Amino acid derivatives, arylation

Several approaches to the 1,2,3-triazole core have been published in 2000. Iodobenzene diacetate-mediated oxidation of hydrazones 152 led to fused 1,2,3-triazoloheterocycles 153 <00SC417>. Treatment of oxazolone 154 with iso-pentyl nitrite in the presence of acetic acid gave 1,2,3-triazole 155, a precursor to 3-(W-l,2,3-triazolyl)-substituted a,P-unsaturated a amino acid derivatives <00SC2863>. Aroyl-substituted ketene aminals 156 reacted with aryl azides to provide polysubstituted 1,23-triazoles 157 <00HC387>. 2-Aryl-2T/,4/f-imidazo[43-d][l,2,3]triazoles 159 were prepared from the reaction of triethyl AM-ethyl-2-methyl-4-nitro-l//-imidazol-5-yl phosphoramidate (158) with aryl isocyanates <00TL9889>. 

Several reports have been made of a successful catalyzed addition/ substitution reaction resulting in direct attachment of phosphorus to aromatic rings. The preparation of mixed triarylphosphines has been accomplished by the reaction of tin- or silicon-substituted diphe-nylphosphines with aryl halides catalyzed by palladium reagents.74 A similar transformation has also been reported using nickel catalysis.75 The addition/substitution of diphenylphosphine to triflate functionalized phenolic linkages has been of use for the preparation of substances as analogues of tyrosine-related amino acid derivatives, accomplished with catalysis by palladium acetate (Equation 4.29).76... 

The C-H insertion a to nitrogen can be extended to acyclic systems. The reaction with jY-benzyl-iV-methylamine is an excellent example of the interplay between steric and electronic effects. The benzylic position would be electronically the most activated, but due to the steric crowding, the C-H insertion occurred exclusively at the iV-methyl site (Equation (27)).86 This is a general method for generating a-aryl-/5-amino acid derivatives. The N,N-dimethylamino group undergoes a very favorable C-H insertion by the donor/acceptor-substituted carbenoids. Indeed, the reaction is so favorable that double C-H insertion was readily achieved to form the elaborated -symmetric amine 10 (Equation (28)).87... 

An enantioselective imino-ene reaction was developed by Lectka to provide ct-amino acid derivatives.27 Aryl alkenes (cr-methyl styrene, tetralene), aliphatic alkenes (methylene cyclohexane), and heteroatom-containing enes, all gave high yields and high ee s of the homoallylic amides (Equation (17)). The mechanism of this reaction has been proposed to proceed through a concerted pathway. This mechanism is evidenced by a large kinetic isotope effect observed in the transfer of H(D). 

Recently, Borner and coworkers described an efficient Rh-deguphos catalyst for the reductive amination of a-keto acids with benzyl amine. E.e.-values up to 98% were obtained for the reaction of phenyl pyruvic acid and PhCH2COCOOH (entry 4.9), albeit with often incomplete conversion and low TOFs. Similar results were also obtained for several other a-keto acids, and also with ligands such as norphos and chiraphos. An interesting variant for the preparation of a-amino acid derivatives is the one-pot preparation of aromatic a-(N-cyclohexyla-mino) amides from the corresponding aryl iodide, cyclohexylamine under a H2/ CO atmosphere catalyzed by Pd-duphos or Pd-Trost ligands [50]. Yields and ee-values were in the order of 30-50% and 90 >99%, respectively, and a catalyst loading of around 4% was necessary. 

Novel highly functionalized dipeptide isosters were synthesized via diastereoselective alkyl-arylation protocol of a glucose-derived (R)-tert-butanesulfinylimine. One of these novel sugar amino acid derivatives, a D-Ala-Ser/Thr isostere, was applied in a peptide synthesis protocol to afford a cyclic tetramer (Fig. 53).69... 

The chiral distinction capability of cinchonan carbamate CSPs for underivatized amino acids has not been fully elucidated yet, in contrast to the large embodiment of A-acylated and A-arylated amino acid derivatives vide infra). However, it seems that chiral amino acids can be successfully resolved into enantiomers if the amino acid side chain R residue) contains a functionality that represents a strongly interactive binding site with the selector such as an extended aromatic ring system like in thyroxin (T4). 

Aryl side chain containing L-a-amino acids, such as phenylalanine (Phe), tyrosine (Tyr), and tryptophan (Trp), are derived through the shikimate pathway. The enzymatic transformation of phosphoenolpyr-uvate (PEP) and erythro-4-phosphate, through a series of reactions, yields shikimate (Scheme 2). Although shikimate is an important biosynthetic intermediate for a number of secondary metabolites, this chapter only describes the conversion of shikimate to amino acids containing aryl side chains. In the second part of the biosynthesis, shikimate is converted into chorismate by the addition of PEP to the hydroxyl group at the C5 position. Chorismate is then transformed into prephenate by the enzyme chorismate mutase (Scheme 3). 

An extensive review of the hetero-Diels-Alder reactions of 1-oxabuta-1,3-dienes has been published. Ab initio calculations of the Diels-Alder reactions of prop-2-enethial with a number of dienophiles show that the transition states of all the reactions are similar and synchronous.Thio- and seleno-carbonyl compounds behave as superdienophiles in Diels-Alder reactions with cyclic and aryl-, methyl-, or methoxy-substituted open-chain buta-1,3-dienes.The intramolecular hetero-Diels-Alder reactions of 4-benzylidine-3-oxo[l,3]oxathiolan-5-ones (100) produce cycloadducts (101) and (102) in high yield and excellent endo/exo-selectivity (Scheme 39). A density functional theoretical study of the hetero-Diels-Alder reaction between butadiene and acrolein indicates that the endo s-cis is the most stable transition structure in both catalysed and uncatalysed reactions.The formation and use of amino acid-derived chiral acylnitroso hetero-Diels-Alder reactions in organic synthesis has been reviewed. The 4 + 2-cycloadditions of A-acylthioformamides as dienophiles have been reviewed. ... 

The logical consequence of using chiral acids as CDAs for amines, as outlined in Figure 6, is that (.R)- and (S)-l-(aryl)ethylamines (Table 1, entries 39 to 43) almost ideally fulfill the requirements of CDAs for separating chiral acids due to the difference in bulkiness of the substituents on the stereogenic centers. Amino acid derivatives such as L-leucinamide also serve well as CDAs. Both types have been highly appreciated as can be seen from the number of applications listed in Table 2. The condensation reactions between the chiral carboxylic acids and amines (CDAs) can be performed in several ways. However, the mildest but quantitative ones will be most appropriate in order to minimize the potential risks of racemization of any stereogenic center. Otherwise, erroneous analytical data or optically impure diaslereomers could be obtained in the course of the preparative separation. 

Reactions of a-amino-substituted carbanion 61 with several electrophiles were investigated and, for instance, ethyl chloroformate was found to give the a-amino acid derivative 63 in 73% yield. This reaction represents a very interesting and unprecedented one-pot synthesis of a-amino acid derivative from 1-chloroalkyl aryl sulfoxide (see Table 2). 

Oxamborolidenes. There are noteworthy advances in the design, synthesis, and study of amino acid-derived oxazaborolidene complexes as catalysts for the Mukaiyama aldol addition. Corey has documented the use of complex 1 prepared from A-tosyl (S)-tryptophan in enantioselective Mukaiyama aldol addition reactions [5]. The addition of aryl or alkyl methyl ketones 2a-b proceeded with aromatic as well as aliphatic aldehydes, giving adducts in 56-100% yields and up to 93% ee (Scheme 8B2.1, Table 8B2.1). The use of 1-trimethylsilyloxycyclopentene 3 as well as dienolsilane 4 has been examined. Thus, for example, the cyclopentanone adduct with benzaldehyde 5 (R = Ph) was isolated as a 94 6 mixture of diastereomers favoring the syn diastereomer, which was formed with 92% ee, Dienolate adducts 6 were isolated with up to 82% ee it is important that these were shown to afford the corresponding dihydropyrones upon treatment with trifuoroacetic acid. Thus this process not only allows access to aldol addition adducts, but also the products of hetero Diels-Alder cycloaddition reactions. 

The palladium catalyzed hydrogenolysis of 3-amino 4-aryl azetidin-2-ones, Fig. 11, constitutes an excellent and reliable strategy to access a-amino acid derived peptides. The discovery, development, and synthetic opportunities of this approach have been reviewed by Ojima [145-148], and will not be covered here. Only the... 

Grigg et al. [61] have recently reported a one-pot reaction involving the initial three-component condensation with a 2-halo-benzylamine 112, ethyl glyoxylate 113 and an aryl boronic acid 114, followed by Pd cyclization in the presence of carbon monoxide to give 116, or in the presence of allene to form dihydroisoquinoline amino acid derivatives 117 (Scheme 7.15). 

Finally, the remarkably simple solution came from Evans et al. [21a] and researchers of DuPont [21b] simultaneously. Their method allows the coupling of structurally and electronically diverse phenols and aryl boronic acids in the presence of copper]11) acetate, trie-thylamine or pyridine, and molecular sieves at ambient temperature (Scheme 5). Even phenolic amino acid derivatives react smoothly without racemization. The only limitation has been observed when using orfho-heteroatom substituted boronic acids which resulted in lower product yields. The initial step in the proposed pathway (Scheme 6) is the trans-metallation of the boronic acid residue with the copper salt. 

For example, N-(2-hydroxyphenyl)imines 9 (R = alkyl, aryl) together with chiral zirconium catalysts generated in situ from binaphthol derived ligands were used for the asymmetric synthesis of a-amino nitriles [17], the diastereo- and/or enantioselective synthesis of homoallylic amines [18], the enantioselective synthesis of simple //-amino acid derivatives [19], the diastereo- and enantioselective preparation of a-hydroxy-//-amino acid derivatives [20] or aminoalkyl butenolides (aminoalkylation of triisopropylsilyloxyfurans, a vinylogous variant of the Mannich reaction) [21]. A good example for the potential of the general approach is the diastereo- and enantioselective synthesis of (2R,3S)-3-phenylisoserine hydrochloride (10)... 

The Hatakeyama group later reported the use of catalyst 103 for the asymmetric aza-MBH reactions of HFIPA with activated aromatic imines [96]. The aza-MBH reactions of four different diphenylphosphinoyl aryl imines (109) with HFIPA were promoted using 10 mol% 103 and afforded the corresponding a-methylene-/ -amino acid derivatives (110) in reasonable yields (42-97%) and moderate -values (54-73% Scheme 6.13). Aliphatic imines were not suitable substrates for the reaction due to imine lability. (For experimental details see Chapter 14.10.3). 

A novel reaction of A-acyl thiazolidinethione enolates with enolizable aldoxime ethers produced thiazolidinethione azetines 1 with excellent diastereoselectivity <03JA3690>. Subsequent addition of an acyl chloride to these azacyclobutene derivatives leads to the formation of the corresponding A -acyl-a,p-disubstituted p-amino acid derivatives, via selective generation of a cyclic four-membered iminium salt. Azetine derivatives were obtained as minor products on irradiating aryl-substituted A-acyl-a-dehydroalanines <03H637>. 

In addition to aryl carboxylic acids, including profens (2-aryl propionic acid NS AIDs) (see Fig. 9.36) [393,398], the terguride-based CSP has shown the potential to re.solve the enantiomers of 2-aryloxypropionic acids [394] and of A-dansyl, A-3,5-dinitrobenzoyl, A-benzoyl, A-P-naphthoyl amino acid derivatives [395]. 

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