Primary Amines-Anti-Selectivity

With ketone donors, both syn and anti selective reactions are possible. Typically, a,p-unsaturated nitro compounds are used as acceptors. The majority of these reactions are syn selective (Scheme 28) [94, 269, 271, 278, 279, 288-309]. This is a result of favored formation of the (fj-configured enamine and favorable electrostatic interactions between the nitro group and the enamine (Scheme 29) [290, 291, 310]. Of the known anti selective reactions, primary amine-thiourea catalysts such as 158 appear to perform best (Scheme 28) [271, 299, 301]. 

Thioamides of primary amines react with two equivalents of n-butyllithium or isopropylmagnesium bromide to give dianions that have been shown to have the (Z)-configuration. These species react with aldehydes to afford predominantly anti aldois (equation 102 Table 14). Again, the magnesium dianions generally show superior stereoselectivity. In certain cases, the degree of stereoselectivity is excellent. This procedure provides a convenient complement to the syn selectivity obtained with thioamides of secondary amines. 

The ET-sensitized photoamination of 1,1-diarylethylenes with ammonia and most primary amines yields the anti-Markovnikov adducts. Photoamination of unsymmetrically substituted stil-benes yields mixtures of regioisomers 15 and 16. Modest re-gioselectivity is observed for p-methyl or p-chloro substituents however, highly selective formation of adduct 15 is observed for the p-methoxy substituent (Table 5). Selective formation of 15 was attributed to the effect of the methoxy substituent on the charge distribution in the stilbene cation radical. This re-gioselectivity has been exploited in the synthesis of intermediates in the preparation of isoquinolines and other alkaloids." Photoamination of 1-phenyl-3,4-dihydronaphthalene yields a mixture of syn and anti adducts 17 and 18 (Scheme 5)." Use of bulky primary amines favors formation of the syn adduct (Table 5), presumably as a consequence of selective anti protonation of the intermediate carbanion. 

On the other hand, chiral primary amine-thiourea catalysts 85 and 90 developed by Tsogoeva [125] and Jacobsen [130], respectively, show an opposite sense of relative stereoinduction in the conjugate addition of acyclic ketones to nitroolefins (see Scheme 2.41 for 90). These anti selective catalysts stand in contrast to the usually obtained results which lead to selective formation of the i yn-conflgured diastereoiso-mers. The unexpected situation suggests participation of a Z-enamine intermediate. Moreover, with respect to the electrophile activation by the urea-type catalysts, it is also demonstrated that only one oxygen of the nitro group is bound to the thiourea moiety in an out-of-plane arrangement [125,130]. 

Anti-selective Mannich reactions have been developed using (R)-3-pyrrolidine-carboxylic acid (75) or primary amine-containing amino acid 21 these catalysts were designed through consideration of mechanism and transition state models. 

Surprisingly, such selectivity was observed only recently in an aldehyde series. Indeed the group of Barbas developed a catalyst able to perform anti-selective Michael addition of aldehydes [26]. To facilitate such a transformation, several parameters were adjusted to promote the formation of (Z)-enamine, which is necessary to obtain an anti-selectivity (i) the classical secondary amine catalyst was changed for primary amine 17, which is less sterically hindered, favoring the (Z)-enamine, and (ii) the substrate was chosen to be able to form a stabilizing intramolecular H-bonding in favor of the (Z)-enamine. For these reasons (tert-butyldimethylsilyloxy)acetaldehyde (18) was selected as pro-nucleophile. Excellent level of enantio- and diastereoselectivity were obtained on combining these both parameters (Scheme 34.1). In the postulated transition state, covalent interaction... 

This retro aldol protocol enabled an ideal catalytic kinetic resolution of racemic aldol adducts that are usually difficult to be obtained through forward processes as illustrated by the resolutions of cyclohexanone aldol adducts. An intriguing feature of this process is that one chiral primary amine (e.g. 29) could catalyze stereoselectively the resolution of both anti- and yn-configured aldol adducts, whereas the forward reactions with the same catalyst yield selectively anti-configured aldol products. In addition, the catalytic power of 29-TfOH on both aldol and retro aldol reactions has also made possible an unprecedented asymmetric transfer aldol reaction that can generate two enantioenriched aldol adducts with opposite chiral induction from a single chiral catalyst (e.g. aldol products 48 and 49 in Scheme 5.14) [27],... 

Following immediately the initial efforts on primary amino acids catalyzed aldol reactions, the application of primary amine acid in Mannich reaction has also been attempted. Cordova reported that simple primary amino acids and their derivatives could catalyze the asymmetric Mannich reactions of ketones with comparable results to those obtained in the catalysis of proline[28]. Later, Barbas [29] and Lu [30] independently reported that L-Trp or 0-protected L-Thr could catalyze anti-selective asymmetric Mannich reactions of a-hydroxyacetones with eiflier preformed or in-situ generated imines. The preference of anii-diastereoselectivity was ascribed to the formation of a Z-enamine, with the assistance of an intramolecular H-bond (Scheme 5.15). 

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