Graphical AbstractTo create your abstract, type over the instructions in the template box below. Fonts or abstract dimensions should not be changed or altered.Peptide foldamers composed of six-membered ring α,α-disubstituted α-amino acids with two changeable chiral acetal moieties IntroductionConformational freedom-restricted oligopeptides have attracted the attention of organic, peptide, and medicinal chemists because they are capable of developing peptide organo-catalysts for asymmetric reactions and are also drug candidates derived from biologically active natural peptides.1 α,α-Disubstituted α-amino acids (dAAs) have been used to restrict the conformational freedom of their peptides. 2Oligopeptides incorporating α-aminoisobutyric acid (Aib; αMeAla) have been shown to preferentially form 310-/α-helical structures, whereas peptides having α-ethylated dAAs, such as diethylglycine and (S)-butylethylglycine, are more likely to assume fully planar conformations.3 Differences in secondary structures (helix and planar conformations) are determined by the peptide-backbone torsion angles φ (C'-N-Cα-C') and ψ (N-Cα-C'-N). For example, the ideal right-handed (P) 310-helix has φ −60° and ψ −30° torsion angles, the right-handed (P) α-helix has φ −57° and ψ −47°, and the fully planar conformation has φ 180° and ψ 180°. The patterns of intramolecular hydrogen bonds also differ in these secondary structures. For example, the 310-helix forms an intramolecular hydrogen bond of the N(i+3)-H···O(i)=C(i) i←i+3 type, whereas the α-helix forms an intramolecular hydrogen bond of the N(i+4)-Moreover, the fully planar conformation forms an intramolecular hydrogen bond of the C5---- * Corresponding author. Tel/fax: +81 95 819 2423; e-mail: matanaka@nagasaki-u.ac.jpBy selecting appropriate dAAs, these secondary structures are partially controlled. However, the preferential conformations of known dAAs are limited to those of helix and planar conformations. Thus, the development of new dAAs with different conformational preferences is greatly desired.One such dAA may be the achiral O,O-isopropylidene-α-hydroxymethylserine {Hms(Ipr)} reported by Toniolo, Leplawy, and co-workers. Hms(Ipr) peptides formed destabilized 310-helical structures, in which hydrogen bonds were detected between peptide main-chain NH and side-chain acetonide -O-.We recently synthesized six-membered ring dAAs with a changeable chiral acetal moiety as well as the preferred secondary structures of their peptides.5 These findings prompted us to change the position of the acetal moiety on the cyclohexane ring and increase the number of acetal moieties on the cyclic amino acid. We designed six-membered ring dAAs with two chiral acetal moieties {(R,R)- Chiral cyclic α,α-disubstituted α-amino acids with four chiral centers at their acetal moieties were synthesized. An X-ray crystallographic analysis of homo-chiral tripeptide with (2R,3R)-butane-2,3-diol acetal moieties revealed that the tripeptide formed both (P) and (M) helical structures, and all peptide main-chain N(i)-H...
A facile regio-and diastereoselective nitrile oxide cycloaddition method using magnesium-coordinated chelation control of chiral α-alkoxymethyl ether nitrile oxide is reported. This reaction could be successfully applied as a key step in both the formal total synthesis of (-)-clausenamide and the total synthesis of (-)-cisclausenamide.The 1,3-dipolar cycloaddition of nitrile oxides has attracted considerable attention in synthetic organic chemistry because of its application in the synthesis of complex natural products. 1 Thus, numerous examples of regio-and/or diastereoselective nitrile oxide cycloaddition reactions have been developed and intensely studied. 2 One of the major advances in this field is the metal-coordinated 1,3-dipolar cycloaddition of benzonitrile oxide with allylic alcohols in the presence of magnesium alkoxides, which introduce a high reaction rate enhancement and absolute regiocontrol, as reported by Kanemasa et al. 3 Recently, Carreira et al. have developed convenient and broadly applicable (i.e., including aliphatic nitrile oxides) reaction conditions for highly diastereoselective cycloaddition reactions by improving upon Kanemasa's methods. 4 In this contribution, we describe the regio-and diastereoselective 1,3-dipolar cycloaddition of α-alkoxy aliphatic nitrile oxides to 3-substituted allylic alcohols. Racemic clausenamide was first isolated from Clausena lansium (Lours.) Skeels, a Chinese folk medicine; (-)-clausenamide (1) has shown potent nootropic activities in many behavioral experiments, and is currently being developed as a promising antidementia drug. 5 Moreover, (-)-cis-clausenamide (2), the C3 isomer of 1, is demonstrated to be nearly twice as active as 1 (Figure 1). 6 Given the important pharmacological activity and interesting molecular structure -namely, a densely substituted pyrrolidinone ring with four contiguous stereocenters -it is clear why the clausenamides are widely studied by synthetic chemists as important synthetic targets. 7 In the context of our study on 1,3-dipolar cycloaddition reactions, we succeeded in the development of a new synthetic route toward the stereocontrolled synthesis of 3,4,5-trisubstituted 2-isoxazolines, including an improvement in cycloaddition diastereoselectivity by use of a combination of alkoxymethyl ether nitrile oxides with magnesium alkoxide. This facile approach to the synthesis of substituted 2-isoxazolines was applied to both a formal total synthesis of 1 and a total synthesis of 2. The outline of our synthesis strategy toward the clausenamides is illustrated in Scheme 1. The clausenamides may be synthesized from 2-isoxazoline A, by (a) oxidation and esterification, (b) selective reduction, and (c) N-O bond cleavage and subsequent recyclization to construct the pyrrolidinone rings. 2-Isoxazoline A may be obtained by a putative 1,3-dipolar cycloaddition of nitrile oxide B with cinnamyl alcohol 3 from the less hindered face in an exo fashion. Scheme 1 Retrosynthetic analysis of clausenamidesOn the basis of our strategy, various chir...
Flurbiprofen axetil (FPA) is an injection product and a prodrug of a non-steroidal anti-inflammatory drug (NSAID). After injection, it is rapidly hydrolyzed to the active form, flurbiprofen (FP). Since frequent injections of FPA can lead to abnormal physiology, an administration strategy is necessary to ensure there is enhancement of the analgesic efficiency of FP after a single dose and to reduce the total number of doses. FP strongly binds to site II of albumin, and thus the free (unbound) FP concentration is low. This study focused on 6-methoxy-2-naphthylacetic acid (6-MNA), the active metabolite of nabumetone (a prodrug of NSAID). We performed ultrafiltration experiments and pharmacokinetics analysis in rats to investigate whether the inhibitory effect of 6-MNA on FP binding to albumin increased the free FP concentration in vitro and in vivo. Results indicated that 6-MNA inhibited the binding of FP to albumin competitively. When 6-MNA was injected in rats, there was a significant increase in the free FP concentration and the area under concentration-time curve (AUC) calculated from the free FP concentration, while there was a significant decrease in the total (bound + free) FP concentration and the AUC calculated from the total FP concentration. These findings indicate that 6-MNA inhibits the protein binding of FP in vivo. This suggests that the frequency of FPA injections can be reduced when administered with nabumetone, as there is increase in the free FP concentration associated with pharmacological effect.
Four isomers of the monomer of peptide nucleic acid (PNA) were derived from (2S,4R)‐4‐hydroxyproline; they had different stereochemistries at the C2 and C4 positions in the pyrrolidine ring. These different backbone conformations corresponding to four different stereochemistries were realized through a combination of inversions at the C2 and the C4 positions in pyrrolidine ring. The obtained backbone frameworks were reacted with N‐benzoyl thymine to give the corresponding PNA monomers. Spectroscopic comparison of the resultant monomers confirmed their stereochemistries. J. Heterocyclic Chem., (2011).
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