Substrate control stereoselectivity

The reagent hydroxylation of lithium enolates Stereoselectivity (substrate control)... 

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. ... 

A sequence of straightforward functional group interconversions leads from 17 back to compound 20 via 18 and 19. In the synthetic direction, a base-induced intramolecular Michael addition reaction could create a new six-membered ring and two stereogenic centers. The transformation of intermediate 20 to 19 would likely be stereoselective substrate structural features inherent in 20 should control the stereochemical course of the intramolecular Michael addition reaction. Retrosynthetic disassembly of 20 by cleavage of the indicated bond provides precursors 21 and 22. In the forward sense, acylation of the nitrogen atom in 22 with the acid chloride 21 could afford amide 20. 

The latter work is a rare example in which a high stereoselectivity was reported for a substrate-controlled Ugi synthesis. In asymmetric Ugi reactions carried out with removable chiral auxiliaries, however, high diastei eoselections were achieved (see Section 1.4.4.3.1.). 

However, the use of ordinary achiral alkylcopper reagents instead of the chiral lithium bis(l-alkenyljcuprate also produced the same level of high diastereoselectivity, and thus it seems that the chirality at the y-position of 1 did not exert a significant influence upon the diastereoselectivity. The stereoselectivity was controlled by the stereogenic centers in the substrate. 

Reactions proceeding through a monocyclic TS with substrate control These reactions exhibit predictable stereoselectivity determined by the monocyclic... 

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... 

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. 

At this juncture, it is useful to look at Table 7-1, in which the syntheses of erythronolide and the ansa chain are used as examples to show that reagent-controlled syntheses are clearly more advantageous than substrate-controlled reactions in terms of three criteria the overall yield, overall stereoselectivity, and number of steps involved in each of the syntheses. A careful examination of Table 7-1 clearly shows the advantages of this strategy. 

Stereoselective cyclization controlled by a substituent remote from the reaction center is often difficult to achieve. However, 1-mediated cyclization of the substrates illustrated in Eq. 9.54 proceeds in a highly stereoselective manner when the hydroxy group is converted to a magnesium alkoxide prior to cyclization [99,100]. The effect of the alkoxide group is much more favorable than that of the corresponding TBS ether. 

Addition of the indium reagent derived from the foregoing (P)-allenylstannane to /8-benzyloxy-a-methylpropanal as the aldehyde substrate at low temperature afforded a 70 30 mixture of anti,anti and anti,syn adducts (Eq. 9.141). The improved dia-stereoselectivity in this case can be attributed to substrate control, reflecting the chelating ability of an OBn versus an ODPS group. The lower temperature may also account for the improved diasteroselectivity. 

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. 

O-Benzyllactaldehyde dimethylhydrazone 230 allows a substrate control in the addition reaction of organomagnesium halides, leading almost exclusively to the 5yn-isomer 231 (equation 155) . The resulting hydrazide can be reduced on Raney Ni to the corresponding iyw-aminoalcohol 232. The stereoselective Grignard addition to a similar A-formyl hydrazone 233 proceeds with 92% diastereoselectivity (equation 156). The silylation of the amide nitrogen by TMSCl provides the pure iyw-adduct . 

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

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.

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. 

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. 

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