Substrate control of diastereoselectivity

Alternatively, substrate control of diastereoselectivity can rely on attractive catalyst substrate interactions. This requires in general special functional groups which allow for a directed hydroformylation, which is summarized in Sect. 6 (vide infra). 

Fig. 3.26. cis-Selective hydration of a chiral, racemic, trisubstituted alkene with induced diastereoselectivity A corresponds to the extent of the substrate control of diastereoselectivity. 

Table 7 summarizes several important aspects of substrate control of diastereoselectivity. Variation of either the relative configuration of the lactone or of the olefin geometry allows access to the opposite diastereochemical series (Table 7, entries 2-5)80. Since only the ( )-olefins are formed, a successful chirality transfer either requires ionization of the lactone from a single conformation B with nucleophilic attack being faster than stereorandomization or an involvement of solely the, mi,.n -7t-allyl complex generated via n-a-n rearrangement prior to C —C bond formation. The soft carbanion attacks the allyl complex charge directed distal to the carboxylate anion. 

The reaction led to two products. The major one had an E-configurated double bond from which we conclude that it must be the anti-Cram isomer 35. Therefore reagent control of diastereoselectivity dominated the reaction. The minor product of the reaction contained a Z-double bond. It must arise via transition state 36 and should therefore be the product of substrate control of diastereoselectivity. 

Hupe, E. Calaza, M. I. Knochel, P. Substrate-controlled highly diastereoselective synthesis of primary and secondary diorganozinc reagents by a hydroboration/B-Zn exchange sequence. Chem. Eur. J. 2003, 9, 2789-2796. 

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. 

If, as in the reaction example in Figure 3.32, during the addition to enantiomerically pure chiral alkenes, substrate and reagent control of diastereoselectivity act in opposite directions, we have a so-called mismatched pair. For obvious reasons it reacts with relatively little diastereoselectivity and also relatively slowly. Side reactions and, as a consequence, reduced yields are not unusual in this type of reaction. However, there are cases in which mismatched paris still give rise to highly diastereoselective reactions, just not as high as the matched pair. 

Conversely, the addition of enantiomerically pure chiral dialkylboranes to enantiomerically pure chiral alkenes can also take place in such a way that substrate control and reagent control of diastereoselectivity act in the same direction. Then we have a matched pair. It reacts faster than the corresponding mismatched pair and with especially high diastereoselectivity. This approach to stereoselective synthesis is also referred to as double stereodifferentiation. 

The substrate control of the diastereoselectivity, which originates from aldehyde B and makes a Felkin-Anh transition state preferred in the attack of the phosphonate ion on the C=0 double bond (compare Figure 8.11, middle). 

This is a LiAlH4 reduction of the a,(3-unsaturated ketone of the seven-membered ring. The low temperature and the use of only 0.25 eq. of LiAlH4 ensures that only the fastest reaction takes place and no reduction of the ketone in the five-membered ring or of the double bonds is observed. This reduction proceeds with substrate control of the diastereoselectivity, because the hydride attacks the molecule mainly from its convex and not from its concave face. This becomes clear when looking at 44 which is a three-dimensional representation of 31. Whether the diastereomeric ratio of 10 1 is important, will become clear in the further synthesis. 

In landmark studies involving the determination of the relative configuration of carbohydrates, Emil Fischer reported in 1889 that the homologation of D-(-t-)-mannose (1) with cyanide gave a single diastereomeric adduct (Equation 1) [34]. Following hydrolysis of the nitrile, heptonic acid 2 was isolated in 87 % yield. This is perhaps the earliest example of acyclic substrate control in diastereoselective carbonyl addition reactions. 

Diastereoselective Hydrogenation since -OH directs the H2, there is a possibility for control of stereochemistry - sensitive to H2 pressure catalyst cone, substrate cone, solvent. 

Diastereoselective hydroformylation can be achieved in special cases through passive substrate control in which conformational preferences are transferred in the corresponding selectivity-determining hydrometalation step [4-6]. A recent example is the highly diastereoselective hydroformylation of a kainic acid derivative (Scheme 17) [64], The selective formation of the major diastereomer has been explained via a reactive substrate conformation in which allylic 1,2-strain has been minimized. In this situation the czs-positioned methylene carbonylmethoxy group controls the catalyst attack to occur from the si face exclusively. 

Scheme 17 Diastereoselective hydroformylation of a kainic acid derivative relying on passive substrate control...

As described hitherto, diastereoselectivity is controlled by the stereogenic center present in the starting material (intramolecular chiral induction). If these chiral substrates are hydrogenated with a chiral catalyst, which exerts chiral induction intermolecularly, then the hydrogenation stereoselectivity will be controlled both by the substrate (substrate-controlled) and by the chiral catalyst (catalyst-controlled). On occasion, this will amplify the stereoselectivity, or suppress the selectivity, and is termed double stereo-differentiation or double asymmetric induction [68]. If the directions of substrate-control and catalyst-control are the same this is a matched pair, but if the directions of the two types of control are opposite then it is a mismatched pair. 

Substrate control This refers to the addition of an achiral enolate (or allyl metal reagent) to a chiral aldehyde (generally bearing a chiral center at the a-position). In this case, diastereoselectivity is determined by transition state preference according to Cram-Felkin-Ahn considerations.2... 

The substrate-controlled diastereoselective addition of lithiated alkoxyallenes to chiral nitrones such as 123, 125 and 126 (Scheme 8.32) furnish allenylhydroxyl-amines as unstable products, which immediately cydize to give enantiopure mono-orbicyclic 1,2-oxazines (Eqs 8.25 and 8.26) [72, 76]. Starting with (R)-glyceraldehyde-derived nitrone 123, cydization products 124 were formed with excellent syn selectivity in tetrahydrofuran as solvent, whereas precomplexation of nitrone 123 with... 

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