Asymmetric amino acid derivatives effect

Belokon et al. (261) subsequently found that salen-Cu(II) complexes are effective catalysts for the asymmetric alkylation of amino acid derivatives. Excellent se-lectivities are observed with 1 mol% of 88b-Cu in toluene at ambient temperature, Eq. 225. Although no stereochemical model is advanced to account for the selec-tivities, these workers suggest the catalyst may be acting as a chiral phase-transfer agent. 

Asymmetric hydrogenation of N-acyl-x-aminocinnamic acids. Rh(I) complexes with either 1 or 2 attached to polymers with suitable swelling characteristics are very effective for asymmetric hydrogenation of dehydroamino acids. Optical yields of about 90% are possible. As expected, polymer-bound Rh(I)-l results in (R)-amino acid derivatives, whereas polymer-bound Rh(I)-2 results in (S)-amino acid derivatives. 

The use of chiral crown ethers as asymmetric phase-transfer catalysts is largely due to the studies of Bako and Toke [6], as discussed below. Interestingly, chiral crown ethers have not been widely used for the synthesis of amino acid derivatives, but have been shown to be effective catalysts for asymmetric Michael additions of nitro-alkane enolates, for Darzens condensations, and for asymmetric epoxidations of a,P-unsaturated carbonyl compounds. 

Catalyst screening experiments resulted in the discovery that copper(salen) complex 33 was a highly effective catalyst for the conversion of alanine derivative 16b into (f )-a-methyl phenylalanine 17 under the conditions shown in Scheme 8.16. The presence of just 1 mol% of catalyst 33 was sufficient to induce the formation of compound 17 with up to 92% ee and in >70% yield [33]. Allyl bromide, 1-chloromethylnaphthalene and ethyl iodide also reacted with substrate 16b to give the corresponding (H)-a-methyl a-amino acids in the presence of 2 mol % of complex 33 [34], Complex 33 also catalyzed the asymmetric mono-alkylation of glycine-derived substrate 34 by benzylic or allylic halides, to give (H)-a-amino acid derivatives 35 with 77-81% ee. and in greater than 90% yield, as shown in Scheme 8.17. 

The power of this methodology lies in the ability to prepare unnatural amino acid derivatives by asymmetric alkylation of prochiral enolates. Several asymmetric alkylations of the alanine derivative 7, catalysed by the C2-symmetrical quaternary ammonium salt 6d, have been reported these reactions yield unnatural amino acids such as 8 in high enantiomeric excess (Scheme 2) [7]. The chiral salen complex 9 has also been shown to be an effective catalyst for the preparation of a,a-dialkyl a-amino acids [8, 9]. For example, benzylation of the Schiff base 10 gave the a-methyl phenylalanine derivative 11 in 92% ee (Scheme 3) [8]. Similar reactions have been catalysed by the TADDOL 12, and also give a,a-dialkyl a-amino acids in good enantiomeric excess [10]. 

Addition of nucleophiles to electrophilic glycine templates has served as an excellent means of synthesis of a-amino acid derivatives [2c, 4—6]. In particular, imines derived from a-ethyl glyoxylate are excellent electrophiles for stereoselective construction of optically active molecules [32], This research and retrosyn-thetic analysis led us to believe that amine-catalyzed asymmetric Mannich-type additions of unmodified ketones to glyoxylate derived imines would be an attractive route for synthesis of y-keto-ce-amino acid derivatives [33], Initially, L-proline-catalyzed direct asymmetric Mannich reaction with acetone and N-PMP-protected a-ethyl glyoxylate was examined in different solvents. The Mannich-type reaction was effective in all solvents tested and the corresponding amino acid derivative was isolated in excellent yield and enantioselectivity (ee >95 %). Direct asymmetric Mannich-type additions with other ketones afford Mannich adducts in good yield and excellent regio-, diastereo- and enantioselectivity (Eq. 8). 

The favorable effect of the enamide function on asymmetric induction is indicated not only by the result with compound I, but also by later results summarized in Table I, where optical purities in the range of 70 to 80% were generally obtained for various derivatives of alanine, phenylalanine, tyrosine, and 3,4-dihydroxyphenylalanine (DOPA). The Paris group found that the Rh-(-)-DIOP catalyst yielded the unnatural R or d -amino acid derivatives, whereas l-amino acid derivatives could be obtained with a (+)-DIOP catalyst. Since the optical purity of the IV-acylamino acids can often be considerably increased by a single recrystallization (fractionation of pure enantiomer from racemate) and the IV-acetyl group can be removed by acid hydrolysis, this scheme provides an excellent asymmetric synthesis route to several amino acids. 

Both intermolecular and intramolecular additions of carbon radicals to alkenes and alkynes continue to be a widely investigated method for carbon-carbon bond formation and has been the subject of a number of review articles. In particular, the inter- and intra-molecular additions of vinyl, heteroatomic and metal-centred radicals to alkynes have been reported and also the factors which influence the addition reactions of carbon radicals to unsaturated carbon-carbon bonds. The stereochemical outcome of such additions continues to attract interest. The generation and use of alkoxy radicals in both asymmetric cyclizations and skeletal rearrangements has been reviewed and the use of fi ee radical reactions in the stereoselective synthesis of a-amino acid derivatives has appeared in two reports." The stereochemical features and synthetic potential of the [1,2]-Wittig rearrangement has also been reviewed. In addition, a review of some recent applications of free radical chain reactions in organic and polymer synthesis has appeared. The effect of solvent upon the reactions of neutral fi ee radicals has also recently been reviewed. ... 

One stoichiometric method that avoids the use of an expensive chiral auxiliary and allows for the use of nonpyrophoric bases is based on diketopiperazine chemistry. The use of this system as a chiral auxiliary is associated with a method that was developed for the preparation of the sweetener aspartame. At the same time, we were looking at the alkylation reactions of amino acid derivatives and dipeptides. These studies showed that high degrees of asymmetric induction were not simple, were limited to expensive moieties as the chiral units, and required the use of large amounts of lithium [25,26]. The cyclic system of the diketopiperazine has been used successfully by other investigators [27,28], and we also chose to exploit the face selectivity of this unit. L-Aspartic acid was chosen as the auxiliary unit because it is readily available and cheap. All of the studies were performed with sodium as the counterion because it is a more cost-effective metal at scale. Finally, we concentrated in the use of aldehydes rather than alkyl halides to allow for a general approach and so as not to limit the reaction to reactive alkyl halides. 

The literature has many examples of ligands that have been developed to effect asymmetric hydrogenations of a variety of functional groups [4—8]. The reductions of enamides to provide a-amino acids derivatives has been of importance since the pioneering work of Knowles and his colleagues at Monsanto [9, 10]. This approach has been used by Monsanto, Searle and now Egis for the production of L-dopa (Fig. 1) [4]. The chemistry related to L-dopa is discussed in more detail in Chapter I 1, by W.S. Knowles. 

Complexation of Rh or Ru center to A-a-phenethyl amides of A-Boc-a-thioamino acids (but not the amino acid derivatives) forms highly effective catalysts for asymmetric hydrogenation of aryl ketones. ... 

The amplitude is considerable (a = 100-270), and it is positive for all the L-amino acid derivatives. A second, negative Cotton effect is observed between 245 and 225 nm. The iV-acetyl derivatives of the selenophenyl esters of L-phenylalanine and L-leucine esters show a negative Cotton effect at 290-295 nm. The reversal is explained by the drastic redistribution of electron density about the asymmetrically substituted a-carbon atom when the charged ammonium group is replaced by a neutral amide group. 

Asymmetric addition of diorganozincs to aldehydes and ketones has been reviewed, focusing on bifunctional catalysts such as those prepared from salens or BINOLs. Regioisomeric chiral amine-sulfonamide organocatalysts give >99% yield and up to 98% ee in addition of diethylzinc to aldehydes. Switching between regioisomers effectively switches the direction of selectivity. Amino-acid-derived (15,l 5)-4,4 -biquinazoline primary amines catalyse ethylation of aryl aldehydes in up to 95%... 

Kobayashi et al. also applied the catalyst to asymmetric 1,4-addition reactions of azlactones with acrylates [66]. The active a-proton of the azlactone (5(4H)-oxazolone) skeleton showed a low pKa value compared to that of the alanine Schiff bases, because the anion formed is stabilized via enol formation and aromatization. After 1,4-addition reactions with acrylates, the 2-substituted glutamic acid derivatives formed could be obtained via hydrolysis using a weak acid. It was found that Pybox 3 prepared from alaninol derivatives was effective for this reaction. The desired products were obtained in good yields with good enantios-electivities. Several amino acid derivatives containing aUcyl chains in the a-position were screened, and the leucine derivative (R = Bu) showed the best enantio-selectivity in this reaction (Table 16, entry 8). 

HOBACPC (p-hexyloxybenzylidene-p -amino-2-chloropropyl-cinnamate) obtained by directly attaching a chlorine atom to the asymmetric carbon closes the distance of dipole and the asymmetric carbon atom even more, resulting in doubling the spontaneous polarization value as compared to DOBAMBC [3,14,15]. 1 suspect that this is the influence from the rotational motion of the entire molecule that offsets the effect of more than one dipole. Furthermore, lactate and amino acid derivatives with directly attached chlorine atoms, bromine atoms, and cyano groups as the chiral source have also been synthesized. 

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