Stereoselectivity in the aldol reaction

Tin(IV) enolates are generated by the reaction of lithium enolates with trialkyltin chlorides. The best stereoselectivity in the aldol reaction with tin(IV) enolates has been achieved by employing tri-phenyltin chloride. Syn/erythro aldol products were predominantly produced irrespective of the geometry of the starting enolates (Scheme 39). However, the aldol condensation via the enolate derived from norbomanone gave the anti/threo product predominantly (Scheme 40). ... 

Table 2 Stereoselectivity in the Aldol Reactions of Chiral Di(cyclopentadienyl)chlorozirconium Enolates...

In the same context, Trombini et al. developed other organocatalysts of this type bearing an imidazolium. Under solvent-free conditions, these catalysts were shown to be highly efficient at a remarkably low catalyst loading of 0.1 mol % to induce excellent stereoselectivities in the aldol reaction of cyclohexanone with aldehydes in the presence of water (Scheme 2.8). Moreover, exceptionally high values of TON (up to 930) were achieved in the case of the most reactive aromatic aldehydes. 

A DFT study of the origins of stereoselectivity in the aldol reaction of bicyclic amino ketones (20) with aromatic aldehydes has been reported (Scheme 18). ° Base-catalysed direct aldolization of a-alkyl-a-hydroxy trialkyl phosphonoacetates with aldehydes proceeds via a fully substituted glycolate enolate intermediate formed by a [l,2]-phosphonate-phosphate rearrangement. High enantioselectivity can be achieved by the application of chiral iminophosphorane catalysts. 

Yamaoka Y, Yamamoto H (2010) Super silyl stereo-directing groups for complete 1,5-syn and -anti stereoselectivities in the aldol reactions of p-siloxy methyl ketones with aldehydes. J Am Chem Soc 132 5354... 

The reactions with preformed enol derivatives provide a way to control the stereoselectivity of the aldol reaction. As with the Michael reaction (15-16), the aldol reaction creates two new chiral centers, and, in the most general case, there are four stereoisomers of the aldol product, which can be represented as... 

Compound 17 is the so-called (+)-Prelog-Djerassi lactonic acid derived via the degradation of either methymycin or narbomycin. This compound embodies important architectural features common to a series of macrolide antibiotics and has served as a focal point for the development of a variety of new stereoselective syntheses. Another preparation of compound 17 is shown in Scheme 3-7.11 Starting from 8, by treating the boron enolate with an aldehyde, 20 can be synthesized via an asymmetric aldol reaction with the expected stereochemistry at C-2 and C-2. Treating the lithium enolate of 8 with an electrophile affords 19 with the expected stereochemistry at C-5. Note that the stereochemistries in the aldol reaction and in a-alkylation are opposite each other. The combination of 19 and 20 gives the final product 17. 

One way to achieve a higher stereoselectivity in these aldol reactions could obviously be the variation of the alkoxy group on the pyrrolidine sidechain of the chiral auxiliary. Thus, Enders and co-workers synthesized the SAMP-analogue (159). While acetone-SAMP-hydrazone leads to a (+)-[3-hydroxyketone in 47% e.e., the corres-... 

From the illustrated (S)-valinol imide (175), the derived dibutylboryl enolates undergo condensation with a broad range of aldehydes in greater than 99% asymmetric induction for both newly formed asymmetric centers 180). Evans et al. have shown that the propionyl sidely chain in (175) may be replaced by other alkanoyl substituents without loss of stereoselectivity in the aldol type reaction 180). 

Organoaluminum and Sn(IV) Lewis acid-mediated [3 + 2] cycloadditions of oxa-zoles and aldehydes or diethyl ketomalonate have been observed [116]. The reactions are highly regioselective, with stereoselectivity highly dependent upon the Lewis acid used (Eq. 76). For example, the (BINOL)AlMe-promoted reaction between benzal-dehyde and the oxazole furnishes the oxazoline with a transicis ratio of 2 98. The selectivity is reversed with SnCU which results in a transicis ratio of 85 15. trans-5-Sub-stituted 4-alkoxycarbonyl-2-oxazolines are synthesized under thermodynamic conditions in the aldol reaction of isocyanoacetates with aldehydes [117]. 

Finally we ll have a quick look at how combinations of these methods have been applied. In the aldol reactions we have looked at so far there has been no chirality at the start. Both the aldehyde and the enolate have been achiral species that have reacted in a stereoselective way to give a particular diastereomer. With the aldol reaction there is a lot of opportunity to introduce aspects of chirality. The enolate could be chiral as could the aldehyde. In addition to this, the whole reaction could be mediated by a chiral catalyst. Although chiral enolates are most commonly associated with asymmetric methods (most famously the method of Evans in Chapter 27) it is important to remember that the components could just as easily be chiral and racemic. The diastereoselectivity that allows the Evans s chemistry to work with optically pure materials will operate whether the auxiliary is optically pure or not. 

If you would like to know more about how the existing chiral centre makes its influence felt then you are directed to the paper43 and a suggestion for transition states.44 For now we continue with the manipulations. The new hydroxyl group that has been formed in the aldol reaction can be used to direct a stereoselective reduction of the ketone in the way that we have already seen. So, P-hydroxyketone 179 is reduced to diol 181. 

When we discussed how -enolates of ethyl ketones such as 207 gave 1,3-control in the aldol reaction, we noted that there was 1,4-control too. Paterson did the same reaction on the corresponding methyl ketones and found that the lithium enolate (M = Li in 234) was unselective. The boron enolate with an achiral group 9 (M = dicyclohexyl-B) was selective giving 88 12 syn anti-235 in 84% yield but with a chiral group [M = (-)-(Ipc)2B] the stereoselectivity was significantly better35 (92 8). 

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). 

Magnesium enolates are similar to alkali metal enolates. For example, often the same stereoselectivity is observed in their formation and in the aldol reactions of these enolates. 

Boron enolates (other names are vinyloxyboranes, enol borinates, or boron enol ethers) are often employed in the aldol reaction because they show higher stereoselectivity than alkali and magnesium enolates. Extensive developmental work in this area has been carried out by Evans, Masamune and Mukaiyama, and their respective coworkers. - - The correspondence between enolate geometry and aldol stereochemistry is exceptional (Z)-enolates give syn/erythro aldol products, whereas ( )-enolates give anti/threo aldol products, albeit with slightly lower selectivity. 

A number of ethyl ketones and propionate esters derived from carbohydrates have been investigated in the aldol reaction. None of the compounds studied give useful levels of stereoselection. The most selective compound from this study is ketone (201 equation 121) syn aldols (202) and (203) are produced in a ratio of 79 21. 

In practice, eight stereogenic centers out of the 10 embedded in the target molecule have been created with remarkable efficiency and stereoselection via the aldol reactions I-III using (29). The overall yield was 30% and overall stereoselectivity approximately 90%. Many other natural product syntheses using the strategy outlined above are now on record. 

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