In this paper, we report a structural study both in the solid state and in solution of barium complexes with the diamine N,N'-bis(2-aminobenzyl)-4,13-diaza-18-crown-6 (L(2)), that allows us to rationalize the template effect of the metal ion in the synthesis of Schiff-base lateral macrobicycles resulting from the condensation of L(2) with different dicarbonyl compounds. The X-ray crystal structures of [Ba(L(2))(ClO(4))](ClO(4)) (3) [triclinic space group P1 with Z = 2, a = 10.467(2) A, b = 10.4755(2) A, c = 16.9911(3) A, alpha = 85.075(1) degrees, beta = 80.907(1) degrees, and gamma = 61.627(4) degrees ] and [Ba(L(2))(NCS)(H(2)O)](SCN) (4) [monoclinic space group P2(1)/n with Z = 4, a = 9.954(5) A, b = 29.193(5) A, c = 11.313(5) A, and beta = 91.371(5) degrees ] demonstrate that in the solid state the barium(II) ion induces an anti conformation of the receptor in the complexes. Variable temperature (1)H and (13)C NMR data point out that in solution compounds 3 and 4 exist as a mixture of syn and anti isomers. The presence of the syn isomer in solution, independent of the counterion employed (perchlorate or thiocyanate), accounts for the effectiveness of the barium(II) ion as a template agent in the synthesis of the lateral macrobicycles resulting from the condensation of L(2) with different dicarbonyl compounds. Density functional theory calculations (at the B3LYP/LanL2DZ level) for [Ba(L(2))](2+) predict the syn conformation to be more stable both in vacuo and in solution (PCM model). In order to asses which of the two isomers predominates in acetonitrile solution, the (13)C NMR shielding tensors of the two isomers of [Ba(L(2))](2+) were calculated for the in vacuo optimized structures by using the GIAO method, and the results were compared with the experimental ones. According to these analyses, a syn stereochemistry is assigned to the major species in solution.

Diastereoselectivity in the conjugate addition of metalated Schöllkopf's bis-lactim ethers 5a-e to (E)- and (Z)-1-propenylphosphonates 4a,b was studied experimentally and theoretically and utilized to achieve a direct and stereocontrolled synthesis of all four diastereoisomers of 2-amino-3-methyl-4-phosphonobutanoic acid, 6a,b and their enantiomers. The relative stereochemistry was assigned from an NMR study of cyclic derivatives 13a,b. According to semiempirical calculations, both in vacuo (PM3) or a dielectric continuum (PM3/COSMO), initial lithium-phosphoryl coordination, without an energy barrier, to form a solvated chelate complex is followed by the rate-determining reorganization to the 1,4-addition product through an eight-membered transition state. The translation of the Z,E geometry into a syn, anti configuration at the adducts originates from an orientational preference in the transition state for a compact disposition of the reaction partners.

Both β-cyclodextrin and sodium dodecyl sulfate micelles shift the benzoylacetone keto-enol equilibrium to the enol tautomer by preferentially binding the enol form. The UV-vis spectroscopic method was used to quantify the temperature and solvent effects on the keto-enol equilibrium of benzoylacetone in aqueous acid medium. The comparison between the thermodynamic parameters resulting from the binding of the benzoylacetone enol to sodium dodecyl sulfate micelles and from the inclusion of both keto and enol tautomers into the β-cyclodextrin cavity allows us to draw a picture of the possible complex formed in each case. 1 H NMR results suggest that benzoylacetoneenol protrudes deeper inside the β-cyclodextrin cavity, whereas the keto tautomer could only have the phenyl ring enclosed in the β-cyclodextrin cavity interior. Nitrosation in acid medium of benzoylacetone in the presence of β-cyclodextrin is reduced below that of free benzoylacetone, indicating that the cyclodextrin complex protects the benzoylacetone enol tautomer, which is in perfect accordance with our picture of the enol‚β-cyclodextrin complex.

Conjugate additions of lithiated bislactim ethers derived from cyclo-[Gly-Val] and cyclo-[Ala-Val] to alpha-, beta-, or alpha,beta-substituted vinylphosphonates allow direct and stereoselective access to a variety of 3- or 4-monosubstituted and 2,3-, 2,4-, or 3,4-disubstituted 2-amino-4-phosphonobutanoic acids (AP4 derivatives) in enantiomerically pure form. The relative stereochemistry was assigned by X-ray diffraction analysis or NMR study of 1,2-oxaphosphorinane derivatives. Competitive eight-membered "compact" and "relaxed" transition-state structures are invoked to rationalize the stereochemical outcome of the conjugate additions.

Electrophilic substitutions on lithiated Schöllkopf's bis-lactim ethers derived from cyclo-[L-AP4-D-Val] take place regio- and stereoselectively at the alpha-position of the phosphonate ester. Subsequent olefination of alpha-silyl-, alpha-phosphoryl-, and alpha-stannyl-stabilized phosphonate carbanions give rise exclusively to vinylphosphonates. Both processes allow a direct and stereoselective access to a variety of 4-substituted and 3,4-disubstituted 2-amino-4-phosphonobutanoic acids (AP4 derivatives) in enantiomerically pure form that may be useful tools for characterizing the molecular pharmacology of metabotropic glutamate receptors (mGluRs) of group III. The relative stereochemistry was assigned from X-ray diffraction analyses or NMR studies of 1,2-oxaphosphorinane and other cyclic derivatives. In accordance to density functional theory (DFT) calculations, the syn-selectivity in the electrophilic substitutions may originate from the intervention of seven- and eight-membered chelate structures in which the bis-lactim ether moiety shields one of the faces of the phosphonate carbanion. DFT calculations for the tin-Peterson olefination of alpha-stannyl stabilized phosphonate carbanions indicate that rate and selectivity are determined in the initial carbon-carbon bond formation step where the unlike transition structures leading to (Z)-vinylphosphonates are favored both in the gas phase and in THF solution.

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A general strategy for the synthesis of 1-deoxy-azasugars from a chiral glycine equivalent and 4-carbon building blocks is described. Diastereoselective aldol additions of metalated bislactim ethers to matched and mismatched erythrose or threose acetonides and intramolecular N-alkylation (by reductive amination or nucleophilic substitution) were used as key steps. The dependence of the yield and the asymmetric induction of the aldol addition with the nature of the metallic counterion of the azaenolate and the gamma-alkoxy protecting group for the erythrose or threose acetonides has been studied. The stereochemical outcome of the aldol additions with tin(II) azaenolates has been rationalized with the aid of density functional theory (DFT) calculations. In accordance with DFT calculations with model glyceraldehyde acetonides, high trans,syn,anti-selectivitity for the matched pairs and moderate to low trans,anti,anti-selectivity for the mismatched ones may originate from (1) the intervention of solvated aggregates of tin(II) azaenolate and lithium chloride as the reactive species and (2) favored chair-like transition structures with a Cornforth-like conformation for the aldehyde moiety. DFT calculations indicate that aldol additions to erythrose acetonides proceed by an initial deprotonation, followed by coordination of the alkoxy-derivative to the tin(II) azaenolate and final reorganization of the intermediate complex through pericyclic transition structures in which the erythrose moiety is involved in a seven-membered chelate ring. The preparative utility of the aldol-based approach was demonstrated by application in concise routes for the synthesis of the glycosidase inhibitors 1-deoxy-d-allonojirimycin, 1-deoxy-L-altronojirimycin, 1-deoxy-D-gulonojirimycin, 1-deoxy-D-galactonojirimycin, 1-deoxy-L-idonojirimycin and 1-deoxy-D-talonojirimycin.