Phenylalanine derivatives, asymmetric

More recently, Burgess et al. (34) used the same approach in the synthesis of a constrained phenylalanine derivative, 3-phenyl-2,3-methanophenylalanine (123). Libraries of metal complexes were screened to determine the best combination for the asymmetric cyclopropanation reaction (35). The ligands shown below were combined with AgSbFg, (CuOTf)2 PhH, RuC12(C10H14)]2, Sc(OTf)3, where tri-... 

An interesting asymmetric transformation is the asymmetric conjugate addition to a-acetamidoacryhc ester 30 giving phenylalanine derivative 31, which has been reported by Reetz (Scheme 3.10) [10]. The addition of phenylboronic acid 2m in the presence of a rhodium complex of l,T-binaphthol-based diphosphinite ligand 32 gave a quantitative yield of 31 with up to 11% enantiomeric excess. In this asymmetric reaction the stereochemical outcome is determined at the hydrolysis step of an oxa-7r-aUylrhodium intermediate, not at the insertion step (compare Scheme 3.7). 

Figure 6.25 The most efficient (thio)urea derivatives in the asymmetric DKR of phenylalanine-derived aziactone (R = Bn Scheme 6.90).

Based on the concept mentioned above, Brown realized the asymmetric deactivation of a racemic catalyst in asymmetric hydrogenation (Scheme 9.18) [35]. One enantiomer of (+)-CHIRAPHOS 28 was selectively converted into an inactive complex 30 with a chiral iridium complex 29, whereas the remaining enantiomer of CHIRAPHOS forms a chiral rhodium complex 31 that acts as the chiral catalyst for the enantioselective hydrogenation of dehydroamino acid derivative 32 to give an enantio-enriched phenylalanine derivative... 

The alkylation of ( )-spirolactones (34a) and (34b) with higher diastereoface selectivity has been modelled by geometry-optimized ab initio 4-31G calculations which suggest that approach of the electrophile occurs at an angle of ca 80° to the plane of the enolate and with some displacement away from the oxygen linked to the metal ion.41 Asymmetric a-methylation of phenylalanine derivatives has been achieved with 82% ee and retention of configuration in the absence of any external chiral source.42... 

Surprisingly, the catalytic potential of proline (1) in asymmetric aldol reactions was not explored further until recently. List et al. reported pioneering studies in 2000 on intermolecular aldol reactions [14, 15]. For example, acetone can be added to a variety of aldehydes, affording the corresponding aldols in excellent yields and enantiomeric purity. The example of iso-butyraldehyde as acceptor is shown in Scheme 1.4. In this example, the product aldol 13 was obtained in 97% isolated yield and with 96% ee [14, 15]. The remarkable chemo- and enantioselectivity observed by List et al. triggered massive further research activity in proline-catalyzed aldol, Mannich, Michael, and related reactions. In the same year, MacMillan et al. reported that the phenylalanine-derived secondary amine 5 catalyzes the Diels-Alder reaction of a,/>-un saturated aldehydes with enantioselectivity up to 94% (Scheme 1.4) [16]. This initial report by MacMillan et al. was followed by numerous further applications of the catalyst 5 and related secondary amines. 

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]. 

Phenylalanine derivatives with various nitrogen substituents R1 and R2 (30) were prepared and their a-methylation was examined (Table 3.2). It turned out that derivatives with an alkoxycarbonyl group on the nitrogen undergo a-methylation with modest asymmetric induction (entries 5-7). The presence of two substituents on the nitrogen seems to be essential for asymmetric induction (entries 1 vs. 7). 

Thorough investigation of nitrogen substituents of phenylalanine for asymmetric induction disclosed that A-MOM-A-lloc derivative 40 gives a-methylated product in 81% ee and in 96% yield without the aid of any external chiral... 

The phenylalanine-derived chiral amine catalyst 10 was used to promote the asymmetric [4-1-3] cycloaddition between 2,5-dialkylfurans and trialkylsilyloxypentadienals to generate seven-membered carbocycles with OTrfo-selec-tivity and 81-90% ee, as represented in Equation (46) <2003JA2058>. However, the absolute configurations of the cycloadducts have not been determined. 

Phenylalanine-derived oxazolidinone has heen used in O Scheme 52 as a chiral auxiliary for as)rmmetric cross-aldolization (Evans-aldol reactions [277,278,279,280,281,282,283,284, 285]). The 6-deoxy-L-glucose derivative 155 has heen prepared by Crimmins and Long [286] starting with the condensation of acetaldehyde with the chlorotitanium enolate of O-methyl glycolyloxazohdinethione 150. A 5 1 mixture is obtained from which pure 151 is isolated by a single crystallization. After alcohol silylation and subsequent reductive removal of the amide, alcohol 152 is obtained. Swem oxidation of 152 and subsequent Homer-Wadsworth-Emmons olefination provides ene-ester 153. Sharpless asymmetric dihydroxylation provides diol 154 which was then converted into 155 (O Scheme 60) (see also [287]). 

Asymmetric hydrogenation of bromo-substituted aromatic a-enamides 14 affords the corresponding bromo-amino acid derivatives 15, which subsequently is subjected to Pd-catalyzed cross-coupling with aryl and vinyl boronic acids. In addition to diverse phenylalanine derivatives 16, a broad array of other novel aromatic and heterocyclic amino acids have been produced rapidly from a small number of bromo-functionalized intermediates [24], This same two-step process may be applied to the production of many other classes of aromatic and heterocyclic chiral building blocks, such as arylalkylamines, amino alcohols, diamines, and directly on peptides as well. 

Amphiphilic diblock copolymers based on 2-oxazoline derivatives with chiral diphosphine 187 were prepared (Scheme 3.61) and used in the asymmetric hydrogenation of methyl (Z)-(z-acelarnido cinnamate 188 in water to give the (R)-phenylalanine derivative 189 in 85% ee [124]. The polymeric catalyst could be recycled. This result illustrated the advantages of using amphiphihc copolymers for the efficient transformation of a hydrophobic substrate in water. 

The asymmetric catalyst is based on the chiral bisphosphine, / ,/ -DlPAMP (18), that has chirality at the phosphorus atoms and can form a hve-membered chelate with rhodium. The asymmetric reduction of the Z-enamide proceeds in 96% ee (Scheme 9.19)." The pure isomer of the protected amino acid intermediate 19 can be obtained upon crystallization from the reaction mixture as it is a conglomerate." Although the catalyst system is amenable to the preparation of a wide variety of amino acids, especially substituted phenylalanine derivatives," " a major shortcoming of the approach is the need to have just the Z-enamide isomer as the substrate. 

Enamide ester, which is a useful synthetic intermediate for a variety of a-amino acids, can be prepared by means of the HWE reaction in the presence of TMG (3) or DBU [20,21]. In the synthesis of teicoplanin aglycon (80) reported by Evans et al. [22], one of the phenylalanine derivatives 79 was synthesized from the aldehyde 75. HWE reaction of aldehyde 75 with phosphonate 76 using TMG (3) in THF gave (Z)-enamide ester 77 in 99% yield. Asymmetric hydrogenation of 77 catalysed by rhodium(I) complex 78 (1 mol%) gave the phenylalanine ester 79 in 96% with 94% ee (Scheme 7.16). 

Even though the use of (S)-proline (1) for the synthesis of the Wieland-Miescher ketone, a transformation now known as the Hajos-Parrish-Eder-Sauer-Wiechert reaetion, was reported in the early 1970s, aminocatalysis - namely the catalysis promoted by the use of chiral second-aiy amines - was rediscovered only thirty years later. The renaissance of aminocatalysis was prompted by two independent reports by List et al. on the asymmetric intermolecular aldol addition catalysed by (S)-proline (1) and by MacMillan et al. on the asymmetric Diels-Alder cycloaddition catalj ed by a phenylalanine-derived imidazolidinone 2. These two reactions represented the archetypical examples of asymmetric carbonyl compound activation, via enamine (Figure ll.lA) and iminium-ion (Figure 11.IB), respectively. 

The first organocatalytic intermolecular asymmetric aldol reaction was reported by List and coworkers in 2000 [23]. The aldol reaction between acetone and a variety of aldehydes was accomplished in excellent yields and high levels of e-nantioselectivity. For example, the aldol product of the coupling with o-butyral-dehyde was formed in 97 % yield and 96 % ee ((1), Scheme 4.10). The remarkable levels of selectivity sparked massive interest in the field of proUne-catalysed aldol, Michael and Mannich reactions. Later that year MacMillan reported a phenylalanine-derived catalyst (35) for the Diels-Alder reaction of a-P-unsaturated aldehydes with up to 94 % ee ((2), Scheme 4.10) [24]. Many further applications of... 

In a related fashion, asymmetric amination of ( )-cinnamic acid yields L-phenylalanine using L-phenylalanine ammonia lyase [EC 4,3,1,5] at a capacity of 10,000 t/year [1274, 1601], A fascinating variant of this biotransformation consists in the use of phenylalanine aminomutase from Taxus chinensis (yew tree), which interconverts ot- to p-phenylalanine in the biochemical route leading to the side chain of taxol [1602], In contrast to the majority of the cofactor-independent C-0 and C-N lyases discussed above, its activity depends on the protein-derived internal cofactor 5-methylene-3,5-dihydroimidazol-4-one (MIO) [1603], Since the reversible a,p-isomerization proceeds via ( )-cinnamic acid as achiral intermediate, the latter can be used as substrate for the amination reaction. Most remarkably, the ratio of a- vs, 3-amino acid produced (which is 1 1 for the natural substrate, R = H) strongly depends on the type and the position of substituents on the aryl moiety While o-substituents favor the formation of a-phenylalanine derivatives, / -substituted substrates predominantly lead to p-amino analogs, A gradual switch between both pathways occurred with m-substituted compounds. With few exceptions, the stereoselectivity remained exceUent (Scheme 2,215) [1604, 1605],... 

A recent example has been described by Brown et al. who have studied the KR of p-nitrophenyl esters of the d- and i-N-tert-butoxycarbonyl derivatives of glutamine and phenylalanine with ethanol or methanol promoted by chiral lanthanide complexes, providing enantioselectivities of up to 99% ee [302]. On the other hand, an enantioselective hydrolysis of phenylalanine derivatives was reported in 1986, providing a perfect enantiomer discrimination (s> 1000), as a result of catalysis with a tripeptide [303]. In 2007, Maruoka et al. reported the KR of differently a,a-disubstituted a-siloxy aldehydes based on an asymmetric rearrangement into the corresponding chiral acyloins using axially chiral organoaluminium Lewis acids, which provided selectivity factors of up to 39.5... 

The use of amide-directed ip -arylation has been successfully utilized in the asymmetric preparation of unnatural a-amino acids (Schane 3.25). " Treatment of electron-deficient phthalimide protected a-amino amides with Pd(TFA)2 and aryl iodides led the formation of novel phenylalanine derivatives in high yield and excellent chemoselectivity. The method displays robnst tolerance for amnltitnde of substituted aromatics with varying electronic properties. Suppression of fcis-arylation was excellent under the reported conditions. This method was also extended toward the preparation homoarylated phenylalanines affording novel aryl differentiated moieties with excellent diastereoselectivities. 

Amino acid-derived primary-tertiary diamine catalysts have been used extensively in aldol reactions. Lu and Jiang [34] documented a direct asymmetric aldol reaction between acetone and a-ketoesters catalyzed by an L-serine-derived diamine 17. Sels et al. [35] found that several primary amino acid-based diamines (18) were efficient catalysts for the syn-aldol reaction of linear aliphatic ketones with aromatic aldehydes. Luo and Cheng utilized L-phenylalanine-derived diamine catalyst 15a for the enantioselective syn-aldol reaction of hydroxyl ketones with aromatic aldehydes [36]. Moreover, a highly enantioselective direct cross aldol reaction of alkyl aldehydes and aromatic aldehydes was realized in the presence of 15a (Scheme 3.8) [37]. Very recently, the same group also achieved a highly enantioselective cross-aldol reaction of acetaldehyde [38]. Da and coworkers [39] discovered that catalyst 22, in combination with 2,4-dinitrophenol, provided good activation for the direct asymmetric aldol reaction (Scheme 3.9). 

For example, (Z)-a-benzylaminocinnamic acid is hydrogenated by [Rh((S,S)-CHIRAPHOS)(S)2]" in THF to afford R-phenylalanine derivative in 99% ee. The kinetic and mechanistic aspects of the asymmetric hydrogenation have been extensively discussed elsewhere. ... 

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