Absolute stereoselectivity

A model for the mechanism of the highly enantioselective AlMe-BINOL-cata-lyzed 1,3-dipolar cycloaddition reaction was proposed as illustrated in Scheme 6.13. In the first step nitrone la coordinates to the catalyst 11b to form intermediate 12. In intermediate 13, which is proposed to account for the absolute stereoselectivity of this reaction, it is apparent that one of the faces of the nitrone, the si face, is shielded by the ligand whereas the re face remains available... 

A rather unexpected discovery was made in connection to these investigations [49]. When the 1,3-dipolar cycloaddition reaction of la with 19b mediated by catalyst 20 (X=I) was performed in the absence of MS 4 A a remarkable reversal of enantioselectivity was observed as the opposite enantiomer of ench-21 was obtained (Table 6.1, entries 1 and 2). This had not been observed for enantioselective catalytic reactions before and the role of molecular sieves cannot simply be ascribed to the removal of water by the MS, since the application of MS 4 A that were presaturated with water, also induced the reversal of enantioselectivity (Table 6.1, entries 3 and 4). Recently, Desimoni et al. also found that in addition to the presence of MS in the MgX2-Ph-BOX-catalyzed 1,3-dipolar addition shown in Scheme 6.17, the counter-ion for the magnesium catalyst also strongly affect the absolute stereoselectivity of the reac-... 

Tab. 6.1 Dependence of absolute stereoselectivity on molecular sieves and counter ion in the reaction of la with 19b catalyzed by 10 mol% MgX2-Ph-BOX catalysts 20...

The real promise of this catalytic reaction is the eventual development of an efficient enantioselective allylboration catalyzed by chiral Lewis acids. A stereoselective reaction using a substoichiometric amount of a chiral director has been reported, but only modest levels of stereo-induction were achieved with an aluminum-BINOL catalyst system (Eq. 19)P Recently, a chiral Brpnsted acid catalyzed system has been devised based on a diol-tin(IV) complex (Eq. 80). In this approach, aliphatic aldehydes provide enantioselectivities (up to 80% ee) higher than those of aromatic aldehydes when using the optimal complex 114. Although the levels of absolute stereoselectivity of this method remain too low for practical uses, promising applications are possible in double diastereoselection (see section on Double Diastereoselection ). 

Theoretically, both reactions will stop at 50% conversion and will give both enantiomers with 100% enantiomeric excess [ee=(R-S)/(R+S)xl00 for R>S], if the enzyme has an absolute stereoselectivity. 

Addition to formaldehyde [378] and other aldehydes [379,380] proceeds with high absolute stereoselectivity for the (5f )-configurated products (configurational reference changes for any substrate larger than formaldehyde ). In contrast, no or only a low level of relative acceptor diastereoselectivity at the chiral C-6 was determined in the reactions with acetaldehyde (6S/6R 1 1) [379] and propionaldehyde (130/131 = 1 2.4) [380] as the stereochemical probes. 

In summary, the novel synthesis of (+)-valienamine and (+)-validamine has been accomplished by our synthetic strategies for the constructing of carbasugars. The absolutely stereoselective hydrogenation of 26 and 27 to give (+)-validamine (29) is particularly noteworthy. 

Control of absolute stereoselectivity in the intramolecular carbolithiation reactions is not a completely solved subject and several approaches have been used ... 

Bahmanyar, S. Houk, K. N. Origins of opposite absolute stereoselectivities in proUne-catalyzed direct mannich and aldol reactions, Org. Lett. 2003, J, 1249-1251. 

In several tests for cannabimimetic activity (Edery et al. 1971 Jones et al. 1974 Martin 1986), (+)-delta-l-THC (31) was ca 13 to 230 times less active than the (-)-isomer. These results indicate pharmacologic enantiomeric preference rather than absolute stereoselectivity. Indeed, Martin pointed out that, while cannabinoid SAR supports the concept of a specific cannabinoid receptor, a disconcerting element is the apparent lack of greater stereoselectivity in some animal models. However, because the starting material (+) verbenol was not necessarily stereochemically pure, this conclusion is tentative at best. 

Heterogeneous catalysts which are active for the catalysis of the MPVO reactions include amorphous metal oxides and zeolites. Their activity is related to their surface basicity or Lewis acidity. Zeolites are only recently being developed as catalysts in the MPVO reactions. Their potential is related to the possibility of shape-selectivity as illustrated by an example showing absolute stereoselectivity as a result of restricted transition-state selectivity. In case of alkali or alkaline earth exchanged zeolites with a high aluminium content (X-type) the catalytic activity is most likely related to basic properties. For zeolite BEA (Si/Al=12), however, the dynamic character of those aluminium atoms which are only partially connected to the framework appear to play a role in the catalytic activity. Similarly, the Lewis acid character of the titanium atoms in aluminium free [Ti]-BEA explains its activity in the MPVO reactions. 

In this section we describe only those systems that lead to the 1,4-conjugate reduction mode. Issues of relative and absolute stereoselectivity are also of considerable importance when sp carbon atoms are converted to potentially asymmetric sp centers. 

Strichartz GR, Hall S, Magnani B, Hong CY, Kishi Y, Debin JA (1995) The potencies of synthetic analogues of saxitoxin and the absolute stereoselectivity of decarbamoyl saxitoxin. Toxicon 33 723-737. doi 004101019500031G [pii]... 

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