Aliphatic amino acid derivatives

The ORD spectra of metal complexes of JV-salicylidene aliphatic amino acid derivatives (65) were also investigated, and it was found that the chelates... 

The Hofmann-type rearrangement of aromatic and aliphatic imides using KBr as the catalyst gives aromatic and aliphatic amino acid derivatives. Using a hypervalent iodine(III) reagent generated in situ, amino acid derivatives are formed via alcoholysis followed by a Hofmann rearrangement promoted by the formation of an imide-A -iodane intermediate (Scheme 170). ... 

With Sulfur Nucleophiles N-Carboxy-protected aziridine-2-carboxylates react with thiols to give P-mercapto-ot-amino acid derivatives. The reaction is usually catalyzed by BF3 and the yields range from fair to excellent [15, 16, 108-111]. With N-unprotected 3-substituted aziridine-2-carboxylates, the ring-opening with thiols usually takes place with anti stereoselectivity, especially in the case of the C-3 aliphatic substituted substrates. In cases in which C-3 is aromatic, however, the stereoselectivity has been found to be a function of the substitution pattern on the aromatic ring 3-p-methoxy ph eri yl-su bs li In led aziridines 143a (Scheme 3.51) and... 

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). 

Less reactive than acyl halides, but still suitable for difficult couplings, are symmetric or mixed anhydrides (e.g. with pivalic or 2,6-dichlorobenzoic acid) and HOAt-derived active esters. HOBt esters smoothly acylate primary or secondary aliphatic amines, including amino acid esters or amides, without concomitant esterification of alcohols or phenols [34], HOBt esters are the most commonly used type of activated esters in automated solid-phase peptide synthesis. For reasons not yet fully understood, acylations with HOBt esters or halophenyl esters can be effectively catalyzed by HOBt and HOAt [3], and mixtures of BOP (in situ formation of HOBt esters) and HOBt are among the most efficient coupling agents for solid-phase peptide synthesis [2]. In acylations with activated amino acid derivatives, the addition of HOBt or HOAt also retards racemization [4,12,35]. 

Table 13.13. Acylation of support-bound aliphatic alcohols with a-amino acid derivatives.

In the first approach, an amino acid derived 4-nitrophenyl carbamate is used as the carbamoylating reagent. 4-Nitrophenyl carbamates are generally not very reactive, and carbamoylations with these reagents only proceed smoothly with sufficiently nucleophilic aliphatic amines. 4-Nitrophenyl carbamates [252] and O-succinimidyl carbamates [253] in combination with A-Fmoc protection have also been used for the solid-phase synthesis of oligoureas. 

In 1997, the first truly catalytic enantioselective Mannich reactions of imines with silicon enolates using a novel zirconium catalyst was reported [9, 10]. To solve the above problems, various metal salts were first screened in achiral reactions of imines with silylated nucleophiles, and then, a chiral Lewis acid based on Zr(IV) was designed. On the other hand, as for the problem of the conformation of the imine-Lewis acid complex, utilization of a bidentate chelation was planned imines prepared from 2-aminophenol were used [(Eq. (1)]. This moiety was readily removed after reactions under oxidative conditions. Imines derived from heterocyclic aldehydes worked well in this reaction, and good to high yields and enantiomeric excesses were attained. As for aliphatic aldehydes, similarly high levels of enantiomeric excesses were also obtained by using the imines prepared from the aldehydes and 2-amino-3-methylphenol. The present Mannich reactions were applied to the synthesis of chiral (3-amino alcohols from a-alkoxy enolates and imines [11], and anti-cc-methyl-p-amino acid derivatives from propionate enolates and imines [12] via diastereo- and enantioselective processes [(Eq. (2)]. Moreover, this catalyst system can be utilized in Mannich reactions using hydrazone derivatives [13] [(Eq. (3)] as well as the aza-Diels-Alder reaction [14-16], Strecker reaction [17-19], allylation of imines [20], etc. 

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. 

Peptides. This isocyanide is preferable to simple aliphatic isocyanides (9, 82) for coupling of amino acid derivatives to peptides. Addition of hydroxysuccinimide (9,246) or 1 -hydroxybenzotriazole (6,288) suppresses racemization. It is important to allow the acid component and the additive to react with the isocyanide for a suitable period before addition of the amine component and triethylamine or DMAP. Coupling to di- and tripeptides in yields of 55-72% have been reported. The byproduct, (N-morpholinoethyl)formamide, is removed by an acid wash. 

The corresponding /i-amino aldehydes are reduced in situ and the corresponding amino alcohols are isolated in good yield with up to >99 % ee. The Mannich reactions proceed with excellent chemoselectivity and inline formation occurs with the acceptor aldehyde at a faster rate than C-C bond-formation. Moreover, the one-pot three-component direct asymmetric cross-Mannich reaction enables aliphatic aldehydes to serve as acceptors. The absolute stereochemistry of the reaction was determined by synthesis and reveled that L-proline provides syn /i-amino aldehydes with (S) stereochemistry of the amino group. In addition, the proline-catalyzed direct asymmetric Mannich-type reaction has been connected to one-pot tandem cyanation and allylation reaction in THF and aqueous media affording functional a-amino acid derivatives [39, 42]. 

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). 

Attention may be called to the fact that the conclusions reached here concerning the isoelectric point must hold irrespective of whether the neutral ampholyte consists of dual ions or of uncharged molecules. Provided the values of ki and k2 are those derived experimentallj they involve no supposition concerning the nature of the groups responsible for them. In the foregoing treatment the assumption has been made that the neutral molecule is RH, as this is true for aliphatic amino-acids, but the results will be quite unchanged if RH= is replaced by RH, as Avould be the case for an amino-benzoic acid or an amino-phenol. 

Alkaloids derived from aliphatic amino acids and nicotinic acid... 

Several factors affect the volatility and stability of a peptide derivative, not least of these being the number and nature of the constituent amino acids. Heterocyclic and aromatic amino acids reduce volatility while those containing sulphur tend to decrease the thermal stability. Small naturally occurring peptides which are not derived from proteins often contain only aliphatic amino acids which lack functional groups in the side chains. Peptides of this type of up to about ten amino acids, after conversion to suitable derivatives, are amenable to analysis by mass spectrometry, e.g. [164]. A variety of derivatives has been reported and include N-trifluoroacetyl peptide esters [136,165], N-acetyl peptide esters [166-168], aromatic N-acyl peptide esters [169-172], and per-methylated N-acyl peptides [173]. The principal modes of the electron impact induced fragmentation of these peptide derivatives are well established and have been summarised in recent reviews [174,175]. Although the spectra of the permethylated derivatives [176] are perhaps the simplest and easiest to interpret and are now frequently used, the N-acyl peptide esters have been widely and successfully employed. 

Quach and Batey299 reported the coupling of primary amines with phenylboronic acids catalyzed by Cu(OAc)2 (10 mol%) without base or ligand but in the presence of 4 A molecular sieves and air in CH2C12 solvent (equation 73). Reactions of potassium phenyl-trifluoroborate also occurred, but in lower yields than reactions of boronic acids. They showed that these reactions occur with a variety of functional groups on the amine, including alkenes, esters, ketones and ketals. a-Amino acid derivatives underwent reaction without detectable epimerization. Anilines were poorer cross-coupling partners under these conditions than were primary and secondary cyclic aliphatic amines. 

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