Relative stereoselective induction

If stoichiometric quantities of the chiral auxiliary are used (i.e., if the chiral auxiliary is covalently bonded to the molecule bearing the prochiral centres) there are in principle three possible ways of achieving stereoselection in an aldol adduct i) condensation of a chiral aldehyde with an achiral enolate ii) condensation of an achiral aldehyde with a chiral enolate, and iii) condensation of two chiral components. Whereas Evans [14] adopted the second solution, Masamune studied the "double asymmetric induction" approach [22aj. In this context, the relevant work of Heathcock on "relative stereoselective induction" and the "Cram s rule problem" must be also considered [23]. The use of catalytic amounts of an external chiral auxiliary in order to create a local chiral environment, will not be considered here. 

Relative stereoselective induction and the "Cram s rule problem" "Double stereodifferentiation ". 

The above observations are quite pertinent here since they introduce us to "relative stereoselective induction" (or "double stereodifferentiation") studied by Heathcock [23]- and to "double asymmetric induction" [29] developed by Masamune [22]. 

Effective 1,4-asymmetric induction has been observed in reactions between 2-(alkoxyethyl)-2-propenylsilanes and aldehydes. The relative configuration of the product depends on the Lewis acid used. Titanium(IV) chloride, in the presence of diethyl ether, gave 1,4-ijn-products with excellent stereoselectivity with boron trifluoride-diethyl ether complex, the amt-isomer was the major product, but the stereoselectivity was less83. 

The asymmetric induction cannot be explained simply by steric interaction because the R group in the aldehyde is far too remote to interact with the tartrate ester. In addition, the alkyl group present in the tartrate ligand seems to have a relatively minor effect on the overall stereoselectivity. It has thus been proposed that stereoelectronic interaction may play an important role. A more likely explanation is that transition state A is favored over transition state B, in which an n n electronic repulsion involving the aldehyde oxygen atom and the /Mace ester group causes destabilization (Fig. 3-6). This description can help explain the stereo-outcome of this type of allylation reaction. 

Rl = large, Rg = small substituent). From the data summarized in Table 39, it is apparent that the asymmetric induction observed is excellent for aldehydes, and that stereoselection generally increases as the aldehyde ligand becomes more sterically demanding. The major aldol adduct, 166, has been rationaUzed as evolving from transition state A. A priori it is difficult to evaluate the relative... 

The reaction of iV-benzyloxycarbonyl L-proline acid chlorides 134 with imine 135 in the presence of triethylamine, at room temperature, gave the corresponding spiro-(3-lactams 136, 137 as a 1 1 mixture of diastereoisomers, which were separated by column chromatography. The Staudinger reaction proceeds with complete stereoselectivity with a cis relative disposition of the pyrrolidine nitrogen and the phenyl group, but no asymmetric induction was observed. However, very... 

Racemate separation by stereoselective ligand exchange occurs when a chiral matrix complex has additional coordination sites that are capable of readily exchanging a racemic substrate ligand. The chiral induction, i. e., the efficiency of the matrix complex, is related to the product distribution which depends on the relative stabilities of the complexes with the two enantiomers of the racemic substrate (Fig. 8.1). The problem to be solved in the design of effective chiral matrix complexes for specific racemic substrates is therefore related to isomeric analyses of the type discussed in Section 8.1. 

Asymmetric Desymmetrization. Desymmetrization of an achiral, symmetrical molecule is a potentially powerful but relatively unexplored concept for the asymmetric catalysis of carbon-carbon bond formation. While the ability of enzymes to differentiate between enantiotopic functional groups is well known, little is known about the similar ability of nonenzymatic catalysts to effect carbon-carbon bond formation. The desymmetrization by the enantiofacial selective carbonyl-ene reaction of prochiral ene substrates with planar symmetry provides an efficient access to remote internal asymmetric induction which is otherwise difficult to attain (eq 6). The (2R,5S)-xyn product is obtained in >99% ee along with more than 99% diastereoselectivity. The desymmetrized product thus obtained can be transformed stereoselectively by a more classical diastereoselective reaction (e.g., hydroboration). 

The effect of substituents on the stereoselectivity has been studied in the acid-catalyzed hydrolysis of a series of aryloxiranes. Work on the influence of temperature on the steric course of the reaction has demonstrated that the tendency towards retention is explained by the high degree of carbocationic nature in the transition state leading to the cis products, the favorable entropy content of the transition state of cis addition, and the relatively low enthalpy barrier of the benzyl C-0 bond. At the same time, almost complete tram selectivity can be observed in aliphatic and cycloaliphatic oxiranes and ionization of the C-0 bond is associated with high enthalpy values. Attempts have been made to separate the inductive, conformational, and stereoelectronic effects. 3,4-Epoxytetrahydropyran was used to study the inductive effect while the corresponding cis- and trans-methyl derivatives were employed to examine the stereochemical and conformational factors. ... 

The addition of chiral allylic bromides of the general type 247 to achiral aldehydes mediated by CrCb proceeds with a high degree of stereocontrol in which the bromide acts as the stereodominant component (Scheme 10-81) [148]. In all cases examined, major diastereomer 248 has an all-.vyn arrangement of the y-vinyl and <5-methyl substituents. On the basis of this stereochemical outcome the following conclusions can be drawn (1) the <5-center determines the stereochemical outcome of the newly created stereocenters (y and //), (2) the relative dia-stereoselection of the reaction is not affected by the presence of stereogenic centers in the allylic bromide, and (3) additional stereocenters in the e- and c-posi-tions of the bromide increase the diastereofacial selectivity but have no influence on the sense of the asymmetric induction. 

These strategies are often chosen when relationships are 1,4- or more remote. In 211 and 216 the relationships between the groups of chiral centres are 1,4 at best. However, it is possible to control 1,4-relationships, and even a few that are more remote, by induction (that is stereoselective reactions) from existing centres and that is the concern of this part of the chapter. We shall first look at some relatively simple methods and then return to the aldol reaction. 

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