- Efficient and Divergent Total Synthesis of (-)-Epicoccin G and (-)-Rostratin A Enabled by Double C(sp3)-H Activation
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Dithiodiketopiperazines are complex polycyclic natural products possessing a variety of interesting biological activities. Despite their interest, relatively few total syntheses have been completed. We herein report the enantioselective, scalable, and divergent total synthesis of two symmetrical pentacyclic dithiodiketopiperazines, (-)-epicoccin G and (-)-rostratin A. A common intermediate was synthesized on a multigram scale from inexpensive, commercially available starting materials using an enantioselective organocatalytic epoxidation and a double C(sp3)-H activation as key steps, with the latter allowing the efficient simultaneous construction of the two five-membered rings. In addition to the cis,cis-fused target (-)-epiccocin G, the more challenging (-)-rostratin A, possessing two trans ring junctions, was obtained for the first time on a 500 mg scale through the optimization of each step and validation on multigram quantities. Both natural products were synthesized with high overall yields (13-20%). This study should facilitate access to this fascinating and yet understudied family of biologically active natural products.
- Thesmar, Pierre,Baudoin, Olivier
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- Stereoretentive N-Arylation of Amino Acid Esters with Cyclohexanones Utilizing a Continuous-Flow System
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The N-arylation of chiral amino acid esters with minimal racemization is a challenging transformation because of the sensitivity of the α-stereocenter. A versatile synthetic method was developed to prepare N-arylated amino acid esters using cyclohexanones as aryl sources under continuous-flow conditions. The designed flow system, which consists of a coil reactor and a packed-bed reactor containing a Pd(OH)2/C catalyst, efficiently afforded the desired N-arylated amino acids without significant racemization, accompanied by only small amounts of easily removable co-products (i. e., H2O and alkanes). The efficiency and robustness of this method allowed for the continuous synthesis of the desired product in very high yield and enantiopurity with high space-time yield (74.1 g L?1 h?1) and turnover frequency (5.9 h?1) for at least 3 days.
- Ichitsuka, Tomohiro,Komatsuzaki, Shingo,Masuda, Koichiro,Koumura, Nagatoshi,Sato, Kazuhiko,Kobayashi, Shū
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supporting information
p. 10844 - 10848
(2021/05/31)
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- Overcoming the Deallylation Problem: Palladium(II)-Catalyzed Chemo-, Regio-, and Stereoselective Allylic Oxidation of Aryl Allyl Ether, Amine, and Amino Acids
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We report herein a Pd(II)/bis-sulfoxide-catalyzed intramolecular allylic C-H acetoxylation of aryl allyl ether, amine, and amino acids with the retention of a labile allyl moiety. Mechanistically, the reaction proceeds through a distinct double-bond isomerization from the allylic to the vinylic position followed by intramolecular carboxypalladation and the β-hydride elimination pathway. For the first time, C-H oxidation of N-allyl-protected amino acids to furnish five-membered heterocycles through 1,3-syn-addition is established with excellent diastereoselectivity.
- Begam, Hasina Mamataj,Jana, Ranjan,Manna, Kartic,Samanta, Krishanu
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supporting information
p. 7443 - 7449
(2020/10/09)
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- Asymmetric Synthesis of α-Amino Acids by Organocatalytic Biomimetic Transamination
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A biomimetic enantioselective transamination of α-keto ester derivatives can be realized under mild conditions by using chiral quaternary ammonium arenecarboxylates in the absence of base additives. The corresponding α-amino acids can be used as versatile intermediates for further synthetic transformations that furnish chiral pyrrolidine and octahydroindolizine derivatives.
- Kang, Qi-Kai,Selvakumar, Sermadurai,Maruoka, Keiji
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supporting information
p. 2294 - 2297
(2019/04/10)
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- Challenges in the Development of a Thiol-Based Broad-Spectrum Inhibitor for Metallo-β-Lactamases
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Pathogens, expressing metallo-β-lactamases (MBLs), become resistant against most β-lactam antibiotics. Besides the dragging search for new antibiotics, development of MBL inhibitors would be an alternative weapon against resistant bacterial pathogens. Inhibition of resistance enzymes could restore the antibacterial activity of β-lactams. Various approaches to MBL inhibitors are described; among others, the promising motif of a zinc coordinating thiol moiety is very popular. Nevertheless, since the first report of a thiol-based MBL inhibitor (thiomandelic acid) in 2001, no steps in development of thiol based MBL inhibitors were reported that go beyond clinical isolate testing. In this study, we report on the synthesis and biochemical characterization of thiol-based MBL inhibitors and highlight the challenges behind the development of thiol-based compounds, which exhibit good in vitro activity toward a broad spectrum of MBLs, selectivity against human off-targets, and reasonable activity against clinical isolates.
- Büttner, Dominik,Kramer, Jan S.,Klingler, Franca-M.,Wittmann, Sandra K.,Hartmann, Markus R.,Kurz, Christian G.,Kohnh?user, Daniel,Weizel, Lilia,Brüggerhoff, Astrid,Frank, Denia,Steinhilber, Dieter,Wichelhaus, Thomas A.,Pogoryelov, Denys,Proschak, Ewgenij
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p. 360 - 372
(2017/12/18)
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- Synthesis of Dipeptides by Boronic Acid Catalysis
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We have found that a boronic acid catalyzed amidation of an N -hydroxy amino acid methyl ester with amino acid tert -butyl esters gave N -hydroxy dipeptide derivatives in good yields without any racemization. The protecting groups on the nitrogen atom could be easily removed by heterogeneous hydrogenation conditions.
- Tsuji, Hiroaki,Yamamoto, Hisashi
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supporting information
p. 318 - 321
(2017/12/06)
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- Recoverable Dendritic Phase-Transfer Catalysts that Contain (+)-Cinchonine-Derived Ammonium Salts
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Four new phosphorus dendrimeric phase-transfer catalysts are prepared that contain 12 (+)-cinchoninium salts on the surface obtained by the quaternisation of the quinuclidinic N atom. The asymmetric alkylation of a glycinate Schiff base with benzyl bromide is used as a benchmark reaction, and the dendrimeric catalyst that contains an allyl group on the O-9 hydroxy group of the cinchonine units is the most active. The recovery and reuse of the catalyst are possible for five consecutive runs without loss of activity and with only a slight decrease in enantioselectivity. If other electrophiles are used, substituted benzyl bromides give better results than other activated alkyl bromides to afford the corresponding R amino acid derivatives. A comparison of these results with those reported previously for similar cinchoninium salts shows that dendrimers could be a better support than other polymers for this type of organocatalysis.
- Rull, Jordi,Jara, José Juan,Sebastián, Rosa M.,Vallribera, Adelina,Nájera, Carmen,Majoral, Jean-Pierre,Caminade, Anne-Marie
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p. 2049 - 2056
(2016/07/07)
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- Rational design of an orthosteric regulator of hIAPP aggregation
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Developing compounds regulating amyloid toxic oligomer but not fibril formation should constitute an effective strategy for the treatment of diabetes. Based on the full understanding of the folding mechanism, we designed an orthosteric helix regulator that can promote hIAPP to assemble into large non-cytotoxic oligomers. As a result, the islet cells were protected. This journal is
- Zhao, De-Sheng,Chen, Yong-Xiang,Li, Yan-Mei
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supporting information
p. 2095 - 2098
(2015/02/05)
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- Peptide fragment coupling using a continuous-flow photochemical rearrangement of nitrones
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Go with the flow: A general approach for amide bond formation by way of a continuous-flow photochemical rearrangement of nitrones was described (see scheme). Simple aryl-alkyl amide bonds as well as complex peptide bonds were constructed efficiently with a residence time less than 20minutes. A tetrapeptide was synthesized in this way and the method could be applied to peptide fragment coupling. Copyright
- Zhang, Yuan,Blackman, Melissa L.,Leduc, Andrew B.,Jamison, Timothy F.
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supporting information
p. 4251 - 4255
(2013/05/08)
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- Asymmetric α-2-tosylethenylation of N,N-dialkyl-l-amino acid esters via the formation of non-racemic ammonium enolates
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Asymmetric α-2-tosylethenylation of (S)-2-(pyrrolidin-1-yl)propanoic acid esters was shown to produce good yields with high enantioselectivities. The reaction proceeds via the formation of a non-racemic ammonium enolate without an external source of chirality.
- Tayama, Eiji,Igarashi, Tomohito,Iwamoto, Hajime,Hasegawa, Eietsu
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supporting information; experimental part
p. 339 - 345
(2012/01/19)
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- Pyrrolinone-pyrrolidine oligomers as universal peptidomimetics
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Peptidomimetics 1-3 were prepared from amino acid-derived tetramic acids 7 as the key starting materials. Calculations show that preferred conformations of 1 can align their side-chain vectors with amino acids in common secondary structures more effectively than conformations of 3. A good fit was found for a preferred conformation of 2 (an extended derivative of 1) with a sheet/β-turn/sheet motif.
- Raghuraman, Arjun,Ko, Eunhwa,Perez, Lisa M.,Ioerger, Thomas R.,Burgess, Kevin
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supporting information; experimental part
p. 12350 - 12353
(2011/10/02)
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- (9H-fluoren-9-yl)methanesuIfonyl (Fms): An amino protecting group complementary to Fmoc
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A sulfonamide-based protecting group (PG), (9H-fluoren-9yl)methanesulfonyl (Fms), which can be used in a similar way to the well-established Fmoc PG, was developed. The advantages of this new PG were demonstrated in the successful formation of a phosphonamide between an N-Fmsprotected a-phosphonoalanine monoester and secondary alkylamines, including (R)-2-phenylethylamine, (S)-phenylalanine iert-butyl ester (H-Phe-OtBu), H-Pro-Gly-OtBu, and H-Phe-Phe-OtBu, without formation of oxazaphospholine, which is a serious problem associated with the Fmoc PG. The success should pave the way to the solid-phase synthesis of unnatural peptides substituted with a-amino phosphonic acid (AP) at essentially any arbitrary position without significant modification of the Fmoc-based chemistry that has been accumulated since Carpino's report in 1970. The N-Fms-AP monomer would attract much attention in the field of peptide mimetics.
- Ishibashi, Yoshitaka,Miyata, Kengo,Kitamura, Masato
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experimental part
p. 4201 - 4204
(2010/10/02)
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- Addition of allylzinc to a-amino acid-derived imines: Synthesis of diamino alcohols by Hydroboration
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Imines obtained by condensation of Z-pro- tected or Boc-protected α-amino aldehydes with α-amino tert-butyl esters or with O-silyl-protected amino alcohols were reacted with preformed allyl zinc yielding homoal- lylamines with yields around 50% and selectivities ranging from 50:50 to 90:10. Hydroboration of the terminal double bond furnished diamino alcohols with yields up to 97%. The configuration of the substrates was determined by X-ray-crystallographic analysis of a hydroboration product and comparison of physical data. Springer-Verlag 2010.
- Virlouvet, Mickael,Goesmann, Helmut,Feldmann, Claus,Podlech, Joachim
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experimental part
p. 177 - 198
(2010/08/05)
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- 9-(4-Bromophenyl)-9-fluorenyl as a safety-catch nitro gen protecting group
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The 9-(4-bromophenyl)-9-fluorenyl (BrPhF) group has been developed as a novel safety-catch amine protection. This relatively acid-stable protecting group can be successfully activated by palladium-catalyzed cross-coupling reaction of the aryl bromide with morpholine and then cleaved effectively under mild conditions using dichloroacetic acid and triethylsilane. Complementary conditions are reported for selective removal of the BrPhF group in the presence of tert-butyl esters and carbamates as well as deprotection of tert-butyl esters and carbamates in the presence of BrPhF amines.
- Surprenant, Simon,Lubell, William D.
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p. 848 - 851
(2007/10/03)
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- Methods and compositions for treating amyloid-related diseases
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Methods, compounds, pharmaceutical compositions and kits are described for treating or preventing amyloid-related disease.
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Page/Page column 137
(2010/11/24)
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- A cyclic hexapeptide comprising alternating α-aminoxy and α-amino acids is a selective chloride ion receptor
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In nonpolar solvents, the cyclic hexapeptide 2, which comprises alternating D-α-amino and D-α-aminoxy acids, adopts a C3-symmetric conformation with alternating eight (N-O turns)- and seven (γ turns)-membered-ring hydrogen bonds. A series of anion-binding studies has suggested that 2 can function as an effective anion receptor that not only displays a high selectivity for chloride ions, but also the capability to extract chloride ions from aqueous solutions into organic phases.
- Yang, Dan,Li, Xiang,Sha, Yao,Wu, Yun-Dong
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p. 3005 - 3009
(2007/10/03)
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- Derivatized Amino Acids Relevant to Native Peptide Synthesis by Chemical Ligation and Acyl Transfer
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Three amino acids were converted into the derivatives 5.2 (from glycine), 6.4a and 6.4b (from alanine), and 8.3a and 8.3b (from O-benzyl serine). These N-alkylated amino acids, which can be deprotected after conversion of the carboxyl into an amide, correspond to the general structure 2.1, a compound class of use in the study of peptide segment coupling by the ligation-acyl transfer method.
- Clive, Derrick L. J.,Hisaindee, Soleiman,Coltart, Don M.
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p. 9247 - 9254
(2007/10/03)
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- Studies on the enantioselective synthesis of α-amino acids via asymmetric phase-transfer catalysis
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In this paper, we describe investigations into the use of cinchona alkaloid-derived quaternary ammonium phase-transfer catalysts for the asymmetric alkylation of a benzophenone-derived glycine-imine. Utility of this process is demonstrated by the enantioselective synthesis of a range of α-amino acid esters.
- Lygo,Crosby,Lowdon,Peterson,Wainwright
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p. 2403 - 2409
(2007/10/03)
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- Comparative conformational analysis of peptides based on the two Ca-tetrasubstituted, Cβ-branched, chiral α-amino acids (αMe) Dip and (αMe)Val
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For the first time a number of terminally protected model peptides (to the pentamer level) of the sterically demanding α-amino acid Cα-methyl, Cα-diphenylmethylglycine, (αMe)Dip, in combination with either Ala or Gly residues, have been synthesized (by solution methods) and fully characterized. In a parallel synthesis the corresponding peptides based on the related α-amino acid Cα-methyl, Cα-isopropylglycine, (αMe)Val, have also been prepared. The results of a comparative conformational analysis, performed by using FTIR absorption, 1H NMR, and X-ray diffraction techniques, favour the conclusion that, in contrast to the potent β-turn and 310-helix promoter (αMe)Val, (αMe)Dip may induce either a folded or a fully extended conformation. These findings indicate that, despite the common Cα-methylated and Cβ-branched features, (αMe)Dip and (αMe)Val are characterized by partially divergent conformational bias.
- Lapena, Yolanda,Lopez, Pilar,Cativiela, Carlos,Kaptein, Bernard,Broxterman, Quirinus B.,Kamphuis, Johan,Mossel, Eric,Peggion, Cristina,Formaggio, Fernando,Crisma, Marco,Toniolo, Claudio
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p. 631 - 636
(2007/10/03)
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- A new class of asymmetric phase-transfer catalysts derived from Cinchona alkaloids - Application in the enantioselective synthesis of α-amino acids
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A new class of Cinchona alkaloid-derived quaternary ammonium phase-transfer catalysts bearing a N-anthracenylmethyl function are presented. These catalysts show high stereocontrol in the asymmetric alkylation of a benzophenone-derived glycine-imine, and application of this process to the enantioselective synthesis of a range of α-amino acid esters (e.e. 67-94%) is investigated.
- Lygo, Barry,Wainwright, Philip G.
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p. 8595 - 8598
(2007/10/03)
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- Enantioselective synthesis of α-amino acids from glycine t-butyl ester
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Enantioselective syntheses of optically active α-amino acids from glycine t-butyl ester through Schiff base employing (+)-N-alkyl-10-camphorsulfonamides as chiral auxiliaries were described. Methylation of Schiff base 5 gave high asymmetric inductions, whereas ethylation, allylation and benzylation gave fair asymmetric inductions. The stereochemistry of the major alkylation product was S configuration at the newly formed stereogenic center with the exception of the benzylation reaction in which the R configuration was generated.
- Yeh, Tsai-Lung,Liao, Chun-Chen,Uang, Biing-Jiun
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p. 11141 - 11152
(2007/10/03)
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- Synthesis of a Wasp Venom Tetradecapeptide, Mastoparan, with a New Cleaving System for 4-Methoxy-2,2,6-trimethylbenzenesulfonyl (Mtr) Amino-Protecting Group
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The 4-methoxy-2,3,6-trimethylbenzenesulfonyl (Mtr) group was introduced for protection of the ε-amino function of lysine and its acid lability was examined.The cleavage of Lys(Mtr) was accelerated by addition of methyl sulfide, as a second scavenger, to methanesulfonic acid-containing trifluoroacetic acid-thioanisole.In order to examine the usefulness of the new cleaving system with methyl sulfide, a wasp venom peptide, mastoparan, was synthesized.This system was found to give a highly pure product in good yield.Keywords - 4-methoxy-2,3,6-trimethylbenzenesulfonyl (Mtr); Nε-4-methoxy-2,3,6-trimethylbenzenesulfonyllysine; methanesulfonic acid-trifluoracetic acid-thioanisole-methyl sulfide deprotection; mastoparan; wasp venom peptide
- Saito, Kazuki,Higashijima, Tsutomu,Miyazawa, Tatsuo,Wakimasu, Mitsuhiro,Fujino, Masahiko
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p. 2187 - 2193
(2007/10/02)
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- Protection of functional groups during reaction and their subsequent restoration
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In the process for preparing an organic compound of the formula in which X is an amino group, a hydroxyl group or a carboxyl group, and A' is the remainder of the molecule, from an organic compound of the formula in which A is the remainder of the molecule which can undergo reaction to form A', by converting A -- X into a compound of the formula in which Z is --NH--, --O-- or a direct C--C bond, and R is a radical of the formula STR1 IN WHICH Y is a direct C--C single bond, the --CH=CH-- group or an arylene group, R1 to R4 each independently is hydrogen, halogen or an alkyl, aryl, aralkyl, alkoxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl or cycloalkylaminocarbonyl radical, or R1 + r2 and R3 + R4 each independently completes a 5- or 6-membered carbocyclic ring, or R1 and R3 conjointly with the grouping --C--Y--C-- forms a carbocyclic ring with 5 or 6 carbon atoms, and Hal is halogen, Thereby to protect X, then converting A -- Z -- COOR into a compound of the formula and then treating the compound A' -- Z -- COOR to restore the group X, the improvement which comprises effecting the treatment of the compound A' -- Z -- COOR with an alkali metal compound of a complex of monovalent cobalt. The process is applicable particularly to aminocarboxylic acids including intermediates from various stages of the synthesis of penicillins and cephalosporins.
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