- Total synthesis of the large non-ribosomal peptide polytheonamide B
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Polytheonamide B is by far the largest non-ribosomal peptide known at present, and displays extraordinary cytotoxicity (EC50 =68 pg ml -1 , mouse leukaemia P388 cells). Its 48 amino-acid residues include a variety of non-proteinogenic d- and l-amino acids, and the absolute stereochemistry of these amino acids alternate in sequence. These structural features induce the formation of a stable β-strand-type structure, giving rise to an overall tubular structure over 30A? in length. In a biological setting, this fold is believed to transport cations across the lipid bilayer through a pore, thereby acting as an ion channel. Here, we report the first chemical construction of polytheonamide B. Our synthesis relies on the combination of four key stages: syntheses of non-proteinogenic amino acids, a solid-phase assembly of four fragments of polytheonamide B, silver-mediated connection of the fragments and, finally, global deprotection. The synthetic material now available will allow studies of the relationships between its conformational properties, channel functions and cytotoxicity.
- Inoue, Masayuki,Shinohara, Naoki,Tanabe, Shintaro,Takahashi, Tomoaki,Okura, Ken,Itoh, Hiroaki,Mizoguchi, Yuki,Iida, Maiko,Lee, Nayoung,Matsuoka, Shigeru
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supporting information; scheme or table
p. 280 - 285
(2010/09/03)
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- RESOLUTION AND USE IN α-AMINO ACID SYNTHESIS OF IMIDAZOLIDINONE GLYCINE DERIVATIVES
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The imidazolidinones (rac.-1 and rac.-2) obtained from pivalaldehyde and glycine amides are resolved efficiently by crystallization of diastereomeric ammonium salts with chiral acids (mandelates and a gulonate respectively).The free bases are acylated under Schotten-Baumann conditions to give enantiomerically pure 1-Bz-, 1-BOC-, 1-Z- or 1-formyl-2-t-butyl-3-methyl- or -3-benzyl-4-imidazolidinones.Diastereoselective alkylation of the 3-methyl derivatives (BMI) with a variety of electrophiles (LDA/THF -70 to +25 degC) gives trans-disubstituted imidazolidinones exclusively (3-22).Some of these are hydrolyzed by a procedure employing excess acidic ion exchange resin to give enantiomerically pure (R)- or (S)-amino acids.The procedure is compared with other methods of generating chiral glycine enolates.
- Fitzi, Robert,Seebach, Dieter
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p. 5277 - 5292
(2007/10/02)
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- Asymmetric Syntheses via Heterocyclic Intermediates, XVIII. - On the Enantioselective Synthesis of (2R)-Serine Methyl Esters or (2R)-Serines Starting with the Bis(lactim) Ether of cyclo-(-L-Val-Gly)
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The lithiated bis(lactim) ether 8a furnishes with aldehydes and ketones in good yields the addition products 11 with (3R) configuration.The asymmetric inductions at C-3 of 11 (d.e. values) amount to more than 95 percent with ketones, with aldehydes they are somewhat smaller.With unsymmetrical ketones or aldehydes C-3' also becomes a chiral center.For the (3R)-major diastereomers the "second induction" at C-3' varies from about 4 t about 87 percent (for benzaldehyde or isobutyraldehyde, respectively), preferably the (3R,3'S) epimers are formed. - Acid hydrolysis of 11 yields (besides methyl L-valinate) the (2R)-serine methyl esters 26.Their e.e. values correspond with the d.e. values of 11. - Dehydratation of 11 furnishes the "Hofmann olefins" 32 and/or the "Saytzeff olefins" 33 which can be transformed in various ways into optically active amino acids.
- Schoellkopf, Ulrich,Groth, Ulrich,Gull, Martin-Reinhold,Nozulak, Joachim
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p. 1133 - 1151
(2007/10/02)
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- ENANTIOSELECTIVE SYNTHESIS OF NON-PROTEINOGENIC AMINO ACIDS VIA METALLATED BIS-LACTIM ETHERS OF 2,5-DIKETOPIPERAZINES
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Bis-lactim ethers 1 of 2,5-diketopiperazines contain a chiral inducing center, an acidic CH-bond and two sites susceptible to hydrolysis.They react with BuLi to give Li compounds of type 4, 15, 29 or 32, which possess a prochiral C atom.They readily add electrophiles (such as alkylating agents or carbonyl compounds) with unusually high diastereoface differentiation.In many cases the d.e-value (d.e. = diastereomeric excess = asymmetric induction) of the adduct exceeds 95percent.On hydrolysis the adducts are cleaved liberating the chiral auxiliary (used to build up the bis-lactim ether 1) and the target molecules, the optically active amino acid methyl esters of type 8, 19, 25 or 36.The two amino acid esters are separable either by fractional distillation or (eventually after further hydrolysis to amino acids) by chromatography.Transition state models are discussed that could explain the exceptionally high asymmetric induction and the predictability of the induced configuration.
- Schoellkopf, Ulrich
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p. 2085 - 2092
(2007/10/02)
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