nevertheless, several studies have employed the (45)-aldeh-yde as a substrate. In analogy to its enantiomer, the reagent exhibits a moderate si enantiofacial preference for the addition of nucleophiles at the carbonyl, affording anti products. This preference for addition is predicted by Felkin-Ahn transition-state analysis, and stands in contrast to that predicted by the Cram chelate model. Thus addition of the lithium (Z)-enolate shown (eq 1) to the reagent affords an 81 19 ratio of products with the 3,4-anti relationship predominating as a result of preferential si-face addition, while the 2,3-syn relationship in each of the diastere-omers is ascribed to a Zimmerman-Traxler-type chair transition state in the aldol reaction. ... 

The directed aldol reaction in the presence of TiC found many applications in natural product synthesis. Equation (7) shows an example of the aldol reaction utilized in the synthesis of tautomycin [46], in which many sensitive functional groups survived the reaction conditions. The production of the depicted single isomer after the titanium-mediated aldol reaction could be rationalized in terms of the chelation-controlled (anft-Felkin) reaction path [37]. A stereochemical model has been presented for merged 1,2- and 1,3-asymmetric induction in diastereoselective Mukaiyama aldol reaction and related processes [47]. 

There is a dichotomy in the sense of syn-anti diastereofacial preference, dictated by the bulkiness of the migrating group [94]. The sterically demanding silyl group results in syn diastereofacial preference but the less demanding proton leads to anti preference (Sch. 35). The anti diastereoselectivity in carbonyl-ene reactions can be explained by the Felkin-Anh-like cyclic transition-state model (Ti) (Sch. 36). In the aldol reaction, by contrast, the now inside-crowded transition state (Ti ) is less favorable than Tg, because of steric repulsion between the trimethylsilyl group and the inside methyl group of aldehyde (Ti ). The syn-diastereofacial selectivity is, therefore, visualized in terms of the anti-Felkin-like cyclic transition-state model (T2 )-... 

The asymmetric total syntheses of mtamycin B and oligomycin C was accomplished by J.S. Panek et al. In the synthesis of the C3-C17 subunit, they utilized a Mukaiyama aldol reaction to establish the C12-C13 stereocenters. During their studies, they surveyed a variety of Lewis acids and examined different trialkyl silyl groups in the silyl enol ether component. They found that the use of BFs OEta and the sterically bulky TBS group was ideal with respect to the level of diastereoselectivity. The stereochemical outcome was rationalized by the open transition state model, where the orientation of the reacting species was anti to each other, and the absolute stereochemistry was determined by the chiral aldehyde leading to the anti diastereomeric Felkin aldol product. 

In the first total synthesis of bafilomycin A by Evans and Calter [16], the syn aldol reaction between ketone 29 and aldehyde 176 was a pivotal transformation (Scheme 9-51). Using a (Z)-enolate, it could be expected that aldehyde 176 would have a small bias for the desired ann-Felkin adduct, however, control from the ketone component would be needed for high stereoselectivity. Use of common metal enolates led to poor stereocontrol however, model studies indicated that the (Z)-chlorophenyl boron enolate, in conjunction with cyclic protection of the C21-C23 diol, induced high selectivity in the desired sense. In practice, the coupling of the required aldehyde 176 and enolate 77 afforded 178 with >95%ds. Compound 178 was then successfully elaborated to give bafilomycin A]. In the second reported synthesis of bafilomycin A, Toshima et al. carried out the same aldol coupling to form the Cn-Cig bond [68]. 

The remainder of the right-hand fragment was prepared (Scheme 5) in accord with our efforts in the theopederin D synthesis. Keto-aldehyde 21, available through the condensation of the enamine of isobutyraldehyde with acetyl chloride, was subjected to a Krische allylation to provide secondary alcohol 22 in 93% ee. Protection as a triethylsilyl ether and exposure to TMSOTf yielded enolsilane 23. The enolsilane was selected as the nucleo-phile for the fragment-coupling aldol reaction based on Evans studies on the influence of various substituents on complex aldol reactions. While the silyloxy group in aldehyde 20 was expected to direct nucleophiles toward the undesired face of the aldehyde, consistent with the extended Felkin model,the methyl group adjacent to the aldehyde was expected to direct the nucleophile to the desired face of the aldehyde, in accord with the... 

A possible transition state based on the Felkin-Anh model was shown in Scheme 23. Judging from the (2/ ,3R,4S)-configuration of the product 31a, the major product is likely formed via the Felkin TS 33 showing the Si face attack of the Rh-( )-enolate. This step could be the catalyst-controlled reaction with the chiral catalyst. According to the prochiral face discrimination in the phebox-Rh-catalyzed reductive aldol reaction with the linear substrate, the Re face attack of the Rh (fij-enolate in TS 34 is unfavorable. In the case of the (R)-aldehyde, the anri-Felkin-Anh s TS 35, which gives the (2R,3R,4R)-product 31b, takes the unfavorable conformation with the bulky phenyl group at the apical position. 

Soon after the first report of the aldol reaction of silyl enol ethers was disclosed, allylsilanes were reported to show similar reactivity toward aldehydes and ketones when activated by a stoichiometric amount of TiCU (Scheme 3-85). This synthetically important reaction has subsequently become the subject of many synthetic chemists and was improved extensively using various kinds of Lewis acid catalysts. Acyclic transition states are proposed to explain diastereoselectivities of the reaction depending on a Lewis acid and reaction conditions. Particularly, synclinal orientation of reactants is suggested to be more preferable rather than an antiperiplanar one particularly for ( )-allylsilanes based on molecular model studies (Scheme 3-86). High diastereoselectivity observed in the reaction of chiral allylsilanes with aldehydes is understood in terms of this transition state model which is based on the Felkin-type induction (Scheme 3-87). ... 

The geometry of the aldol transition state was interpreted in terms of the variation in mode of the aldehyde/catalyst complexation [Felkin-Ahn (nonchelating) model versus chelating model] and size of KSA. The same complex efficiently catalyzes the Michael reaction of a,/9-unsaturated ketones with KSA [124],... 

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. 

In practice, aldehydes bearing an adjacent stereogenic center, particularly one devoid of a bulky group, typically provide only modest aldol stereoselectivity. For example, consider the reaction of aldehyde 28 with Z boron enolate 27 as shown in Scheme 3a. According to the models just discussed, one would expect this reaction to provide only 1,2-syn products with anti-Felkin- Ahn stereoselectivity. Indeed, that conjecture proved to be true for the most part as exclusively 1,2-syn aldol adducts resulted with 29, a compound whose stereotriad reflected anti-Felkin—Ahn selectivity, constituting the predominant product. However, a fair amount of the alternate 1,2-syn Felkin- Ahn adduct (30) was also observed, such that the final ratio of 29 to 30 was a disappointing 1.75 1. 

Lithium enolates, in contrast, either give predominantly the product predicted by the Cram-Felkin-Anh model or react more or less non-stereoselectively. Thus, the favored formation of the syn-aldol product in the reaction of 2-phenylpropanal with the lithium enolates of acetone, pina-colone, methyl acetate, or N,N-dimethylacetamide is in accordance with Cram s rule or the Felkin-Anh model (Eq. (35)). However, a rather moderate syyr.anti ratio of 3 1 is typical of this type of reaction [51, 67]. 

---