71 -Face selectivity, boron enolates

Polar effects appear to be important for 3 -alkoxy substituents in enolates. 3-Benzyloxy groups enhance the facial selectivity of /(-boron enolates, and this is attributed to a TS I in which the benzyloxy group faces toward the approaching aldehyde. This structure is thought to be preferable to an alternate conformation J, which may be destabilized by electron pair repulsions between the benzyloxy oxygen and the enolate oxygen.109... 

Although the results are easily rationalised in the case of the a-alkylation (attack of the electrophile at the Re face, i.e., attack from the less hindered a face), in the aldol condensation it is somewhat more difficult to rationalise and several factors should be considered. According to Evans [14] one possible explanation for the diastereofacial selection observed for these chiral enolates is illustrated in Scheme 9.14. In the aldol reactions, the more basic carbonyl group of the aldehyde partner interacts with the chelated boron enolate 45 to give the "complex" A which may... 

Although iV-acyloxazolidinones 88 and iV-acylthiazolidinethiones 90 lead to an anti aldol, the respective products 89 and 91 present a different anti configuration. Consequently, the corresponding derived magnesium enolates exhibit the opposite face selection in these reactions. On the basis of previous results involving enolates of various metal complexes such as boron, titanium, lithium or sodium enolates, the (Z)-metal enolate... 

In a more complex scenario, the /J-substituents were also found to participate in partially matched or mismatched reactions577. Examples of double induction pave the route of polypropionate and polyketide synthesis and it was emphasized that the relative influence of the enolate or aldehyde component may be enhanced, depending on the coordinating metal employed in the double stereodifferentiating aldol reaction. Thus, it was found that, in spite of their modest synlanti selectivity, lithium enolates are effective in double stereodifferentiating aldol reaction578. In the matched and partially matched cases, lithium enolate face selectivity is opposite to that which is found for their boron or titanium counterparts. This is perfectly illustrated in a recent work by Roush and coworkers reporting a partial synthesis of Bafilomycin Aj (Scheme 122)579. 

Chiral oxazolidinone auxiliaries based on D-glucose were used for aldol reactions by Koell et al. [160]. The highest select vities were observed with auxiliaries equipped with the pivaloyl protecting group. The pivaloylated oxazolidinone 228 was transformed into the boron enolate according to the procedure of Evans [161] and subsequently reacted with aliphatic and aromatic aldehydes. The best results were obtained with isobutyric aldehyde (Scheme 10.77). The syn-dldo 229 was formed in 16-fold excess over the a/i Z-diastereomer and with an acceptable yield of 59%. The authors explain the stereoselectivity by a chair-like transition state according to Zimmermann-Traxler. The electrophile approaches at the less hindered r -face of the (Z)-configured enolate double bond. For A -phenacetyl substituents, an inversed stereoselectivity was observed as described above for these oxazolidinone auxiliaries. 

Deprotonation of a-silyloxy ketones with LDA furnishes (Z)-lithium enolates, whereas treatment of ketones with n-Bu2BOTf in the presence of /-Pr2EtN gives the corresponding (Z)-(0)-boron enolates. Interestingly, reaction of the Li-enolates with r-PrCHO proceeds with opposite facial preference to that of the boron enolates. Thus, the Si face of the Li-enolate adds to the Si face of the aldehyde and the Si face of the boron enolate adds to the Re face of the aldehyde to furnish the chiral P-hydroxy ketone enantiomers shown below. The reason for the different face selectivity between the lithium enolate and the boron enolate is that lithium can coordinate with three oxygens in the aldol Zimmerman-Traxler transition state, whereas boron has only two coordination sites for oxygen. 

Treatment of N-acyloxazolidinones with di-n-butylboron triflate in the presence of Et3N furnishes the (Z)-(O) boron enolates. These on treatment with aldehydes give the corresponding 2,3-syn aldol products (the ratio of syn- to anti- isomers is typically 99 1 ). On hydrolysis they produce chiral a-methyl-(3-hydroxy carboxylic acids, as exemplified below. The facial selectivity of the chiral boron enolate is attributed to the favored rotomeric orientation of the oxazolidinone carbonyl group, where its dipole is opposed to the enolate oxygen dipole. At the Zimmerman-Traxler transition state, the aldehyde approaches the oxazolidinone appendage from the face of the hydrogen rather than from the benzyl substituent. 

Under kinetic control, the reactions of prochiral aldehydes with Z-enolates generally lead to syn aldols, while E-enolates lead to anti aldols. The presence of bulky R groups on the enolates, however, may alter these selectivities. The highest diastereoselectivities are observed with boron or titanium enolates. These selectivity trends are interpreted by a concerted cyclic mechanism. The favored transition state resembles a distorted chair, in line with the Zimmermann-Traxler proposals [57, 160, 253] (Figure 6.70). This model has been supported by theoretical studies [9, 40, 41, 125, 1249], Transition states analogous to C2 and C4 (Figure 6.70) are destabilized by 1,3-ecIipsing interactions between the C-R, M-L and C-R bonds, so that models Ci and C3 are more favorable. For the sake of simplification, only the reaction on one face of the enolates is shown in these models, but enolate face selectivity will be discussed later. In some cases, boatlike transition-state models are invoked to interpret selectivity inversions [401, 402, 666], Moreover, Heathcock and coworkers [105] obtained evidence for the influence of an excess of n-B BOTf on the stereoselectivity of the aldol reactions of Z-enolates. In such reactions, anti aldols can be formed preferentially (see bdow). 

The titanium enolate of IV-propionyloxazolidinone 5.30 (R = Me) reacts highly selectively with s-trioxane at -78°C. The least hindered face of the chelate 6.89 is attacked [666, 1042] (Figure 6.77). Unexpectedly, the reaction of the boron enolate of 5.30 (R = Me, -Bu, PI1CH2) with hexafluoroacetone leads to compound 6.90, probably through an open transition state [1261] (Figure 6.77). 

The chiral auxiliary is the oxazolidinone (24) derived from IS,2R) norephedrine. Acylation with propionyl chloride gives (25) and this is deprotonated to afford exclusively the internally chelated Z-enolate, which reacts with methallyl iodide from the face opposite the methyl and phenyl groups of the auxiliary. The product (26), a 97 3 mixture of diastereomers, is purified to a ratio of better than 500 1. Reductive removal of the auxiliary and careful oxidation of the primary alcohol under non-racemising conditions affords the chiral (5)-aldehyde (27). This in turn is reacted with the boron enolate of (25), which furnishes with remarkable selectivity the u aldol product (28). The reason for the choice of boron rather than lithium is to invert the facial selectivity of the reaction— the enolate is no longer constrained to be planar by internal chelation and rotates in order to place the bulky dibutyl borinyl group on the opposite side to the methyl and phenyl ... 

If a chiral aldehyde reacts with an achiral enolate the induced stereoselectivity is determined by the inherent preference of the aldehyde to be attacked from its Re or Si face. If, however, a chiral aldehyde is combined with a chiral enolate one must consider whether the inherent selectivities of the two reagents will be consonant in one of the combinations ( matched pair ), but dissonant in the other combination ( mismatched pair ). Thus, different diastereoselectivity results from each combinations. The problem of insufficient stereoselectivity in the mismatched combination can be solved by means of highly efficient chiral enolates which can outplay the inherent selectivity of the aldehyde. The concept has been applied extensively in the context of boron enolates, a topic that has been reviewed comprehensively [52] and is discussed in detail in Chapter 3 of Part I of this book. 

Oppolzer s auxiliary opened, in addition, an access to a/iti-configured aldol adducts 272 (Scheme 4.62). For this purpose, silyl ketene N,0-acetal 271 was prepared from propionic sultam 92, obtained as a single diastereomer, according to the NMR spectra of the crude product, and isolated as a crystalline compound it was characterized as a cis-silicon enolate by a crystal structure analysis. For the subsequent Mukaiyama aldol addition, titanium tetrachloride was found to be the optimum Lewis acid to yield the awti-diastereomers 272 in excellent diastereoselectivity. Their formation under attack of the enolate to the Re-face of the aldehyde is consistent with an open transition state 275, wherein the Lewis acid-coordinated aldehyde is located on the face opposite to the sulfonyl group (Scheme 4.62) [136b]. An alternative approach to the a fi-aldol adducts was also elaborated, based upon cA-boron enolates 267 when they are reacted with aldehydes in the presence of titanium tetrachloride, an ti-selective aldol addition occurs leading to the products 272 rather than to sy -aldols 268 that result in the absence of the Lewis acid [136c]. 

Paterson I, Wallace DJ, Velazquez SM. Studies in polypropionate synthesis high -rr-face selectivity in syn and anti aldol reactions of chiral boron enolates of lactate-derived ketones. Tetrahedron Lett. 1994 35 9083-9086. 

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