Substrate control of stereoselectivity

P-anomeric compounds led cleanly to the expected 6,7-trans adduct 22, a-galac-tosides were practically completely converted to the corresponding 6,7-cis product 24. This finding is particularly surprising, because the locus of structural change is relatively distant from the reaction center. As no conclusive pattern for substrate control of stereoselectivity was evident, a more systematic approach was desirable. 

The stereochemical result is no longer characterized solely by the fact that the newly formed stereocenters have a uniform configuration relative to each other. This was the only type of stereocontrol possible in the reference reaction 9-BBN + 1-methylcyclohexene (Figure 3.25). In the hydroborations of the cited chiral alkenes with 9-BBN, an additional question arises. What is the relationship between the new stereocenters and the stereocenter(s) already present in the alkene When a uniform relationship between the old and the new stereocenters arises, a type of diastereoselectivity not mentioned previously is present. It is called induced or relative diastereoselectivity. It is based on the fact that the substituents on the stereocenter(s) of the chiral alkene hinder one face of the chiral alkene more than the other. This is an example of what is called substrate control of stereoselectivity. Accordingly, in the hydroborations/oxidations of Figures 3.26 and 3.27, 9-BBN does not add to the top and the bottom sides of the alkenes with the same reaction rate. The transition states of the two modes of addition are not equivalent with respect to energy. The reason for this inequality is that the associated transition states are diastereotopic. They thus have different energies—just diastereomers. 

In the discussion of the hydroboration in Figure 3.26, you saw that one principle of stereoselective synthesis is the use of substrate control of stereoselectivity. But there are quite a few problems in stereoselective synthesis that cannot be solved in this way. Let us illustrate these problems by means of two hydroborations from Section 3.3.3 ... 

As minor products we expect the racemic trialkylboranes F and/or G F is favored by reagent and disfavored by substrate control of stereoselectivity, whereas for G it is exactly the opposite. 

The condition for the occurrence of a mutual kinetic resolution is therefore that considerable substrate control of stereoselectivity and considerable reagent control of stereoselectivity occur simultaneously. 

For the discussion in Sections 3.4.4 and 3.4.5, we will assume ( ) that k6 > k7 that is, the reagent control of stereoselectivity is more effective than the substrate control of stereoselectivity. The justification for this assumption is simply that it makes additional thought experiments possible. These are useful for explaining interesting phenomena associated with stereoselective synthesis, which are known from other reactions. Because the thought experiments are much easier to understand than many of the actual experiments, their presentation is given preference for introducing concepts. 

Fig. 3.31. Thought experiment I products from the addition of a racemic chiral dialkylborane to a racemic chiral alkene. Rectangular boxes previously discussed reference reactions for the effect of substrate control (top box reaction from Figure 3.26) or reagent control of stereoselectivity [leftmost box reaction from Figure 3.30 (rewritten for racemic instead of enantiomer-ically pure reagent)]. Solid reaction arrows, reagent control of stereoselectivity dashed reaction arrows, substrate control of stereoselectivity red reaction arrows (kinetically favored reactions), reactions proceeding with substrate control (solid lines) or reagent control (dashed lines) of stereoselectivity black reaction arrows (kinetically disfavored reactions), reactions proceeding opposite to substrate control (solid lines) or reagent control (dashed lines) of stereoselectivity.

Fig. 3.27. Thought experiment III Reagent control of stereoselectivity as a method for enhancing the substrate control of stereoselectivity (matched pair situation).

Although significant progress in the field of asymmetric hydroformylation has been made, it is limited to a rather narrow substrate scope. An alternative approach to a stereoselective hydroformylation might employ substrate control of a chiral alkenic starting material. Of particular use... 

Stereoselective Hydration of Unsymmetrical Alkenes and Substrate Control of the Stereoselectivity... 

Our earlier statements on substrate and reagent control of stereoselectivity during hydro-borations are incorporated in Figure 3.31. Because of the obvious analogies between the old and the new reactions, the following can be predicted about the product distribution shown ... 

At the beginning of Section 3.4, we wondered whether 3-ethyl-l-methylcyclohexene could also be hydroborated/oxidized/hydrolyzed to furnish the cis, trans-con 11 gured alcohol. There is a solution (Figure 3.32) if two requirements are fulfilled. First, we must rely on the assumption made in Section 3.4.3 that this atkene reacts with the cyclic borane in such a way that the reagent control of stereoselectivity exceeds the substrate control of the stereoselectivity. Second, both the alkene and the borane must be used in enantiomerically pure form. 

Fig. 3. 32. Thought experiment II reagent control of stereoselectivity as a method for imposing on the substrate a diastereoselectivity that is alien to it (mismatched pair situation).

Section 3.4.6—which, by the way, referred to Sharpless epoxidations—you learned that catalytic asymmetric syntheses are among the most elegant asymmetric syntheses and that they can rely on a substrate reacting (exclusively) with an enantiomerically pure reagent that is formed in situ from an achiral precursor molecule and a catalytic amount of an enantiomerically pure additive. It was emphasized that an exclusive reaction of this precursor molecule/additive complex with the substrate takes place if it is much more reactive than the achiral precursor molecule without the enantiomerically pure additive. If under these circumstances additive control of stereoselectivity occurs, this principle even allows recovery of the enantiomerically pure additive after the conversion, which is more convenient than if it could only be released from the product via a chemical reaction. 

The control of stereoselectivity in acyclic substrates is more difficult than in cyclic substrates. As discussed previously, palladium can serve as a template to provide rigidity in an acyclic system thus favoring higher stereoselectivity. Palladium(0)-mediated substitution of the chiral nonracemic ally acetate depicted below yields only racemic material68, n-o-n Rearrangement of the intermediate 7t-allyl complex involving the unsubstituted allyl terminus is probably faster than nucleophilic attack. 

Whereas the examples above used substrate control for stereoselective transannular aldol or related reactions, reagent control has also been reported for the transannular aldol reactions. One example is synthesis of the musk ordorants (R)-muscone and (R,Z)-5-muscenone by Knopff and co-workers. It involved enantioselective formation of 73 by the transannular aldol condensation of the symmetrical macrocyclic 1,5-diketone 72 using sodium ephedrate for desymmetrization (Scheme 20.19). The reaction was assumed to proceed by a reversible transannular aldol reaction followed by an enantioselective dehydration reaction. 

Stereoselective epoxidation can be realized through either substrate-controlled (e.g. 35 —> 36) or reagent-controlled approaches. A classic example is the epoxidation of 4-t-butylcyclohexanone. When sulfonium ylide 2 was utilized, the more reactive ylide irreversibly attacked the carbonyl from the axial direction to offer predominantly epoxide 37. When the less reactive sulfoxonium ylide 1 was used, the nucleophilic addition to the carbonyl was reversible, giving rise to the thermodynamically more stable, equatorially coupled betaine, which subsequently eliminated to deliver epoxide 38. Thus, stereoselective epoxidation was achieved from different mechanistic pathways taken by different sulfur ylides. In another case, reaction of aldehyde 38 with sulfonium ylide 2 only gave moderate stereoselectivity (41 40 = 1.5/1), whereas employment of sulfoxonium ylide 1 led to a ratio of 41 40 = 13/1. The best stereoselectivity was accomplished using aminosulfoxonium ylide 25, leading to a ratio of 41 40 = 30/1. For ketone 42, a complete reversal of stereochemistry was observed when it was treated with sulfoxonium ylide 1 and sulfonium ylide 2, respectively. ... 

Ketone 13 possesses the requisite structural features for an a-chelation-controlled carbonyl addition reaction.9-11 Treatment of 13 with 3-methyl-3-butenylmagnesium bromide leads, through the intermediacy of a five-membered chelate, to the formation of intermediate 12 together with a small amount of the C-12 epimer. The degree of stereoselectivity (ca. 50 1 in favor of the desired compound 12) exhibited in this substrate-stereocontrolled addition reaction is exceptional. It is instructive to note that sequential treatment of lactone 14 with 3-methyl-3-butenylmagnesium bromide and tert-butyldimethylsilyl chloride, followed by exposure of the resultant ketone to methylmagnesium bromide, produces the C-12 epimer of intermediate 12 with the same 50 1 stereoselectivity. 

An interesting way to control the stereoselectivity of metathesis-reactions is by intramolecular H-bonding between the chlorine ligands at the Ru-centre and an OH-moiety in the substrate [167]. With this concept and enantiomerically enriched allylic alcohols as substrates, the use of an achiral Ru-NHC complex can result in high diastereoselectivities like in the ROCM of 111-112 (Scheme 3.18). If non-H-bonding substrates are used, the selectivity not only decreases but proceeds in the opposite sense (product 113 and 114). 

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