Diastereoselective aldol

V. KINETICALLY CONTROLLED ALDOL DIASTEREOSELECTION ACHIRAL REACTION PARTNERS... 

The correlation of metal enolate geometry and aldol product stereochemistry via diastereomeric chair-preferred transition states has been widely accepted (2,5,6,16). The observations that the steric bulk of the enolate ligand Rj and attendant aldol diastereoselection are directly coupled are consistent with the elaborated Zimmerman model illustrated in Scheme 3 for chair-preferred transition states. For example, for ( )-enoIates, transition state Q is predicted to be destabilized relative to Ci because of the Rj R3 variable steric... 

The basic assumption of the chair-preferred transition state (for tetrahedral metal centers) is clearly tenuous, and diastereomeric boat transition state geometries should not be discounted. For example, the diastereomeric chair and boat transition states for (Z)-enolates are illustrated in Scheme 4, For this enolate geometry it is entirely reasonable to consider that the heat of formation of boat transition state B2 might actually be less than chair transition state C4 for certain combinations of substituents Ri, R2, and R3. For example, boat transition state B2 not only disposes substituents R2 and R3 in a staggered conformation as in chair transition states C3 and C4, but also minimizes Rj R3 eclipsing, which must be significant in chan-transition state C3. The change in kinetic aldol diastereoselection of... 

Lithium, magnesium, and aluminum enolates appear to afford comparable levels of kinetic aldol diastereoselection for a given enolate of defined structure. 

The enolates derived from 2,6-disubstituted phenyl propionates appear to exhibit the higliest levels of threo aldol diastereoselection yet reported for lithium-mediated condensations (33). These substrates should enjoy widespread use in stereoselective synthesis. 

The kinetic aldol diastereoselection observed for a range of amide lithium enolates is reported in Table 12. It is significant that the... 

Extensive studies have been carried out on the metal enediolates of carboxylic acids and the influence of substrate structure on kinetic aldol diastereoselection (eq. [26]). For all but the most sterically demanding substituents (Rj = t-C4H9, mesityl, 1-adamantyl) the condensations exhibit only modest threo diastereoselection (Table 13). The reader is referred to Table 4 for the analogous thermodynamically controlled aldol data. 

The enolization (LDA, THF) and subsequent condensation of a-amino ester 53a under kinetic conditions affords low levels of kinetic aldol diastereoselection. From the preceding discussion it is probable that the major enolate derived from 53a possesses the E)-geometry. The observation that moderate levels of erythro diastereoselection are observed with benzaldehyde (Table 16) are consistent... 

As noted in Table 21, for a given boron ligand there is a small but consistent improvement in aldol diastereoselection when the less polar solvents are employed. This trend is observed for both enolates 60 and 61. In subsequent studies it has been noted that aldol diastereoselection in methylene chloride is comparable to that observed... 

In the titanium tetrachloride-promoted aldol condensations of stereochemically defined enolsilanes (eq. [58]) variable levels of aldol diastereoselection have been noted (Table 26) (73). A detailed analysis of this reaction in terms of probable intermediates and transition state awaits further studies however, some experimental observations suggest that titanium enolates may not be involved (73b). 

The influence of temperature on aldol diastereoselection has been noted in several instances. The condensation of zinc enolates 85a to... 

Recently, the issue of aldehyde diastereoface selection has been examined for the enolates 99 to 103 (2,26,33,64). For these substituted enolates, aldol diastereoselection has been demonstrated to... 

Extensive investigations have been directed toward the development of chiral ester enolates that might exhibit practical levels of aldol asymmetric induction. Much of the early work in this area has been reviewed (111). In general, metal enolates derived from chiral acetate and propionate esters exhibit low levels of aldol asymmetric induction that rarely exceed 50% enantiomeric excess. The added problems associated with the low levels of aldol diastereoselection found with most substituted ester enolates (cf. Table 11) further detract from their utility as effective chiral enolates for the aldol process. Recent studies have examined the potential applications of the chiral propionates 121 to 125 in the aldol condensation (eq. [94]), and the observed erythro-threo diastereoselection and diastere-oface selection for these enolates are summarized in Table 31. For the six lithium enolates the threo diastereoselection was found to be... 

The first chapter in this volume is a particularly timely one given the recent surge of activity in natural product synthesis based upon stereocontrolled Aldol Condensations. D. A. Evans, one of the principal protagonists in this effort, and his associates, J. V. Nelson and T. R. Taber, have surveyed the several modem variants of the Aldol Condensation and discuss models to rationalize the experimental results, particularly with respect to stereochemistry, in a chapter entitled Stereoselective Aldol Condensations. The authors examine Aldol diastereoselection under thermodynamic and kinetic control as well as enantioselection in Aldol Condensations involving chiral reactants. 

A further step towards improved selectivity in aldol condensations is found in the work of David A. Evans. The work of Evans [3a] [14] is based in some early observations from Meyers laboratory [15] and the fact that boron enolates may be readily prepared under mild conditions from ketones and dialkylboron triflates [16]. Detailed investigations with Al-propionylpyrrolidine (31) indicate that the enolisation process (LDA, THE) affords the enolate 32 with at least 97% (Z>diastereoselection (Scheme 9.8). Finally, the observation that the inclusion of potential chelating centres enhance aldol diastereoselection led Evans to study the boron enolates 34 of A(-acyl-2-oxazolidones (33), which allow not only great diastereoselectivity (favouring the 5yn-isomer) in aldol condensations, but offer a possible solution to the problem of enantioselective total syntheses (with selectivities greater than 98%) of complex organic molecules (see below, 9.3.2), by using a recyclisable chiral auxiliary. 

An improvement in aldol diastereoselection for a given boron ligand is obtained when less polar solvents are employed, presumably due to transition state compression in nonpolar solvents. This solvent effect is also significant in enolate chirality transfer in asymmetric aldol reactions. 

Evans used a combination of titanium tetrachloride and diisopropylethyl-amine, which proved to be efficient and general for many different kinds of substrates [28]. The syn aldol diastereoselectivity was comparable with that of boron-mediated processes. Isolated yields with titanium enolates are considerably higher than from boron enolates. Furthermore, syn-selectivity... 

---