Differential O-3/O-4 selectivity in the glycosylation of N-dimethylmaleoyl-protected hexosamine acceptors: effect of a conformationally armed (superarmed) glycosyl donor.

An assessment of the relative O-3/O-4 reactivities of both α- and ß-methyl glycosides of N-dimethylmaleoyl (DMM) glucosamine and allosamine acceptors protected at O-6 with a benzyl group using a d-glucopyranosyl conformationally armed donor (superarmed donor) counterpart is presented. The glycosylation of glucosamine derivatives followed the trends already observed for disarmed donors. On the other hand, the glycosylation of allosamine derivatives gave exclusively substitution on the equatorial O-4, in spite that with a disarmed donor the point of substitution is exclusively on the more hindered, electronically-preferred O-3.

Structural analysis of methyl 6-O-benzyl-2-deoxy-2-dimethylmaleimido-α-D-allopyranoside by X-ray crystallography, NMR, and QM calculations: hydrogen bonding and comparison of density functionals.

The crystal structure of methyl 6-O-benzyl-2-deoxy-2-dimethylmaleimido-α-D-allopyranoside was solved in order to gain insight into the hydrogen bond features which can be determining features in the glycosylation regioselectivity observed for this compound. An intramolecular hydrogen bond between the hydroxyl H(O)3 and a carbonyl oxygen from the dimethylmaleoyl (DMM) group was observed. This was in agreement with previous NMR temperature shift determinations and molecular modeling. The determination has also found an intermolecular hydrogen bond between the second hydroxyl H(O)4 and the other carbonyl oxygen (generated by symmetry) from DMM. The crystal structure was optimized by five different functionals, namely the hybrid methods B3LYP, M06-2X, B3PW91, and PBE0, and the pure functional PBE, and the optimized geometries were compared with the crystal geometry and with MM3. An excellent coincidence of the geometries was found with the five quantum methods, with minor details deviating from this coincidence. PBE tends to yield larger bond distances, whereas M06-2X fails slightly to match the exocyclic torsion angles for the sugar moiety. In any case, the differences are small, implying that any of these functionals can accurately emulate the geometries of a complex carbohydrate derivative like this one.

Regioselectivity of the glycosylation of N-dimethylmaleoyl-protected hexosamine acceptors. An experimental and DFT approach.

Both anomers of the methyl glycoside of 6-O-benzyl-N-dimethylmaleoyl-D-allosamine (6 and 7) are glycosylated exclusively on O3 when reacting with the trichloroacetimidate of peracetylated α-D-galactopyranose (5). This regioselectivity is expected for 6, the α-anomer, as a strong hydrogen bond of its H(O)3 with the carbonyl group of the dimethylmaleoyl group occurs, as shown by NMR temperature dependence. However, this hydrogen bond was not encountered experimentally for 7, the ß-anomer. A DFT study of the energies implied in an analog of the glycosylation reaction charged intermediate has explained neatly this behavior, in terms of strong hydrogen bonds occurring at these charged intermediates. This approach explains both the experimental regioselectivities found for 6 and 7, but furthermore the calculations have shown a marked agreement with the regioselectivities found for other related compounds in the literature.

A comparative study of the O-3 reactivity of isomeric N-dimethylmaleoyl-protected D-glucosamine and D-allosamine acceptors.

Four isomeric N-dimethylmaleoyl 4,6-O-benzylidene-protected d-hexosamine acceptors (2, 3, 4, and 5) with all possible configurations at C-1 and C-3 (e.g., derived from d-glucosamine and D-allosamine) were prepared, and the assessment of their O-3 relative reactivity through competition experiments using the known per-O-acetylated D-galactopyranosyl trichloroacetimidate donor (15) was then carried out. The reactivities are in the order 4≫2>5>3. The analysis of the NMR spectra of 2-5 at different temperature and modeling experiments carried out on analogs of 2-5 (DFT) and on the acceptors themselves (MM) are coincident, and have helped to establish the stability of the different hydrogen bonds, and of the conformers which carry them. The whole results suggest that the electronic effects (hydrogen bonds) are required to explain the observed trend, in spite of the axial conformation of the most reactive hydroxyl group. The steric effects appear only when hydrogen bonds are weak.

Conformational and electronic effects on the regioselectivity of the glycosylation of different anomers of N-dimethylmaleoyl-protected glucosamine acceptors.

In a previous paper (Bohn et al., Carbohydr. Res., 2007, 342, 2522) the relative O3/O4 reactivities of both alpha- and beta-methyl glycosides of N-dimethylmaleoyl (DMM) glucosamine acceptors protected at O6 with three different groups were assessed by us, using two glycosyl donors. The alpha-anomers showed preferential or exclusive substitution at O3, whereas the beta-anomers gave preferential or exclusive substitution at O4. A DFT study of analogs of the reported acceptors indicates that whereas the beta-anomers carry the DMM ring parallel to the C2-H2 bond for steric reasons, the alpha-anomers tilt this ring producing a strong hydrogen bond between the H(O)3 and one of the DMM carbonyl groups. In this way, the O3 group becomes more nucleophilic and thus more reactive: both charge and Fukui functions on O3 and O4 in the model compounds support the experimental results. Surprisingly, the previously mentioned hydrogen bond is not the only driving force for the slant of the DMM group: the axial methoxyl group of the alpha-anomers also plays a role. The ease of rotation around the C2-N2 bond for DMM-protected analogs was assessed with different models. MP2 calculations using higher basis sets yield similar relative energy and charge values to those calculated using DFT.

Differential O-3/O-4 regioselectivity in the glycosylation of alpha and beta anomers of 6-O-substituted N-dimethylmaleoyl-protected D-glucosamine acceptors.

An assessment of the relative O-3/O-4 reactivities of both methyl alpha- and beta-d-glycosides of N-dimethylmaleoyl (DMM) d-glucosamine acceptors protected at O-6 with benzoyl (Bz), benzyl (Bn), and tert-butyldiphenylsilyl (TBDPS) groups is presented using per-O-benzoylated beta-d-galactofuranosyl and per-O-acetylated alpha-d-galactopyranosyl trichloroacetimidates as glycosyl donors. Using the former donor, the alpha anomer of the 6-O-benzoylated compound gave exclusive substitution at O-3, whereas the other two compounds with alpha-configuration kept this site as preferential. The beta anomer of the 6-O-benzoylated compound gave the same amounts of reaction products on O-3 and O-4, whereas the other beta analogs carried a more reactive O-4. The same reactions were carried out using as donor the less-reactive per-O-acetylated alpha-d-galactopyranosyl trichloroacetimidate. Although the same trend was found to occur, the O-4 was always relatively more reactive with the pyranosyl donor than with the furanosyl donor, when keeping the remaining factors constant. Furthermore, the beta anomers of the acceptor gave almost exclusive substitution at O-4. These observations confirm and extend the utility of these 'matching' donor and acceptor reactivities.

A comparative study of the influence of some protecting groups on the reactivity of D-glucosamine acceptors with a galactofuranosyl donor.

Competitive glycosylation experiments with a galactofuranosyl trichloroacetimidate donor were performed with glucosamine acceptors having a free 4-OH group and carrying different protecting groups at N-2, O-3, and O-6. The most reactive acceptor is the N-dimethylmaleimido 3,6-di-O-benzylated derivative (6c), which reacts even faster than the oxazolidinone 1a. Molecular orbital calculations have helped to rationalize these experimental facts in terms of a hard-hard reaction occurring between the donor and the acceptor.

The quest for quinine: those who won the battles and those who won the war.

For a long time, the synthesis of quinine constituted an elusive target. In 2004, which marked the 60th anniversary of the publication of the approach used by Woodward and Doering to synthesize quinine, two new stereocontrolled total syntheses of the natural product were accomplished. Together with the well-publicized first stereocontrolled total synthesis of quinine by Stork in 2001, these publications evidence the revival of interest of organic chemists in the synthesis of this compound, once considered a miracle drug. The recently disclosed syntheses of quinine also testify in a remarkable manner the huge progress made by organic synthesis during the last three decades since the first series of partially controlled syntheses of quinine by the group of Uskokovic. Following an account of the historical importance of quinine as an antimalarial drug and a brief description of the experiments which contributed to its isolation and structural elucidation, the first reconstructions of quinine and the total syntheses of the natural product are discussed.

(-)-Parasantonic acid and its enol lactone, (+)-parasantonide: observation of the rare acid-to-acid catemeric hydrogen-bonding mode in a gamma,epsilon-diketocarboxylic acid.

The title diketo acid, (-)-alpha,3a,7-trimethyl-5,8-dioxo-1,4-ethanoperhydropentalene-1-acetic acid, C(15)H(20)O(4), is shown to aggregate in the solid state as acid-to-acid hydrogen-bonded catemers, whose chains follow 2(1) screw axes from each carboxyl H atom to the C=O group of a neighboring carboxyl group [O.O = 2.672 (4) A and O.H-O = 173 degrees ]. Two parallel counterdirectional screw-related single-strand hydrogen-bonded chains pass through the cell in the a direction. Two intermolecular C=O.H-C close contacts are present in this compound. Both this diketo acid and its enol lactone, (+)-parasantonide [systematic name: (-)-alpha,3a,7-trimethyl-5-oxo-1,4-ethenoperhydropentalene-1,8-carbolactone], C(15)H(18)O(3), have an R configuration at the methylated chiral center adjacent to the carboxyl group, unlike the precursor from which they are derived, viz. (-)-santonic acid.