Hubertus Ahlbrecht

Minimal Molecular Determinants of Substrates for Recognition by the Intestinal Peptide Transporter

Proton-dependent electrogenic transporters for di- and tripeptides have been identified in bacteria, fungi, plants, and mammalian cells. They all show sequence-independent transport of all possible di- and tripeptides as well as of a variety of peptidomimetics. We used the mammalian intestinal peptide transporter PEPT1 as a model to define the molecular basis for its multisubstrate specificity. By employing computational analysis of possible substrate conformations in combination with transport assays using transgenic yeast cells and Xenopus laevis oocytes expressing PEPT1, the minimal structural requirements for substrate binding and transport were determined. Based on a series of medium chain fatty acids bearing an amino group as a head group (ω-amino fatty acids, ω-AFA), we show that electrogenic transport by PEPT1 requires as a minimum the two ionized head groups separated by at least four methylene groups. Consequently, a > 500 pm < 630 pm distance between the two charged centers (carboxylic carbon and amino nitrogen) is sufficient for substrate recognition and transport. Removal of either the amino group or the carboxyl group in ω-AFA maintained the affinity of the compound for interaction with the transporter but abolished the capability for electrogenic transport. Additional groups in the ω-AFA backbone that provide more hydrogen bonding sites appear to increase substrate affinity but are not essential. The information provided here does (a) explain the capability of the peptide carrier for sequence-independent transport of thousands of different substrates and (b) set the molecular basis for a rational drug design to increase the absorption of peptide-based drugs mediated by PEPT1.

Structure and Reactivity of Lithiated α‐Amino Nitriles

Investigations aimed at elucidating the structure of lithiated α-amino nitriles B have led to the identification of N-lithio α-amino nitrile anions as characteristic structural features. Their preparations, crystal structures, and solution structures under the reaction conditions, are described. X-ray crystal structure analyses of crystalline 3 and (S, S)-4 reveal the presence of dimeric aggregates B4 with Ci symmetry, held together by four-membered NLiNLi rings, coordinatively saturated at lithium by four THF ligands. The crystal structure of (S, S)-6 shows polymeric aggregation with dimeric subunits similar to those of 3 and (S, S)-4. The solution structure has been investigated by IR and Raman spectroscopy of 2, (S, S)-4 and (S, S)-6, by NMR spectroscopy of 3, (S, S)-5 and (S, S)-6, and by cryoscopic measurements of (S, S)-6 in THF. Trapping experiments complement the results. In THF, which constitutes the principal reaction medium, the lithiated amino nitriles B are found to exist as monomeric species B6 between −110 and +25°C. In less polar solvents, higher aggregation is presumed. NMR spectroscopic studies of 3 show that the favored orientations of the amine and phenyl groups are similar to their conformations in the solid state. In the light of the results obtained, a transition state is proposed to account for the relative topicity observed in the 1,4-additions of enantiopure lithiated α-amino nitriles (S, S)-4, (S, S)-5, and (S, S)-6 to Michael acceptors.

α-Metallierte Amine durch Deprotonierung aliphatischer N-Methylamine

Abstract Aliphatic N-methylamines can be deprotonated directly by means of s-butyllithium/potassium t-butoxide to give dialkylaminomethyl potassium or after metal exchange the more nucleophilic dialkylaminomethyl lithium.

Bestimmung der ionenpaar-basizitǎt von lithium- und kaliumamiden

Abstract Ion pair basicities of lithio and potassio salts of some secondary amines were determined by equilibration with benzyl compounds. With these bases it is possible to span a range of about 19 pK-units from pK = 27 up to 46. The structural dependence of thermodynamic as well as kinetic basicity is discussed. Some new effective amide bases for preparative purposes are recommended. For the first time the pK-value of toluene has been determined by direct equilibration. It amounts to 40.7 in tetrahydrofuran.

Chiral homoenolate equivalents. I. Asymmetric synthesis of β-substituted aldehydes via metalated chiral allylamines

Abstract Metalated chiral allylamines of type 2 (M = Li, K) are used as chiral homoenolate equivalents and allow after alkylation and acidic hydrolysis asymmetric CC bond formations to β-substituted aldehydes in enantiomeric excesses up to 67%.

Derivatives of 1-phenyl-3-methylpyrazol-2-in-5-thione and their oxygen analogues in the crystalline phase and their tautomeric transformations in solutions and in the gas phase

Abstract 1-Phenyl-3-methylpyrazol-2-in-5-thione, crystallised from methanol, was shown to exist in the tautomeric NH-form, stabilised by intermolecular NH⋯S hydrogen bonds. In solutions, however, the molecule is found predominantly as the SH-tautomer, accompanied (in low-polar solvents) by a small amount of the CH-tautomer. 1-Phenyl-3-methyl-4-benzoylpyrazol-2-in-5-thione occurs in the crystal as well as in solution in the SH-tautomeric form, stabilised by an intramolecular SH⋯O bridge. In dimethylsulfoxide solution indications were found for an additional SH-tautomer in a conformation lacking the intramolecular H-bridge. The structure of 1-phenyl-3-methylpyrazol-2-in-5-one was redetermined by X-ray single crystal diffraction at 120°K in order to obtain more accurate geometry and hydrogen bonding parameters.

The geometry of allyl-alkali-metal compounds. A 13C NMR reinvestigation

Abstract The spatial positions of the hydrogens in allyl-alkali-metal compounds are controversial: in agreement with the X-ray structures of those allyl compounds of which the positions of the hydrogen atoms have been determined, calculations predict strongly bent out inner hydrogens H1(3) and a weakly bent out central hydrogen H2. On the other hand, since the coupling constant 1J(13CH2) of allyl-alkali-metal compounds is even smaller than the already small coupling constant 1J(13CH1(3)), it has been proposed that H2 is much more bent out than H1(3) [8]. We conclude from the essentially identical coupling constants 1J(13CH2) (133 ± 2 Hz) in (1) the contact and the solvent-separated ion pair of phenylallyllithium (potassium), (2) allyllithium and 1,3-diphenylallyllithium, and (3) allyl-lithium, -sodium, -potassium, -rubidium, -cesium that this coupling constant is not a function of an out-of-plane distortion at C2. A similar argument applies for C1(3) Rather, it is the angle widening at C2 that causes the small coupling constants 1J(13CH2), as supported by the larger coupling in 1-phenylcyclohexenyl- and, especially, 1,3-diphenylcyclopentenyl-lithium, and in agreement with both calculations and X-ray data for allyllithium.

On the reason for opposite diastereoselectivities of benzyllithium compounds containing lithium amide and lithium alkoxide functionalities

Abstract The carbolithiation of N-methyl-3-phenyl-prop-2-enylamine with tert-butyllithium leads to the monomeric benzyllithium compound 7 in good yield. The consecutive reaction with electrophiles exhibits a high anti diastereoselectivity, opposite to what has been earlier found for the oxygen analogue 3. PM3 semiempirical calculations on the intermediates show a preference of the anti configuration which is confirmed by 1H NMR. Measurements of the degree of aggregation show the dilithio compound 3 to exist as a dimer and higher aggregates in THF. PM3 calculations on this dimer can explain the different diastereoselectivity.

Carbolithiation of cinnamyl methyl ethers and 2-cinnamyl-2-methyl-1,3-dioxolane: High diastereoselectivity after electrophilic substitution

Abstract The carbolithiation of cinnamyl methyl ether 4 with tert-butyllithium, benzyllithium, and allyllithium is achieved in good yields. Consecutive treatment with electrophiles yields in all three cases a good diastereoselectivity thus confirming earlier results obtained in the reaction of secondary and tertiary cinnamyl amines. The ethylene acetal of 4-phenyl-3-buten-2-one 20 can also be carbolithiated with tert-butyllithium and the products exhibit even higher diastereomeric excesses. tert-Butyllithium has been added to α-methylcinnamyl methyl ether 17 showing complete diastereoselection in the nucleophilic addition step.

Asymmetric Synthesis of β-Methylated Aliphatic Ketones via Lithiated 3-[(S)-2-(Methoxymethyl)pyrrolidino]hex-3-ene☆

3-Substituted aliphatic ketones 10 have been obtained in excellent optical yields by alkylation of the aminoallyllithium compound endo-8, a homoenolate equivalent of hexane-3-one, using prolinol ether (SMP) as the chiral auxiliary. The intermediate endo-8 was generated by tin–lithium exchange of the 3-stannylated enamine 7a with butyllithium. An improved hydrolysis procedure for the resulting enamines is described. Some mechanistic implications with respect to the formation as well as the alkylation of endo-8 are discussed.