Asymmetric reactions group-selective

Interligand asymmetric induction. Group-selective reactions are ones in which heterotopic ligands (as opposed to heterotopic faces) are distinguished. Recall from the discussion at the beginning of this chapter that secondary amines form complexes with lithium enolates (pp 76-77) and that lithium amides form complexes with carbonyl compounds (Section 3.1.1). So if the ligands on a carbonyl are enantiotopic, they become diastereotopic on complexation with chiral lithium amides. Thus, deprotonation of certain ketones can be rendered enantioselective by using a chiral lithium amide base [122], as shown in Scheme 3.23 for the deprotonation of cyclohexanones [123-128]. 2,6-Dimethyl cyclohexanone (Scheme 3.23a) is meso, whereas 4-tertbutylcyclohexanone (Scheme 3.23b) has no stereocenters. Nevertheless, the enolates of these ketones are chiral. Alkylation of the enolates affords nonracemic products and O-silylation affords a chiral enol ether which can... 

In the second category, a functional site adjacent to that at which an asymmetric reaction is to be effected is reacted with an optically pure reagent (the chiral auxiliary or chiral adjuvant) to give an optically pure modified reactant. In the subsequent reaction to form the new chiral site, two diastereoisomers would be formed in unequal proportions (the reaction is then said to be diastereo-selective). When the chiral auxiliary is then subsequently removed, one of the enantiomers would be present in a greater proportion [e.g. (c), where the optically pure auxiliary reacts with the carboxyl group, and the subsequent reaction is controlled by the chirality of the auxiliary]. A further point to note is that frequently the mixture of diastereoisomers may be separated readily by one of the latest chromatographic techniques (Section 2.31), in which case removal of the auxiliary leads to the isolation of the pure enantiomers. 

The asymmetric synthesis of (—)-denticulatin A (30) shows an interesting application of the boron aldol chemistry (Scheme 6) [23]. In a group-selective aldol reaction between the weso-aldehyde 27 and (5)-28, the hydroxyalde-hyde 29 was formed with > 90 % de, which spontaneously cyclized to the lactol 31. The configuration at the stereocenters of C-2 and C-3 in 29 is in accordance with the induction through the sultam auxiliary as well as with preference of an a-chiral aldehyde to react to the ant/-Felkin diastereomer in an aldol reaction which is controlled by the Zimmermann-Traxler model [24, 25]. 

Compounds with asymmetric centers can be obtained from prochiral starting molecules by either face-selective reactions [1] (stereoheterotopic facial addition) or group-selective reactions (stereoheterotopic ligand substitution). The transition states of these selective stereodivergent reactions must be diastereomeric, and the kinetics are the same as those of parallel reactions with different products (enantiomers or diastereo-mers). The selectivity in the stereoselective event leading to the different transition states can never be exceeded by the final yield of the major stereoisomer. 

Relatively limited work on profene synthesis via carbonylation of benzyl-X derivatives has been reported from university groups. One exception is the stero-selective carbonylation of racemic benzylic bromides. The asymmetric reaction toward enantiomerically pure profenes could a priori proceed either by a kinetic resolution or by true asymmetric induction via the intermediacy of a trigonal substrate. Results from Arzoumanian et al. [35] strongly suggest that the carbonylation of 1-methylbenzyl bromide with oxazaphospholene-palladium complexes is a kinetic resolution process with a discriminative slow oxidative addition step. Best enantiomeric excess is about 64 % ee at 9 % chemical yield. Another possible way to synthesize enantiomerically pure profenes is to start from optically pure benzyl derivatives. Baird et al. investigated the carboxylation of optically active benzyl carbonates with palladium catalysts. The enantiomeric excess was only modest [36]. Thus, the development of an efficient catalytic asymmetric carbonylation of C-X derivatives is still an existing challenge. 

The next milestone appeared in the 1950s in the context of the development of asymmetric reactions. Various stereochemical reactions induced by facial discrimination of the carbonyl group have always been pivotal in this field. Cram s rule inspired an explosion of studies on diastereoselective reactions followed by enan-tioselective versions. The recent outstanding progress in the non-linear effect of chirality or asymmetric autocatalysis heavily relies on the carbonyl addition reactions. Thanks to these achievements, natural products chemistry has enjoyed extensive advancement in the synthesis of complex molecules. It is no exaggeration to say that we are now in a position to be able to make any molecules in as highly selective a manner as we want. 

Is there an asymmetric aspect to the reaction Are we, for instance, attacking one of two enantio-topic groups selectively ... 

The benzylic oxidation depicted in the second step of Scheme 8.28b is actually a formal group-selective differentiation of diastereotopic C-H bonds, since asymmetric epoxidation occurs prior to hydroxylation [125]. However, the reaction is an interesting example of a kinetic resolution that depends on the fact that the catalyst used reacts with the two epoxides at different rates, apparently because the chiral catalyst system ... 

Scheme 8.28. Formally group-selection insertion of oxygen into enantiotopic C-H bonds, (a) An asymmetric Kharasch reaction [124], The catalyst is similar to that shown in Scheme 8.12, except that each oxazoline bears two methyl substituents at C-5. (b) Kinetic resolution of dihydronaphthalenes [125]. The reaction uses a Jacobsen epoxidation catalyst (Scheme 8.6, type A).

The group-selective stereodifferentiation of C-C bonds has been investigated in the context of ring-expansion chemistry. In a symmetrical ketone like 4-tert-butylcyclohexanone, the two methylene groups adjacent to the ketone are enantiotopic. Several groups interested in the overall oxidation of these bonds have developed asymmetric versions of the classical Baeyer-Villiger and Beckmann reactions (Scheme 8.29a). 

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