Stereoselectivity reagent 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. ... 

In addition to the problems of substrate- or reagent-controlled stereoselectivity, the problem of simple synjanti diastereoselectivity arises. Most studies have been performed on the crotyl derivatives. Table 2 summarizes some of these under the latter aspect. Essentially all types of reagents related to the appropriate 2-propenylmetal reagents collected in Table 1 are known. 

With Reagent-Controlled Stereoselectivity With Auxiliary Control... 

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. 

P-Allyl-to-(isopinocampheyl)borane exhibits high stereoselectivity in reactions with chiral a-substituted aldehydes.40 The stereoselectivity is reagent controlled, in that there is no change in stereoselectivity between the two enantiomeric boranes in reaction with a chiral aldehyde. Rather, the configuration of the product is determined by the borane. Both enantiomers of (Ipc)2BH are available, so either enantiomer can be prepared from a given aldehyde. 

These reagents exhibit reagent control of stereoselectivity and have proven to be very useful in stereoselective synthesis of polyketide natural products, which frequently contain arrays of alternating methyl and oxygen substituents.44... 

Reagent-controlled stereoselectivity can provide stereochemical relationships over several centers when a combination of acyclic and chelation control and cyclic TS resulting from transmetallation is utilized. In reactions mediated by BF3 or MgBr2 the new centers are syn. Indium reagents can be used to create an anti relationship between two new chiral centers. The indium reagents are formed by transmetallation and react... 

Extension of this strategy enables syntheses of both protected D-threonine and L-allo-threonine, in which reagent-controlled stereoselective epoxidation of a common intermediate is the key step (Scheme 4.8).53... 

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. 

In this section an approach is discussed whereby absolute configurational assignment is based on auxiliary- or reagent-controlled stereoselective key reactions. The stereochemical outcome of the reaction used for the assignment must be predictable, from either the absolute configuration of the auxiliary or the reagent, by a rule or (better) a well-defined model of the transition state220. 

In the cases where auxiliary- or reagent-controlled stereoselectivity is employed for the assignment of absolute configurations, it must always be considered that the normal stereochemical outcome of the particular reaction may be reversed depending on both the structure of the starting material and/or the reaction conditions. Some examples are discussed ... 

Whereas the thermodynamic route described above relied on reagent control to establish the spongistatin C19 and C21 stereocentres, the discovery of highly stereoselective 1,5-anti aldol reactions of methyl ketones enabled us to examine an alternative,16 substrate-based stereocontrol route to 5. Regioselective enolisation of enantiomerically pure ketone 37, derived from a readily available biopolymer, gave end... 

Stereoselective chelate-controlled addition of Grignard reagents to tetrahydrooxepine derivatives (Equation 3) involves Zr-catalyzed kinetic resolution with (i )-[EBTHI]Zr-BINOL (BINOL= l,l -bi-2-naphthol) <1996JA4291, 1997JA6205, 1999JOC854>. 

The known allylic alcohol 9 derived from protected dimethyl tartrate is exposed to Sharpless asymmetric epoxidation conditions with (-)-diethyl D-tartrate. The reaction yields exclusively the anti epoxide 10 in 77 % yield. In contrast to the above mentioned epoxidation of the ribose derived allylic alcohol, in this case epoxidation of 9 with MCPBA at 0 °C resulted in a 65 35 mixture of syn/anti diastereomers. The Sharpless epoxidation of primary and secondary allylic alcohols discovered in 1980 is a powerful reagent-controlled reaction.12 The use of titanium(IV) tetraisopropoxide as catalyst, tert-butylhydro-peroxide as oxidant, and an enantiopure dialkyl tartrate as chiral auxiliary accomplishes the epoxidation of allylic alcohols with excellent stereoselectivity. If the reaction is kept absolutely dry, catalytic amounts of the dialkyl tartrate(titanium)(IV) complex are sufficient. 

BBN effects the hydration of the C=C double bond of 1-methylcyclohexene according to Figure 3.25 in such a way that after the oxidative workup, racemic 2-methyl-l-cyclohexanol is obtained. This brings up the question Is an enantioselective H20 addition to the same alkene possible The answer is yes, but only with the help of reagent control of stereoselectivity (cf. Section 3.4.2). 

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 ... 

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. 

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).

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. 

BBN attacks the C=C double bond of 3-ethyl-l-methylcyclohexene according to Figure 3.20 exclusively from the side that lies opposite the ethyl group at the stereocenter. Consequently, after oxidation and hydrolysis, a fra s,fra s-configured alcohol is produced. The question that arises is Can this diastereoselectivity be reversed in favor of the cis,trans isomer The answer is possibly, but, if so, only by using reagent control of stereoselectivity (cf. Section 3.4.4). 

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