The following acetate aldol reaction gives no diasteroselectivity:

Evans' acetate aldol showing little diastereoselectity

Because I don't know what the basis of above statement is (I heard it in a lecture and read it on some internet web pages), I expect the two products are formed as a racemic mixture.

For the related propionate aldol we can draw two (considering R of aldehyde to always be equatorial) possible transition states:

Transition states for Evans' aldol reactions

The question is why we don't get good selectivity if we compare the acetate aldol with the same transition states for the propionate aldol?

As a side-note: in practice chlorine is used instead of Me to obtain good selectivity and the chlorine will be eliminated finally by use of Zn/AcOH.

  • $\begingroup$ Quick reaction :) But still it's amide not ester. $\endgroup$
    – Mithoron
    Jul 3 '15 at 22:26
  • $\begingroup$ The Evans auxiliary is an imide. $\endgroup$
    – laminin
    Jul 3 '15 at 22:33
  • $\begingroup$ Yeah, is it hydrolyzed later? Btw your question is very narrow - it lowers chances for good answer $\endgroup$
    – Mithoron
    Jul 3 '15 at 23:17
  • $\begingroup$ With $\ce{LiOH/H2O2/NaHSO3}$ it can be hydrolized to a $\beta$-hydroxy-carboxylic acid. $\endgroup$
    – laminin
    Jul 3 '15 at 23:38
  • $\begingroup$ Do you have any sources for the transition states and the reactions itself? What are we talking about when we say failed selectivity, ist it racemic or only slight discrimination? $\endgroup$ Jul 4 '15 at 12:00

1. The acetate aldol reaction

Before looking at selective variants, its worth pointing out what an acetate aldol is.

An acetate aldol (below), is the simplest kind of aldol in which the β-hydroxyketone product has no methyl group at the α-position to the carbonyl. This is in contrast to the (more usual?) propionate aldol reaction in which the α-position contains a methyl group (as is common in polyketides).

enter image description here

Source: Modern methods in stereoselective aldol reactions, Wiley.

Early studies into acetate aldols quickly established that it was far harder to set a single stereo centre than to introduce two stereocentres concomitantly. This was due to the cyclic transition states involved (Zimmerman-Traxler model) in which the methyl group bound to the enolate (in the propionate aldol) exhibits a level of control which isn't present in the acetate aldol.

2. The Evans' auxiliary and its applications in the aldol reaction

Whilst many aldol reactions exhibit diastereoselectivity, they show no inherent enantioselectivity. Several approaches were developed to fix this including chiral auxiliaries and chiral reagents. One of the most 'famous' of these was Dave Evans' oxazolidinone auxiliaries.

These are used to gain enantioselectivity, but can also be used to override substrate control to get the desired product.

enter image description here

Source: Dave Evans' CHEM206 Lecture notes, Harvard

With propionate aldols, this works excellently (see above), giving d.r.'s well in excess of 20:1 (about the maximum NMR can detect), with a 300:1 d.r. being quoted by Evans'. With acetate aldols however, the selectivity drops down to 1:1.

Let us consider the TS for the propionate aldol.

enter image description here

Source: Dave Evans' CHEM206 Lecture notes, Harvard

Evans' himself discusses the two diastereomeric TS structures. The favoured on top we now rationalise by opposing the dipoles between the auxiliary and enolate.

An alternate reason for why the disfavoured TS was disfavoured was provided by computational work, in which it appears that the methyl group in the propionate system clashes with the auxiliary.

enter image description here

Source: Evans' and Houk.

By disfavouring one TS (Steric clash) and favouring another (opposing dipoles), we gain good diastereoselectivity.

When the α-methyl group is taken away (as it is in the acetate aldol), we lose the unfavourable interaction (no more steric clash between the enolate and the auxiliary) leaving us only with the favourable dipole-dipole minimisation.

There is perhaps also another argument here which is that without the α-methyl group the enolate is considerably smaller, meaning that the TS doesn't even need to be quite so organised in order for the reaction to proceed.

3. Selective acetate aldols

As a closing point, switching from boron --> tin, and using a slightly modified auxiliary does allow for selectivity to be achieved.

enter image description here

Source: Unknown

This works because the sulfur and tin remain coordinated throughout the reaction rather than with the Evans' chemistry where the oxygen points into space to allow the dipoles to oppose. This results in a much more ordered TS.

  • $\begingroup$ The dipole-dipole interaction will remain the same for both acetate and propanoate enolates, and this would lead to some stereoselectivity in both cases, but the steric interaction is diminished for acetate, hence there is no stereoselectivity. This makes me conclude that the steric factor is the only important factor here, am I right? By the way, great question and answer. $\endgroup$
    – EJC
    Jul 24 '16 at 22:43

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