Functionalized chiral amine synthesis

Enantioenriched aziridines are important building blocks for the synthesis of functionalized chiral amines such as amino acid derivatives and hgands. In 2(X)8, Hashimoto et al. reported an axially chiral dicarboxyUc acid (66a)-catalyzed asymmetric aziridination of IV-Boc intines 64 with diazoacetantides 65, which resulted in trans-selective aziridine products 67 with up to 99% ee (Scheme 2.19) [30a]. The use of diazoacetantide 65 instead of diazoacetate as nucleophiles could lower the acidity of the a-proton of diazo carbonyls, thus leading to the formation of aziridine other than Mannich-type products. With this success, the same group recently established the asymmetric construction of... 

After the methodology for asymmetric reduction of imines with trichlorosilane employing model substrates had been firmly established, the focus of research in the field gradually shifted towards the synthesis of functionalized chiral amines, which represent important building blocks for pharmaceutical, agricultural, and fine chemical industries. 

Waldmann used (R) and (5>aminoacid methyl esters and chiral amines as chiral auxiliaries in analogous aza-Diels-Alder reactions with cyclodienes.111 The diastereoselectivity of these reactions ranged from moderate to excellent and the open-chain dienes reacted similarly. Recently, the aza-Diels-Alder reaction was used by Waldmann in the asymmetric synthesis of highly functionalized tetracyclic indole derivatives (Eq. 12.45), which is useful for the synthesis of yohimbine- and reserpine-type alkaloids.112... 

The Catalysis Concept of Iminium Activation In 2000, the MacMillan laboratory disclosed a new strategy for asymmetric synthesis based on the capacity of chiral amines to function as enantioselective catalysts for a range of transformations that traditionally use Lewis acids. This catalytic concept was founded on the mechanistic postulate that the reversible formation of iminium ions from a,p-unsaturated aldehydes and amines [Eq. (11.10)] might emulate the equilibrium dynamics and 7i-orbital electronics that are inherent to Lewis acid catalysis [i.e., lowest unoccupied molecular orbital (LUMO)-lowering activation] [Eq. (11.9)] ... 

In continuation of our investigations on asymmetric nucleophilic acylations with lithiated a-aminonitriles [40], we envisaged the asymmetric synthesis of 3-substituted 5-amino-4-oxo esters A, bearing both a-amino ketone and 5-amino ester functionalities (Scheme 1.1.14) [41]. Since a-amino ketones are precursors of chiral p-amino alcohols [42, 43] and chiral amines [43], their asymmetric synthesis has the potential to provide valuable intermediates for the synthesis of biologically active compounds, including peptidomimetics [44]. The retrosynthetic analysis of A leads to the a-aminoacyl carbanion B and p-ester carbocation... 

The Mn mediated radical additions offer an inherently flexible carbon carbon bond construction approach to amine synthesis. Because of the broad functional group compatibility in both the radical precursor and the aldehyde hydrazone acceptor, the roles of these precursors can be switched to result in the construction of either of two C C bonds at the chiral amine (Scheme 2.10) with excellent stereocontrol. The epimeric configuration can be selected by either (a) employing the enantiomeric auxiliary or (b) interchanging the roles of R and in the alkyl halide and aldehyde precursors [47]. By combining these two tactics, the optimal roles of R and with respect to yield and selectivity can be chosen. Such strategic flexibility contributes to the synthetic potential of these radical addition reactions. 

Catalytic asymmetric aza MBH reactions and related reactions provide a direct and efficient synthetic approach to a variety of functionalized nonamino acid derived chiral amines under mild conditions. These novel chiral amines can be directly used to prepare many other useful chiral building blocks in organic synthesis. A variety of transformations of the chiral aza MBH adducts were recently demonstrated by Raheem and Jacobsen (Scheme 13.30) [9]. 

The Ugi reaction is the synthesis of an a-amino acid amide by reaction of an aldehyde with an amine and an isonitrile in the presence of zinc chloride and formic acid. )3-D-Galactosylamine has been proposed as a chiral amine partner whose alcohol functions are protected by esterification with pivalate groups (reaction 8.7) (Kunz and Pfrengle 1988). The reaction is carried out in oxolane between -75 and -25°C. The diastereomeric mixture obtained corresponds to a d/l ratio close to 95 5. The pure D-isomer is obtained by recrystallization in heptane. It is known that the bond between a sugar molecule and nitrogen is easy to cleave in glycosylamines (see Section 3.6.2). 

This reaction is arguably the most useful and certainly the most widely used application of the electrophilic C-amination of enolates in organic synthesis. A number of 4- and 4,5-substituted 2-oxazolidinones are commercially available in both enantiomeric forms and the chiral auxiliary is easily recovered.430 Reactions of A-acyloxazolidinonc enolates with azo esters431,432 and arenesulfonyl azides433 are rapid even at very low temperatures (—100°) and the diastereochemical outcome is reliably predictable. The facile removal of the chiral auxiliary and ready conversion of the azide or hydrazino ester functionalities into amines makes these reactions a standard method for the preparation of d- and L-a-amino acids. 

The hydroamination of alkynes is a highly atom-efficient approach to the synthesis of enamines and imines, as well as to the synthesis of A-heterocyclic compounds such as indoles and pyrroles, which are widely occurring functional groups in biologically active molecules. Also included in this section is the hydroamination of allenes and alkenes, as the reaction of these substrates with chiral bimetallic catalysts has been shown to yield the chiral amine products with high enantioselectivity. 

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