Chiral alkyl halides synthesis

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. 

Fundamentally, the Michaelis-Becker reaction, and the first step in the mechanism of the Arbuzov reaction, involves 8 2 substitution at the carbon atom and as such should lead to stereospecific formation of the C—P bond (with inversion of configuration at the carbon atom) when chiral alkyl halides are used. Secondary alkyl halides, in most cases, favor elimination instead of substitution, in contrast to epoxides that react with phosphorus nucleophiles without elimination and with excellent stereoselectivity. The later reaction was successfiiUy used in a synthesis of glycosylphosphonate analog 3 of T>-myo-inositol-1,4,5-triphosphate (Scheme 47.2). ... 

Clerici and Porta reported that phenyl, acetyl and methyl radicals add to the Ca atom of the iminium ion, PhN+Me=CHMe, formed in situ by the titanium-catalyzed condensation of /V-methylanilinc with acetaldehyde to give PhNMeCHMePh, PhNMeCHMeAc, and PhNMeCHMe2 in 80% overall yield.83 Recently, Miyabe and co-workers studied the addition of various alkyl radicals to imine derivatives. Alkyl radicals generated from alkyl iodide and triethylborane were added to imine derivatives such as oxime ethers, hydrazones, and nitrones in an aqueous medium.84 The reaction also proceeds on solid support.85 A-sulfonylimines are also effective under such reaction conditions.86 Indium is also effective as the mediator (Eq. 11.49).87 A tandem radical addition-cyclization reaction of oxime ether and hydrazone was also developed (Eq. 11.50).88 Li and co-workers reported the synthesis of a-amino acid derivatives and amines via the addition of simple alkyl halides to imines and enamides mediated by zinc in water (Eq. 11.51).89 The zinc-mediated radical reaction of the hydrazone bearing a chiral camphorsultam provided the corresponding alkylated products with good diastereoselectivities that can be converted into enantiomerically pure a-amino acids (Eq. 11.52).90... 

An enantioselective synthesis of both (R)- and (5)-a-alkylcysteines 144 and 147 is based on the phase-transfer catalytic alkylation of fert-butyl esters of 2-phenyl-2-thiazoline-4-carboxylic acid and 2-ort/ro-biphenyl-2-thiazoline-4-carboxylic acid, 142 and 145 <06JOC8276>. Treatment of 142 and 145 with alkyl halides and potassium hydroxide in the presence of chiral catalysts 140 and 141 gives the alkylated products, which are hydrolyzed to (R)- and (S)-a-alkylcysteines 144 and 147, respectively, in high enantioselectivity. This method may have potential for the practical synthesis of chiral a-alkylcysteines. 

Although the tin hydride reductions of alkyl halides seem simple, one must be careful because these reactions occur by a free radical mechanism. This is important, because the carbon radical produced in the reaction can isomerize68,78 and one often obtains two different stereoisomers from the synthesis. Another problem is that chiral centres can be lost in tin hydride reductions when an optically active halide is reduced. One example of this is the reduction of benzyl-6-isocyanopenicillanate with tributyltin deuteride78 (Scheme 14). The amount of isomerization depends on the temperature, the concentration of the tin hydride and the presence of and /-substituents78-82. However, some authors have reported tin hydride reductions where no racemization was observed78. 

Intermolecular reactions of hydroxylamines with secondary alkyl halides and mesylates proceed slower than with alkyl triflates and may not provide sufficiently good yield and/or stereoselectivity. A nseful alternative for these reactions is application of more reactive anions of 0-alkylhydroxamic acids or 0-alkoxysulfonamides ° like 12 (equation 8) as nucleophiles. The resulting Af,0-disubstituted hydroxamic acids or their sulfamide analogs of type 13 can be readily hydrolyzed to the corresponding hydroxylamines. The same strategy is also helpful for synthesis of hydroxylamines from sterically hindered triflates and from chiral alcohols (e.g. 14) through a Mitsunobu reaction (equation 9). 

Synthetic applications as well as mechanistic considerations were reviewed recently24. Extension of the methodology to the seven-membered ring resulted in the first asymmetric synthesis of chiral benzazepines by alkylation with primary alkyl halides (92-96% ee) in 57-82% yield25. 

The phase-transfer-catalyzed asymmetric alkylation of 1 has usually been performed with achiral alkyl halides, and hence the stereochemistry of the reaction with chiral electrophiles has scarcely been addressed. Nevertheless, several groups have tackled this problem. Zhu and coworkers examined the alkylation of 1 with stereo-chemically defined (5S)-N-benzyloxycarbonyl-5-iodomethyl oxazolidine using 4d to prepare (2S,4R)-4-hydroxyornithine for the total synthesis of Biphenomycin. Unexpectedly, however, product 7 with a 2 R absolute configuration was formed as a major isomer, and the diastereomeric ratio was not affected by switching the catalyst to pseudoenantiomeric 2d and even to achiral tetrabutylammonium bromide (TBAB), indicating that the asymmetric induction was dictated by the substrate (Scheme 2.3) [21]. 

In particular, it is not only the cinchona alkaloids that are suitable chiral sources for asymmetric organocatalysis [6], but also the corresponding ammonium salts. Indeed, the latter are particularly useful for chiral PTCs because (1) both pseudo enantiomers of the starting amines are inexpensive and available commercially (2) various quaternary ammonium salts can be easily prepared by the use of alkyl halides in a single step and (3) the olefin and hydroxyl functions are beneficial for further modification of the catalyst. In this chapter, the details of recent progress on asymmetric phase-transfer catalysis are described, with special focus on cinchona-derived ammonium salts, except for asymmetric alkylation in a-amino acid synthesis. 

Besides the glycinate ester derivatives described above, other types of enolate-forming compounds have proved to be useful substrates for enantioselective alkylation reactions in the presence of cinchona alkaloids as chiral PTC catalysts. The Corey group reported the alkylation of enolizable carboxylic acid esters of type 57 in the presence of 25 as organocatalyst [69]. The alkylations furnished the desired a-substituted carboxylate 58 in yields of up to 83% and enantioselectivity up to 98% ee (Scheme 3.23). It should be added that high enantioselectivity in the range 94-98% ee was obtained with a broad variety of alkyl halides as alkylation agents. The product 58c is a versatile intermediate in the synthesis of an optically active tetra-hydropyran. 

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. 

Camphor and camphor-derived analogues are used frequently as chiral auxiliaries in asymmetric synthesis (cf Chapter 23). There have been numerous reports in the use of camphor imine as templates to direct enantioselective alkylation for the synthesis of a-amino acids, a-amino phos-phonic acids, a-substituted benzylamines, and a-amino alcohols (e.g., Scheme 5.9).43 47 Enantiomeric excesses of the products range from poor to excellent depending on the type of alkyl halides used. 

Chiral quaternary carbon centers. Meyers et al. have reported an enantioselective synthesis of chiral ot,(t-disubstituted- y-keto acids (6) via the lactam 3 prepared from l-valinol (1) and the y-keto acid 2. Alkylation of 3 with primary alkyl halides gives mainly the endo-isomer (4). /dkylation of 4 also proceeds with endo-selectivity to give 5 with a... 

Asymmetric Synthesis of a-Amino Acids. Chiral ketimines prepared from the title ketone and glycinates can be deprotonated and treated with electrophiles, such as alkyl halides (eq 1), or Michael acceptors, to give a-subsdtuted a-amino acids with moderate to excellent levels of diastereoselectivity. 

In the laboratory of T.F. Jamison, the synthesis of amphidinolide T1 was accomplished utilizing a catalytic and stereoselective macrocyclization as the key step. ° The Myers asymmetric alkylation was chosen to establish the correct stereochemistry at the C2 position. In the procedure, the alkyl halide was used as the limiting reagent and almost two equivalents of the lithium enolate of the A/-propionyl pseudoephedrine chiral auxiliary was used. The alkylated product was purified by column chromatography and then subjected to basic hydrolysis to remove the chiral auxiliary. 

In the laboratory of T.-J. Lu, a highly stereoselective method for the asymmetric synthesis of a-amino acids was developed by the alkylation of a chiral tricyclic iminolactone derived from (+)-camphor. The iminolactone can be considered a glycine equivalent. The synthesis commenced with the Riley oxidation of (+)-camphor to obtain the corresponding (+)-camphorquinone. Amino acids are obtained by first alkylating the a-position of the lactone with various alkyl halides and then hydrolyzing the monosubstituted products. The advantage of this technique was that the chiral auxiliary could be fully recovered without the loss of any optical activity. 

Salto, T., Sakairi, M., Akiba, D. Enantioselective synthesis of aziridines from imines and alkyl halides using a camphor-derived chiral sulfide mediator via the imino Corey-Chaykovsky reaction. Tetrahedron Lett. 2001,42, 5451-5454. 

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