Chiral alkyl halides resolution

The Gabriel synthesis is a classical but useful preparative method for primary amines. Reaction of an alkyl bromide (24) with potassium phthalimide (25) gives the corresponding A -alkylphthalinude (26), which upon treatment with hydrazine followed by KOH affords the primary amine (27). When a chiral alkyl halide is used in the Gabriel synthesis, a chiral primary amine is obtained. However, preparation of optically active alkyl halides is not easy. If optical resolution of 26 which has a chiral alkyl group can be done, a new preparative method for optically active amines can be established by a combination of the resolution with the Gabriel synthetic method. Some examples of the combination method are described. 

Oxathiane 101 is readily deprotonated using s-BuLi, and the resulting anion reacts with alkyl halides, ketones, and benzonitrile (85JOC657). The majority of work in this area, however, is due to Eliel and coworkers and has involved chiral 1,3-oxathianes as asymmetric acyl anion equivalents. In the earliest work it was demonstrated that the oxathianes 102 and 103, obtained in enantiomeri-cally pure form by a sequence involving resolution, could be deprotonated with butyllithium and added to benzaldehyde. The products were formed with poor selectivity at the new stereocenter, however, and oxidation followed by addition... 

Simple alkylation of the chiral chelate complex leads to formation of chiral dialkylacetic acids (Scheme 109).3S5 388 Simpler chiral enamines can also be used. The formation of chiral propanoic acids results from a resolution of racemic alkyl halides by the interaction of a chiral lithiooxazoline, which recognizes and reacts with one enantiomer at the expense of the other (Scheme 110).389 The above aspects of the asymmetric carbon—carbon bond formation from chiral oxazolines have been reviewed by Meyers.390... 

With regards to studies on the stereoselective functionalization of prochiral glydne Dpm amide derivative 22, Maruoka and coworkers found that chiral ammonium enolate generated from lg and 22 had an ability to recognize the chirality of P-branched primary alkyl halides, which provides impressive levels of kinetic resolution during the alkylation with racemic halide 29, allowing for two a- and y-stereocenters of 30 to be controlled, as exemplified in Scheme 5.16 [22]. 

Further application of the in-situ generation of chiral quaternary ammonium fluorides from the corresponding hydrogen sulfates has also been shown in the facile preparation of optically active esters via the alkylative kinetic resolution of secondary alkyl halides. For example, simple stirring of the mixture of 3-phenylpropionic acid, l-(l-bromoethyl)naphthalene, (S,S)-6b (X = HS04 2 mol%) and KF-2H20 (5 equiv.)... 

The enantioselective complexation technique can also be applied as one step in the reaction sequence, providing chiral substrates for the next step. We will now discuss the example of Gabriel synthesis between potassium phthalimide 41 and alkyl bromide 42, which leads to optically active amines (Scheme 1) [51], Instead of the complicated preparation of chiral alkyl bromides (halides), imides (43), which are reaction intermediates, have been resolved. Upon treatment with hydrazine and KOH, these gave optically active amines. The chiral host (S,S)-(-)-6 or the chiral biaryl host (,S>(-j-40 was used for the effective resolution of the intermediates 43. Racemic mixtures 43a-d were resolved by complex formation with the host (S,S)-(-)-6 in a mixture of diethyl ether and light petroleum. 

The nucleophilic character ofdialkyl sulfides is illustrated by their nucleophilic addition reaction with alkyl halides to form the corresponding sulfonium salts (35) (Scheme 13). Asymmetric sulfonium salts (36) have a tetrahedral configuration therefore, like the analogous chiral saturated carbon compounds, they can be resolved into optical enantiomers (see Chapter 6, p. 81). They are, however, generally less optically stable than sulfoxides, but in sulfonium salts the unshared electron pair can hold its configuration at ordinary temperatures, unlike nitrogen in quaternary ammonium salts, enabling their resolution to be achieved. 

A very recent paper described the first examples of asymmetric Suzuki coupling reactions of unactivated alkyl halides.These transformations take advantage of the fact that oxidative addition of secondary alkyl halides to Ni(0) proceeds through radical intermediates. This leads to scrambling of stereochemistry when achiral catalysts are employed, but can be exploited to achieve dynamic kinetic resolution with chiral catalysts. For example, use of a catalyst composed of Ni(COD)2 and chiral 1,2-diamine ligand 55 for the coupling of 52 with 53 gave 54 in 78% yield and 90% ee. 

The chiral glycinate anion 2 is alkylated with a potentially carcinogenic or lachrymatory benzylic halide to give the adduct 3, usually as a diasteromeric mixture which has to be separated by high resolution chromatography. 3 has, then, to be cleaved into the auxiliary (here valine methyl ester (4)) and the desired amino ester 2-OMe-l-NAL (5), whose ee-value is 92 %. The pro and cons of this method are summarized in Figure 6. 

Reactions.—Kinetic resolution of secondary alkyl bromides and iodides can be achieved by reaction of two molar equivalents of the halide with the chiral lithio-oxazoline (69) and isolation of excess halide (Scheme 33). The lithio derivative (69) reacts preferentially with (S )-halide [as in (70) with smaller than R J leaving enriched (R)-halide of 30-50% enantiomeric purity. 

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