Unsubstituted Enolates

Simple diastereoselectivity does not arise when an a-unsubstituted enolate or an cnolate with two identical a-substituents is combined with an aldehyde. Provided that neither the aldehyde nor the enolate are chiral molecules, the products 6a and 6b are enantiomers. 

In addition to ketone enolates, azaenolatcs with chiral auxiliary groups attached to the nitrogen atom are suitable for the introduction of an a-unsubstituted enolate of the keto-type into an aldehyde in a stereoselective manner (see Section D.1.3.5.). 

However, addition of the corresponding oc-unsubstituted enolate, derived from (4S)-3-acetyl-4-isopropyl-1,3-oxazolidin-2-one (3), under similar conditions delivers a 52 48 mixture of dia-slcreomers6 93. 

The proline derived diamines 2 and 4 (vide supra) are also suitable chiral additives in enantiose-lective additions of a-unsubstituted enolates. Best results are obtained with the naphthyl derivative, as demonstrated in the tin(II) triflate mediated addition of the O-silylketene thio-acetal l-toT-butylthio-l-trimethylsilyloxyethane to aldehydes which delivers 3-hydroxythio esters in optical purities of up to 95% ee and chemical yields between 50 and 90 %24... 

Tryptophan derived catalyst 17 also allows the additions of a-unsubstituted enol ethers to aldehydes to be directed in an enantioselective manner38. 

Selenski investigated the use of chiral enol ether auxiliaries in order to adapt method F-H for enantioselective syntheses. After surveying a variety of substituted and unsubstituted enol ethers derived from a vast assortment of readily available chiral alcohols, she chose to employ enol ethers derived from trans-1,2-phenylcyclohexanol such as 73 and 74 (Fig. 4.37). These derivatives were found to undergo highly diastereoselective cycloadditions resulting in the formation of 75 and 76 in respective... 

The addition of doubly deprotonated HYTRA to achiral4 5 as well as to enantiomerically pure aldehydes enables one to obtain non-racemic (3-hydroxycarboxylic acids. Thus, the method provides a practical solution for the stereoselective aldoi addition of a-unsubstituted enolates, a long-standing synthetic problem.7 As opposed to some other chiral acetate reagents,7 both enantiomers of HYTRA are readily available. Furthermore, the chiral auxiliary reagent, 1,1,2-triphenyl-1,2-ethanediol, can be recovered easily. Aldol additions of HYTRA have been used in syntheses of natural products and biological active compounds, and some of those applications are given in Table I. (The chiral center, introduced by a stereoselective aldol addition with HYTRA, is marked by an asterisk.)... 

The utility of chiral oxazoline enolates in asymmetric synthesis has elegantly been demonstrated by Myers (106,120). The stereoselective aldol condensations of these enolates have been examined in a hmited number of cases (eq. [107]) (32,121). Assuming that the enolate formed has the geometry indicated in 164 (120b), the diastereoselection observed for both the aldol condensation and the previously reported alkylations favors electrophile attack on the Re face as indicated. In contrast, the unsubstituted enolate 163b exhibits significantly poorer diastereoface selection with a range of aldehydes (eq. [108]) (121). 

This reaction is similar to the attack of an alkene on a halogen, resulting in addition of the halogen across the double bond. The pi bond of an enol is more reactive toward halogens, however, because the carbocation that results is stabilized by resonance with the enol —OH group. Loss of the enol proton converts the intermediate to the product, an a-haloketone. We can stop the acid-catalyzed reaction at the monohalo (or dihalo) product because the halogen-substituted enol intermediate is less stable than the unsubstituted enol. Therefore, under acid-catalyzed conditions, each successive halogenation becomes slower. 

Stereoselective Aldol Reactions. The (R)- and (S)-2-hydroxy-1,2,2-triphenylethyl acetates (HYTRA) offer a simple soludon for a stereoselecdve aldol addition of a-unsubstituted enolates. When a suspension of HYTRA is treated in THF with 2 equiv of Lithium Diisopropylamide, a clear soludon of the enolate forms (eq 1). Subsequent dilution with 2-methylbutane followed by the addition of 2-methylpropanal affords predominantly the (R,R)-diastereomeric adduct. Alkaline hydrolysis not only delivers (/ )-3-hydroxy-4-methylpentanoic acid in 86-94% ee but also liberates the optically pure auxiliary reagent (/ )-1,2,2-triphenylethane-1,2-diol, which can be removed and reused (eq 1). - ... 

Another explanation takes into account that boat- and twist-shaped six-membered, closed transition states can successfully compete with the chair model. " Evans et al. pointed out that in a-unsubstituted enolate reactions, missing allyl strain interactions lead to lower selectivity in diastereoselective aldol reactions.Calculations indicate that a twist-boat can easily be formed from the U-configuration of a-unsubstituted enolates. The possible transition state in this case has a geometry like 34 and is favored by the chelating character of the complexation mode for the zinc cation and the outward-pointing substituents of the oxazolidinone moiety. This twist-boat transition state correctly predicts the stereochemical outcome of the reaction. 

Many of the previously mentioned auxiliaries do not lead to high selectivity with unsubstituted enolates. In this case, the use of Nagao s acetate aldol methodology is frequently applied [30]. For example, in a recent synthesis of pate-amine A, two such aldol reactions of 46 were used, both of which proceeded with >95%ds (Scheme 9-15) [31]. 

Very recently, Reissig has examined catalyst 26 with regard to the synthesis of non-racemic 2-siloxycyclopropanecarboxylate derivatives [45]. Catalyst 26 was active for the cyclopropanation of terminal enol ethers, but no cyclopropanated product was observed with internal enol ethers. The corresponding trans cyclopropane compound was isolated from the unsubstituted enol ether with moderate diastereoselectivity and moderate to low enantioselectivities, Eq. (10). Conversely, the corresponding cfs-cyclopropane was preferentially formed from 1-substituted enol ethers with moderate diastereomeric ratios and enantioselectivities. 

Structural parameters and relative energies for unsubstituted enol and thiol are reported in Table 1. Corresponding enegy curves are displayed in figure 1. 

The stability of the initially formed enolates has a crucial bearing on the direction of ring closure. a-Alkyl substituents destabilize the enolate in solution and the nonsubstituted enolate is favored. Diethyl 2-methylheptanedioate (14) cyclizes preferentially through the unsubstituted enolate (15a) rather than the substituted enolate (15b) to give (16) rather than (17). ° This is also the thermodynamic preference since the enolate (16b) is more stable than the enolate (17b) (Scheme 20). 

The problem of simple diastereoselectivity does not arise in aldol additions vhen an a-unsubstituted enolate 29 (R = H) or an enolate vith tv o identical a-substituents reacts vith an aldehyde or a prochiral ketone. The products 32a and 32b obtained from this combination are enantiomers, if neither the aldehyde nor the enolate is a chiral molecule. 

It is highly desirable that chiral a-unsubstituted enolates should be available by simple methods from enantiomerically pure starting materials that are inexpensive and readily accessible in both enantiomeric forms. This postulate seems to be fulfilled to a reasonable extent by (R)- and (S)-2-hydroxy-l,l,2-triphenylethyl acetate 83 ( HYTRA ) [53, 128, 129]. It is readily prepared from methyl mandelate vhich is first converted into triphenylglycol 82 and subsequently converted into the acetic ester 83 by treatment vith acetyl chloride (Eq. (34)). Both enantiomers of the reagent are readily accessible, because both (R)- and (S)-mandelic acid are industrial products [130]. Diol 82 and acetate 83 are commercially available. 

Oppolzer s sultams also provided a solution to the problem of the asymmetric acetate aldol addition based upon a Mukaiyama reaction of sUyl ketene N,0-acetal 276, derived from N-acetylsultam 92 (R = H). In the titanium tetrachloride-mediated reaction with various aldehydes, the diastereoselectivity is not particularly high - as typical for aldol additions of a-unsubstituted enolates. 

The Ipc ligands are highly effective for sy -selective aldol additions, as shown in Scheme 4.67 for 3-pentanone. The enolization with (—)-292 in the presence of the sterically demanding Hiinig s base leads to c/s-enolate 293 that upon reaction with methacrolein and crotonaldehyde yields sy -adducts 294 in excellent diastereoselectivity and fair enantioselectivity. The application of the procedure to acetone reveals a drastic decrease in enantioselectivity in the formation of aldols 296 - notorious for a-unsubstituted enolates. What is surprising is the opposite topicity c/s-enolate 293 adds predominantly to the Si-face of the... 

In many applications of Lewis acidic boron catalysts for Mukaiyama aldol additions of a-unsubstituted enolates, it turned out that it was particularly difficult... 

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