Adsorption properties of the penicillin derivative DTPA on gold substrates.

Despite the large number of articles and patents dealing with penicillin and other beta-lactam antibiotics, there have been no reports about the self-assembly of such substances as monolayers on gold surfaces. The main reason stems from the high reactivity of the beta-lactam ring, which hinders the development of molecules possessing this entity together with a metal-anchoring function. Herein, we present the synthesis of a novel molecule, 6-[(R,S)-5-(1,2-dithiolan-3-yl)pentanoyl-amino]-penicillanic acid, which combines the beta-lactam ring and a metal-anchoring group. Using spectroscopic tools, we demonstrate the chemisorption of this compound on gold as self-assembled monolayers without any alteration of the penicillin pharmacophore and document its reactivity towards a penicillin-binding protein, BlaR-CTD. Our work is a preliminary step towards the development of new biosensors and well-ordered protein arrays, both based on the high affinity of penicillin for penicillin-binding proteins.     

Metal Cluster Terminated “Molecular Wires”

The gold complexes Au(C≡CC₆H₄C≡CC₆H₄Me)(PPh₃) (3) and {Au(PPh₃)}₂(μ-C≡CC₆H₄C≡CC₆H₄C≡CC₆H₄C≡C) (6), prepared from the reaction of AuCl(PPh₃) with the corresponding terminal or trimethylsilyl protected alkynes, react readily with Ru₃(CO)₁₀(μ-dppm) to afford phenylene ethynylene derivatives featuring the Ru₃(μ-AuPPh₃)(μ-C₂R)(CO)₇ cluster “end-caps”. The hydrido cluster Ru₃(μ-H)(μ-C₂C₆H₄C≡CC₆H₄Me)(CO)₇ (4a) has also been obtained. There are significant differences in the absorption spectra of the organic precursors, the gold complexes and the clusters indicate a mixing of electronic states between the cluster and phenylene ethynylene moieties, while the presence of the Ru₃ and in particular Ru₃(μ-AuPPh₃) cluster end-caps leads to a quenching of the phenylene ethynylene centred emission. The crystallographically determined structures of 3, 4a and Ru₃(μ-AuPPh₃) (μ-C₂C₆H₄C≡CC₆H₄Me)(CO)₇ (4b) are reported.Dedicated to Professor B.F.G. Johnson, one of the pioneers of cluster chemistry, in recognition of his outstanding contributions to the field.     

Preparation of tertiary amides from carbamoyl chlorides and organocuprates

[reaction: see text] Reaction of carbamoyl chlorides with cyano-Gilman cuprates affords tertiary amides in good to excellent yields. The reaction is general due to the possibility of using reagents made either from organolithium or from Grignard compounds. The characterization of the main side products allowed for the suggestion of a possible mechanism.     

LZnX complexes of tripodal ligands with intramolecular RN-H hydrogen bonding groups: structural implications of a hydrogen bonding cavity, and of X/R in the hydrogen bonding geometry/strength

Tripodal ligands N(CH2Py)3-n(CH2Py-6-NHR)n(R=H, n=1-3 L1-3, n=0 tpa; R=CH2tBu, n=1-3 L'1-3) are used to investigate the effect of different hydrogen bonding microenvironments on structural features of their LZnX complexes (X=Cl-, NO3-, OH-). The X-ray structures of [(L2)Zn(Cl)](BPh4)2.0.5(H2O.CH3CN), [(L3)Zn(Cl)](BPh4)3.CH3CN, [(L'1)Zn(Cl)](BPh4) 1', [(L'2)Zn(Cl)](BPh4)2'.CH3OH, and [(L'3)Zn(Cl)](BPh4)3' have been determined and exhibit trigonal bipyramidal geometries with intramolecular (internal) N-HCl-Zn hydrogen bonds. The structure of [(L'2)Zn(ONO2)]NO3 4'.H2O with two internal N-HO-Zn hydrogen bonds has also been determined. The axial Zn-Cl distance lengthens from 2.275 A in [(tpa)Zn(Cl)](BPh4) to 2.280-2.347 A in 1-3, 1'-3'. Notably, the average Zn-N(py) distance is also progressively lengthened from 2.069 A in [(tpa)Zn(Cl)](BPh4) to 2.159 and 2.182 A in the triply hydrogen bonding cavity of 3 and 3', respectively. Lengthening of the Zn-Cl and Zn-N(py) bonds is accompanied by a progressive shortening of the trans Zn-N bond from 2.271 A in [(tpa)Zn(Cl)](BPh4) to 2.115 A in 3 (2.113 A in 3'). As a result of the triply hydrogen bonding microenvironment the Zn-Cl and Zn-N(py) distances of 3 are at the upper end of the range observed for axial Zn-Cl bonds, whereas the axial Zn-N distance is one of shortest among N4 ligands that induce a trigonal bipyramidal geometry. Despite the rigidity of these tripodal ligands, the geometry of the intramolecular RN-HX-Zn hydrogen bonds (X=Cl-, OH-, NO3-) is strongly dependent on the nature of X, however, on average, similar for R=H, CH2tBu.     

Molecular and multidimensional polyoxotungstates functionalized by {Cu(bpy)}2+ groups

Five new materials built from polyoxotungstates and Cu(ii) ions as linkers have been synthesized by hydrothermal reactions from a mixture of sodium tungstate, copper chloride and bipyridine. The value of the initial pH, the nature of the heteroelement (P or Si) and of the ligand (2,2'- and/or 4,4'-bipyridine) permit the control of the nature of the polyoxotungstate clusters and their connectivity via the copper ions, and hence the dimensionality of the framework. A single phase has been obtained with silicon as heteroelement at an initial pH of 5, namely the 2D material [SiW(12)O(40)][Cu(2,2'-bpy)(2)](2).10H(2)O (1) with saturated Keggin polyoxotungstates linked by {Cu(2,2'-bpy)(2)}(2+) groups. With phosphorous as heteroelement and at the same initial pH, three different structures have been isolated according to the nature of the ligand. Indeed, the two 1D materials [{Cu(5)(2,2'-bpy)(5)(H(2)O)(HPO(4))(PO(4))}PW(11)CuO(39)].6H(2)O (2) with 2,2'-bpy and [4,4'-Hbpy][{Cu(2)(2,2'-bpy)(2)(4,4'-bpy)(2.5)}PW(11)CuO(39)].16H(2)O (3) with a mixture of 2,2'- and 4,4'-bpy have been characterized, and a coordination polymer with polyoxometalate guests Na(3)[4,4'-Hbpy]{Cu(4)(4,4'-bpy)(8)(H(2)O)(8)}[PW(11)CuO(39)(H(2)O)][PW(10)Cu(2)O(38)(H(2)O)(2)].38H(2)O (4) with 4,4'-bpy has been obtained. Finally, in basic medium (pH = 10) the unprecedented molecular cluster Na(2)[{Cu(8)(2,2'-bpy)(8)}(PW(8)O(31))(2)].15H(2)O (5) has been evidenced. Magnetic studies of compound 2 revealed that the predominant interactions involve only 4 paramagnetic centers, which are interacting within pairs, among the 6 Cu(ii) centers. The chi(M)T=f(T) curve can be fitted using the dinuclear expression appropriate to the HDVV isotropic exchange Hamiltonian H=-JS(1)xS(2), with S(1)=S(2)=(1/2) and J=-105.4 cm(-1), showing strong antiferromagnetic interactions within the two Cu(ii) pairs.     

Asymmetric Phase-Transfer Catalysis by Quaternary Ammonium Ions Derived from Cinchona-Alkaloid Analogs Containing 1,1′-Binaphthalene Moieties

The synthesis and catalytic properties of a new type of enantioselective phase-transfer catalysts, incorporating both the quinuclidinemethanol fragment of Cinchona alkaloids and a 1,1′-binaphthalene moiety, are described. Catalyst (+)-(aS,3R,4S,8R,9S)- 4 with the quinuclidine fragment attached to C(7′) in the major groove of the 1,1′-binaphthalene residue was predicted by computer modeling to be an efficient enantioselective catalyst for the unsymmetric alkylation of 6,7-dichloro-5-methoxy-2-phenylindanone ( 1 ; Scheme 1, Fig. 1). Its synthesis involved the selective oxidative cross-coupling of two differently substituted naphthalen-2-ols to afford the asymmetrically substituted 1,1′-binaphthalene derivative (±)- 17 in high yield (Scheme 3). Chromatographic optical resolution via formation of diastereoisomeric camphorsulfonyl esters and functional-group manipulation gave access to the 7-bromo-1,1′-binaphthalene derivative (−)-(aS)- 11 (Scheme 4). Nucleophilic addition of lithiated (−)-(aS)- 11 to the quinuclidine Weinreb amide (+)-(3R,4S,8R)- 8 afforded the two ketones (aS,3R,4S,8R)- 27 and (aS,3R,4S,8S)- 28 as an inseparable mixture of diastereoisomers (Scheme 6). Stereoselective reduction of this mixture with DIBAL-H (diisobutylaluminum hydride; preferred formation of the C(8)−C(9) erythro-pair of diastereoisomers with 18% de) or with NaBH₄ (preferred formation of the threo-pair of diastereoisomers with 50% de) afforded the four separable diastereoisomers (+)-(aS,3R,4S,8S,9S)- 29 , (+)-(aS,3R,4S,8R,9R)- 30 , (−)-(aS,3R,4S,8S,9R)- 31 , and (+)-(aS,3R,4S,8R,9S)- 32 (Scheme 6). A detailed conformational analysis, combining ¹H-NMR spectroscopy and molecular-mechanics computations, revealed that the four diastereoisomers displayed distinctly different conformational preferences (Figs. 2 and 3). These novel Cinchona-alkaloid analogs were quaternized to give (+)-(aS,3R,4S,8R,9S)- 4 , (+)-(aS,3R,4S,8S,9S)- 5 , (+)-(aS,3R,4S,8R,9R)- 6 , and (−)-(aS,3R,4S,8S,9R)- 7 (Scheme 7) which were tested as phase-transfer agents in the asymmetric allylation of phenylindanone 1 . Without any optimization work, (+)-(aS,3R,4S,8R,9S)- 4 was found to catalyze the allylation of 1 yielding the predicted enantiomer (+)-(S)- 3b in 32% ee. The three diastereoisomeric catalysts (+)- 5 , (+)- 6 , and (−)- 7 gave access to lower enantioselectivities (6 to 22% ee's), which could be rationalized by computer modeling (Fig. 4).     

Coordination Mode and Kinetic Behavior of the Tetracarbonatozirconate Ion

The behavior of [Zr(CO₃)₄]⁴⁻ complex in solution is studied by determining the coordination mode of the carbonato ligands and the kinetic law of the equilibrium between free and complexed carbonates. Raman polarization and dynamic ¹³C-NMR experiments show that complexed carbonates are bidentate. Magnetization-transfer experiments give the values of pseudo-first-order rate constants for the equilibrium with no net chemical transformation. The treatment of these parameters suggests a second-order rate law. As no solvent effect is noticed, an associative mechanism of ligand exchange is proposed.     

Synthesis of 1,2,5-Thiadiazolidin-3-one 1,1-Dioxide Derivatives and Evaluation of Their Affinity for MHC Class-II Proteins

1,2,5-Thiadiazolidin-3-one 1,1-dioxide derivatives (±)- 1a – d and (±)- 2 were designed by molecular modeling as MHC (major histocompatibility complex) class-II inhibitors. They were prepared from the unsymmetrically N,N′-disubstituted acyclic sulfamides (±)- 4a – d (Scheme 1) and (±)- 11 (Scheme 2). These N-alkyl-N′-arylsulfamide precursors were synthesized by nucleophilic substitution of either a sulfamoyl-chloride or a N-sulfamoyloxazolidinone. Extension of base-induced cyclization methods from aliphatic to aromatic sulfamides gave access to the desired target molecules. The N-alkyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide derivatives (±)- 3a – c were also prepared by the oxazolidinone route (Scheme 4) for coupling to a tetrapeptide fragment. The X-ray crystal structure of 1,2,5-thiadiazolidin-3-one 1,1-dioxide (±)- 21a was solved, and the directionality of the H-bond donor (N−H) and acceptor (SO₂) groups of the cyclic scaffold determined (Figs. 1 and 2). The pK_a value of the N−H group in (±)- 21a was determined by ¹H-NMR titration as 11.9 (Fig. 3). Compounds (±)- 1a – d were shown to inhibit competition peptide binding to HLA-DR4 molecules in the single-digit millimolar concentration range.     

Versatile Ligands for Palladium-Catalyzed Asymmetric Allylic Alkylation

Palladium complexes of the chiral diphosphanes 1 and 2 which possess a rigid backbone and a large bite angle catalyze the alkylation of allyl compounds with both high enantioselectivities and reaction rates, particularly with less sterically demanding substrates. 1 : R=Me, X=S; 2 : R=H, X=C(CH₃)₂.