- Catalytic amidation of unactivated ester derivatives mediated by trifluoroethanol
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A catalytic amidation method has been developed, employing 2,2,2-trifluoroethanol to facilitate condensation of unactivated esters and amines, enabling the synthesis of a range of amide products in good to excellent yields. Mechanistic studies indicate the reaction proceeds through a trifluoroethanol-derived active ester intermediate.
- Caldwell, Nicola,Jamieson, Craig,Simpson, Iain,Watson, Allan J. B.
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Read Online
- Synthesis of amides and esters containing furan rings under microwave-assisted conditions
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In this work, we present a novel method for the synthesis of ester and amide derivatives containing furan rings (furfural derivatives) under mild synthetic conditions supported by microwave radiation. N-(Furan-2-ylmethyl)furan-2-carboxamide and furan-2-ylmethyl furan-2-carboxylate were produced using 2-furoic acid, furfurylamine, and furfuryl alcohol. The reactions were carried out in a microwave reactor in the presence of effective coupling reagents: DMT/NMM/TsO? or EDC. The reaction time, the solvent, and the amounts of the substrates were optimized. After crystallization or flash chromatography, the final compounds were isolated with good or very good yields. Our method allows for the synthesis of N-blocked amides using N-blocked amino acids (Boc, Cbz, Fmoc) and amine. As well as compounds with a monoamide and ester moiety, products with diamides and diester bonds (N,N-bis(furan-2-ylmethyl) furan-2,5-dicarboxamide, bis(furan-2-ylmethyl) furan-2,5dicarboxylate, and furan-3,4-diylbis(methylene) bis(furan-2-carboxylate)) were synthesized with moderate yields in the presence of DMT/NMM/TsO– or EDC, using 2,5-furan-dicarboxylic acid and 3,4-bis(hydroxymethyl)furan as substrates.
- Janczewski, ?ukasz,Zieliński, Dariusz,Kolesińska, Beata
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p. 265 - 280
(2021/03/17)
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- Cytotoxic activity of synthetic chiral amino acid derivatives
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Cancer is a chronic degenerative disease considered one of the most important causes of death worldwide. In this context, a series of dual-protected amino acid derivatives was synthesized and evaluated as potential novel anticancer agents. The 40 derivatives were prepared in up to three reaction steps. The cytotoxic activities were screened in vitro against a panel of tumor and non-tumor cells using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Among the synthesized derivatives, three of them showed promising activity against cancer cells with half-maximal inhibitory concentration (IC50) ranging between 1.7-6.1 μM. The most promising derivative, bearing both a lipophilic N-alkyl diamine moiety and a protected amino acid scaffold showed a selectivity index of 3.4 towards tumor cells. The N-alkyl diamine moiety seems to play a crucial role in the enhancement of the anticancer activity. On the other hand, the incorporation of an amino acid scaffold resulted in increase in the selectivity towards cancer cell lines.
- de Castro, Pedro P.,Siqueira, Raoni P.,Conforte, Luiza,Franco, Chris H.J.,Bressan, Gustavo C.,Amarante, Giovanni W.
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p. 193 - 200
(2019/12/28)
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- Graphene oxide: A convenient metal-free carbocatalyst for facilitating amidation of esters with amines
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Herein, we report a graphene oxide (GO) catalyzed condensation of non-activated esters and amines, that can enable diverse amides to be synthesized from abundant ethyl esters forming only volatile alcohol as a by-product. GO accelerates ester to amide conversion in the absence of any additives, unlike other catalysts. A wide range of ester and amine substrates are screened to yield the respective amides in good to excellent yields. The improved catalytic activity can be ascribed to the oxygenated functionalities present on the graphene oxide surface which forms H-bonding with the reactants accelerating the reaction. Improved yields and a wide range of functional group tolerance are some of the important features of the developed protocol.
- Patel, Khushbu P.,Gayakwad, Eknath M.,Shankarling, Ganapati S.
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p. 2661 - 2668
(2020/02/20)
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- Catalytic dehydrative peptide synthesis with gem-diboronic acids
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Alkane-gem-diboronic acids have emerged as versatile organoboron catalysts for dehydrative amidation of α-Amino acids. A phenol-substituted multiboron catalyst with a B-C-B structure outperformed simple arylboronic acids in the condensation of α-Amino acids with suppressed epimerization of electrophiles. gem-diboronic acid catalysis were compatible with various O, N, and S-functionalized α-Amino acids bearing N-protecting groups including common carbamates used in peptide synthesis (Boc, Cbz, Fmoc). N-Trifluoroacetyl protection enabled an unprecedented catalytic dehydrative peptide synthesis at room temperature. Preliminary mechanistic studies revealed carboxylate-binding nature of gem-diboronic acids, orthogonal to the activation of carboxylic acids by arylboronic acids. The distinctive reactivity of the gem-diboronic acids would open prospects for mild catalytic peptide condensation.
- Michigami, Kenichi,Sakaguchi, Tatsuhiko,Takemoto, Yoshiji
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p. 683 - 688
(2020/01/02)
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- Water-Tolerant and Atom Economical Amide Bond Formation by Metal-Substituted Polyoxometalate Catalysts
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A simple, safe, and inexpensive amide bond formation directly from nonactivated carboxylic acids and free amines is presented in this work. Readily available Zr(IV)- and Hf(IV)-substituted polyoxometalates (POM) are shown to be catalysts for the amide bond formation reaction under mild conditions, low catalyst loading, and without the use of water scavengers, dry solvents, additives for facilitating the amine attack, or specialized experimental setups commonly employed to remove water. Detailed mechanistic investigations revealed the key role of POM scaffolds which act as inorganic ligands to protect Zr(IV) and Hf(IV) Lewis acidic metals against hydrolysis and preserve their catalytic activity in amide bond formation reactions. The catalysts are compatible with a range of functional groups and heterocycles useful for medicinal, agrochemical, and material chemists. The robustness of the Lewis acid-POM complexes is further supported by the catalyst reuse without loss of activity. This prolific combination of Zr(IV)/Hf(IV) and POMs inaugurates a powerful class of catalysts for the amide bond formation, which overcomes key limitations of previously established Zr(IV)/Hf(IV) salts and boron-based catalysts.
- De Azambuja, Francisco,Parac-Vogt, Tatjana N.
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p. 10245 - 10252
(2019/11/03)
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- Dual-protected amino acid derivatives as new antitubercular agents
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Tuberculosis is an infectious disease with high incidence and growing drug-resistant rates. In an attempt to develop new antitubercular agents, 35 compounds were synthesized, most of them bearing a carbamate and enantiopure amino acid moiety. These compounds had their activity evaluated toward a Mycobacterium tuberculosis strain (ATCC 27294) and cytotoxicity against fibroblast MRC-5 cells (ATCC CCL-171). Three of the prepared derivatives presented a good antimicrobial inhibition and two of them a moderate cytotoxicity. The lipophilicity seems to play a vital role in the cell growth activity, with best results for the derivatives with a higher logP.
- de Castro, Pedro P.,Campos, Débora L.,Pavan, Fernando R.,Amarante, Giovanni W.
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p. 1576 - 1580
(2018/06/06)
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- Enantioseparation of Sulfoxides and Nitriles by Inclusion Crystallization with Chiral Organic Salts Based on l-Phenylalanine
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Enantioselective inclusion of aromatic sulfoxides and nitriles was achieved in a host framework created by organic salts comprising achiral benzoic acids and a chiral primary amine (1a) derived from l-phenylalanine. Tuning of the combined achiral acid component successfully changed the chiral recognition ability of the organic salts. The guest molecules were hydrogen-bonded to form three-component inclusion crystals, and the enantiomers of nitriles and sulfoxides were separated with high selectivity up to 92 and 98 % ee. As far as we know, this is the first example of the enantioseparation of non-functionalized aromatic nitriles.
- Kodama, Koichi,Kanai, Hayato,Shimomura, Yuki,Hirose, Takuji
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supporting information
p. 1726 - 1729
(2018/04/24)
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- Study on anti-proliferative activity in cancer cells and preliminary structure–activity relationship of pseudo-peptide chiral thioureas
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In our previous studies, we have shown that thiourea compounds containing phosphate esters have potent antitumor activity and can be used as a novel strategy for the development of antitumor agents. Herein, a series of novel phosphonate thioureas 5–38 have been synthesized, which were fully characterized by 1H NMR,13C NMR spectrum, elemental analysis. Three human cancer cell lines (Bcap-37, BGC-823, and PC-3) have been used to investigate these compounds’ antitumor activities. After the summarization of the structure–activity relationships, we found that the variation of R, R1, and R2 in these novel phosphonate thioureas contribute to the antitumor activities. All these SAR-guided efforts may lead to novel antitumor drugs in the market in the near future.
- Liao, Peng,Hu, Shi-Qin,Zhang, Hong,Xu, Liang-Bi,Liu, Jing-Zi,He, Bin,Liao, Shang-Gao,Li, Yong-Jun
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p. 300 - 304
(2018/02/15)
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- Facile direct synthesis of amides from trichloroethyl esters using catalytic DBU
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A practical method for the direct synthesis of amide compounds is described. Using small quantities of DBU as a catalyst, the direct conversion of 2,2,2-trichloroethyl esters to their corresponding amides was readily achieved. Based on this protocol, various amide compounds were successfully synthesized in high yield, suggesting a promising approach for the practical one-pot aminolysis from 2,2,2-trichloroethyl protected esters.
- La, Minh Thanh,Kim, Hee-Kwon
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p. 1135 - 1141
(2018/11/25)
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- Protecting-Group-Free Amidation of Amino Acids using Lewis Acid Catalysts
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Amidation of unprotected amino acids has been investigated using a variety of ‘classical“ coupling reagents, stoichiometric or catalytic group(IV) metal salts, and boron Lewis acids. The scope of the reaction was explored through the attempted synthesis of amides derived from twenty natural, and several unnatural, amino acids, as well as a wide selection of primary and secondary amines. The study also examines the synthesis of medicinally relevant compounds, and the scalability of this direct amidation approach. Finally, we provide insight into the chemoselectivity observed in these reactions.
- Sabatini, Marco T.,Karaluka, Valerija,Lanigan, Rachel M.,Boulton, Lee T.,Badland, Matthew,Sheppard, Tom D.
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supporting information
p. 7033 - 7043
(2018/05/04)
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- Amidation of unactivated ester derivatives mediated by trifluoroethanol
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A catalytic amidation protocol mediated by 2,2,2-trifluoroethanol has been developed, facilitating the condensation of unactivated esters and amines, furnishing both secondary and tertiary amides. The complete scope and limitations of the method are described, along with modified conditions for challenging substrates such as acyclic secondary amines and chiral esters with retention of chiral integrity.
- McPherson, Christopher G.,Caldwell, Nicola,Jamieson, Craig,Simpson, Iain,Watson, Allan J. B.
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p. 3507 - 3518
(2017/04/26)
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- [...] - Orn (ClCH2NH) - AA - benzylamine, its synthesis, activity and application (by machine translation)
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The invention discloses the following formula of 13 for β - Carboline -3 - formyl - Orn (ClCH2 NH) - AA - NHCH2 C6 H5 (In the formula AA is selected from L - Arg, L - Asn, L - Asp, L - Glu, L - Gly, L - Ile, L - Leu, L - Met, L - Phe, L - Pro, L - Thr, L - Trp, L - Val residue), discloses a process for their preparation, discloses their inhibition of tumor cell growth, therefore this invention discloses their use as anti-tumor medicament. (by machine translation)
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Paragraph 0041; 0120; 0121
(2017/08/27)
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- l-tert-Leucine-Derived AmidPhos-Silver(I) Chiral Complexes for the Asymmetric [3+2] Cycloaddition of Azomethine Ylides
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The l-tert-leucine-derived AmidPhos/silver(I) catalytic system has been developed for the asymmetric [3+2] cycloaddition of azomethine ylides with electronic-deficient alkenes with or without Et3N. Under optimal conditions, highly functionalized endo-4-pyrrolidines were obtained with modest to high yields (up to 99% yield) and enantioselectivities (up to 98% ee).
- Zhou, Zhipeng,Zheng, Xiaojun,Liu, Jialin,Li, Jinlei,Wen, Pushan,Wang, Haifei
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supporting information
p. 999 - 1003
(2017/05/05)
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- Zirconium-catalyzed direct amide bond formation between carboxylic esters and amines
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Development of catalytic amide bond formation reactions from readily available starting materials remains a challenging task for modern organic chemistry. Herein, we report that unactivated carboxylic esters and amines react in the presence of 10 mol % of zirconocene dichloride (Cp2ZrCl2) in toluene at 110 °C to afford amides in very good to excellent conversions. The Zr-catalyzed reaction is amenable for the amidation of aliphatic and aromatic carboxylic esters with primary and secondary amines. The reaction proceeds with almost complete retention of configuration for chiral esters and chiral amines.
- Lenstra, Danny C.,Nguyen, D. Thao,Mecinovi?, Jasmin
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p. 5547 - 5553
(2015/08/03)
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- Catalytic chemical amide synthesis at room temperature: One more step toward peptide synthesis
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An efficient method has been developed for direct amide bond synthesis between carboxylic acids and amines via (2-(thiophen-2-ylmethyl)phenyl)boronic acid as a highly active bench-stable catalyst. This catalyst was found to be very effective at room temperature for a large range of substrates with slightly higher temperatures required for challenging ones. This methodology can be applied to aliphatic, α-hydroxyl, aromatic, and heteroaromatic acids as well as primary, secondary, heterocyclic, and even functionalized amines. Notably, N-Boc-protected amino acids were successfully coupled in good yields with very little racemization. An example of catalytic dipeptide synthesis is reported.
- Mohy El Dine, Tharwat,Erb, William,Berhault, Yohann,Rouden, Jacques,Blanchet, Jér?me
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p. 4532 - 4544
(2015/05/13)
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- A lactate-derived chiral aldehyde for determining the enantiopurity of enantioenriched primary amines
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In this paper we describe the use of a chiral aldehyde derived from lactate esters for determining the enantiopurity of primary amines, via the formation of diastereomeric imines. The method was shown to be suitable for reproducibly determining the enantiopurity of a diverse set of chiral amines. Both enantiomers of the aldehyde can be prepared in two steps from commercially available materials.
- Gibson, Samantha M.,Lanigan, Rachel M.,Benhamou, Laure,Aliev, Abil E.,Sheppard, Tom D.
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p. 9050 - 9054
(2015/09/01)
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- Lanthanum(III) triflate catalyzed direct amidation of esters
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Lanthanum trifluoromethanesulfonate is an effective single-component catalyst for synthesizing a variety of amides directly from esters and amines under mild conditions. Highly selective amidation of esters and amines, as well as catalyst-controlled amidation of esters, demonstrated the effectiveness of the catalyst system.
- Morimoto, Hiroyuki,Fujiwara, Risa,Shimizu, Yuhei,Morisaki, Kazuhiro,Ohshima, Takashi
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supporting information
p. 2018 - 2021
(2014/05/06)
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- Direct synthesis of amides from carboxylic acids and amines using B(OCH2CF3)3
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B(OCH2CF3)3, prepared from readily available B2O3 and 2,2,2-trifluoroethanol, is as an effective reagent for the direct amidation of a variety of carboxylic acids with a broad range of amines. In most cases, the amide products can be purified by a simple filtration procedure using commercially available resins, with no need for aqueous workup or chromatography. The amidation of N-protected amino acids with both primary and secondary amines proceeds effectively, with very low levels of racemization. B(OCH2CF3)3 can also be used for the formylation of a range of amines in good to excellent yield, via transamidation of dimethylformamide.
- Lanigan, Rachel M.,Starkov, Pavel,Sheppard, Tom D.
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p. 4512 - 4523
(2013/06/05)
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- Se -(9-fluorenylmethyl) selenoesters; Preparation, reactivity, and use as convenient synthons for selenoacids
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Se-(9-Fluorenylmethyl) selenoesters are readily prepared, stable precursors to selenocarboxylates, which they liberate on treatment with DBU. Fm selenoesters are compatible with the use of TFA for the removal of Boc groups and with simple peptide bond for
- Fecourt, Fabien,Delpech, Bernard,Melnyk, Oleg,Crich, David
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supporting information
p. 3758 - 3761
(2013/08/23)
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- Direct amidation of amino acid derivatives catalyzed by arylboronic acids: Applications in dipeptide synthesis
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The direct amidation of amino acid derivatives catalyzed by arylboronic acids has been examined. The reaction was generally slow relative to simple amine-carboxylic acid combinations though proceeded at 65-68 °C generally avoiding racemization. 3,4,5-Trifluorophenylboronic and o-nitrophenylboronic acids were found to be the best catalysts, though for slower dipeptide formations, high catalyst loadings were required and an interesting synergistic catalytic effect between two arylboronic acids was discovered. Arylboronic acids can be used to catalyze the direct amide formation of protected amino acid derivatives. For less reactive amino acids, cooperative catalysis can be used involving two arylboronic acids, one electron-rich and one electron-deficient, at high catalyst loadings to give good conversions at moderate temperatures. Copyright
- Liu, Shouxin,Yang, Yihua,Liu, Xinwei,Ferdousi, Farhana K.,Batsanov, Andrei S.,Whiting, Andrew
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p. 5692 - 5700
(2013/09/12)
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- Sodium methoxide: A simple but highly efficient catalyst for the direct amidation of esters
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A simple NaOMe catalyst provides superior accessibility to a wide variety of functionalized amides including peptides through direct amination of esters in an atom-economical and environmentally benign way.
- Ohshima, Takashi,Hayashi, Yukiko,Agura, Kazushi,Fujii, Yuka,Yoshiyama, Asako,Mashima, Kazushi
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supporting information; scheme or table
p. 5434 - 5436
(2012/07/03)
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- L -amino acid amides via dynamic kinetic resolution
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Racemic natural and non-natural N-Boc-amino acid thioesters undergo enzyme-catalyzed ammoniolysis and aminolysis with concomitant base-catalyzed racemization of the non-transformed D-enantiomer with the formation of the corresponding L-amides in good yields and excellent enantiomeric purity all above 98% ee. This is the first example of a dynamic kinetic resolution of amino acid derivatives with amides formation. Copyright
- Tessaro, Davide,Cerioli, Lorenzo,Servi, Stefano,Viani, Fiorenza,D'Arrigo, Paola
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experimental part
p. 2333 - 2338
(2011/10/19)
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- Catalyst and solvent-free amidation of inactive esters of N-protected amino acids
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A catalyst free procedure for the preparation of amides from inactive esters of N-protected amino acids and various amines is demonstrated under mild reaction conditions. Our effort to recover excess amine and generated alcohol is an approach towards environment friendly and cost effective synthesis under easy operational conditions.
- Nadimpally, Krishna Chaitanya,Thalluri, Kishore,Palakurthy, Nani Babu,Saha, Abhijit,Mandal, Bhubaneswar
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supporting information; experimental part
p. 2579 - 2582
(2011/06/21)
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- Chiral relay in NHC-mediated asymmetric β-lactam synthesis II; asymmetry from NHCs derived from acyclic 1,2-diamines
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The synthesis of a range of imidazolinium salts derived from acyclic 1,2-diamines, and an evaluation of the reactivity and asymmetric induction of the corresponding NHCs as catalysts for the asymmetric synthesis of β-lactams, is reported. An N-methyl-substituted NHC derived from (1R,2R)-1,2-diphenylethanediamine shows optimal reactivity and enantioselectivity in this series, in contrast to that observed with NHCs derived from (1R,2R)-cyclohexane-1,2-diamine.
- Duguet, Nicolas,Donaldson, Adele,Leckie, Stuart M.,Kallstroem, Eddy A.,Campbell, Craig D.,Shapland, Peter,Brown, Thomas B.,Slawin, Alexandra M.Z.,Smith, Andrew D.
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experimental part
p. 601 - 616
(2010/08/20)
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- Synthesis and in vitro study of pseudo-peptide thioureas containing α-aminophosphonate moiety as potential antitumor agents
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Twenty pseudo-peptide thioureas IIa-l containing α-aminophosphonate moiety were synthesized from the reaction of chiral α-amino carboxamide derivatives Ia-c with O,O′-dialkylisothiocyanato(phenyl)methylphosphonate 5. The synthesized compounds were completely characterized by elemental analysis, physical and spectral (IR, 1H NMR, 13C NMR) data. According to the preliminary studies on antitumor activities, compounds IIa-l could inhibit tumor cells PC3, Bcap37 and BGC823. These compounds displayed low to high activity by MTT assays. Among them, L-IIk, D-IIa and D-IIe were identified as potent inhibitors, with IC50 values ranging from 4.7 to 11.2 μM according to in vitro assay.
- Liu, Jing-Zi,Song, Bao-An,Fan, Hui-Tao,Bhadury, Pinaki S.,Wan, Wen-Ting,Yang, Song,Xu, Weiming,Wu, Jian,Jin, Lin-Hong,Wei, Xue,Hu, De-Yu,Zeng, Song
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experimental part
p. 5108 - 5112
(2011/01/04)
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- Kinetic resolution of racemic carboxylic acids by an L-histidine-derived sulfonamide-induced enantioselective esterification reaction
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(Chemical Equation Presented) The direct and catalytic kinetic resolution of racemic carboxylic acids bearing a Bronsted base such as O-protected α-hydroxy carboxylic acids and N-protected α-amino acids has been accomplished through an L-histidine-derived sulfonamide-induced enantioselective esterification reaction with tert-butyl alcohol for the first time. Highly asymmetric induction [S(kfast/kslow) = up to 56] has been achieved under the equilibrium between a chiral catalyst and two diastereomeric acylammonium salts through an intramolecular hydrogen-bonding interaction.
- Ishihara, Kazuaki,Kosugi, Yuji,Umemura, Shuhei,Sakakura, Akira
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supporting information; experimental part
p. 3191 - 3194
(2009/05/27)
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- Carboxamidation of carboxylic acids with 1-tert-butoxy-2-tert-butoxycarbonyl-1,2-dihydroisoquinoline (BBDI) without bases
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Formation of carboxamides of a variety of carboxylic acids with the coupling reagent BBDI is described. This procedure permits a one pot and simple operation without the need of any bases and no base was?required for even use of amine hydrochlorides. In addition, an approach to BBDI-catalyzed carboxamidation is examined.
- Saito, Yukako,Ouchi, Hidekazu,Takahata, Hiroki
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experimental part
p. 11129 - 11135
(2009/04/11)
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- PAR-2 ANTAGONISTS
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Compounds represented by the general formula(1) or salts thereof or solvates of both; PAR-2 antagonists containing the compounds; and preventive or therapeutic agents for PAR-2 related diseases containing the antagonists as the active ingredient: (1) wherein R1 is hydrogen, halogeno, or a group represented by the general formula (2): (wherein R11 is straight-chain or branched C1-6 alkylene or the like; and R12 and R13 together with the nitrogen atom adjacent to them form a 5- to 7-membered ring) ; R2 is straight-chain or branched C1-6 alkyl or the like; R3 and R4 are each independently hydrogen,one to three halogen atoms, or the like; and A1 - A2 - A3 is a tripeptide residue composed of alpha-amino acids each independently selected from the group consisting of glycine, alanine, cyclohexylalanine, and so on
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Page/Page column 15
(2008/06/13)
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- Synthesis of chiral C2-symmetric methylene- and boron-bridged bis(imidazolines)
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A series of C2-symmetric boron-bridged bis(imidazolines) was obtained by lithiation of 2-imidazolines and subsequent reaction with dialkyl- or diarylhaloboranes. The corresponding 2-imidazolines were prepared by an efficient four-step sequence starting from N-tert-butoxycarbonyl-protected α-amino acids. C2-Symmetric methylenebis(imidazolines) were readily synthesized from chiral diamines by condensation with diethyl malonimidate. The bis(imidazolines) were used as ligands in the enantioselective cyclopropanation of styrene and allylic oxidation of cyclic alkenes. Georg Thieme Verlag Stuttgart.
- Ramalingam, Balamurugan,Neuburger, Markus,Pfaltz, Andreas
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p. 572 - 582
(2008/01/03)
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- Efficient transamidation of primary carboxamides by in situ activation with N,N-dialkylformamide dimethyl acetals
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Two protocols for the transamidation of primary amides with primary and secondary amines, forming secondary and tertiary amides, respectively, are described. Both processes employ N,N-dialkylformamide dimethyl acetals for primary amide activation, producing N-acyl-N,N-dialkylformamidines as intermediates, as widely documented in the literature. Although the latter intermediates react irreversibly with amines by amidinyl transfer, we show that in the presence of certain Lewis acid additives efficient acyl transfer occurs, providing new and useful methods for amide exchange. In one protocol for transamidation, the N-acyl-N,N-dialkylformamidine intermediates are purified by flash-column chromatography and the purified intermediates are then treated with an amine (typically, 2.5 equiv) in the presence of scandium triflate (10 mol %) in ether to form in high yields the products of transamidation. In a second procedure, N-acyl-N,N-dialkylformamidines are generated in situ and, without isolation, are subjected to transamidation in the presence of zirconium chloride (0.5 equiv) and an amine (typically 2 equiv). A variety of different primary amides and amines are found to undergo efficient transamidation using the methods described.
- Dineen, Thomas A.,Zajac, Matthew A.,Myers, Andrew G.
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p. 16406 - 16409
(2007/10/03)
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- Activation of carboxylic acids by Burgess reagent: An efficient route to acyl ureas and amides
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Carboxylic acids upon treatment with Burgess reagent are converted to novel mixed sulfocarboxy anhydrides. Subsequent treatment of such mixed anhydrides with amines at elevated temperatures yields acyl ureas and amides. The ratio of the two products appears to be temperature controlled. The method provides a simple and convenient route to diverse acyl ureas starting from carboxylic acids and amines.
- Wodka, Derek,Robbins, Michael,Lan, Ping,Martinez, Rogelio L.,Athanasopoulos, John,Makara, Gergely M.
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p. 1825 - 1828
(2007/10/03)
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- Efficient cleavage of carboxylic tert-butyl and 1-adamantyl esters, and N-Boc-amines using H2SO4 in CH2Cl2
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A new procedure for the deprotection of carboxylic tert-butyl and 1-adamantyl esters, and N-Boc-amines using H2SO4 in CH2Cl2 is described. The proposed method is simple, cheap, eco-friendly and represents a valid alternative to existing ones, with special significance in large scale applications.
- Strazzolini, Paolo,Misuri, Nazareno,Polese, Pierluigi
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p. 2075 - 2078
(2007/10/03)
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- Development of potent bifunctional endomorphin-2 analogues with mixed μ-/δ-opioid agonist and δ-opioid antagonist properties
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The C terminus of endomorphin-2 (EM-2) analogues (Tyr-Pro-Phe-NH-X) was modified with aromatic, heteroaromatic, or aliphatic groups (X = phenethyl,benzyl, phenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, tert-butyl, cyclohexyl, or adamantyl; 3-18) to study their effect on opioid activity. Only 9 (1-naphthyl), 11 (5-quinolyl), 16 (cyclohexyl), and 18 (2-adamantyl) exhibited μ-opioid receptor affinity in the nanomolar range (Ki = 2.41-6.59 nM), which, however, was 3-to 10-fold less than the parent peptide. Replacement of Tyr1 by Dmt (2′,6′-dimethyl-L-tyrosine) (19-32) exerted profound effects: (i) acquisition of high μ-opioid receptor affinity (Ki = 0.11-0.52 nM) except 23 (Ph); (ii) presence of potent functional μ-opioid receptor agonism (IC50 1]EM-2), 27 (1-naphthyl), 29 (5-quinolyl), and 32 (5-isolquinolyl); (iii) association of weak δ-opioid antagonist activity (pA2 = 5.41-7.18) except 19 ([Dmt1]EM-2), 20 (H), 27 (1-naphthyl), and in particular 29 (5-quinolyl) with its potent δ-agonism (IC50 = 0.62 nM, pA2 = 5.88); (iv) production of antinociception after ic administration of 32 (5-isoquinolyl) in mice, a bioactivity absent in the corresponding Tyr1 analogue (14); and (v) preferential cis orientation (cis/trans = 3:2 to 7:3) at the Dmt-Pro amide bond, in contrast to the Tyr-Pro amide trans orientation (cis/trans = 1:2 to 1:3). Thus, [Dmt1]EM-2 analogues with hydrophobic C-terminal extensions provide model compounds with potent μ-opioid receptor bioactivity and dual functional agonism.
- Fujita, Yoshio,Tsuda, Yuko,Li, Tingyou,Motoyama, Takashi,Takahashi, Motohiro,Shimizu, Yoshiro,Yokoi, Toshio,Sasaki, Yusuke,Ambo, Akihiro,Kita, Atsuko,Jinsmaa, Yunden,Bryant, Sharon D.,Lazarus, Lawrence H.,Okada, Yoshio
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p. 3591 - 3599
(2007/10/03)
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- Development of Potent Inhibitors of Botulinum Neurotoxin Type B
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Botulinum neurotoxins are the most potent toxins known to date. They are zinc-metalloproteases able to cleave selectively an essential component of neurotransmitter exocytosis, causing the syndrome of botulism characterized by a flaccid paralysis. There is a great interest in designing antagonists of the action of these toxins. One way is to inhibit their catalytic activity. In this study, we report the design of such inhibitors directed toward BoNT/B. A study of the S1 subsite specificity, using several β-amino thiols, has shown that this subsite prefers a p-carboxybenzyl moiety. The specificity of the S1′ and S2′ subsites was studied using two libraries of pseudotripeptides containing the S1 synthon derived from the best β-amino thiol tested. Finally, a selection of various non natural amino acids for the recognition of the "prime" domain led to the most potent inhibitor of BoNT/B described to date with a Ki value of 20 nM.
- Anne, Christine,Turcaud, Serge,Quancard, Jean,Teffo, Franck,Meudal, Hervé,Fournié-Zaluski, Marie-Claude,Roques, Bernard P.
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p. 4648 - 4656
(2007/10/03)
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- Novel syntheses of enantiopure hexahydroimidazo[1,5-b]isoquinolines and tetrahydroimidazo[1,5-b]isoquinolin-1(5H)-ones via iminium cation cyclizations
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Condensations of chiral diamines 11a-c with benzotriazole and formaldehyde gave benzotriazolyl intermediates 12a-c; similar condensations of α-amino-amides 10a-c with benzotriazole and paraformaldehyde gave 14a-c. Subsequent treatment of 12a-c and 14a-c with AlCl3 led to enantiopure tricyclic 1,2,3,5,10,10a-hexahydroimidazo[1,5-b]isoquinolines 1a-c and 2,3,10,10a-tetrahydroimidazo[1,5-b]isoquinolin-1(5H)-ones 15a-c, respectively, via Lewis acid promoted iminium cation cyclizations.
- Katritzky, Alan R.,Suzuki, Kazuyuki,He, Hai-Ying
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p. 8224 - 8229
(2007/10/03)
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- Novel inhibitors of HIV protease: Design, synthesis and biological evaluation of picomolar inhibitors containing cyclic P1/P2 scaffolds
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A novel series of HIV protease inhibitors containing cyclic P1/P2 scaffolds has been synthesized and evaluated for biological activity. The trans 3,5-dibenzyl-2-oxo pyrrolidinone ring system resulted in a 50 pM enzyme inhibitor against HIV protease in vitro when combined with an indanolamine derived P'-backbone. This compound also shows comparable activity to currently marketed drugs in the MT-4 cell-based antiviral assay. (C) 2000 Elsevier Science Ltd. All rights reserved.
- Spaltenstein, Andrew,Almond, Merrick R.,Bock, William J.,Cleary, Darryl G.,Furfine, Eric S.,Hazen, Richard J.,Kazmierski, Wieslaw M.,Salituro, Francesco G.,Tung, Roger D.,Wright, Lois L.
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p. 1159 - 1162
(2007/10/03)
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- Automated synthesis and purification of amides: Exploitation of automated solid phase extraction in organic synthesis
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Automated parallel synthesis of small organic molecules, either as single entities or as mixtures, offers the potential for the rapid optimization of physical and biological properties of a molecule Currently, emphasis has been placed on solid phase synthesis technology to accomplish the rapid preparation of large numbers of molecules. Automated solution phase synthesis is an alternative approach which has the advantages of having shorter development times and being more amenable to scaleup. Utilizing commercially available liquid handlers for reaction setup and exploiting automated solid phase extraction for product purification, a procedure has been developed to prepare and purify up to 100 amide analogs, simultaneously. Both carbodiimide mediated couplings and p-nitro-phenyl ester displacements have been carried out using this procedure. Product amides having overall neutral or basic character have been prepared in good yield and with good to excellent purities.
- Lawrence, R. Michael,Biller, Scott A.,Fryszman, Olga M.,Poss, Michael A.
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p. 553 - 558
(2007/10/03)
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- Activation of carboxylic acids by pyrocarbonates: Synthesis of alkylamides of N-protected amino acids
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Alkylamides of amino acids were prepared with high yields via activation of N-protected amino acids by di-tert-butyl pyrocarbonate-pyridine reagent in the presence of alkylamine hydrochlorides and potassium hydrocarbonate.
- Pozdnev
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p. 241 - 244
(2007/10/03)
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- AZIRIDINE DERIVATIVES, THEIR PRODUCTION AND USE
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The present invention relates to a compound of the formula: STR1 wherein R 1 and Q are independently an optionally esterified or amidated carboxyl group; R 2 is hydrogen, an acyl group or an optionally substituted hydrocarbon residue; X is a divalent hydrocarbon residue which may be substituted; or a salt thereof, which is useful as prophylactic and therapeutic agents of bone diseases and as agents for inhibiting thiol protease.
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- L-phenylalanine cyclohexylamide: A simple and convenient auxiliary for the synthesis of optically pure α,α-disubstituted (R)- and (S)-amino acids
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This work describes L-phenylalanine cyclohexylamide (5c) as a simple, cheap, and powerful chiral auxiliary for the synthesis of a series of optically pure α,α-disubstituted (R)- and (S)-amino acids of type 1, such as (R)- and (S)-2-methyl-phenylalanine (1a), (R)- and (S)-2-methyl-2-phenylglycine (1b), and (R)- and (S)-2-methylvaline (1c). These amino acids were efficiently transformed into the suitably protected and activated amino-acid building blocks (R)- and (S)-12b and (R)- and (S)-12c which are ready for incorporation into peptides by solution or solid-phase techniques. Based on the crystal structures of 6b, 6c, and 7a belonging to the diastereoisomeric peptides series 6 and 7, the absolute configurations of each member of the series were determined. β-Turn geometries of type II' and I were observed for 6b and 7a, respectively, whereas 6c crystallized in an extended conformation. The impacts of side-chain variation on conformation and crystal packing of these triamides are discussed.
- Obrecht,Bohdal,Broger,Bur,Lehmann,Ruffieux,Schonholzer,Spiegler,Muller
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p. 563 - 580
(2007/10/02)
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- Reductive Acylation of α-Keto Azides Derived from L-Amino Acids using N-Protected L-Aminothiocarboxylic S-Acids
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Several homochiral N-protected α-aminothiocarboxylic S-acids have been synthesised from natural amino acids and used for reductive acylation of homochiral α,α'-amino keto azides, also derived from natural amino acids.
- McKervey, M. Anthony,O'Sullivan, Michael B.,Myers, Peter L.,Green, Richard H.
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- N-Haloacetyl-amino-acid amides as active-site-directed inhibitors of papain and cathepsin B
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A series of N-haloacetyl-amino-acid amides were synthesized and tested as models of cysteine-protease inhibitors. They irreversibly inactivated papain and cathepsin B via a reversible enzyme-inhibitor intermediate. Apparent second-order rate constants of inactivation ranging from 65 to 16,700 M-1 s-1 were observed. Reactivity against papain, as compared to glutathione, was increased 16,400-fold for N-bromoacetyl-leucine isopentylamide and 25,700-fold for the corresponding iodoacetyl derivative; these increases are probably due to proximity effects. No inhibition of trypsin, chymotrypsin and porcine pancreatic elastase was observed. Haloacetamides represent an interesting class of easily synthesized, efficient, irreversible inhibitors of cysteine proteases, which have low non-specific alkylating properties.
- Girodano,Gallina,Ottaviano,Consalvi,Scandurra
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p. 865 - 873
(2007/10/02)
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- Studies on Neurokinin Antagonists. 2. Design and Structure-Activity Relationships of Novel Tripeptide Substance P Antagonists, Nα-α-(Nα-Acetyl-L-threonyl)-N1-formyl-D-tryptophyl>-N-methyl-N-(phenylmethyl)-L-ph
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Continuing studies on the chemical modification of the previously reported novel tripeptide SP antagonist, Nα-α-α-(tert-butyloxycarbonyl)glutaminyl>-N1-formyl-D-tryptophyl>phenylalanine benzyl ester Boc-Gln
- Hagiwara, Daijiro,Miyake, Hiroshi,Morimoto, Hiroshi,Murai, Masako,Fujii, Takashi,Matsuo, Masaaki
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p. 3184 - 3191
(2007/10/02)
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- A Novel Synthesis of Peptide Based on the Photochemistry of 5-Azido-1,3,4-oxadiazoles
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A novel approach to the synthesis of peptides is described.Various N-protected amino acid hydrazides 17 were converted to the salts 18 by condensation with carbon disulfide in methanolic potassium hydroxide.Thermal cyclization of 18 to the heterocycles 19 was followed by reaction with methyl iodide to yield the sulfides 20.After oxidation of 20 to the corresponding sulfones 21, the title compounds 22 were prepared by treating 21 with sodium azide.Deprotection then yielded the free bases 23.Utilization of 22 and 23 in peptide synthesis, relying on a photochemical degradation of the title heterocycle present in these compounds, is described.The scope and limitations of this new methodology are also discussed.
- Confalone, Pat N.,Woodward, Robert B.
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p. 902 - 906
(2007/10/02)
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