Proton-dependent electrogenic transporters for diand tripeptides have been identified in bacteria, fungi, plants, and mammalian cells. They all show sequenceindependent 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 (-amino fatty acids, -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 -AFA maintained the affinity of the compound for interaction with the transporter but abolished the capability for electrogenic transport. Additional groups in the -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.

In order to determine whether a-metalated (lithiated) amines are carbenoids, as are a-lithiated halides and ethers, we have determined the crystal structures of the title compounds. In does not bridge to the indole nitrogen atom because it is a weak donor. The C-N bond length to the anionic C atom is slightly longer (2 -3 pm) than in the non-lithiated compound. Other a-lithiated amines, which have been published, although not analyzed so far under this particular aspect, show also a marginal C-N bond lengthening. However, since alithiated amines -in contrast to a-lithiated halides and ethers -until now have not been reported in the literature to react with nucleophiles RLi, there is no need to include them into the group of the above mentioned carbenoids -at least not to date.

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Benzyllithium compounds carrying a benzylthio substituent (6), a benzylseleno substituent (8), and an isopropyl(methyl)amino substituent (14) have been generated. Racemization barriers have been determined in THF by monitoring the coalescence of signals of diastereotopic groups in the 1H‐NMR spectra. The barrier for 6 amounts to a ΔH≠ of 7.5 kcal mol−1 and ΔS≠ of −12 cal mol−1 K−1 corresponding to a ΔG 213≠ of 9.9 kcal mol−1. The barrier for the other compounds investigated varies from 9 to 10 kcal mol−1. The rate‐determining step for the racemization is discussed to be the transformation of the contact ion pair to the solvent‐separated ion pair.

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