Complete stereochemistry of neamphamide A and absolute configuration of the beta-methoxytyrosine residue in papuamide B

The absolute stereochemistry of the three unresolved structural components in neamphamide A (1) was determined to be (R)-beta-methoxy-L-tyrosine, (2R,3R,4S)-4-amino-7-guanidino-2,3-dihydroxyheptanoic acid, and (2R,3R,4R)-3-hydroxy-2,4,6-trimethylheptanoic acid. Stereochemical assignments were made by chemical degradation of 1, derivatization of the resulting products, and then spectroscopic and chromatographic comparison of the derivatives with synthetically prepared standards. Using the same analytical protocol developed for 1, the beta-methoxytyrosine residue in papuamide B (2) was found to be (R)-beta-methoxy-D-tyrosine. This represents a rare example of divergent stereochemistry in an unusual amino acid residue that is present in two closely related classes of peptides.     

Rational design and synthesis of a novel class of active site-targeted HIV protease inhibitors containing a hydroxymethylcarbonyl isostere. Use of phenylnorstatine or allophenylnorstatine as a transition-state mimic.

A novel class of HIV-1 protease inhibitors containing a hydroxymethylcarbonyl (HMC) isostere were designed from the substrate transition state and synthesized. Phenylnorstatine [Pns; (2R,3S)-3-amino-2-hydroxy-4-phenylbutyric acid] and the 2S diastereomer, (2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid, named allophenylnorstatine (Apns) were effective transition-state mimics, and incorporation of Pns-Pro or Apns-Pro at the P1-P1' site gave potent and specific HIV-1 protease inhibitors. In the inhibitory assays, the chemically synthesized [Ala67,95] HIV-1 protease was used.     

Total synthesis of cyclic tetrapeptide FR235222, a potent immunosuppressant that inhibits mammalian histone deacetylases

[structure: see text] The total synthesis of FR235222, a potent immunosuppressant with in vivo activities, has been achieved. The key steps include assembling its (2S,9R)-2-amino-9-hydroxy-8-oxodecanoic acid residue via an olefin cross-metathesis of a methyl (R)-lactate-derived homoallyl ketone with protected allyl amino acid and constructing its trans-(2R,4S)-4-methylproline unit from protected (R)-pyroglutamic acid in seven steps.     

Diastereoselective hydroxylation of 6-substituted piperidin-2-ones. An efficient synthesis of (2S,5R)-5-hydroxylysine and related alpha-amino acids

The synthesis of (2S,5R)-5-hydroxy-6-oxo-1,2-piperidinedicarboxylates (5) and related (3S,6R)-3-hydroxy-6-alkyl-2-oxo-1-piperidinecarboxylates has been developed. The approach is based on the asymmetric hydroxylation of enolates generated from the corresponding N-protected-6-substituted piperidin-2-ones. The utility of 5a as a precursor in the synthesis of (2S,5R)-5-hydroxylysine (1), an amino acid unique to collagen and collagen-like proteins, has also been demonstrated. (2S)-6-oxo-1,2-piperidinedicarboxylates (6) required for hydroxylation studies were prepared in 38-74% yield, starting from conveniently protected aspartic acid as inexpensive chiral adduct. Hydroxylation of 6 to 5 proceeds in high yield and excellent diastereoselectivity by treatment of their Li-enolate with (+)-camphorsulfonyloxaziridine at -78 degrees C. Ring opening of di-tert-butyl (2S,5R)-6-oxo-1,2-piperidinedicarboxylate ((5R)-5a) under reductive conditions afforded the corresponding 1,2-diol (17) in 91%, which was further transformed to (2S,5R)-5-hydroxylysine in four steps (84%). 17 is also a versatile intermediate in the preparation of tert-butyl (2S,5R)-2-[(tert-butoxycarbonyl)amino]-5-hydroxy-6-iodohexanoate (3) and tert-butyl (2S)-2-[(tert-butoxycarbonyl)amino]-4-[(2R)-oxiranyl]butanoate (4), two amino acid derivatives used in the total synthesis of the bone collagen cross-link (+)-pyridinoline (2a).     

Asymmetric transfer hydrogenation of alpha-aminoalkyl alpha'-chloromethyl ketones with chiral Rh complexes

Asymmetric transfer hydrogenation of N-substituted (3S)-3-amino-1-chloro-4-phenyl-2-butanones in the presence of CpRhCl[(R,R)-Tsdpen] (S/C = 1000) with a mixture of formic acid/triethylamine gave N-substituted (2R,3S)-3-amino-1-chloro-2-hydroxy-4-phenylbutanes with up to 93% de in a quantitative yield, and reduction with the enantiomeric catalyst CpRhCl[(S,S)-Tsdpen] gave (2S,3S)-diastereomeric alcohol with up to 96% de.     

Nitrile biotransformations for highly enantioselective synthesis of oxiranecarboxamides with tertiary and quaternary stereocenters; efficient chemoenzymatic approaches to enantiopure alpha-methylated serine and isoserine derivatives

[reaction: see text] Biotransformations of a number of differently substituted and configured oxiranecarbonitriles using Rhodococcus sp. AJ270, a microbial whole-cell catalyst that contains nitrile hydratase/amidase, were studied. While almost all trans-configured 3-aryl-2-methyloxiranecarbonitriles and 2,3-dimethyl-3-phenyloxiranecarbonitrile were efficiently hydrated by the action of the less enantioselective nitrile hydratase, the amidase exhibited excellent 2S,3R-enantioselectivity against 2-methyl-3-(para-substituted-phenyl)oxiranecarboxamides. Under very mild conditions, biotransformations of nitriles provided an efficient and practical synthesis of 2R,3S-(-)-3-aryl-2-methyloxiranecarboxamides, electrophilic epoxides with tertiary and quaternary stereocenters, in excellent yield with enantiomeric excess greater than 99.5%. The synthetic applications of the resulting enantiomerically pure epoxides were demonstrated by convenient and straightforward syntheses of polyfunctionalized chiral molecules possessing a quaternary stereocenter such as R-(+)-2-hydroxy-2-methyl-3-phenylpropionic acid, 2R,3R-(-)-3-amino-2-hydroxy-2-methyl-3-phenylpropionic acid, and 2S,3S-(+)-2-amino-3-hydroxy-2-methyl-3-phenylpropionic acid, employing the regio- and stereospecific epoxide ring opening reactions of 2R,3S-(-)-2-methyl-3-phenyloxiranecarboxamide as the key steps.     

Five new nortropane alkaloids and six new amino acids from the fruit of Morus alba LINNE growing in Turkey

Investigation of the constituents of the fruits of Morus alba LINNE (Moraceae) afforded five new nortropane alkaloids (1-5) along with nor-psi-tropine (6) and six new amino acids, morusimic acids A-F (7-12). The structures of the new compounds were determined to be 2alpha,3beta-dihydroxynortropane (1), 2beta,3beta-dihydroxynortropane (2), 2alpha,3beta,6exo-trihydroxynortropane (3), 2alpha,3beta,4alpha-rihydroxynortropane (4), 3beta,6exo-dihydroxynortropane (5), (3R)-3-hydroxy-12-[(1S,4S)-4-[(1S)-1-hydroxyethyl]-pyrrolidin-1-yll-dodecanoic acid-3-O-beta-D-glucopyranoside (7), (3R)-3-hydroxy-12-[(1S,4S)-4-[(1S)-1-hydroxyethyl]-pyrrolidin-1-yll-dodecanoic acid (8), (3R)-3-hydroxy-12-1(1R,4R,5S)-4-hydroxy-5-methyl-piperidin-1-yll-dodecanoic acid-3-O-beta-D-glucopyranoside (9), (3R)-3-hydroxy-12-[(1R,4R,5S)-4-hydroxy-5-methyl-piperidin-1-yll-dodecanoic acid (10), (3R)-3-hydroxy-12-[(1R,4R,5S)-4-hydroxy-5-hydroxymethyl-piperidin-1-yl]-dodecanoic acid-3-O-beta-D-glucopyranoside (11), and (3R)-3-hydroxy-12-[(1R,4S,5S)-4-hydroxy-5-methyl-piperidin-1-yl]-dodecanoic acid (12) on the basis of spectral and chemical data.     

Preparation of optically active threo-2-amino-3-hydroxy-3-phenylpropanoic acid (threo-beta-phenylserine) via optical resolution

To obtain optically active threo-2-amino-3-hydroxy-3-phenylpropanoic acid (1), (2RS,3SR)-2-benzoylamino-3-hydroxy-3-phenylpropanoic acid [(2RS,3SR)-2] was first optically resolved using (1S,2S)- and (1R,2R)-2-amino-1-(4-nitrophenyl)-1,3-propanediol as the resolving agents to afford (2R,3S)- and (2S,3R)-2 in yields of 73% and 66%, based on half of the starting amount of (2RS,3SR)-2. Next, the racemic structures of ammonium and some organic ammonium salts of (2RS,3SR)-2 were examined based on melting point, solubility, and infrared spectrum, with the aim of optical resolution by preferential crystallization. The benzylammonium salt of (2RS,3SR)-2 was suggested to exist as a conglomerate at room temperature, although it forms a racemic compound at the melting point. The optical resolution by preferential crystallization of the racemic salt afforded the (2R,3S)- and (2S,3R)-salts with optical purities of 90-97%. The (2R,3S)- and (2S,3R)-2 obtained from the purified salts were hydrolyzed by reflux in hydrochloric acid to give (2R,3S)- and (2S,3R)-1.     

Metabolism of a novel antiangiogenic agent KR-31831 in rats using liquid chromatography-electrospray mass spectrometry

KR-31831 ((2S,3R,4S)-4-(((1H-imidazol-2-yl)methyl)(4-chlorophenyl)amino)-6-amino-2-(dimethoxymethyl)-2-methyl-3,4-dihydro-2H-chromen-3-ol) is a novel antiangiogenic agent. In vitro and in vivo metabolism of KR-31831 in rats has been investigated using LC-MS and LC-MS/MS analysis. Incubation of rat liver microsomes and hepatocytes with KR-31831 produced three metabolites (M1-M3). M1, M2, and M3 were identified as N-((1H-imidazol-2-yl)methyl)-4-chlorobenzenamine, (2R,3R,4S)-4-(((1H-imidazol-2-yl)methyl)(4-chlorophenyl) amino)-6-amino-2-(hydroxymethyl)-2-methyl-3,4-dihydro-2H-chromen-3-ol, and N-((2S,3R,4S)-4- (((1H-imidazol-2-yl)methyl)(4-chlorophenyl)amino)-2-(dimethoxymethyl)-3-hydroxy-2-methyl-3,4-dihydro-2H-chromen-6yl)acetamide, respectively, by co-chromatography with the authentic standards and by comparison with product ion spectra of the authentic standards. Those in vitro metabolites were also detected in bile, plasma, or urine samples after an intravenous administration of KR-31831 to rats. The metabolic routes for KR-31381 included the metabolism of acetal group to hydroxymethyl group (M2), N-dealkylation to M1, and N-acetylation at the 6-amino group (M3).     

Stereoselective synthesis of (2s,3s,4r)-4-amino-3-hydroxy-2-methyl-pentanoic acid,an amino acid constituent of bleomycin,by aldold condensation)

(2S,3S,4R)-4-Amino-3-hydroxy-2-methylpentanoic acid, a novel amino acid constituent of bleomycin, has been synthesized stereoselectively through aldol condensation of (R)-2-aminopropionaldehyde derivatives and E-vinyloxyboranes.     

Renin inhibitors. II. Synthesis and structure-activity relationships of N-terminus modified inhibitors containing a homostatine analogue.

The synthesis and structure-activity relationships of N-terminus modified renin inhibitors containing the homostatin analogue, (2RS,4S,5S)-5-amino-2-ethyl-4-hydroxy-7-methyloctanoic acid, are described. The compounds having a 3-alkyl (or aryl)sulfonylpropionyl residue at the N-terminus are found to be potent inhibitors which contain two amino acids. (2RS,4S,5S)-N-Isobutyl-5-[N-[(2S)-3-ethylsulfonyl-2-(1- naphthylmethyl)propionyl]-L-norleucyl]-amino-2-ethyl-4-hydroxy-7- methyloctanamide (20) has an IC50 of 0.5 nM against human plasma renin and the oral bioavailability of 20 is 0.73% in rats. Interaction between renin and the N-terminus of 1 and 20 is discussed in molecular modeling studies.     

Synthesis of nonproteinogenic amino acids to probe lantibiotic biosynthesis

The synthesis of six nonproteinogenic amino acids appropriately protected for Fmoc-based solid-phase peptide synthesis is described. These amino acids are (2S,3R)-vinylthreonine, (2S)-(E)-2-amino-5-fluoro-pent-3-enoic acid (fluoroallylglycine), (S)-beta(2)-homoserine, (S) and (R)-beta(3)-homocysteine, and (2R,3R)-methylcysteine. Once incorporated into peptides, these compounds were envisioned to serve as alternative substrates for the lantibiotic synthases that dehydrate serine and threonine residues in their peptide substrates and catalyze the subsequent intramolecular Michael-type addition of cysteines to the dehydroamino acids.     

Rational design of MOFs constructed from modified aromatic amino acids

Three Phe and Tyr derivatives, 2-amino-3-(4-aminophenyl)-propionic acid (AAP), 3E-[5-(2-amino-2-carboxyethyl)-2-methoxyphenyl]-acrylic acid (AMPA) and 3-(4-aminophenyl)-2-(carboxymethyl-amino)-propionic acid (ACP) have been chosen as the ligands to construct four kinds of novel metal-organic frameworks (MOFs) (five structures). These structures are, [Cd(II){(R)-AAP}(Py)(H(2)O)](ClO(4)), (R)-1; [Cd(II){(S)-AAP}(H(2)O)(2)](ClO(4)), (S)-2; [Zn(2) (II){(R,S)-AMPA}(H(2)O)], (R,S)-3; [Zn(2) (II){(R)-ACP}(Py)(3)](ClO(4))(2), (R)-4; and the inversion twin of (R)-1. Rational design to adjust the "depth" and the "width" of ligands can mediate the size and the shape of the grids of these 2D layers. Additionally, among these compounds, three pure chiral coordination polymers are obtained, owing to the inducement of chirality by the modified amino acids. This property makes them potential NLO materials.     

Analogs of D(+)-pantothenic acid. VI. Synthesis of D-, L-, and DL-4′-amino-4′-deoxypantothenic acid

A new analog of pantothenic acid, DL-4-amino-2-hydroxy-3,3-dimethylbutanoic acid, has been synthesized and it has been separated into stereoisomer. D-, L-, and DL-N-(4-Amino-2-hydroxy-3,3-dimethylbutyryl)-β-alanines — amino analogs of pantothenic acid — have been synthesized by the condensation of the N-hydroxysuccinimide esters of N-BOC-D-, -L-, and -DL-4-amino-2-hydroxy-3,3-dimethylbutanoic acids with β-alanine, followed by the elimination of the protective groups.     

Direct and indirect high-performance liquid chromatography enantioseparation of trans-4-hydroxy-2-nonenoic acid

trans-4-Hydroxy-2-nonenoic acid (HNEA) is a marker of lipid peroxidation resulting from the metabolism of trans-4-hydroxy-2-nonenal (HNE). Direct and indirect RP-HPLC methods for the separation of HNEA enantiomers were developed and compared. The indirect method involved pre-column derivatization with a chiral amino agent, (1S,2S)-(+)-2-amino-1-(4-nitrophenyl)-1,3-propanediol, and subsequent separation of diastereomers on a Spherisorb ODS2 column. The direct separation of HNEA enantiomers was performed using the chiral stationary phase, Chiralpak AD-RH. Validation parameters including limit of quantification, linear range, accuracy and precision were determined. The indirect separation method was successfully applied for the determination of enantiomeric ratio of HNEA in rat brain mitochondrial lysate, and showed that HNEA was formed (R)-enantioselectively from HNE.     

Acyclic stereocontrolled synthesis of (−)-detoxinine

Allylic oxidation of (2S)-N-$\text{t}$-butoxycarbonyl-2-amino-4-pentenoic acid methyl ester afforded, stereoselectively, a (2S,3R)-2-amino-3-hydroxyl derivative, which was converted to the unusual amino acid (?)-detoxinine $\text{via}$ a chelation controlled aldol condensation followed by a pyrrolidine ring formation.     

Synthesis of pyrido[1,2-a]pyrimido[4,5-d]pyrimidin-5-ones. Cyclization reaction of 4-[(3-hydroxy-2-pyridyl)amino]-2-phenyl-5-pyrimidinecarboxylic acid with acetic anhydride

Treatment of 4-[(3-hydroxy-2-pyridyl)amino]-2-phenyl-5-pyrimidinecarboxylic acid (X) with acetic anhydride under refluxing conditions afforded 10-hydroxy-2-phenyl-5H-pyrido[1,2-a]-pyrimido[4,5-d]pyrimidin-5-one acetate (IX). The intermediate X was prepared from 4-chloro-2-phenyl-5-pyrimidinecarboxylic acid ethyl ester (V). The reaction of V with the sodium salt of 2-amino-3-hydroxypyridine at room temperature gave 4-(2-amino-3-pyridyloxy)-2-phenyl-5-pyrimidinecarboxylic acid ethyl ester (VI). Treatment of VI with a hot aqueous sodium hydroxide solution and subsequent acidification gave X. Involvement of 4-[(3-hydroxy-2-pyridyl)amino]-2-phenyl-5-pyrimidinecaroboxylic acid ethyl ester (VIII) (Smiles rearrangement product) as an intermediate in the above alkaline hydrolysis reaction of VI to X was demonstrated by the isolation of VIII and its subsequent conversion into X under alkaline hydrolysis conditions. Acetylation of VIII with acetic anhydride in pyridine solution gave 4-[(3-hydroxy-2-pyridyl)amino]-2-phenyl-5-pyrimidinecarboxylic acid ethyl ester acetate (XI), which afforded IX on fusion at 220°. This alternative synthesis of IX from XI supported the structural assignment of IX. Fusion of VI gave 10-hydroxy-2-phenyl-5H-pyrido[1,2-a]pyrimido]4,5-d]pyrimidin-5-one (VII). The latter was also obtained when VIII was fused at 210°. Acetylation of VII with acetic anhydride afforded IX.     

Synthesis of optically active homocysteine from methionine and its use in preparing four stereoisomers of cystathionine

In order to synthesize four stereoisomers of cystathionine (CYT), D- and L-homocysteines (D- and L-Hcy) were synthesized from methionine (Met) by a facile procedure. L-Met was reacted with dichloroacetic acid in concentrated hydrochloric acid under reflux to give (4S)-1,3-thiazane-2,4-dicarboxylic acid hydrochloride [(4S)-TDC.HCl]. L-Hcy was obtained by treatment of (4S)-TDC.HCl with hydroxylamine. D-Hcy was also synthesized from D-Met via (4R)-TDC.HCl intermediate. The obtained D- and L-Hcy were condensed with (R)- and (S)-2-amino-3-chloropropanoic acid hydrochlorides under alkaline conditions to give four stereoisomers of CYT.     

Synthesis and single cell pharmacology of potential heterocyclic bioisosteres of the excitatory amino acid antagonist glutamic acid diethyl ester

A series of heterocyclic analogues of glutamic acid diethyl ester (GDEE), an antagonist at central excitatory amino acid receptors, have been synthesized and tested biologically. (RS)-Ethyl alpha-amino-alpha-(3-ethoxyisoxazol-5-yl)acetate (7), (RS)-ethyl 2-amino-3-(3-ethoxy-5-methylisoxazol-4-yl)propionate (16) and closely related analogues were synthesized. Compound 7, a diethyl derivative of the naturally occurring excitatory amino acid ibotenic acid (IBO), was synthesized from 3-hydroxy-5-methylisoxazole (1) via 3-ethoxyisoxazol-5-ylacetic acid (5) and its ethyl ester. Nitrosation of this ester followed by catalytic reduction gave 7. The ethyl ester of IBO, 9, was synthesized in a similar manner from 3-benzyloxyisoxazol-5-ylacetic acid (8). Ethyl derivatives of the synthetic excitatory amino acid 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) were synthesized from 3-hydroxy-4,5-dimethylisoxazole (10) through a diethyl acetylaminomalonate derivative, which upon deprotection gave the 3-ethoxy derivative of AMPA (15). Esterification of 15 gave the diethyl derivative 16 and the ethyl ester of AMPA (18) as well as N-ethylated derivatives of AMPA, 21 and 22 were synthesized. The final products were tested microelectrophoretically. The derivatives 7, 9, 15, 16 and 18 were weak and non-selective excitatory amino acid antagonists, whereas 21 and 22 were found to be inactive.     

Preferred 3D-structure of peptides rich in a severely conformationally restricted cyclopropane analogue of phenylalanine

Terminally blocked, homo-peptide amides of (R,R)-1-amino-2,3-diphenylcyclopropane-1-carboxylic acid (c3diPhe), a chiral member of the family of Calpha-tetrasubstituted alpha-amino acids, from the dimer to the tetramer, and diastereomeric co-oligopeptides of (R,R)- or (S,S)-c3diPhe with (S)-alanine residues to the trimer level were prepared in solution and fully characterized. The synthetic effort was extended to terminally protected co-oligopeptide esters to the hexamer, where c3diPhe residues are combined with achiral alpha-aminoisobutyric acid residues. The preferred conformations of the peptides were assessed in solution by FT-IR absorption, NMR, and CD techniques, and for seven oligomers in the crystal state (by X-ray diffraction) as well. This study clearly indicates that c3diPhe, a sterically demanding cyclopropane analogue of phenylalanine, tends to fold peptides into beta-turn and 3(10)-helix conformations. However, when c3diPhe is in combination with other chiral residues, the conformation preferred by the resulting peptides is also dictated by the chiral sequence of the amino acid building blocks. The (S,S)-enantiomer of this alpha-amino acid, unusually lacking asymmetry in the main chain, strongly favors the left-handedness of the turn/helical peptides formed.