Enantioselective creation strategies

In the last 20 years a great deal of effort has been focused towards the immobilization of chiral catalysts [2] and disparate results have been obtained. In order to ensure the retention of the valuable chiral hgand, the most commonly used immobihzation method has been the creation of a covalent bond between the ligand and the support, which is usually a solid, hi many cases this strategy requires additional functionalization of the chiral hgand, and this change - together with the presence of the very bulky support - may produce unpredictable effects on the conformational preferences of the catalytic complex. This in turn affects the transition-state structures and thus the enantioselectivity of the process. 

Lasubines I and II are alkaloids containing a 4-arylquinolizidine substructure that have been isolated from plants of the Lythraceae family and have attracted the attention of synthetic chemists for some time. While numerous racemic syntheses of these and related compounds have been reported, only a few enantioselective syntheses are known. Some examples of these syntheses are given below, and the strategies involved in these examples are summarized in Scheme 92. Three of these syntheses involve the creation of the quinolizidine system by formation of one bond at the a- or 7-positions, while the fourth approach is based on a ring transformation associated with a photochemical Beckmann rearrangement. 

It is thus dear that the combination of epPCR and saturation mutagenesis constitutes an efficient way to explore protein sequence space with respect to enantioselectivity. Indeed, this strategy led to the creation of several other highly (S)-selective variants (ee = 88 - 91 % E= 20 - 25) [9,42], all of them being the descendents of the parent wild-type lipase, which is only slightly (S)-selective. 

List and coworkers reported an excellent approach to the enantioselective synthesis of P branched a amino phosphonates, which involved the extension of the dynamic kinetic resolution strategy (Scheme 3.53) [110] that was previously applied to the enantioselective reductive amination of a branched aldehydes by his research group (see Scheme 3.45). The method combines dynamic kinetic resolution with the parallel creation of an additional stereogenic center. They successfully accomplished the direct three component Kabachnik Fields reaction of 1 equiv each of the racemic aldehyde, p anisidine, and di(3 pentyl)phosphite in the presence of newly developed chiral phosphoric acid It. The corresponding p branched a amino phosphonates were obtained in high diastereo and enantioselectivities, especially for the aldehydes bearing a secondary alkyl group at the a position. 

Alternatively, enantioselective nucleophilic addition to imines followed by intramolecular trapping of the transient amino intermediate with creation of a new C-N bond constitutes a powerful strategy for the synthesis of various heterocycles of synthetic and biologic interest. In this field, the formation of six-membered rings largely leads the way, and one of the first examples was reported in 2(X)3 by Ohsawa s group [4a] for the direct synthesis of the 3-carboline core via a Mannich/aza-Michael cascade promoted by (5)-proline and subsequentiy applied to the total synthesis of e t-dihydrocorynantheol (Scheme 16.3) [4b]. 

The development of new strategies in organic synthesis with a minimum of chemical steps has become more and more necessary for the efficient creation of complex molecular structures. The ability of palladium(O) catalysts to exercise control in bond forming has made it an excellent candidate for the synthesis of biologically active molecules. Allylic alkylations catalyzed by palladium have widely been studied and have proved unusually productive because of the extraordinary chemo-, regio-, and diastereoselectivity and the continuing possibility for the development of enantioselectivity. 

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