Dipeptides, asymmetric synthesis

The highly unstable endoperoxides of imidazoles, sometime spectroscopically detected [81a], rearrange to dioxetanes or hydroperoxides or rapidly fragment or polymerize so that from the synthetic perspective, the reaction has a poor scope [54,67,81]. One interesting application has been pointed out by Lipshutz as a general asymmetric synthesis of TV-protected amino acids/dipeptides via appropriately substituted imidazoles (Sch. 48) [82],... 

Sometimes the natural products that are needed are immediately obvious from the structure of the target molecule. An apparently trivial example is the artificial sweetener aspartame (marketed as Nutrasweet), which is a dipeptide. Clearly, an asymmetric synthesis of this compound will start with the two members of the chiral pool, the constituent (natural) (S)-amino acids, aspartic acid and phenylalanine. In fact, because phenylalanine is relatively expensive for an amino acid, significant quantities of aspartame derive from synthetic (S)-phenylalanine made by one of the methods discussed later in the chapter. 

An example of diastereoface differentiation is provided in an asymmetric synthesis of the dipeptide Ala-Ala [70]. The element of chirality is that of one of the alanine groups, and the faces are those of a Schiff base, > C=N—. The material undergoing a catalytic reduction is the isobutyl ester of the benzylamine Schiff base of N-pyruvoyl-(5)-alanine, 54. The ratio of R S (55) to S S dipeptide was 82 18 for an optical purity of 64%. 

The non-equivalence of enantiomers through the spontaneous breaking of mirror-symmetry in nature is amplified by asymmetric autocatalytic reaction [34], e.g. Frank s spontaneous asymmetric synthesis [35, 36] (Fig. 7-8). Alberts and Wyn-berg have reported in enantioselective autoinduction that chiral lithium alkoxide products may be involved in the reaction to increase the enantioselectivity (Eq. (7.9)) [37]. The product % ee however does not exceed the level of catalyst % ee. In asymmetric hydrocyanation catalyzed by cyclic dipeptides, the (Si-cyanohydrin product complexes with the cyclic peptide to increase the enantioselectivity in the (S)-cyanohydrin product, the reaction going up to 95.8% ee (Eq. (7.10)) [38]. In the presence of achiral amine, (/ )-l-phenylpropan-l-ol catalyzed carbonyl-addition reaction of diethylzinc has been reported to show lower % ee than that of the catalyst employed [39]. 

Allylic silanes can be converted into allylic tosylamides by the reaction with PhINTs in the presence of copper salts. In particular, the copper(I)-catalyzed enantioselective amidation of the chiral ( )-crotylsilanes 659 (Scheme 3.263) has been used in the asymmetric synthesis of ( )-olefin dipeptide isosteres [806]. 

Myers AG, Barbay JK, Zhong B (2001) Asymmetric synthesis of chiral organofluorine compounds use of nonracenuc fluoroiodoacetic acid as a practiced electrophile and its application to the synthesis of monofluoro hydroxyethylene dipeptide isosteies within a novel series of HIV protease inhibitors. J Am Chem Soc 123 7207-7219... 

Some other catalysts based on primary amino acid structures, such as 3-amino acids, dipeptides, and primary amine-amides/sulfonamides (19-22), have also been applied to asymmetric synthesis. 

A breakthrough in the asymmetric synthesis of cyanohydrins with the use of small-molecuie catalysts was disclosed with Inoue s discovery in 1981 that the cyclic dipeptide 256 (R= Ph) as an organic catalyst mediates the addition of HCN to a variety of aldehydes to yield the corresponding (R)-cyanohydrins in high optical purity (up to 97 % (x) [169]. The structurally similar dipeptide 257 (R = i-Pr), in contrast, furnishes (S)-cyanohydrins, albeit in lower enantiomeric excess (38-81% ee) (170). Even higher enantioselectivity was obtained by Jackson with the Inoue catalyst 256 after careful freeze-drying or recrystallization of the dipeptide catalyst under anhydrous conditions (Scheme 2.33) [171]. In this manner, cyanohydrin 259 could be obtained in 98 % yield and >99 % ee and subsequently utilized in a synthesis of the insecticide (-)-tembamide (260). 

Piperazine-2,5-diones can be symmetric or asymmetric. Symmetric DKPs are readily obtained by heating amino acid esters,1179-181 whereas asymmetric DKPs are obtained directly from the related dipeptides under basic or, more properly, acid catalysis, or by cyclocondensation of dipeptide esters.1182-185 As an alternative procedure hexafluoroacetone can be used to protect/activate the amino acid for the synthesis of symmetric DKPs or of the second amino acid residue for synthesis of the dipeptide ester and subsequent direct cyclocondensation to DKPs.1186 The use of active esters for the cyclocondensation is less appropriate since it may lead to epimerization when a chiral amino acid is involved as the carboxy component in the cyclization reaction. Resin-bound DKPs as scaffolds for further on-resin transformations are readily prepared using the backbone amide linker (BAL) approach, where the amino acid ester is attached to the BAL resin by its a-amino group and then acylated with a Fmoc-protected amino acid by the HATU procedure, N -deprotection leads to on-resin DKP formation1172 (see Section 6.8.3.2.2.3). 

Synthetic pathways towards the dimethylene isosteres comprise several disconnections, indicated by the essential bond forming reactions (Scheme 2). Several methods yield racemic dipeptide analogues. These are usually incorporated into the peptide sequence and the resulting epimeric peptides are separated. When either R1 or R2 = H, asymmetric syntheses towards the required enantiomer are available. When both R1 and R2 H, only the reduction of the i )[CH=CH] precursor yields homochiral compounds. As many co-amino acids (R1 = R2 = H) are commercially available, their synthesis needs not be discussed here. 

The synthesis of threonine can be made stereospecific using optically active complexes of the type L-[Co(en)2Gly]2+ but with low asymmetric yield.442 In the case of dipeptide complexes only... 

Ecteinascidin 743 262 (Scheme 12.37) represents a powerful antitumor agent, which has been submitted to clinical trial. This complex polyazacydic, polyaromatic compound was isolated from the marine tunicate, Ecteinascidia turbinate [131]. A total synthesis of this natural product, which featured an Ugi four-component reaction as pivotal step, was recently reported by Fukuyama and co-workers [132]. The highly decorated phenylglycinol 263 was obtained via an asymmetric Mannich-type reaction [133], and was engaged in a multicomponent condensation process involving the protected amino acid 264, p-methoxyphenyl isocyanide 265 and acetaldehyde to afford dipeptide 266 in high yield. This com-... 

Scheme 2. Asymmetric Strecker synthesis with cyclic dipeptide 2 (Lipton and co-workers).

Asymmetric aldol reactions may also be controlled with high diasteroselectivity, but this time for the anti isomer, in reactions of A -tosyl derivatives of esters derived from 7 (eq 3). Diastereoselectivities of up to 99 1 were achieved in the illustrated titanium(IV)-mediated reaction, which has been employed for the synthesis of dipeptide isosteres for incorporation into pharmaceutical building blocks.The selectivity reverses... 

Asymmetric Peptide Synthesis. The reagent activates amino acids through 1,3-Dicyclohexylcarbodiimide (DCC) coupling to the N-hydroximide for subsequent coupling with chiral amino acids. The asymmetric center induces preferential reaction with L-amino acids and high optical purities of L-L-dipeptides can be achieved (eq 2). Enantioselectivity is improved if the 5-methyl group is replaced by isobutyl. ... 

Iyer, M. S., Gigstad, K. M., Namdev, N. D., Lipton, M. Asymmetric catalysis of the Strecker amino acid synthesis by a cyclic dipeptide. Amino Acids 1996, 11, 259-268. 

Narumi, T., Niida, A., Tomita, K., et al. (2006) A novel one-pot reaction involving organocop-per-mediated reduction/transmetalation/asymmetric alkylation, leading to the diastereoselective synthesis of functionalized (Z)-fluoroalkene dipeptide isosteres. Chem. Commun., 4720-4722. 

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