Relative diastereoselective induction

In all the examples commented upon so far, we have dealt with reactions with internal diastereoselective induction. However, when a chiral centre is already present in one of the components [12] we must refer then to a relative diastereoselective induction, and Cram s rule [13] must be taken into account when the chiral centre is present at the a-position of the aldehyde (28). For instance, in the reaction shown in Scheme 9.7 of the four possible diastereomers only two are formed, the Cram-i yn-aldol 30a being the predominant diastereomer (see below 9.3.3). 

Carbonyl-Ene Reaction. BINOL-TiX2 reagent exhibits a remarkable level of asymmetric catalysis in the carbonyl-ene reaction of prochiral glyoxylates, thereby providing practical access to a-hydroxy esters. These reactions exhibit a remarkable positive nonlinear effect (asymmetric amplification) that is of practical and mechanistic importance (eq 19). The desymmetrization of prochiral ene substrates with planar symmetry by the enantiofacial selective carbonyl-ene reaction provides an efficient solution to remote internal asymmetric induction (eq 20). The kinetic resolution of a racemic allylic ether by the glyoxylate-ene reaction also provides efficient access to remote but relative asymmetric induction (eq 21). Both the dibromide and dichloride catalysts provide the (2R,5S)-syn product with 97% diastereoselectivity and >95% ee. 

Seven-membered ring lactones can be accessed in excellent yields by the Smia-mediated intramolecular Reformatsky reaction as well. Although several substitution patterns provide exceptional relative asymmetric induction in this process (equation 62), it is clear that high diastereoselectivity cannot be achieved for all substitution patterns in the formation of seven-membered ring lactones. ... 

Asymmetric induction from a stereocenter in a chiral group bound to N has also been studied, and good to excellent levels of relative diastereoselection have been observed (Scheme 35). Interestingly, incorporation of a N-phenethyl unit of appropriate absolute stereochemistry into (214) resulted in substantially improved selectivity for the 1,3-syn product diastereomer (compare results with 210, Scheme 34) 120b jhis is an example of double stereodifferentiation, a synthetic strategy that is discussed in Section 1.1.5. 

Of course this is no more than the problem of relative asymmetric induction which was first examined systematically by Cram (J) and Prelog (S.) nearly thirty years ago. Using various erythro or threo selective reagents even though one can reasonably control simple diastereoselection one still obtains mixtures of Cram" and "anti-Cram diastereomers ... 

Desymmetrization of an achiral, symmetrical molecule through a catalytic process is a potentially powerful but relatively unexplored concept for asymmetric synthesis. Whereas the ability of enzymes to differentiate enantiotopic functional groups is well-known [27], little has been explored on a similar ability of non-enzymatic catalysts, particularly for C-C bond-forming processes. The asymmetric desymmetrization through the catalytic glyoxylate-ene reaction of prochiral ene substrates with planar symmetry provides an efficient access to remote [28] and internal [29] asymmetric induction (Scheme 8C.10) [30]. The (2/ ,5S)-s> i-product is obtained with >99% ee and >99% diastereoselectivity. The diene thus obtained can be transformed to a more functionalized compound in a regioselective and diastereoselective manner. 

A high asymmetric induction in intramolecular hetero Diels-Alder reactions was found using chiral 1-oxa-1,3-butadienes with a stereogenic center in the tether [54]. Such compounds can easily be obtained by a Knoevenagel condensation of a 1,3-dicarbonyl compound such as iV,N-dimethylbarbituric acid with a chiral aldehyde bearing a dienophile moiety [169 a] (Scheme 2-3). With the stereogenic center in a-position relative to the oxadiene or dienophile moiety an excellent induced diastereoselectivity is obtained for the nearly exclusively formed trans-cycloadduct (simple diastereoselectivity = 97.9 2.1 and 98.3 1.7,... 

Several examples of chiral auxiliaries that rely on relatively remote stereogenic centres to control diastereoselectivity are known. Eor example, alkylation of the enolates of 1.44 and 1.46 to 1.45 and 1.47 is controlled via 1,4- and 1,3-asymmetric induction, respectively. 

Finally, examples of highly diastereoselective hydroxy enoate iodo-cyclizations will be mentioned. In the first case, the homoallylic asymmetric induction in the formation of 2,4-disubsti-tuted tetrahydrofurans was investigated41. When the ( )-substrates 3 were iodo-cyclized, the diastereomeric products 4 were formed in ca. 86% yield their relative abundance depended both on the nature of R and the solvent. The effect of the substituent R was interpreted by means of AM 1 calculations41. 

High 1,2-asymmetric induction was also observed when the substituent contains a heteroatom (e.g., oxygen or nitrogen), the best diastereoselectivity was achieved with a 3-hydroxy-4-alkene thioimidate. The relative stereochemistry of the product 4 was established either by transformation to known compounds or by H-NMR spectroscopy131 132. 

The diastereoselectivity in the intramolecular aziridination of 3-amino-4(3//)-quinazolinones bearing a chiral alkenyl substituent at C-2 is dependent on the size of the fused ring which forms, the relative position of the stereogenic centers (only examples of 1,3- or 1,4-asymmetric induction have been described), and the substitution pattern of the alkene22 37,38. 

On the basis of the desymmetrization concept, the kinetic optical resolution of a racemic substrate [66] can be recognized as an intermolecular version of desymmetrization. The kinetic resolution of a racemic allylic ether by the glyoxylate-ene reaction also provides efficient access to remote but relative [64] asymmetric induction. The reaction of allylic ethers catalyzed by the (f )-BINOL-derived complex (1) provides the 2R,5S)-syn products with > 99 % diastereoselectivity and > 95 % ee (Sch. 18). The high diastereoselectivity, coupled with the high ee, strongly suggests that the cata-lyst/glyoxylate complex efficiently discriminates between the two enantiomeric substrates to accomplish the effective kinetic resolution. In fact, the relative rates of the reactions of the enantiomers, calculated by use of the equation ... 

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