A-branched amines

A parallel solution-phase asymmetric synthesis of a-branched amines has been reported by Ellman and coworkers based on stereoselective addition of organomag-nesium reagents to enantiomerically pure tert-butanesulfinyl imines [156]. Micro-wave heating was utilized in two of the steps of this synthesis of asymmetric amines, both for the imine formation and for the resin capture (Scheme 7.128). 

Addition of amines 8a-k to acrylamide 3 resulted in good yields (71 -92%) of di-/3-peptoids 9a-k, with conversions of the starting resin being >95% in all cases except 9i, j, and 1 (Table 6.1). The a-branched amines typically required longer reaction times for completion. Because double treatments were used in... 

Scheme 17 Reductive amination of ketones for the preparation of a-branched amines...

The synthesis of a-branched amines caught our attention, as these compounds exhibit parhcular biological activity. In several of our ongoing projects involving the synthesis of biologically achve compounds, we required the asymmetric synthesis of a-branched chiral amines. a-Branched amines can be prepared by various routes, all performed in an asymmetric fashion. Currently, enzymatic and chemical separation of racemic a-branched amines and also diastereoselective methods still play a major role on an industrial scale [25]. However, due to poor separation by the latter methods and for economic reasons, catalytic approaches will be favored. 

Recently, various methods have been applied to synthesize a-branched amines. In general, imines serve as valuable starhng materials since organyl groups or hydrogen can be delivered enantiospecifically at the C=N double bond. 

In a-branched amines, however, protonation induces considerable deshieldings a to the amino function, as demonstrated in the series t-butyl-, di-iso-propyl-, and t-butyl-dimethylamine, while shieldings are found for fi carbons as usual [338]. 

The hydroamination of alkynes is an efficient way to obtain aldimines with the advantage of avoiding formation of by-products. As shown in Scheme 8.65, the method has been developed into a multicomponent synthesis of a-branched amines. Aldimines 154 are formed using a titanium derivative as catalyst and reacted in situ with an organolithium reagent [141]. 

Arylboronic acids have been added diastereo- and enantio-selectively to (a) sulflnyl aldimines and (b) phosphinoyl aldimines, using rhodium(I) catalysts.52 These two methods should prove useful in preparing a-branched amines. 

The previous examples are selected asymmetric reductive animations of ketones to give chiral, a-branched amines (Eq. 32) however, the corresponding reactions of aldehydes are unknown. We reasoned that such a process might be realized if enolizable, a-branched aldehydes are used. Their asymmetric reductive amination should give -branched amines via an enantiomer-differentiating kinetic resolution (Eq. 33). 

A chiral, nonracemic oxirane, (3 )-2-[(R)-fluoro(phenyl)methyl]oxirane, can react with (chiral) amines under the influence of lithium perchlorate using either heat or microwave irradiation. This reaction sequence provides a material from which the ee of chiral a-branched amines can be determined <2005OL3829>. Guanidines serve as a useful nitrogen nucleophile for the direct conversion of epoxides to aziridines <2004JOC8504>. 

A comparative study revealed organoli-thiums as the reagents of choice. Reductive cleavage afforded a-branched amines. 

Chiral hydrazines, supported on Merri-field resin, were reacted with various aldehydes, affording the corresponding hydrazones. These compounds allowed stereoselective preparation of a-branched amines, through 1,2-addition of both aromatic and aliphatic nucleophiles to the C=N double bond of the hydrazones. Reductive cleavage released the desired amine from the resin. Moderate to good enantiomeric excesses (50-86%) were achieved. 

Stereoselective Synthesis of a-Branched Amines by Nucleophilic Addition of Unstabilized Carbanions to Imines... 

The preparation of a branched amines from the corresponding carbonyl deriva tives typically requires three steps (1) imine formation (2) nucleophilic addition and... 

One of the most practical methodologies used to generate a branched amines relies on the stoichiometric use of covalently bonded chiral auxiliaries on the nitrogen substituent. As such, a large number of chiral amines have been applied toward the generation of chiral imines suitable for nucleophilic addition chemistry (Figure 1.4). 

The N tert butanesulfinyl chiral auxiliary 32 has become the reagent of choice for the preparation of a branched amines due to its excellent level of diastereocontrol and the fact that the steric hindrance caused by the tert butyl group aids in the minimization of side reactions [32d]. The preparation of this chiral auxiliary in enantiomerically pure form is easily achieved in two steps and 65% overall yield starting from di tert butyl disulfide (Scheme 1.15) [55]. The nucleophilic addition of... 

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