1-Methyl-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid (MTCA) and 1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid (TCCA), both precursors of mutagenic N-nitroso compounds (N-nitrosamines, 1-methyl-2-nitroso-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid and 2-nitroso-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid), were detected in various food-stuffs, urine from healthy human subjects and human milk. A purification procedure, involving a chemically-bonded material followed by HPLC combined with fluorometric detection, was used for the quantitative determination of these compounds, allowing the separation of two diastereoisomers of MTCA. An HPLC and mass spectrometry method was also developed for their identification. Comparing the concentration of MTCA and TCCA in fermented products and raw materials suggested that tetrahydro-beta-carbolines may have been produced through fermentation or by condensation of tryptophan and acetaldehyde formed from ethanol added as a food preservative. This is the first report of excretion of tetrahydro-beta-carbolines in human urine and human milk. A comparison of the concentrations of tetrahydro-beta-carbolines in urine from human infants and human milk indicates that tetrahydro-beta-carbolines may be synthesized endogenously in humans. A possible pathway of tryptophan metabolism in plants and animals is presented.
The first asymmetric synthesis of alpha-amino acids based on diastereoselective carbon radical addition to glyoxylic imine derivatives is reported. The addition of an isopropyl radical, generated from i-PrI, Bu(3)SnH, and Et(3)B in CH(2)Cl(2) at 25 degrees C, to achiral glyoxylic oxime ether 1 proceeded regioselectively at the imino carbon atom of the oxime ether group to give an excellent yield of the C-isopropylated product 2. The competitive reaction using glyoxylic oxime ether 1 and aldoxime ether 4 showed that the reactivity of the glyoxylic oxime ether toward nucleophilic carbon radicals was enhanced by the presence of a neighboring electron-withdrawing substituent. Thus, the alkyl radical addition to glyoxylic oxime ether 1 proceeded smoothly even at -78 degrees C, in contrast to the unactivated aldoxime ether 4. A high degree of stereocontrol in the carbon radical addition to the glyoxylic oxime ether was achieved by using Oppolzer's camphorsultam as a chiral auxiliary. The stannyl radical-mediated reaction of the camphorsultam derivative 6 with an isopropyl radical at -78 degrees C afforded a 96:4 diastereomeric mixture, 7a, of the C-isopropylated product. The reductive removal of the benzyloxy group of the major diastereomer (R)-7a, by treatment with Mo(CO)(6) and the subsequent removal of the sultam auxiliary by standard hydrolysis, afforded the enantiomerically pure D-valine (R)-12 without any loss of stereochemical purity. To evaluate the new methodology, a variety of alkyl radicals were employed in the addition reaction which gave the alkylated products 7 with excellent diastereoselectivity, allowing access to a wide range of enantiomerically pure natural and unnatural alpha-amino acids. Even in the absence of Bu(3)SnH, treatment of 6 with alkyl iodide and Et(3)B at 20 degrees C gave the C-alkylated products 7 with moderate diastereoselectivities. The use of Et(2)Zn as a radical initiator, instead of Et(3)B, was also effective for the radical reaction. The enantioselective isopropyl radical addition to 1 using (R)-(+)-2, 2'-isopropylidenebis(4-phenyl-2-oxazoline) and MgBr(2) gave excellent chemical yield of the valine derivative 2 in 52% ee.
The efficient total synthesis of (−)-balanol, a potent inhibitor of the protein kinase C, is described. (−)-Balanol consists of a chiral hexahydroazepine-containing fragment and a benzophenone fragment, both of which were prepared via novel synthetic routes. The hexahydroazepine fragment was prepared in racemic form through either Bu3SnH- or SmI2-promoted radical cyclization of oxime ethers 2ab intramolecularly connected with the formyl group. SmI2-promoted radical cyclization of 2b was found to be particularly successful in the selective synthesis of the seven-membered trans-amino alcohol 8b. Preparation of the enantiomerically pure hexahydroazepine-containing fragment was achieved through the enantioselective enzymatic acetylation of racemic alcohol 9, employing the immobilized lipase from Pseudomonas sp. The benzophenone fragment was prepared in short steps through a biomimetic oxidative anthraquinone ring cleavage starting from commercially available natural chrysophanic acid 15c. This reaction proceeded via [4 + 2]-cycloaddition of singlet oxygen to anthracene derivative 17c, followed by Baeyer−Villiger-type rearrangement of the resulting hydroperoxide to afford the benzophenone derivatives 22 and 23.
A new synthetic method for the preparation of benzofurans has been developed. The key step of this method is the [3,3]‐sigmatropic rearrangement of N‐trifluoroacetyl‐ene‐hydroxylamines, which was triggered by acylation of oxime ethers. TFAA has been proved to be the best reagent to induce [3,3]‐sigmatropic rearrangement for the synthesis of cyclic oracyclic dihydrobenzofurans. On the other hand, the TFAT‐DMAP system is found to be the most effective for constructing various benzofurans. Synthetic utility of this reaction is demonstrated by the short synthesis of natural benzofurans without protection of the hydroxy group. The synthesis of Stemofuran A was accomplished via condensation of ketones with aryloxyamine and subsequent reaction with TFAT‐DMAP in a four‐step synthesis with 72 % overall yield. Similarly, Eupomatenoid 6 and Coumestan were synthesized through the reaction of oxime ether with TFAT‐DMAP. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)
Alkynyl oxime ether underwent a gold-catalyzed domino reaction involving cyclization and subsequent Claisen-type rearrangement to afford trisubstituted isoxazoles in a direct, efficient, and regioselective manner. The products were successfully applied to the synthesis of unusual heterocycles as an illustration of the potential utility of the reaction.
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