Enantiotopic group selectivity

Nickel(O) complexes catalyse [2+2+2] cycloaddition. Catalytic asymmetric synthesis of isoquinoline derivative 134 is possible based on enantiotopic group-selective formation of the nickelacyclopentadiene 133 from 132 using the Ni(0) complex coordinated by a chiral ligand under acetylene atmosphere [56]. 

Direct intermolecular aldol reactions, catalysed by proline, between tetrahydro-4H-thiopyranone (25) and racemic aldehydes exhibit enantiotopic group selectivity and dynamic kinetic resolution, with ee% of >98% in some cases.109... 

Aldol reaction. Aldol reaction catalyzed by proline and derivatives has been reviewed. A ball-mill operation on cycloalkanones, ArCHO with (5)-proline leads to predominantly anri-aldol products. The aldol reaction between 4-tetrahydrothiapyrone with the racemic 3-aldehyde based on the same heterocycle shows excellent enantiotopic group-selectivity and thence manifesting dynamic kinetic resolution. ... 

Scheme 8.10. Reaction of divinyl carbinol under (+)-AE conditions as an example of enantiotopic group selectivity in epoxidation chemistry. Matched cases of enantiofacial selectivity are shown with bold arrows. Qualitative rate differences are on the order kj k2, ks k4 (without specifying an order for k2 vi. k3 (however, cf. Scheme 8.8b). Note that the products arising from the pairs ki/k3 and k2/k4 are enantiomers.

Some reactions proceed with enantiotopic group selectivity (see appendix) in the sense that a kinetic resolution is coupled to an initial asymmetric reaction. An example is the enzyme-catalyzed partial hydrolysis of achiral meso-diol diacetate esters to chiral, optically pure monoesters (Y.-F. Wang, 1984). The pro-S group of the diacetate is preferentially cleaved by pig pancreatic lipase. The other group is cleaved somewhat more slowly = 15.6). 

An enantioselective direct aldol reaction was reported in 2005 by Ward et al., who showed that proline-catalysed reactions of tetrahydro-4//-thiapyranone with l,4-dioxa-8-thia-spiro[4.5]decane-6-carboxaldehyde and with mesoldl 1,4-dioxa-8-thiaspiro[4.5]decane-6,10-dicarboxaldehyde proceeded via DKR and gave single adducts with excellent enantioselectivities (Scheme 2.100). " The high enantiotopic group selectivity resulted from the high intrinsic diaster-eofacial selectivity of the aldehydes. Since the first reaction depicted in Scheme 2.100 was complicated on a larger scale, it was carried out more recently in the... 

Sugai and coworkers [30] have studied the substrate specificity and enantio-selectivity of NHase and amidase from R. rhodochrous IFO 15564 by applying a series of a,a-disubstituted malononitriles, which the NHase converted into the corresponding malonic diamides. Subsequently, the amidase preferentially hydrolyzed the pro-(R) amide in an enantiotopic group-selective manner. The introduction of a fluorine atom at the a-position caused an inhibitory effect on the amidase. A direct application of this route led to the synthesis of ( )-a-cyano- -fluoro-a-phenylacetic acid (CFPA). 

Ward DE, Jheengut V, Akinniisi OT. Enantioselective direct intermolecular aldol reactions with enantiotopic group selectivity and dynamic kinetic resolution. Org. Lett. 2005 7 1181-1184. 

Inoue T, Kitagawa O, Saito A, Taguchi T. Catalytic asymmetric iodocarbocyclization reaction of 4-alkenylmalonates and its application to enantiotopic group selective reaction. J. Org. Chem. 1997 62(21) 7384-7389. 

This point is also strikingly demonstrated in the enantiotopic group and diastereofacial selective allylboration of the me so complex 5 that provides the (45,65)-diastereomer with 45 1 diastereoselectivity and >98%ee85b. 

Schreiber et al.47 have described a mathematical model that combines enantiotopic group and diastereotopic face selectivity. They applied the model to a class of examples of epoxidation using several divinyl carbinols as substrates to predict the asymmetric formation of products with enhanced ee (Scheme 4-28). 

Many instances of stereospecific selection of enantiotopic groups or faces may be found in nature. One such is extracted from the tricarboxylic acid cycle and is shown in Exercise 1.6. At each step, achiral reactants are transformed to achiral products with high stereospecificity ... 

Rehwinkel, H., Skupsch, J., and Vorbrtiggen, H., E- or Z-selective Homer-Wittig reactions of suhsti-tuted bicyclo[3.3.0]octane-3-ones with chiral phosphonoacetates. Tetrahedron Lett., 29, 1775, 1988. Tiillis, J.S., Vares, L., Kann, N., Norrby, P.-O., and Rein, T., Reagent control of geometric selectivity and enantiotopic group preference in asymmetric Horner-Wadsworth-Emmons reactions with meso-dialdehydes, J. Org. Chem., 63, 8284, 1998. 

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... 

There are two (limiting) possibilities that could explain the enantioselectivity a group-selective metal insertion distinguishing the enantiotopic allylic protons, or a face-selective addition that distinguishes the enantiotopic double bond faces. Figure... 

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). 

Because biological reactions involve chiral enzymes, enantiotopic groups and faces typically show different reactivity. For example, the two methylene hydrogens in ethanol are enantiotopic. Enzymes that oxidize ethanol, called alcohol dehydrogenases, selectively remove the pro-/ hydrogen. This can be demonstrated by using a deuterated analog of ethanol in the reaction. 

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