Imides desymmetrization

A related enantiotopos-differentiating desymmetrization, the CBS-reduction of cyclic meso imides, was reported in 1997 by Hiemstra et al. [18]. 

Mechanistic studies41"43 by Dixon and Jones excluded the possibility of dimeric catalytic species because a linear dependence was observed between the catalyst s enantiopurity and the reaction s enantioselectivity.43 The test reaction was the desymmetrization of meso-imide 22 using chiral oxazaborolidine catalysts. The sense of the enantioselectivity of the reduction was established by conversion of hydroxy lactam 23 to the known ethoxy lactam 24 (Scheme 17.6). 

Modification of the amidine function to chiral versions has been examined. For example, C2-symmetrical chiral bicylic amidine 5 was prepared for studies on molecular recognition and were proven to differentiate analytically between the enantiomers of chiral carboxylic acids [13]. Near the same time, a mannose-based amidine 6 was synthesized as a potential mannosidase inhibitor, but not a chiral auxiliary [14]. Three enantiopure hydroxyl substituted amidines 7 of the DBN-type were synthesized from 5-(phenylsulfonyl)pyrror-idine-2-one by an oxazaborolidine-catalysed reductive desymmetrization of meso-imide followed by functionalization through N-acyliminium ion [15] (Figure 3.3). 

A second-generation process ronte was developed that improves upon the initial process route (Scheme 6). - - In this simplified process approach, the molecular symmetry of the starting caronic anhydride was maintained to the latest stage possible. Caronic anhydride (30) was initially converted directly to imide 40 by heating with either ammonium hydroxide or formamide with DMAP under Dean-Stark conditions. In an alternative two-step protocol, heating of 30 with benzyl amine produced an intermediate benzyl imide, which was deprotected to 40 under catalytic hydrogenation conditions. Reduction of imide 40 with lithium aluminum hydride afforded 41, which was desymmetrized under oxidative conditions to produce racemic imine 42. Diastereoselective cyanation favored trans-43, which underwent methanolysis under Pinner conditions. Finally, classical resolution by crystallization with D-DTTA afforded 24 as the D-DTTA salt with >95% ee. 

Weinreb exploited a synthetic strategy for the synthesis of bis indolyl maleimides to furnish maleimide 135 from indole-Grignard 134 and imide 134a [43]. DDQ mediated oxidative cyclization of 135 resulted N-benzyl imide 136. To complete the synthesis, Clemmenson reduction was performed for desymmetrizing 136, to produce the corresponding lactam 137 (Scheme 21). 

The 2b-catalyzed reduction of j or 8-keto esters provided the corresponding hydroxy esters with high enantioselectivity (Scheme 11.9) [5b], while the reduction of a-keto esters was less effective [6b, 44b, 59]. Desymmetrization of meso-imides 31 via stereoselective reduction is one of the most powerful transformations to provide products with three new chiral centers. Such transformations with good enantioselectivities were achieved by OABs-catalyzed reductions (Scheme 11.10) [60-62], The hydroxy lactams 32 obtained were easily converted into ethoxy lactams 33 by acidic ethanoly-sis, and were transformed into chiral lactones 34 by sodium borohydride reduction. 

Scheme 11.10 Desymmetrization of meso-imides via 2a-catalyzed reduction.

---