Entropy-driven hydrogen bonding: stereodynamics of a protonated, N,N-chiral "proton sponge"

The C2-symmetric ("[DL]") and achiral ("[meso]") diastereoisomers of the hydrogen iodide salt of 1,8-bis-(N-benzyl-N-methylamino)naphthalene ([2H]-[I] ) interconvert in solution. Direct interconversion of the diastereoisomers of [2H]+ must involve hydrogen bond fission (to give "[nonHB-2H+]") and rotation-inversion of the non-protonated nitrogen centre. The global activation parameters (deltaH++ and deltaS++) for diastereoisomer interconversion in [D7]DMF have been determined from rate data obtained by temperature-drop and magnetisation-transfer 13C NMR spectroscopy over a temperature range of 170 degrees C. The process is found to have a high entropy of activation in both directions (deltaS++=163(+/-4) and 169(+/-4) JK(-1)mol(-1)) and this is suggested to arise through hydrogen bonding of the ammonium centre in [nonHB-2H+] with the solvent ([D7]DMF). Comparison of the enthalpy of activation (deltaH++) with that earlier found for diastereoisomer interconversion of the free-base form 2 suggests that the intramolecular hydrogen bond in [2H]+ is roughly equal in enthalpic strength (deltaH) with that made with the solvent ([D7]DMF) in the non-hydrogen-bonded intermediate [nonHB-2H+]. As such, the hydrogen bonding in [2H]+ may be considered as predominantly an entropically driven process, without any unusual enthalpic strength.     

The synthesis of peptides and proteins containing non-natural amino acids

Methods for the incorporation of non-natural amino acids into proteins have advanced significantly over recent years and in this tutorial review we aim to give a general overview of the area. These techniques offer the possibility of modulating the structures and functions of proteins and thus permit the generation of novel designed systems for both biocatalytic and mechanistic studies. Four complementary approaches are discussed in detail along with examples of their application. The advantages and disadvantages of each technique are also discussed.     

X-ray spectroscopy of enzyme active site analogues and related molecules: bis(dithiolene)molybdenum(IV) and -tungsten(IV,VI) complexes with variant terminal ligands

The X-ray absorption spectra at the molybdenum and selenium K-edges and the tungsten L2,3-edges are acquired for a set of 14 Mo(IV) and W(IV,VI) bis(dithiolene) complexes related to the active sites of molybdo- and tungstoenzymes. The set includes square pyramidal [MoIVL(S2C2Me2)2]- (L = O2-, R3SiO-, RO-, RS-, RSe-) and [WIV(OR)(S2C2Me2)2]-, distorted trigonal prismatic [MoIV(CO)(SeR)(S2C2Me2)2]- and [WIV(CO)L(S2C2Me2)2]- (L = RS-, RSe-), and distorted octahedral [WVIO(OR)(S2C2Me2)2]-. The dithiolene simulates the pterin-dithiolene cofactor ligand, and L represents a protein ligand. Bond lengths are determined by EXAFS analysis using the GNXAS protocol. Normalized edge spectra, non-phase-shift-corrected Fourier transforms, and EXAFS data and fits are presented. Bond lengths determined by EXAFS and X-ray crystallography agree to < or = 0.02 A as do the M-Se distances determined by both metal and selenium EXAFS. The complexes [MoIV(QR)(S2C2Me2)2]- simulate protein ligation by the DMSO reductase family of enzymes, including DMSO reductase itself (Q = O), dissimilatory nitrate reductase (Q = S), and formate dehydrogenase (Q = Se). Edge shifts of these complexes correlate with the ligand electronegativities. Terminal ligand binding is clearly distinguished in the presence of four Mo-S(dithiolene) interactions. Similarly, five-coordinate [ML(S2C2Me2)2]- and six-coordinate [M(CO)L(S2C2Me2)2]- are distinguishable by edge and EXAFS spectra. This study expands a previous XAS investigation of bis(dithiolene)metal(IV,V,VI) complexes (Musgrave, K. B.; Donahue, J. P.; Lorber, C.; Holm, R. H.; Hedman, B.; Hodgson, K. O. J. Am. Chem. Soc. 1999, 121, 10297) by including a larger inventory of molecules with variant physiologically relevant terminal ligation. The previous and present XAS results should prove useful in characterizing and refining metric features and structures of enzyme sites.     

3-Substituted Sydnone Derivatives. Structures of 3-Cyclohexylsydnone and of Two Forms of 3-(3-Pyridyl)sydnone

The crystal and molecular structures of three sydnone derivatives are reported. The compound 3-cyclohexylsydnone crystallizes in space group C2/c of the monoclinic system with sixteen molecules in a cell of dimensions a = 19.326 (3), b = 9.471 (2), c = 20.005 (4)Å, β = 106.85(1)°. The structure has been refined to a final value of 0.0581 for the conventional R-factor based on 2222 independent observed intensities. Form I of 3-(3-pyridyl)sydnone crystallizes in space group P2/n of the monoclinic system with eight molecules in a cell of dimensions a = 7.317(2), b = 9.283 (2), c = 20.891 (6) Å, β = 99.61(2)°. The structure has been refined to a final value of 0.0514 for the conventional R-factor based on 1208 independent observed intensities. Form II of 3-(3-pyridyl)sydnone crystallizes in space group P2₁/c of the monoclinic system with eight molecules in a cell of dimensions a=9.073 (2), b = 22.267 (5). c = 7.494(2)Å, β = 112.15 (2)°. The structure has been refined to a final value of 0.0462 for the conventional R-factor based on 1330 independent observed intensities. Each of the three structures contains two crystallographically independent molecules in the cell. In the case of 3-cyclohexylsydnone, one of the independent molecules exhibits disorder around the exocyclic bond at N(3). A comparison of bond lengths indicates that the (electron donating) cyclohexyl group brings about enhanced electron density in the N(3)-C(4) bond, and possibly in the N(3)-N(2) bond. All three structures studied here exhibit intermolecular hydrogen bonding involving C(4)-H(4)…O(6) interactions. Although there are no stacking interactions in the cyclohexyl derivative, there is evidence for such interactions in the 3-pyridyl derivatives.     

Synthesis of the β-lactam antibiotic (+)- thienamycin via an intermediate π-allyltricarbonyliron lactone complex

The π-allyltricarbonyliron lactone complex (7), formed by reaction of E-1,2-epoxy-2-methyl-6,6-dimethoxyhex-3-ene(5) with co-ordinatively unsaturated iron carbonyl species, was reacted with benzylamine to give a lactam complex (8) by an S_N'-like mechanism. This complex upon oxidation with Ce(IV) afforded cis-3-isopropenyl-4-[(2',2'-dim (9) which was chemically modified into trans-3-(1'-hydroxyethyl)-4-[(2',2-dimethoxy)ethyl] azetidin-2-one (13), a key intermediate previously used in the synthesis of the antibiotic thienamycin. Similar reaction with (S)-(-)--methylbenzylamine afforded a separable mixture of diastereoisomeric iron lactam complexes (16 and 17). These complexes could be individually converted to the corresponding optically active β-lactam derivatives (27 and 28) and, hence, are precursors for the synthesis of either natural (+)-thienamycin or unnatural (-)-thienamycin.     

The infrared spectra (600-140 cm−1 of the imidazole,pyrazine and pyrimidine adducts of cobalt(II), nickel(II) and zinc(II) acetylacetonates

Summary The complexes M(acac)₂(imidazole)₂ (M = Co or NO and [M(acac)₂B]_n (M = Co, Ni or Zn; B = pyrazine or pyrimidine) have been prepared and their i.r. spectra determined over the 600–140 cm^–1. range. The metal-oxygen and metal-nitrogen stretching frequencies, (M-O) and v(M-N), are assigned on the basis of the band shifts induced by deuteriation of the adducted base and by substitution of the metal ion. Three or fourv(M-O) bands are observed within the 600-200 cm^–1 range. The twov(M-O) bands of higher frequency are considered to the coupled with internal ligand modes. TwovM-N) bands are observed within the 280–170 cm^–1. range. The metal-ligand stretching frequencies are in good agreement with the values previously established for these vibrations in the [M(imidazole)₆]²⁺ and Ni(acac)₂(pyridine)₂ complexes.     

Should dithiophosphinate esters function as RAFT agents?

[graph: see text] High-level ab initio calculations indicate that *CH3 addition to the sulfur center of S=P(Z)(Z')SCH3 (Z,Z' = CH3, CN, OCH3, Ph) is considerably less exothermic than addition to the corresponding RAFT agents, S=C(Z)SCH3. This suggests that dithiophosphinate esters may have only limited use in controlling free-radical polymerization, but should make excellent radical chain carriers in organic synthesis. The results cast doubt on the notion that phosphoranyl radicals are more "intrinsically" stabilized than carbon-centered radicals.     

Total synthesis of erythromycin B

We report the details of the first total synthesis of erythromycin B using two different strategies for the end game. The first of these follows a classical approach in which the desosamine and cladinose residues are sequentially appended to a macrocyclic lactone, which was formed by cyclization of a seco acid derivative, to give a bis-glycosylated macrolide intermediate that is converted into erythromycin B. The second strategy features an abiotic approach in which a seco acid bearing a desosamine residue is cyclized to give a monoglycosylated macrocyclic lactone that is then transformed into erythromycin B via a sequence of steps involving refunctionalizations and a glycosylation to introduce the cladinose moiety. Attempts to prepare a bis-glycosylated seco acid by de novo synthesis were unsuccessful. The syntheses of the key seco acid intermediates feature the oxidative transformation of a furan containing C(3)-C(10) to provide a dioxabicyclo[3.3.1]nonenone that served as a template on which to create the stereocenters at C(6) and C(8). A stereoselective aldol reaction was used to establish the C(11)-C(15) segment, and a stereoselective crotylation was implemented to introduce the propionate subunit comprising C(1)-C(2).     

Synthesis and spectroscopic studies of non-heme diiron(III) species with a terminal hydroperoxide ligand: models for hemerythrin

Two compounds, [Fe2(mu-OH)(mu-Ph4DBA)(TMEDA)2(OTf)] (4) and [Fe2(mu-OH)(mu-Ph4DBA)(DPE)2(OTf)] (7), where Ph4DBA(2-) is the dinucleating bis(carboxylate) ligand dibenzofuran-4,6-bis(diphenylacetate), have been prepared as synthetic models for the dioxygen-binding non-heme diiron protein hemerythrin (Hr). X-ray crystallography reveals that, in the solid state, these compounds contain the asymmetric coordination environment found at the diiron center in the reduced form of the protein, deoxyHr. M?ssbauer spectra of the models (4, delta = 1.21(2), DeltaE(Q) = 2.87(2) mm s(-1); 7, delta(av) = 1.23(1), DeltaE(Qav) = 2.79(1) mm s(-1)) and deoxyHr (delta = 1.19, DeltaE(Q) = 2.81 mm s(-1)) are also in good agreement. Oxygenation of the diiron(II) complexes dissolved in CH2Cl2 containing 3 equiv of N-MeIm (4) or neat EtCN (7) at -78 degrees C affords a red-orange solution with optical bands at 336 nm (7300 M(-1) cm(-1)) and 470 nm (2600 M(-1) cm(-1)) for 4 and at 334 nm (6400 M(-1) cm(-1)) and 484 nm (2350 M(-1) cm(-1)) for 7. These spectra are remarkably similar to that of oxyHr, 330 nm (6800 M(-1) cm(-1)) and 500 nm (2200 M(-1) cm(-1)). The electron paramagnetic resonance (EPR) spectrum of the cryoreduced, mixed-valence dioxygen adduct of 7 displays properties consistent with a (mu-oxo)diiron(II,III) core. An investigation of 7 and its dioxygen-bound adduct by extended X-ray absorption fine structure (EXAFS) spectroscopy indicates that the oxidized species contains a (mu-oxo)diiron(III) core with iron-ligand distances in agreement with those expected for oxide, carboxylate, and amine/hydroperoxide donor atoms. The analogous cobalt complex [Co2(mu-OH)(mu-Ph4DBA)(TMEDA)2(OTf)] (6) was synthesized and structurally characterized, but it was unreactive toward dioxygen.