Mohamed Selkti

Expeditious Enantioselective Biomimetic Synthesis of the Nitraria Alkaloids (+)‐Isonitramine and (−)‐Sibirine

The reaction of glutaraldehyde with (R)- or (S)-phenylglycinol as the source of nitrogen and the chirality inductor directly provides the spiropiperidine skeleton [Eq. (a)] of the alkaloids sibirine and isonitramine. The title compounds are available in a total of three and four steps, respectively.

N-[2-(Indan-1-yl)-3-mercapto-propionyl] amino acids as highly potent inhibitors of the three vasopeptidases (NEP, ACE, ECE): In vitro and In vivo activities.

We have previously reported the design of a lead compound 1a for the joint inhibition of neprilysin (NEP, EC 3.4.24.11), angiotensin converting enzyme (ACE, EC 3.4.15.1) and endothelin converting enzyme (ECE-1, EC 3.4.24.71), three metallopeptidases which are implicated in the regulation of fluid homeostasis and vascular tone. We report here the synthesis and biological activities of analogues derived from this lead with inhibitory potencies in the nanomolar range for the three enzymes. Compounds 8b and 15c are the most potent triple inhibitors described to date.

ADDITION OF DIAZOMETHANE TO 3 AND 4-NITROPHTHALODINITRILES

The reaction of two nitrophthalodinitriles with diazomethane is described. If the nitro group is at position 3, only one of the two nitrile functions reacts giving three isomeric N-methyl 1,2,3-triazoles. In contrast, if the nitro group is at position 4, both nitriles react, each producing a 2-N-methyl 1,2,3-triazole. The reactivity was accounted for in terms of electronic densities, which were determined for several nitrile compounds. Interestingly, for 4-nitrophthalodinitrile, original methylation of the aromatic ring at position 5 was also observed. I n t r o d u c t i o n In a previous study (1) on the addition of diazomethane to different nitriles, we showed that the addition reaction requires the presence of an electroattractive group. We describe here the reactivity of the 3and 4-nitrophthalodinitriles 2 and 3, and compare it with the unreactivity of phthalodinitrile 1. The nitrophthalodinitriles were stirred during several days with a solution of diazomethane in diethyl ether. The reaction was followed by thin-layer chromatography. Resu l t s In the case of 3-nitrophthalodinitrile 2, three N-methyl 1,2,3-triazoles 4, 5 and fLderived from the cyano group at position 2 were isolated (cf figure 1).

Synthesis, Characterization, and Reactivity of Alkyldisulfanido Zinc Complexes

The alkyldisulfanido zinc complexes Tp(iPr,iPr)Zn(SSR) and Tp(Ph,Me)Zn(SSR) where Tp(iPr,iPr) is hydridotris-((3,5-isopropyl)pyrazolyl)borate, Tp(Ph,Me) is hydridotris-((3-phenyl,5-methyl)pyrazolyl)borate, and (SSR) is tert-butyldisulfanido or triphenylmethanedisulfanido were synthesized by reaction between the corresponding hydroxo complexes TpZn(OH) and the synthetic persulfide RSSH. All the complexes were characterized by elemental analysis and (1)H NMR spectroscopy, and representative members of the class were also structurally characterized. The reactivity of the alkyldisulfanido TpZn(SSR) complexes with thiols was studied. In the absence of base, a simple exchange reaction between the alkyldisulfanido ligand and the thiol was observed in dichloromethane; when in the presence of base, the corresponding hydrogen(sulfido) complexes TpZn(SH) were obtained. The mechanism of the latter reaction has been studied and does not involve the coordinated alkyldisulfanido group. Reaction of the hydrogen(sulfido) complexes Tp(iPr,iPr)Zn(SH) with the thiosulfonate PhCH(2)S-SO(2)CF(3) did not yield the expected alkyldisulfanido complex but benzyltrisulfide and a new complex tentatively assigned as Tp(iPr,iPr)Zn(O(2)SCF(3)).

Interactions of a new α-aminophosphinic derivative inside the active site of TLN (thermolysin): a model for zinc-metalloendopeptidase inhibition

A new alpha-aminophosphinic compound able to inhibit both zinc-containing exopeptidases and endopeptidases has been crystallized with TLN as a model in order to investigate the mode of zinc recognition by the phosphinic moiety and to evaluate the potential role of the free alpha-amino group in the formation of enzyme-inhibitor complexes. In addition to the main interactions between the backbone of the inhibitor and the enzyme active site, it is observed that the phosphinic group acts as a distorted bidentate ligand for the zinc ion, while the free alpha-amino function does not directly participate in interactions within the active site. Association of the present data and the K(i) values of various analogues of the inhibitor towards TLN and neprilysin suggests differences in the hydrophobicity of the S(1)-S(2) domains of the enzymes. This could be taken into account in the design of selective inhibitors.

Asymmetric synthesis of 5-(1-hydroxyalkyl)-5-methyl-5H-furan-2-ones

The reactivity of 5-methyl-4-(pyrrolidin-1-yl)-5 H -furan-2-one with aldehydes and with acyl chlorides followed by reduction was studied. The aldol condensation gave predominantly the anti aldol product when the acylation–reduction sequence led exclusively to the syn product. The use of a chiral pyrrolidine, ( S )-2-methoxymethylpyrrolidine (SMP), allowed the synthesis of enantio-enriched compounds, the acylation–reduction leading to the ( R , R ) addition product.

1,3-Dipolar cycloaddition of nitrilimines to 2,4-disubstituted-3H-1,5-benzodiazepines: remarkable effect of C4-substituent on diastereoselectivity

The one-step synthesis of new bis[1,2,4-triazolo][4,3-a:3′,4′-d][1,5] benzodiazepines by way of completely regio- and diastereoselective 1,3-dipolar cycloaddition of nitrilimines to 2,4-dimethyl-3H-1,5-benzodiazepines is reported and a tentative rationalization for the observed diastereoselectivity, which underline the key effect of the C4-dipolarophile substituent, is proposed.

Characterization of cobalt(III) hydroxamic acid complexes based on a tris(2-pyridylmethyl)amine scaffold: reactivity toward cysteine methyl ester.

Six Co(III) complexes based on unsubstituted or substituted TPA ligands (where TPA is tris(2-pyridylmethyl)amine) and acetohydroxamic acid (A), N-methyl-acetohydroxamic acid (B), or N-hydroxy-pyridinone (C) were prepared and characterized by mass spectrometry, elemental analysis, and electrochemistry: [Co(III)(TPA)(A-2H)](Cl) (1a), [Co(III)((4-Cl(2))TPA)(A-2H)](Cl) (2a), [Co(III)((6-Piva)TPA)(A-2H)](Cl) (3a), [Co(III)((4-Piva)TPA)(A-2H)](Cl) (4a) and [Co(III)(TPA)(B-H)](Cl)(2) (1b), and [Co(III)(TPA)(C-H)](Cl)(2) (1c). Complexes 1a-c and 3a were analyzed by (1)H NMR, using 2D ((1)H, (1)H) COSY and 2D ((1)H, (13)C) HMBC and HSQC, and shown to exist as a mixture of two geometric isomers based on whether the hydroxamic oxygen was trans to a pyridine nitrogen or to the tertiary amine nitrogen. Complex 3a exists as a single isomer that was crystallized. Its crystal structure revealed the presence of an H-bond between the pivaloylamide and the hydroximate oxygen. Complexes 1a, 2a, and 4a are irreversibly reduced beyond -900 mV versus SCE, while complexes 1b and 1c are reduced at less negative values of -330 and -190 mV, respectively. The H-bond in 3a increased the redox potential up to -720 mV. Reaction of complex 1a with L-cysteine methyl ester CysOMe was monitored by (1)H NMR and UV-vis at 2 mM and 0.2 mM in an aqueous buffered solution at pH 7.5. Complex 1a was successively converted into an intermediate [Co(III)(TPA)(CysOMe-H)](2+), 1d, by exchange of the hydroximate with the cysteinate ligand, and further into Co(III)(CysOMe-H)(3), 5. An authentic sample of 1d was prepared and thoroughly characterized. A detailed (1)H NMR analysis showed there was only one isomer, in which the thiolate was trans to the tertiary amine nitrogen.

Einfache enantioselektive biomimetische Synthese der Nitraria‐Alkaloide (+)‐Isonitramin und (−)‐Sibirin

Die Umsetzung von Glutaraldehyd mit (R)- oder (S)-Phenylglycinol als Stickstoffquelle und Chiralitatsinduktor ergibt direkt das Spiropiperidingerust [Gl. (a)] der Alkaloide Sibirin und Isonitramin. Mit insgesamt nur drei bzw. vier Schritten kommt man zu den Zielverbindungen.

Highly efficient asymmetric access to 1-azaspiro[4.4]nonane skeleton

Vinylogous Mukaiyama aldol type reaction of chiral non-racemic silyloxypyrroles followed by acidic treatment affords an efficient asymmetric access to 1-azaspiro[4.4]nonanes in high diastereoisomeric excess (un to 79%).