Discrimination in resolving systems. VI. Comparison of the diastereomers of deoxyephedrinium and ephedrinium 4'-fluoromandelates.

(-)-(R)-Deoxyephedrine forms poorly discriminating diastereomeric salts with 4'-fluoromandelic acid from 95% ethanol. Both less-soluble (L) (S)-4'-fluoromandelate and more-soluble (M) (R)-4'-fluoromandelate phases are monoclinic and unsolvated. Their solubility ratio (M/L) in 95% ethanol is only 1.2, which correlates with the similarity and small differences in their respective heats of fusion and fusion temperatures. The (R)-deoxyephedrinium and the related (1R;2S)-ephedrinium 4'-fluoromandelate systems show L-salts with higher ion-pair volumes and lower densities than their M-salts. (R)-Deoxyephedrinium salts have higher volumes than the comparable (1R;2S)-ephedrinium salts even though the resolving base (R)-deoxyephedrine lacks the benzylic hydroxy. In the solids, bilayered structures segregate polar and nonpolar molecular regions. The principle interionic interactions are hydrogen bonds between protonated secondary ammonium ions and carboxylates forming infinite chains with a six-atom repeating unit H-N(+)-H...O-C(-)-O [C(2)(2)(6)]. These are buttressed by mandelate hydroxy to carboxylate hydrogen bonds. Differing interactions between phenyl and 4'-fluorophenyl rings in the nonpolar layers of the salts correlate with the density and stability inversion.

Discrimination in resolving systems. V. Pseudoephedrine - fluoromandelic acid diastereomers.

Resolution of the isomeric 2'-, 3'-, and 4'-fluoromandelic acids with (+)-(1S;2S)-pseudoephedrine in 95% ethanol produces both well and poorly discriminating, hydrated and unsolvated binary salts. Seven observed diastereomeric phases are represented by five crystal structure types including three of the four types observed in the pseudoephedrine mandelates. Type a: monoclinic hemihydrate less-soluble (L) (R)-3'-fluoromandelate and more-soluble (M) (R)-4'-fluoromandelate (I); type b: orthorhombic unsolvated M (S)-2'-fluoromandelate; type c: orthorhombic unsolvated L (R)-2'-fluoromandelate; type d: orthorhombic dihydrate M (S)-3'-fluoromandelate and L (S)-4'-fluoromandelate; type e: monoclinic unsolvated M (R)-4'-fluoromandelate (II). Largest (15-fold) discriminating solubilities in 95% ethanol are found between the diastereomers with 2'-fluoromandelic acid, 50% more than in the corresponding ephedrine system. Principle interionic interactions are hydrogen-bonds between protonated secondary ammonium ions and carboxylates. Infinite chains of these are found in type c, with a four-atom repeating unit H-N(+)-H.O(-C(-)-O) [C(2)(1)(4)], and in types b and d, with a six-atom repeating unit H-N(+)-H.O-C(-)-O [C(2)(2)(6)]. Water of crystallization intervenes in the chains of type a but not of type d hydrated salts, according with higher average dehydration temperatures in the former. Hydrated salts in general are excessively soluble in 95% ethanol.

Na2[(mu-N,N'-C10H12N2O8)(mu-O)(mu-S)-Mo2O2].2H2O.

Analogs of bridging-oxo complexes of dimolybdenum(V) where sulfide replaces one or both bridges are known. After reduction of [(MoO3)2(mu-edta)]4- (edta is ethylenediaminetetraacetate) with dithionite at pH 6 in the absence of dioxygen, slow replacement of bridging oxide with sulfide produced in situ produces the title compound, disodium mu-(ethylenediaminetetraacetato)-mu-oxo-mu-sulfido-bis[oxomolyb denum(V)] dihydrate, Na2-[Mo2O3S(C10H12N2O8)].2H2O. IR and NMR spectroscopic analyses are consistent with an unsymmetrical complex. In the molecular structure, the Mo centers have distorted octahedral coordination, with an average Mo-S distance of 2.320 (1) A and an average bridging Mo-O distance of 1.938 (3) A. The Mo...Mo contact distance [2.666 (1) A] is intermediate between those in comparable di-mu-oxo and di-mu-sulfido complexes. The two Na+ ions have five and six nearest O atoms in their coordination spheres, which each include one disordered water oxygen.

Pseudoacids. II. 2-Acylbenzoic acid derivatives.

Structures of derivatives of cyclic o-acylbenzoic acids, including the chloride, endo- and exocyclic amides, esters and anhydrides, are examined. 3-Chloro-1(3H)-isobenzofuranone (1), orthorhombic, Pbca, a = 11.616 (5), b = 8.120 (3), c = 15.640 (9) A; 3-methoxy-3-phenyl-1(3H)-isobenzofuranone (3), orthorhombic, P2(1)2(1)2(1), a = 6.923 (2), b = 8.291 (4), c = 21.551 (8) A; 3-hydroxy-3-phenyl-N-propyl-1(3H)-isoindolone (4), orthorhombic, P2(1)2(1)2(1), a = 8.662 (4), b = 9.551 (7), c = 17.649 (14) A; 3-(N-morpholino)-1(3H)-isobenzofuranone (5), triclinic, P1, a = 6.172 (4), b = 11.163 (7), c = 17.33 (2) A, alpha = 105.91 (6), beta = 99.85 (6), gamma = 97.57 (5) degrees; 3-(2'-benzoylbenzoyloxy)-3-phenyl-1(3H)-isobenzofuranone (7), triclinic, P1, a = 9.694 (3), b = 10.505 (4), c = 11.163 (4) A, alpha = 80.58 (3), beta = 80.41 (3), gamma = 76.49 (3) degrees; bis[1(3H)-isobenzofuranone-3-yl]ether (8), monoclinic, I2/a, a = 15.31 (2), b = 6.111 (12), c = 28.30 (5) A, beta = 101.61 (12) degrees. An open oxoacid tertiary amide is also described: N-morpholino 2'-benzoylbenzamide (6): monoclinic, P2(1)/c, a = 6.844 (4), b = 15.696 (8), c = 14.154 (7) A, beta = 99.43 (4). Pseudoacid derivatives form planar isobenzofuran and isoindole rings, and the former aldehyde/ketone carbon-heteroatom endocyclic and exocyclic bond distances show bond length variations which correlate with the relative basicities of the attached groups. Structures of both endocyclic and exocyclic nitrogen pseudoamides are reported as well as examples of the normal-pseudoanhydride and the dipseudoanhydride.

Structural and enzymatic studies of a new analogue of coenzyme B12 with an alpha-adenosyl upper axial ligand.

A new analogue of coenzyme B12 (5'-deoxyadenosylcobalamin, AdoCbl), in which the configuration of the N-glycosidic bond in the Ado ligand is inverted [(alpha-ribo)AdoCbl], has been synthesized and its crystal structure determined by X-ray diffraction [MoKalpha, lambda = 0.71073 A, monoclinic P212121, a = 16.132(12) A, b = 21. 684(15) A, c = 27.30(3) A, 9611 independent reflections, R1 = 0. 0708]. As suggested by molecular mechanics modeling before the structure was known, the Ado ligand lies over the southern quadrant of the molecule, as is the case for AdoCbl. The most striking feature of the structure is disorder in the orientation of the adenine (Ade) moiety relative to the ribose of the Ado ligand. This was resolved with a two-state model in which in the major (0.57 occupancy) conformer the A16(O)-A11-A9(N)-A8 dihedral angle is 1.9 degrees and the Ade is virtually perpendicular to the corrin ring; in the minor conformer, the Ade is tilted down, and this dihedral is -48.7 degrees. The Co-C and axial Co-N bond lengths and the Co-C-C bond angle are quite similar to those in AdoCbl. The corrin ring is considerably flatter than that of AdoCbl, with a fold angle of 11.7 degrees. The molecule was successfully modeled by molecular mechanics (MM), and rotation of the Ado ligand relative to the corrin gave rise to four locally minimum structures with the Ado in the southern, eastern, northern, or western quadrant, with the southern conformation as the global minimum, as is the case with AdoCbl itself. Nuclear Overhauser effects (nOe's) observed by two-dimensional (2D) NMR were incorporated as restraints in molecular dynamics (MD) and simulated annealing (SA) calculations. A MD simulation at 300 K showed that only the southern conformation is populated with the Ado ligand confined to an arc from over C15 to over C12, while the Ade ring oscillates from perpendicular to parallel to the corrin ring. Twenty-seven structures were collected by MD-SA. Most of these annealed into the southern conformation, but examples of the other conformations were also found. The new analogue is a partially active coenzyme for the ribonucleotide reductase from Lactobacillus leichmanii with maximal activity that is 9.7% of that of AdoCbl itself, and a very high Km value (245 microM compared to 0.54 microM for AdoCbl). In addition, the rate constant for enzyme-induced carbon-cobalt bond cleavage of (alpha-ribo)AdoCbl is 160-fold smaller than that for AdoCbl, and only 1/3 as much cob(II)alamin is produced at the active site.

Pseudoacids. I. 4- and 5-oxoacids.

Certain 4- and 5-oxoacids may exist in their cyclic lactol (or pseudoacid) forms. These commonly occur in compounds with proximate carboxylic acid and carbonyl (aldehyde or ketone) functions for the formation of five- or six-membered rings. Examples include trans-2,3-disubstituted aliphatic, (Z)-2,3-olefinic and o-disubstituted aromatic acids. Crystal structures of compounds in these categories are reported: trans-4-methyl-3-oxo-6-hydroxytetrahydropyran-3-carboxylic acid (6), monoclinic, C2/c, a = 25.412 (5), b = 6.291 (1), c = 10.757 (2) A, beta = 104.84 (3) degrees; penicillic acid (7), 4-methoxy-5-hydroxy-5-(2'-propenyl)dihydrofuran-2-one, tetragonal, P4(2)/n, a = b = 15.83 (2), c = 7.016 (11) A; mucochloric acid (8), (Z)-3,4-dichloro-5-hydroxydihydrofuran-2-one, triclinic, P1, a = 6.227 (5), b = 8.085 (5), c = 12.369 (9) A, alpha = 99.50 (5), beta = 102.38 (6), gamma = 90.29 (6) degrees; 2-methanoylbenzoic acid (9), 3-hydroxy-1-(3H)-isobenzofuranone, monoclinic, P2(1), a = 4.006 (1), b = 11.489 (2), c = 7.347 (1) A, beta = 97.50 (3) degrees; 2-ethanoylbenzoic acid (10), 3-hydroxy-3-methyl-1-(3H)-isobenzofuranone, orthorhombic, P2(1)2(1)2(1), a = 5.199 (6), b = 9.651 (14), c = 15.950 (17) A; 2-(2'-oxoethyl)benzoic acid (11), 3-hydroxy-3,4-dihydroisobenzopyran-1-one, monoclinic, P2(1)/n, a = 4.651 (3), b = 11.886 (7), c = 14.312 (11) A, beta = 90.86 (6) degrees. These compounds also exist in the cyclic forms in chloroform solution. A trimeric cyclic trioxane structure, analogous to paracetaldehyde, is confirmed as the solid form of 5-oxopentanoic acid (1), triclinic, P1, a = 5.640 (4), b = 8.571 (8), c = 18.962 (13) A, alpha = 78.68 (6), beta = 84.34 (5), gamma = 80.38 (6) degrees. In solution (NMR), mixtures of the open aldoacid, trimeric acid and cyclic pseudoacid exist. In both furanoid and pyranoid pseudoacids, endocyclic lactol C-O bond lengths are lengthened (1.46-1.48 A), while the exocyclic C-O(H) bonds are shortened (1.38 A). Pseudoacids commonly form hydrogen-bonded chains linking the lactol hydroxy and carbonyl groups, but 3-hydroxy-3,4-dihydroisobenzopyran-1-one forms distinctive hydrogen-bonded dimers.

Discrimination in resolving systems. II: Ephedrine-substituted mandelic acids.

Binary diastereomeric (-) (1R,2S)-ephedrine salts of various mandelic acids obtained from 95% ethanol show considerable differences in solubility. Structures and some properties of the less-soluble (L) and more-soluble (M) solid phases of (-)-ephedrine with unsubstituted mandelic acid, 2-, 3-, and 4-monosubstituted halo (F, Cl, Br) mandelic acids, and 3- and 4-methylmandelic acids have been determined. Salts were found to be binary, without solvent of crystallization, and composed of double-layered arrays of alternating anions and cations linked by H-bonds normal to the layers. H-bonding links charged donors and acceptors usually along a crystallographic 2-fold screw axis. A striking discrimination is evident in that the (2R)-mandelate salts typically display a compact four-atom chain as the H-bonding repeating unit [+N--H...O(-C(-)--O)...H-N', C2(1)(4)] while the (2S)-mandelate salts adopt a more dimensionally variable six-atom chain repeating unit [+N--H...O--C(-)--O...H--N', C2(2)(6)]. Two distinct packing schemes display the shorter H-bonding chain of the (2R)-mandelates which always occurs with ephedrinium ions in the fully extended conformation. Slightly greater packing efficiency and H-bonding energies of the (2R)-mandelate salts correlates with increased fusion points, lower solubilities (95% ethanol), and higher heats of fusion relative to the phase adopted by their diastereoisomers. In contrast, (2S)-mandelate salts exhibit considerably more structural variability involving all three major ephedrinium conformations, and at least four distinct packing motifs. Mandelates with larger 3'-substituents (Cl, Br, methyl) show similar property discriminations, but these occur with an opposing trend, that is, between phases in which the less-soluble salts contain (2S)-mandelates. Salts with 2-bromomandelate do not show property disparities and their structures are dissimilar to the other phases.

Discrimination in resolving systems: ephedrine-mandelic acid.

Resolution of mandelic acid with (-)-(1R,2S)-ephedrine in water and ethanol produces intermediate diastereomeric salts with greatly disparate solubilities and melting points. Single crystal X-ray analysis of the less (L) and more (M) soluble (-)-ephedrinium mandelates (I, II) shows crystal structures which are isosteric, each crystallizing in the monoclinic system, space group C2. Protonated ephedrines occupy the same relative positions in the L- and M-salts, and mandelates are in the same general locations. Hydrogen bonds link alternating protonated ephedrine nitrogens and mandelate carboxylate oxygens in each salt forming columns of ions. The helical H-bonded chain winds down the crystallographic 2-fold screw axis. Additional H-bonds form between 2-fold related mandelates in the L-salt. Mixed crystals, containing both mandelate isomers, (2R)- and (2S)-mandelates, are obtained from the resolving system partly depleted of the L-salt. A specimen with nearly equal amounts of the mandelates (III) is also isosteric with the commensurate structures. I (294K), L-salt: a = 18.160(7), b = 6.538(2), c = 13.898(4) A, beta = 92.02(3) degrees, V = 1649.1(9) A3; IIa (294K), M-salt: a = 17.978(11), b = 7.164(4), c = 13.574(6)A, beta = 96.41(4) degrees, V = 1737.3(16) A3; IIb (223K), M-salt: a = 17.805(8), b = 7.115(2), c = 13.50(5) A, beta = 96.89(3) degrees, V = 1697.9(15) A3; III (294K), mixed-salt: a = 18.184(22), b = 6.792(7), c = 13.808(19) A, beta = 93.74(10) degrees, V = 1701.7(35) A3.

Structure of (+-)-6-methyl-6,12-methano-6H,12H,13H-[1]benzopyran[4,3-d] [1,3]benzodioxocin-13-one.

A derivative of warfarin, racemic C19H14O4, Mr = 306.32, monoclinic, Cc, a = 9.594 (2), b = 20.437 (4), c = 7.793 (2) A, beta = 109.94 (3) degree, V = 1436.4 (11) A3, Z = 4, Dx = 1.416 g cm-3, lambda(CuK alpha) = 1.5418 A, mu = 7.742 cm-1, F(000) = 640, T = 293 K, final R = 0.053 for 1224 observations. The title molecule, formed by spontaneous dehydration of 2'-hydroxy-warfarin, is a cyclic ketal in which the side-chain phenyl is disposed pseudoaxially and is linked through a 2'-oxygen to the ketal carbon in a fixed cis 1,3-diaxial configuration. Two dihydropyran rings are formed; one fused with the benzopyran ring adopts an e,f-diplanar conformation, the other is a chroman and is in a similar conformation.

Proton magnetic resonance studies of the decomposition of 4-hydroxycyclophosphamide, a microsomal metabolite of cyclophosphamide.

The proposed tautomeric equilibrium between the microsomal metabolite of cyclophosphamide, 4-hydroxycyclophosphamide, and the open chain aldophosphamide, and the subsequent facile ß-elimination to generate acrolein and phosphoramide mustard have been confirmed by proton magnetic resonance studies. When 4-hydroxycyclophosphamide, initially maintained in CDC13 at -20°C, was allowed to equilibrate at 15°C, a singlet at 9.76 δ and a triplet at 2.88 δ appeared concomitantly which were assigned to the aldehydic proton and the protons α to the carbonyl of aldophosphamide, respectively. Further reaction led to the appearance of several NMR signals that indicated the irreversible formation of acrolein (multiplet at 9.55 δ) and phosphoramide mustard. Polymerization occurred approximately 2 hours after the initiation of the reaction. The kinetic data of the reaction sequence are discussed.

Structure of a Gla-containing dipeptide. The crystal structure of (+/-)-N-carbobenzoxy-(gamma,gamma'-DI-tertbutyl)-gamma-carboxyglutamylglycine ethyl ester.

The crystal and molecular structure of a dipeptide containing a blocked gamma-carboxyglutamyl (Gla) residue is presented. Two intermolecular hydrogen bonds link the amides with carbonyl groups in the dipeptide backbone, but the protected gamma-carboxy groups on the modified glutamic acid are not hydrogen bonded.

Conformations of selected 3-substituted 4-hydroxycoumarins in solution by nuclear magnetic resonance. Warfarin and phenprocoumon.

The chemical shift position of the benzylic proton, Hx, has been found to be diagnostic in indicating the preferred conformations of selected 3-substituted 4-hydroxycoumarins. In general, the nonrigid open-chain compounds, e.g., to open-chain tautomer of warfarin and phenprocoumon, are found to exist in equal populations of the two conformations in which the benzylic proton is in the plane of the coumarin ring and is either cis or trans to the 3,4 double bond. The cyclic compounds, e.g., cyclocumoral, are constrained to two limiting conformations defined as axial2 or trans or intermediate conformations between these limits. Evidence is presented that suggests that the antivitamin K activity of warfarin is due to its open side-chain tautomeric form.

Anomalous chiroptical properties of warfarin and phenprocoumon.

The configurationally similar enantiomers of warfarin and phenprocoumon are found to exhibit circular dichroism curves which are nearly mirror related in the range of 240-340 nm. This effect is interpreted as being due to spatial similarities of the preferred conformations of opposite configurations of the two drugs in solution. An inherently dissymmetric chromophore (theta approximately 1.2 x 10(5)) is observed at approximately 220 nm for warfarin, the cyclic hemiketal tautomeric forms, and the cyclic methyl ketals.

Structure of warfarin in solution.

Warfarin in solution is shown to consist of three interconverting tautomeric structures, two of which are cyclic diastereomeric hemiketals, while the third and minor component is the open-chain intermediate form. The configurations of all the tautomers as well as the major conformations of the cyclic tautomers are assigned. The assignments are supported by comparison with the chemical shift and coupling constant parameters of structurally fixed model compounds.