Intramolecular reactions anti-aldols

The 1,5-anti-aldol reaction was performed with chiral boron enolate of 325 and aldehyde 327, prepared by Evans asymmetric alkylation, cross metathesis, and Wittig homologation (Scheme 72), to afford 324 with a 96 4 diastereoselectivity. Stereoselective reduction of C9-ketone provided the 5y -l,3-diol, which was exposed to catalytic f-BuOK to give 2,6-cis-tetrahyderopyran 333 via an intramolecular Michael reaction. Finally, methyl etherification, deprotection, hydrolysis of ester, and Yamaguchi macrolac-tonization yielded the leucascandrolide macrolide 201 (Scheme 73). 

The mixed Tishchenko reaction involves the reaction of the aldol prodnct 113 from one aldehyde with another aldehyde having no a-hydrogens to yield an ester The products were proposed to be formed through an aldol step (equation 33), followed by addition of another aldehyde (equation 34) and an intramolecular hydride transfer (equation 35). However, several aspects of this mechanism need to be clarified. As part of the continuing mechanistic studies carried out by Streitwieser and coworkers on reactions of alkali enolates ", it was found that the aldol-Tishchenko reaction between certain lithium eno-lates and benzaldehyde proceeded cleanly in thf at room temperature". Reaction of the lithium enolate of isobutyrophenone (Liibp) with 1 equiv of benzaldehyde in thf at — 65 °C affords a convenient route to the normal aldol product 113 (R = R" = Ph, R = Me). At room temperature, however, the only product observed after acid workup was the diol-monoester 116, apparently derived from the corresponding lithium ester alcoholate (115, R = R" = Ph, R = Me), which was quantitatively transformed into 116 after quenching. As found in other systems", only the anti diol-monoester diastereomer was formed. 

The aldolization reaction is certainly the most popular reaction for creating carbon-carbon bonds and much effort has been made to achieve the reactions in smooth conditions with a high degree of stereoselectivity. The reaction involves activated carbonyl compounds (enol, enolates, various enol ethers) which add on another carbonyl compound or various electrophiles in related reactions. As most of the activated compounds are compatible with water, it is not surprising that the aldolization in aqueous conditions became an efficient process in view of the negative activation volume of the reaction. The diastereo-selectivity depends greatly on the reaction conditions. Thus, in a intramolecular aqueous aldolization, the acid-induced reaction of a keto aldehyde provided a syn hydroxy ketone while the base-catalyzed reaction led to the anti isomer (Scheme 35) [179]. 

As the reasons for the diastereoselectivity of syn-selective aldol reactions are well established we will focus on the selectivity of the ring closure. We have carried out studies on intramolecular oxymercurations of a series of simple alkenols related to 8 and have found that they consistently close to give predominantly syn and not anti products (Fig. 3). 

In an intramolecular case, it was shown that, in an aqueous medium, the nature of the acidic or basic catalyst had a dramatic effect on the outcome of the aldolisation (Denmark and Lee, 1992). Acid-induced aldol condensation of ketoaldehyde 1 provided the syn hydroxyketone 2, while the anti isomer 3 arose from base-catalyzed reactions ... 

The aqueous medium influences not only the reaction rate but also the stereoselection of the aldol addition. One significant example [13] is the intramolecular cyclization of ketoaldehyde depicted in Scheme 7.2. In organic solvents there is a preference for syn or anti adduct depending on the presence of coordinating cations (K, Na, Li, MgBr ) or a complexing agent such as... 

These phenomena can be explained as follows. First, in the absence of water or in the presence of a small amount of water, THF predominantly coordinates to Yb(OTf)3 and the activity of THF-coordinated Yb(OTf)3 as a Lewis acid is low. The reaction proceeds slowly via the cyclic six-membered transition state with anti preference [24]. On the other hand, when the moles of water are gradually increased, water is prone to coordinate to Yb(OTf)3 instead of tetrahydrofuran (THF), and Yb(OTf)3 dissociates to form the active Yb cation. The solid-state structure of Yb(0Tf)3 9H20 has been investigated [7dj. When Yb(0Tf)3 9H20 (prepared according to the literature) was used, the aldol reactions proceeded, but faster hydrolysis of the silyl enol ethers was observed. At this stage, intramolecular and intermolecular exchange reactions of water molecules occur frequently [25]. There is a chance for an aldehyde to coordinate to Yb instead of to water molecules and the aldehyde is activated ... 

Quinine 84 and quinidine 85 are well-known medicinally important alkaloids as well as mother structures for organocatalysts. Hatakeyama and co-workers reported on organocatalytic asymmetric synthesis of a key intermediate for these alkaloids. They performed the intramolecular direct aldol reaction of bis aldehyde 79 in the presence of L-proline 57. After reduction of the ketone, syn-diol 80 and anti-diol 81 were obtained with high enantiose-lectivity (Scheme 27.14). The mixture was converted into the common intermediate 83 for quinine 84 and quinidine 85 via ketone 82. Quinine 84 and quinidine 85 were... 

Following immediately the initial efforts on primary amino acids catalyzed aldol reactions, the application of primary amine acid in Mannich reaction has also been attempted. Cordova reported that simple primary amino acids and their derivatives could catalyze the asymmetric Mannich reactions of ketones with comparable results to those obtained in the catalysis of proline[28]. Later, Barbas [29] and Lu [30] independently reported that L-Trp or 0-protected L-Thr could catalyze anti-selective asymmetric Mannich reactions of a-hydroxyacetones with eiflier preformed or in-situ generated imines. The preference of anii-diastereoselectivity was ascribed to the formation of a Z-enamine, with the assistance of an intramolecular H-bond (Scheme 5.15). 

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