Synthesis and stereochemistry of JBIR-81, a peptide enamide derived from aspergilli

The absolute stereochemistry of an aspergilli-derived peptide enamide, JBIR-81, was determined to be 12S, 15S by the first synthesis of (12S,15S)-JBIR-81 and its epimer. The overall yield was 56% over six steps from N-methyl-l-leucine. The (Z)-enamide structure was effectively constructed with use of a copper (I) catalyzed coupling reaction between a vinyl halide and a carboxamide.     

Novel phosphine-phosphite and phosphine-phosphinite ligands for highly enantioselective asymmetric hydrogenation

Two novel phosphine-phosphite (S,R)-o-BINAPHOS and phosphine-phosphinite (S)-o-BIPNITE ligands based on ortho phenyl substituted (S)-BINOL have been synthesized. Extremely high enantioselectivity (over 99% ee in most cases) has been achieved for the Rh-catalyzed asymmetric hydrogenation of α-dehydroamino acid derivatives.     

A convenient solid phase synthesis of S-palmitoyl transmembrane peptides

S-Palmitoylated peptides are important tools as models for integral membrane proteins to study peptide-lipid interactions. Herein, we report a convenient solid phase synthesis of S-palmitoyl transmembrane peptides. The highly acid labile S-(4-methoxytrityl) group is preferred over the S-(tert-butylsulfanyl) group for protection of the cysteine side chain since the latter gives rise to quantitative desulfurization during on-resin deprotection. The resulting free thiol function is modified with palmitic acid via a carbodiimide-mediated coupling and the title compounds are obtained in good yields and purity.     

(S)-Threonine/α,α-(S)-diphenylvalinol-derived chiral ionic liquid: an immobilized organocatalyst for asymmetric syn-aldol reactions

Chiral ionic liquids containing (S)- or (R)-threonine amide and α,α-(S)-diphenylvalinol units were synthesized In the presence of the (S)-threonine-derived catalyst reactions between ketones with secondary carbon atom(s) at the α-position with respect to the carbonyl group and aromatic (heteroaromatic) aldehydes afforded the corresponding syn-aldols in high yields (up to 99%) and with high diastereo-(syn/anti up to 97:3) and enantioselectivity (up to 99% ee), which was maintained over three reaction cycles.     

One-pot synthesis of α-aminophosphonates catalyzed by antimony trichloride adsorbed on alumina

SbCl₃ adsorbed on Al₂O₃ is found to be an efficient and recyclable catalyst in promoting three-component coupling reactions of aldehydes (aromatic and aliphatic), amines (aryl amines, aliphatic amines and esters of S-α-amino acids) and dialkylphosphites to afford the corresponding α-aminophosphonates in high yields. The ethyl ester of S-phenylalanine was observed to yield the corresponding α-aminophosphonate with S,S-diastereoisomer formed in dominance over the S,R-diastereoisomer.     

Efficient chemoenzymatic synthesis of (2S,3R)-3-hydroxy-3-methylproline,a key fragment in polyoxypeptin A and FR225659

We report an efficient synthesis of protected (2S,3R)-3-hydroxy-3-methylproline that proceeds in three steps with complete stereoselectivity. This route represents a significant improvement over previous approaches to this noncanonical amino acid. Key to this success is the development of a one-pot chemoenzymatic procedure for the preparation of (2S,3S)-3-methylproline from l-isoleucine. This work lays the foundation for future chemoenzymatic syntheses of polyoxypeptin A and FR225659.     

Direct observation of aziridinium ions in a 2-(N,N-dibenzylamino)- to 1-(N,N-dibenzylamino)phosphonate rearrangement

Aziridinium mesylates stable in the reaction medium for several hours to over a week were observed in a rearrangement of dimethyl (1R,2S)-2-(N,N-dibenzylamino)-1-mesyloxyethylphosphonates substituted at C2 with Bn, i-Pr and t-Bu to the respective 1-(N,N-dibenzylamino)-2-mesyloxyethylphosphonates. Rates of formation of these aziridinium mesylates and rates of their reactions with poorly nucleophilic mesylate anion were governed by steric and electronic factors. The conformation of (2S,3S)-1,1-dibenzyl-2-(tert-butyl)-3-(dimethoxyphosphoryl)aziridinium mesylate in solution was established based on ¹H and ¹³C NMR spectroscopic studies including a NOESY experiment.     

HPLC separation and VCD spectroscopy of chiral pyrazoles derived from (5R)-dihydrocarvone

(4S,7R)-(−) and (4S,7S)-(+)-4-isopropylidene-7-methyl-4,5,6,7-tetrahydro-2(1)H-indazoles 2a and 2b have been successfully separated by using HPLC over a Chiralpak AS column as the stationary phase, yielding up to 700 mg of each diastereomer. Their absolute configurations were determined by using vibrational circular dichroism (VCD) studies. This latter method proved not only very useful for determination of the conformers’ distribution, but also for analysis of the 1H,2H tautomers.     

Stereochemical basis for the anti-chlamydial activity of the phosphonate protease inhibitor JO146

JO146, a mixture of two diastereomers of a peptidic phosphonate inhibitor for Chlamydial HtrA (CtHtrA), has reported activity against Chlamydia species in both human and koala. In this study we isolated the individual diastereomers JO146-D1 and JO146-D2 (in ≥90% purity) and assessed their individual inhibitory activity against the serine protease human neutrophil elastase (HNE) which is structurally and functionally related to CtHtrA, as well as in Chlamydia trachomatis cell culture. JO146-D2 [S,S,R-Boc-Val-Pro-Val^P(OPh)₂], the isomer with the physiologically relevant valine at P1, had an approximate 2.5 – fold increase in in vitro HNE inhibition potency over JO146-D1 [S,S,S-Boc-Val-Pro-Val^P(OPh)₂] and greater than 100 – fold increase in cellular anti-chlamydial activity compared to JO146-D1 which possesses the unnatural valine at P1. JO146 and the individual diastereomers had excellent selectivity for the serine protease HNE over the potential off-target serine proteases trypsin and chymotrypsin. Docking studies supported the biological data with a geometrically unfavoured interaction observed between the P1 valine residue of JO146-D1 and the enzyme S1 sub-pocket.     

A total synthesis of (R,S)S-glucoraphanin

A total synthesis of (R,S)_S-glucoraphanin (GRP) has been completed by a novel, simple and convenient method in high overall yield (17% over seven steps). The study describes a method for the synthesis of natural and unnatural (methylsulfinyl)alkyl glucosinolates (GLs) and also opens useful pathways to synthesize GRP as well as other sulfinyl GLs.     

Synthesis of a water-soluble chiral NMR shift reagent: (S)-PDTA

A five-step synthesis of the water-soluble chiral polydentate ligand, (S)-PDTA [(S)-PDTA = N,N,N′,N′-tetrakis[(hydroxycarbonyl)methyl]-(S)-1,2-diaminopropane] starting from l-alanine has been worked out, via steps with retention of chirality. Total yield is 50.7% (average of ～88% for each step), while published methods report 33.4% total yield over four steps.     

Enthalpic changes on mixing two couples of S- and R-enantiomers of benzyl-(1-phenyl-ethyl)-amine, 1-phenylethylamine, 1-phenyl-ethanol,butyric acid oxiranylmethyl ester, 4-methyl-[1,3]dioxolan-2-one, 2-chloro-methyloxirane and 3-hydroxyisobutyric acid methyl ester at T = 298.15 K

Enthalpies of mixing of (R)- and (S)-enantomers of liquid chiral compounds such as benzyl-(1-phenyl-ethyl)-amine (1), 1-phenylethylamine (2), 1-phenyl-ethanol (3), butyric acid oxiranylmethyl ester (4), 4-methyl-[1,3]dioxolan-2-one (5), 2-Chloromethyloxirane (6) and 3-hydroxyisobutyric acid methyl ester (7) have been measured over the whole range of mole fractions at 298.15 K, albeit very small values. Mixing of heterochiral liquids of R-1 + S-1, R-5 + S-5, and R-7 + S-7 realized enthalpic stabilization over the whole range of mole fractions, whereas that of R-2 + S-2, R-3 + S-3, R-4 + S-4, and R-6 + S-6 realized enthalpic destabilization over entire compositions. The extreme values of enthalpies of mixing and the intermolecular interaction obtained by the molecular mechanics calculations showed a linear correlation, except few the compounds measured.     

Synthesis,Characterization, and Antiproliferative Activity of Novel Chiral [QuinoxP*AuCl2]+ Complexes

Herein is reported the synthesis of two Au(III) complexes bearing the (R,R)-(–)-2,3-Bis(tert-butylmethylphosphino)quinoxaline (R,R-QuinoxP*) or (S,S)-(+)-2,3-Bis(tert-butylmethylphosphino)quinoxaline (S,S-QuinoxP*) ligands. By reacting two stoichiometric equivalents of HAuCl₄.3H₂O to one equivalent of the corresponding QuinoxP* ligand, (R,R)-(–)-2,3-Bis(tert-butylmethylphosphino)quinoxalinedichlorogold(III) tetrachloroaurates(III) (1) and (S,S)-(+)-2,3-Bis(tert-butylmethylphosphino)quinoxalinedichlorogold(III) tetrachloroaurates(III) (2) were formed, respectively, in moderate yields. The structure of (S,S)-(+)-2,3-Bis(tert-butylmethylphosphino)quinoxalinedichlorogold(III) tetrachloroaurates(III) (2) was further confirmed by X-ray crystallography. The antiproliferative activities of the two compounds were evaluated in a panel of cell lines and exhibited promising results comparable to auranofin and cisplatin with IC₅₀ values between 1.08 and 4.83 µM. It is noteworthy that in comparison to other platinum and ruthenium enantiomeric complexes, the two enantiomers (1 and 2) do not exhibit different cytotoxic effects. The compounds exhibited stability in biologically relevant media over 48 h as well as inert reactivity to excess glutathione at 37 °C. These results demonstrate that the Au(III) atom, stabilized by the QuinoxP* ligand, can provide exciting compounds for novel anticancer drugs. These complexes provide a new scaffold to further develop a robust and diverse library of chiral phosphorus Au(III) complexes.     

Mechanistic investigations of the reaction network in chemo-bio catalyzed synthesis of R-1-phenylethyl acetate

The kinetics and reaction network of the one-pot synthesis of R-1-phenylethyl acetate was investigated at 70°C in toluene over a combination of three different catalysts: PdZn/Al₂O₃ as a catalyst for acetophenone hydrogenation, lipase as an enzymatic catalyst for R-1-phenylethanol acylation with ethyl acetate and Ru/Al₂O₃ as a racemization catalyst for S-1-phenylethanol. In addition to the desired reactions, other reactions, namely hydrogenolysis and dehydration of (R, S)-1-phenylethanol and debenzylation of (R, S)-1-phenylethyl acetate also occurred. The kinetic results revealed that ethylbenzene formation was enhanced with higher amounts of PdZn/Al₂O₃, whereas lipase did not catalyze ethylbenzene formation. Furthermore, ethylbenzene was formed in the hydrogenolysis of (R, S)-phenylethanol and in the debenzylation of (R, S)-1-phenyl-ethylacetate over Pd/Al₂O₃ catalyst. The presence of Ru/Al₂O₃ catalyst, in which Ru was in the oxidation state of 3⁺, enhanced the formation of R-1-phenylethyl acetate, although no clear racemization of S-1-phenylethanol during the one-pot synthesis of R-1-phenylethyl acetate was observed. Dynamic kinetic resolution of (R, S)-1-phenylethanol in toluene, was, however, demonstrated over Ru/Al₂O₃ and lipase.     

Sharpless asymmetric dihydroxylation as the key step in the enantioselective synthesis of spirocyclic σ1 receptor ligands

The enantioselective synthesis of fluorinated spirocyclic σ₁ ligands involved three key steps: (1) the Sharpless asymmetric dihydroxylation of 2-bromostyrene 5 provided enantiomerically pure diols (R)-6 and (S)-6 establishing the stereogenic center; (2) the intramolecular opening of the oxirane ring of (R)-11 and (S)-11, which occurred with excellent regioselectivity and complete inversion of configuration giving access to enantiomerically pure alcohols (S)-7a and (R)-7a; (3) the treatment of alcohols (S)-7b and (R)-7b with DAST, which led to the fluoromethyl derivatives (S)-1 and (R)-1 without racemization. X-ray crystal structure analysis of the tosylate (R)-13 confirmed the absolute configuration of the spirocyclic compounds as well as the enantioselectivity during the Sharpless asymmetric dihydroxylation of 5. The (S)-configured fluoromethyl derivative (S)-1 revealed a high σ₁ affinity (K_i = 1.8 nM), high eudismic ratio (factor 8) and high selectivity over the σ₂ subtype (667-fold).     

Fine tuning of the structure of phosphine–phosphoramidites: application for rhodium-catalyzed asymmetric hydrogenations

Diastereomers of (4-(diphenylphosphino)pentan-2-yl)-N-isopropyl-{dinaphtho[2,1-d:1′,2′-f][1,3,2]dioxa-phosphepin-2-yl}-4-amine, (S)-(2S,4S)-1, and (S)-(2R,4R)-3; the octahydro derivative 4 of (S)-(2S,4S)-1, and derivative 2 of (S)-(2S,4S)-1 containing a 1,3-propanediyl backbone, have been synthesized and used for rhodium-catalyzed asymmetric hydrogenations of prochiral olefins in order to study the role of the stereogenic elements in the backbone and in the terminal moiety. The central chirality in the bridge has been found to determine the configuration of the product with a cooperative effect from the terminal groups. Excellent ee’s (up to 99.9%) were obtained in the hydrogenation of methyl (Z)-α-acetamidocinnamate using a rhodium complex with the matched arrangement (S)-(2S,4S)-1. The hydrogenation is accomplished in a highly enantioselective manner by using green solvents such as propylene carbonate.     

An efficient asymmetric synthesis of Fmoc-l-cyclopentylglycine via diastereoselective alkylation of glycine enolate equivalent

Stereoselective alkylation of the enolate derived from benzyl (2R,3S)-(−)-6-oxo-2,3-diphenyl-4-morpholinecarboxylate (1) with cyclopentyl iodide afforded anti-α-monosubstituted product, benzyl (2R,3S,5S)-(−)-6-oxo-2,3-diphenyl-5-cyclopentyl-4-morpholinecarboxylate (3) in 60% yield. Catalytic hydrogenolysis over PdCl₂ cleaved the auxiliary ring system to give l-cyclopentylglycine (4) in 84% yield. Subsequent protection of the α-amino function with Fmoc-OSu gave Fmoc-l-cyclopentylglycine (5) in high yield.     

Synthesis and crystal structures of the first C2-symmetric bis-aldimine NCN-pincer complexes of platinum and palladium

(S,S)-2,6-bis[(N-α-methylbenzyl)imino]phenylpalladium bromide was synthesised by oxidative addition of palladium(0) to (S,S)-1-bromo-2,6-bis[(N-α-methylbenzyl)imino]benzene. In contrast, (S,S)-2,6-bis[(N-α-methylbenzyl)imino]phenylplatinum chloride was synthesised by direct C-H activation from the reaction of potassium tetrachloroplatinate with (S,S)-1,3-bis[(N-α-methylbenzyl)imino]benzene. The X-ray crystal structures of both pincer complexes were obtained. Treatment of both complexes with silver hexafluoroanimonate gave effective but not stereoselective catalysts for a Michael reaction between methyl vinyl ketone and methyl 2-cyanopropanoate.     

Thiomidoyl approach to the synthesis of α-sialosides

Novel sialosyl donors, S-benzoxazolyl (SBox) and S-thiazolyl (STaz) sialosides, have been synthesized and applied to the stereoselective synthesis of α-sialosides. It was also demonstrated that it is possible to selectively activate SBox sialyl donor over ethyl thioglycoside, allowing the direct synthesis of disaccharide donors that could be used in subsequent glycosylations without further manipulations.     

Backbone extended pyrrolidine PNA (bepPNA): a chiral PNA for selective RNA recognition

Synthesis of cationic, chiral PNA analogues with an extra atom in the backbone (bepPNA) is reported. The (2S,4S) geometry of the pyrrolidine ring, and an additional carbon atom in the backbone of homopyrimidine-bepPNAs resulted in the optimization of the inter-nucleobase distance, such that selective binding to complementary RNA over DNA was observed in the triplex mode. It was evident from circular dichroism studies that oligomers with mixed aminoethylglycyl-bep (aeg-bep) repeating units, and also bepPNA with homogeneous backbone attained structures quite different from those of aegPNA₂:RNA/DNA complexes. The bepPNA, when incorporated in a duplex forming mixed purine-pyrimidine sequence, also showed a preference for binding complementary RNA over DNA.