Chiral cascade molecules

Scheme 21. Chiral building blocks as core units in the synthesis of cascade molecules.

The third group of target molecules comprises chiral carboxylic acid and their derivatives esters, amides and nitriles. Enantiomerically pure esters are prepared in an analogous manner to the enantiomerically pure alcohols discussed earlier [i.e. by esterase- or lipase-catalyzed hydrolysis or (trans)esterification]. However, these reactions are not very interesting in the present context of cascade reactions. Amides can be produced by enantioselective ammoniolysis of esters or even the... 

Two chiral [2.2.1]cryptands, one incorporating the methyl 4,6-O-benzylidene-a-D-mannopyranoside unit (70), the other the methyl 4,6-0-[(S)-phenylethylidene]-a-D-mannopyranoside unit (77), may exhibit the same two different modes of complexa-tion as before binding of primary alkylammonium cations via hydrogen bonds between the NH-f group and the heteroatoms of the ligand or cascade complexation of ion pairs. Chart 2 shows the constitutions of the two cryptands 70 and 77 and is also indicative that the approach of guest molecules may occur from the more sterically hindered side. 

Chen and co-workers [72] reported an asymmetric quadruple amino catalytic domino reaction catalyzed by secondary amines. The reaction consists of a quadruple iminium-enamine-iminium-enamine cascade reaction initiated by a Michael addition of oxindole 114 to the enal and a subsequent intramolecular Michael reaction between the enamine formed in the previous step and the unsaturated oxindole to yield intermediate 116. Next, this intermediate reacts with another molecule of enal via a Michael addition of the oxindole to the enal. The sequence ends with an intramolecular aldol reaction between the preformed enamine and the aldehyde. This organocascade reaction affords highly complex spirooxindoles 118 bearing six contiguous chiral centers in excellent yields and with excellent diastereo- and enantioselectivities (Scheme 10.31). 

The reason that cascade reactions on nitrile-containing compounds are not mainstream yet in chemical synthesis is the fact that chiral molecules are mainly used in the pharmaceutical industry, a small and conservative industry because of health care regulations. Enzyme usage in food or detergent appHcations has taken off to much larger volumes, resulting in higher quantities and more... 

Nicolaou and coworkers completed the enantioselective synthesis of these two natural products molecules through a short and equally efficient route (12 steps from commercially available material with the 4% overall yield) involving a series of cascade reactions and novel skeletal rearrangements [107b]. This unique route commenced with a CBS asymmetric reduction of ketone 288 that is easily generated from the resveratrol monomer (Scheme 10.55). The chiral benzylic alcohol 289 was obtained in 85% yield and 95% ee in the presence of one equivalent of catecholborane and catalytic amount of (/ )-(+)-2-methyl-CBS-oxazaborolidine. This newly formed C8a center would be served as a chiral source by which other stereocenters within the architectnre... 

Inspired by the success of intramolecular addition and tautomerization of aldehydes with a pendant alkyne through cooperative catalysis of a secondary amine and an An complex, in 2008, Yang et al. reported a cascade reaction with the combination of a copper complex and an achiral secondary amine catalyst for the synthesis of attractive carbocycles [48]. This chemistry merged a pyrrolidine-promoted Michael addition via iminium ion intermediates and a Cu-catalyzed cycloisomerization protocol (Scheme 9.54). Various ketones and alkyne-tethered active methylene compounds could be converted into densely functionalized cyclopentene derivatives. Although the asymmetric version was not given, the chemistry described here was amenable for the implementation of asymmetric synthesis of such functionalized molecules by a combination of chiral amines and suitable Au complexes. 

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