Amino acids isosterism

Paulvannan, K., and Stille, J.R., Conformationally restricted P-amino acid isosteres prepared through regioselectivity controlled aza-annulation. Tetrahedron Lett., 34, 8197, 1993. 

As described in Section 2.3.2, vinylaziridines are versatile intermediates for the stereoselective synthesis of (E)-alkene dipeptide isosteres. One of the simplest methods for the synthesis of alkene isosteres such as 242 and 243 via aziridine derivatives of type 240 and 241 (Scheme 2.59) involves the use of chiral anti- and syn-amino alcohols 238 and 239, synthesizable in turn from various chiral amino aldehydes 237. However, when a chiral N-protected amino aldehyde derived from a natural ot-amino acid is treated with an organometallic reagent such as vinylmag-nesium bromide, a mixture of anti- and syn-amino alcohols 238 and 239 is always obtained. Highly stereoselective syntheses of either anti- or syn-amino alcohols 238 or 239, and hence 2,3-trans- or 2,3-as-3-alkyl-2-vinylaziridines 240 or 241, from readily available amino aldehydes 237 had thus hitherto been difficult. Ibuka and coworkers overcame this difficulty by developing an extremely useful epimerization of vinylaziridines. Palladium(0)-catalyzed reactions of 2,3-trons-2-vinylaziri-dines 240 afforded the thermodynamically more stable 2,3-cis isomers 241 predominantly over 240 (241 240 >94 6) through 7i-allylpalladium intermediates, in accordance with ab initio calculations [29]. This epimerization allowed a highly stereoselective synthesis of (E) -alkene dipeptide isosteres 243 with the desired L,L-... 

This approach has been mainly applied to peptide-based inhibitors of proteases, where the inhibitory molecule is a peptide with a transition state isostere appended to it, and the cognate substrate is simply a peptide of the same amino acid sequence, but lacking the isostere functionality. Examples where good correlations between the free energy of inhibitor binding and the free energy of kcJKM have been found, include peptide-trifluoromethyl ketone inhibitors of human leukocyte elastase (Stein et al., 1987) and peptide-phosphonamidate inhibitors of the metalloprotease ther-molysin (Bartlett and Marlowe, 1983). 

Weik and Rademann have described the use of phosphoranes as polymer-bound acylation equivalents [65]. The authors chose a norstatine isostere as a synthetic target and employed classical polymer-bound triphenylphosphine in their studies (Scheme 7.54). Initial alkylation of the polymer-supported reagent was achieved with bromoacetonitrile under microwave irradiation. Simple treatment with triethyl-amine transformed the polymer-bound phosphonium salt into the corresponding stable phosphorane, which could be efficiently coupled with various protected amino acids. In this acylation step, the exclusion of water was crucial. 

Fig. 1. FTase inhibitors in which amide bonds were replaced by isosteric amines and ethers, and which incorporate non-natural amino acids...

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... 

Another major site of peptide metabolism is the blood and especially blood serum and plasma. From an extensive compilation of peptide tm values (over 100 peptides, plus derivatized and cyclized analogues, D-amino acid stereoisomers, peptide bond isosteres, etc.), it appears that the differences between serum, heparinized plasma, and whole blood are fairly limited [161]. Interspecies differences are larger, particularly between humans and rats, with most human/rat t1/2 ratios ranging from 1 1 to 25 1 ... 

Piperazines and derivatives are archaetypical scaffolds and can be considered as efficient, however, structurally simple peptidomimics. The scaffolds combine conformational rigidity with peptide-like spacial placement of amino acid side chains or isosteres thereof. Moreover, piperazines can be used to confine compounds with beneficial properties such as water solubihty. Piperazines are therefore in the center of synthetic interest and many different synthetic pathways have been designed [16-19]. A preferred way to synthesize different piperazine scaffolds with plenty of variabihty provides MCR chemistry. Several piperazine scaffolds are currently only accessible by isocyanide-based MCR. Likely they could be assembled by sequential synthesis as well however, the synthetic efficiency, the diversity, and the size of the alternative chemical space will be inferior. The application of... 

The preparations of Glyi/r[CF=CH]Gly (4) and Phei/r[CF=CH]Gly (5) were described by Allmendinger and his coworkers [46,47]. The Gly-Gly fluoroolefin dipeptide isostere (4) was synthesized from cyclic acetal (6), obtained by the procedure of Dehmiow [48] involving a carbene insertion and reexpansion reaction. Further elaboration as detailed in Scheme 1 ultimately afforded the A/-protected amino acids (4). 

Bartlett etal. [14] described the synthesis of a series of fluoroolefin tripeptide isosteres Cbz-Glyi/r[(Z)-CF=CH]LeuXaa (Xaa = Gly, Ala, Leu, Phe, and NH2) (10) (Scheme 3) as the ground-state analog inhibitors of thermolysin. Treatment of acid (15) with ammonia gave 10e. The inhibitors 10a-d are formed by conventional amide acid coupling reactions of suitably protected amino acids followed by saponification with lithium hydroxide. 

K.W. Laue, C. Muck-Lichtenfeld, G. Haufe, Enantioselective syntheses of 2-amino-4-fluoropent-4-enoic acids. Isosteres of asparagine, Tetrahedron 55 (1999) 10413-10424. 

Methods to prepare vinylogous (NH2—CHR—CH=CH—C02H)[1113], alkynylogous (NH2-CHR-OC-C02H), 14 and NH2-CHR-CH2-CH2-C02H 15 amino acids have been reported. These are lacking one carbon atom to be isosteric with a dipeptide, and therefore are not treated here. 

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. 

In a parallel study, Wipf and Fritch11041 have shown that also urethane-protected (Boc), and even amino acid segments, are tolerated as acyl compounds on the aziridine nitrogen. The best results were obtained with alkylcopper reagents derived from CuCN and an alkyl-lithium in the presence of boron trifluoride-diethyl ether complex. Some 6-alkylated compounds (11-15%) were isolated as well. This work was extended to a solid-phase procedure that resulted in resin-bound alkene isosteres that could immediately be used in further peptide synthesis.11051 For this purpose, the 2-nitrophenylsulfonyl (oNbs) group was used for nitrogen protection and aziridine activation. It could be readily cleaved with benzenethio-late, which was compatible with the acid-sensitive Wang linker used. 

One of the earliest syntheses of r )[CH20] (methyleneoxy) peptide isosteres was reported by Rubini et alJ1,2l These authors used an intermolecular Williamsons reaction between a urethane-protected amino alcohol and tert-butyl bromoacetate (Scheme 1)J1,2] However, this method resulted in low yields and was not applicable to bulky amino acids. Thus, only isosteres containing glycine as the C-terminal component could be synthesized by this method. 

Chen et al.[57] reported the synthesis of the 2-hydroxyethylene isostere using two methods. The first method is initiated with readily available a-amino acids and utilizes the Evans chiral aldol condensation to control the stereochemistry (Scheme 25). The second method does not start with a-amino acids, and thus allows for the synthesis of isosteres having side chains other than those obtained from the available a-amino acids (Scheme 26). Thus, this synthesis relies on an anti-aldol product for the 2-hydroxyethylene isosteres via an E-selective ethyl hydrocinnamate enolization. 

The method of Kim et al.[89-93] starts from the synthesis of the three-carbon phosphonium salt according to the modified method of Corey et alJ94,95] The Wittig reaction of the phosphonium salt with a Z-protected a-amino aldehyde using potassium hexamethyldisilazanide provides the ds-alkene without racemization. Efficient hydrolysis of the orthoester without double bond migration is achieved by acidolytic hydrolysis with aqueous hydrochloric acid in tert-butyl alcohol under reflux conditions. Then, an a-amino acid methyl ester is coupled. The desired epoxide product is obtained by treatment with 3-chloroperoxybenzoic acid. The epoxidation reaction is stereoselective and predominantly provides one isomer (R,S S,R = 4-10 1). The trans-epoxide can also be prepared using a trans-alkene-containing peptide. A representative synthetic procedure to obtain the ds-epoxide isostere is detailed below. 

The presence of the additional p-carbon atom in Tau analogues offers the opportunity to study the influence of functionalization at this p-position as compared to functionalization at the a-position. Naturally occurring a-amino acids can be used as starting materials for the synthesis of homochiral P-substituted methylene sulfinamide and sulfonamide transition-state isosteres incorporated in peptides.11201... 

The retro-peptide bond is a true isosteric peptide bond surrogate and as such may offer an important tool to study topics such as the functional role of the peptide backbone in peptide hormone-receptor interactions, and modulation of metabolic stability and bioavailability. Partially modified retro-inverso-peptides (PMRI-peptides) (e.g., 2-4, 7 Scheme 1) result from a retro-inverso transformation of one or several peptide bonds in an amino- and carboxy-free peptide (e.g., 5 Scheme 1). Evidently, partial or exhaustive retro-inverso transformations result in the introduction of two non-amino acid residues into the... 

Other modified amino acids have been used as y-turn inducers. For example, Toniolo et al. 21 utilized a reduced peptide isostere (-CH2NH-) moiety and incorporated it into the neurotransmitter tripeptide -Pro-Leu-Gly-. The X-ray diffraction structure of the N-terminal Boc-or Z-protected tripeptide Boc(or Z)-Prot i[CH2NH]Leu-Gly-NH2 2 provides unequivocal proof of the existence of a y-turn (Scheme 3). 

Further discussion and additional references to the synthesis of peptides containing dide-hydro-a-amino acids, reduced peptide isosteres, TV-hydroxy amides and hydrazides, and Ca-tetrasubstituted amino acids including 2,3-methano amino acids can be found in Sections 11.1,10.7,10.8, and 10.3, respectively. 

Figure 13.4 The double sieve analogy for the editing mechanism of the isoleucyl-tRNA synthetase. The active site for the formation of the aminoacyl adenylate can exclude amino acids that are larger than isoleucine but not those that are smaller. On the other hand, a hydrolytic site that is just large enough to bind valine can exclude isoleucine while accepting valine and all the smaller amino acids. (In some enzymes, the hydrolytic site offers specific chemical interactions that enable it to bind isosteres of the correct amino acid as well as smaller amino acids.)...

The is-olefin was prepared as a trans-amide bond replacement. A number of compounds incorporating substituents to mimic both natural and unnatural amino acid sidechains were prepared by adapting chemistry developed by Ibuka for the synthesis of Zs-olefin peptide isosteres (see Scheme l).40,41 The key step involved anti-SN2 displacement of vinyl mesylate 8 by boron trifluoride-activated cuprate addition. Compounds containing butyl, propyl, and benzyl substituents at the allylic positions to mimic the aj and sidechains produced potent FTase inhibitors (Table 4). 

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