- Fast Cyclization of a Proline-Derived Self-Immolative Spacer Improves the Efficacy of Carbamate Prodrugs
-
Self-immolative (SI) spacers are sophisticated chemical constructs designed for molecular delivery or material degradation. We describe herein a (S)-2-(aminomethyl)pyrrolidine SI spacer that is able to release different types of anticancer drugs (possessing either a phenolic or secondary and tertiary hydroxyl groups) through a fast cyclization mechanism involving carbamate cleavage. The high efficiency of drug release obtained with this spacer was found to be beneficial for the in vitro cytotoxic activity of protease-sensitive prodrugs, compared with a commonly used spacer of the same class. These findings expand the repertoire of degradation machineries and are instrumental for the future development of highly efficient delivery platforms.
- Belvisi, Laura,Borlandelli, Valentina,Corno, Cristina,Dal Corso, Alberto,Gennari, Cesare,Perego, Paola,Pignataro, Luca
-
supporting information
p. 4176 - 4181
(2020/02/05)
-
- INHIBITORS OF HEPATITIS C VIRUS REPLICATION
-
The present invention relates to compounds of formula (I) that are useful as hepatitis C virus (HCV) NS5A inhibitors, the synthesis of such compounds, and the use of such compounds for inhibiting HCV NS5A activity, for treating or preventing HCV infections and for inhibiting HCV viral replication and/or viral production in a cell-based system.
- -
-
Paragraph 0734-0735
(2019/05/15)
-
- Mechanistic Insight Facilitates Discovery of a Mild and Efficient Copper-Catalyzed Dehydration of Primary Amides to Nitriles Using Hydrosilanes
-
Metal-catalyzed silylative dehydration of primary amides is an economical approach to the synthesis of nitriles. We report a copper-hydride(CuH)-catalyzed process that avoids a typically challenging 1,2-siloxane elimination step, thereby dramatically increasing the rate of the overall transformation relative to alternative metal-catalyzed systems. This new reaction proceeds at ambient temperature, tolerates a variety of metal-, acid-, or base-sensitive functional groups, and can be performed using a simple ligand, inexpensive siloxanes, and low catalyst loading.
- Liu, Richard Y.,Bae, Minwoo,Buchwald, Stephen L.
-
supporting information
p. 1627 - 1631
(2018/02/17)
-
- Total syntheses of smenothiazoles A and B
-
Concise total syntheses of smenothiazoles A (1) and B (2), two distinguished vinyl chloride containing natural products isolated from the marine sponge S. aurea, have been developed. Silastannation, Stille reaction and a carefully controlled desilylchlorination were employed as key steps to construct unique polyketide acid fragments, and the optimized reaction conditions avoided migration of 2,5-diene to a 2,4-conjugated system. This report unambiguously confirmed the structures of both natural products.
- Ma, Xiao,Chen, Yajie,Chen, Sigui,Xu, Zhengshuang,Ye, Tao
-
p. 7196 - 7203
(2017/09/07)
-
- A N-benzyloxycarbonyl-L-prolinamide method for the preparation of
-
The invention relates to a preparation method of N-carbobenzoxy-L-prolinamide. The preparation method is characterized by comprising following steps of (1) putting L-proline and alkali into a solvent and dropwise adding benzyl chloroformate; at the end of reaction, heating up till backflow, separating out water, cooling down to obtain liquid N-carbobenzoxy-L-proline; (2) dropwise adding sulfoxide chloride into the liquid N-carbobenzoxy-L-proline, heating up till backflow, distilling at reduced pressure to obtain N-carbobenzoxy-L-prolyl chloride solution; and (3) introducing ammonia gas into the N-carbobenzoxy-L-prolyl chloride solution, and at the end of reaction, concentrating at reduced pressure till drying the solvent, adding dichloromethane, cooling down, regulating pH value of the system to be 12-13, standing to separate liquid to obtain a water layer, decoloring, filtering to obtain distilled residue, crystallizing, filtering, washing by petroleum ether, drying to obtain the N-carbobenzoxy-L-prolinamide. The preparation method is simple, has high yield, can prepare the product with high purity and optical purity and no inorganic salt, and can be used for industrial production of N-carbobenzoxy-L-prolinamide in large scale.
- -
-
Paragraph 0026
(2018/02/04)
-
- One-pot synthesis of orthogonally protected dipeptide selenazoles employing Nα-amino selenocarboxamides and α-bromomethyl ketones
-
A simple and efficient protocol for the synthesis of selenazole containing dipeptidomimetics using Nα-amino selenocarboxamides and α-bromomethyl ketones is described. All the compounds made were isolated in good yields and fully characterized.
- Madhu, Chilakapati,Panguluri, Nageswara Rao,Narendra,Panduranga,Sureshbabu, Vommina V.
-
supporting information
p. 6831 - 6835
(2015/01/09)
-
- Glycosylation mediated - BAIL in aqueous solution
-
The use of Br?nsted acid ionic liquid (BAIL) as a catalyst for the activation of unreactive and unprotected glycosyl donors has been demonstrated for the first time in aqueous solution.
- Delacroix, Sébastien,Bonnet, Jean-Pierre,Courty, Matthieu,Postel, Denis,Van Nhien, Albert Nguyen
-
-
- A convenient method for the one-step synthesis of phosphonic peptides
-
A novel and efficient method for the synthesis of peptidyl derivatives of 1-aminoalkylphosphonate diaryl esters is presented. Phosphonic peptides were obtained in one step via an amidoalkylation reaction using amides of N-protected amino acids or peptides, triphenyl phosphite, and an appropriate aldehyde.
- Skoreński, Marcin,Oleksyszyn, Józef,Sieńczyk, Marcin
-
supporting information
p. 4975 - 4977
(2013/09/02)
-
- Enzymatic C-terminal amidation of amino acids and peptides
-
Herein, we describe two versatile and high yielding enzymatic approaches for the conversion of semi-protected amino acid and peptidyl C-terminal α-carboxylic acids into their corresponding amides. In the first approach, the lipase Candida antarctica lipase-B (Cal-B), and in the second approach, the protease Subtilisin A, are used, respectively. We found that by using the ammonium salt of the α-carboxylic acid instead of separate ammonia sources, the enzymatic amidation reactions proceeded much faster without side reactions and gave near to quantitative yields of products.
- Nuijens, Timo,Piva, Elena,Kruijtzer, John A.W.,Rijkers, Dirk T.S.,Liskamp, Rob M.J.,Quaedflieg, Peter J.L.M.
-
experimental part
p. 3777 - 3779
(2012/09/22)
-
- Enantioselective total synthesis of (S)-(+)-lennoxamine through asymmetric hydrogenation mediated by l-proline-tetrazole ruthenium catalyst
-
A novel asymmetric synthetic strategy to prepare isoindolobenzazepine based lennoxamine alkaloid has been achieved in high ee% starting from 2-(benzo[d][1,3]dioxol-5-yl)ethanamine and 1-(chloromethyl)-2,3-dimethoxybenzene in 5 steps and with a 34% overall yield. The potentiality of this route involved the Bischler-Napieralsky cyclization that leads to tetracyclic indolinium skeleton, generation of chiral center through asymmetric hydrogen-transfer reaction employing l-proline-tetrazole as chiral ligand with Ru/Ir/Rh, and anodic oxidation as the key steps in the synthesis.
- Mirabal-Gallardo, Yaneris,Piérola, Johanna,Shankaraiah, Nagula,Santos, Leonardo S.
-
scheme or table
p. 3672 - 3675
(2012/10/07)
-
- Synthesis of dysideaproline e using organocatalysis
-
(S)-4,4-Dichloro-3-methylbutanoic acid was prepared in 51% overall yield from commercially available starting materials using an organocatalytic transfer hydrogenation to 4,4-dichloro-3-methylbut-2-enal in the key step. The (S)-dichloro acid was used as an intermediate in the first total synthesis of dysideaproline E and a diastereomer confirming the structure of the natural product.
- Owusu-Ansah, Ernest,Durow, Amanda C.,Harding, John R.,Jordan, Angela C.,O'Connell, Susan J.,Willis, Christine L.
-
scheme or table
p. 265 - 272
(2011/02/24)
-
- INHIBITORS OF HEPATITIS C VIRUS REPLICATION
-
The present invention relates to compounds of formula (I) that are useful as hepatitis C virus (HCV) NS5A inhibitors, the synthesis of such compounds, and the use of such compounds for inhibiting HCV NS5A activity, for treating or preventing HCV infections and for inhibiting HCV viral replication and/or viral production in a cell-based system.
- -
-
Page/Page column 115-116
(2010/11/04)
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- ANTIVIRAL COMPOUNDS COMPOSED OF THREE LINKED ARYL MOIETIES TO TREAT DISEASES SUCH AS HEPATITIS C
-
The present invention relates to novel Linked Tricyclic Aryl Compounds, compositions comprising at least one Linked Tricyclic Compound, and methods of using Linked Tricyclic Aryl Compounds for treating or preventing HCV infection in a patient. in one aspect, the present invention provides Compounds of Formula (I): and pharmaceutically acceptable salts thereof, wherein: Non-limiting examples of the Compounds of Formula (II) include compound 56
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-
Page/Page column 94-95
(2010/12/26)
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- Synthesis of substituted 5-(pyrrolidin-2-yl)tetrazoles and their application in the asymmetric Biginelli reaction
-
A series of chiral substituted 5-(pyrrolidin-2-yl)tetrazoles have been synthesized and evaluated as organocatalysts for the asymmetric Biginelli reaction. The relationship between catalytic activity and the different catalyst structures is briefly discussed. By using the optimized catalyst C10 (10 mol-%), a series of 3,4-dihydropyrimidin-2(1H)-one (DHPM) derivatives have been obtained in 63-88% yields and 68-81 % ee values within 24 h at room temperature.
- Wu, Yong-Yong,Chai, Zhuo,Liu, Xin-Yuan,Zhao, Gang,Wang, Shao-Wu
-
experimental part
p. 904 - 911
(2009/07/19)
-
- Synthesis, characterisation and in vitro cytotoxicity studies of a series of chiral platinum(II) complexes based on the 2-aminomethylpyrrolidine ligand: X-ray crystal structure of [PtCl2(R-dimepyrr)] (R-dimepyrr = N-dimethyl-2(R)-aminomethylpyrrolidine)
-
A series of platinum(II) complexes were synthesised based on the enantiomerically pure amino acid proline. Novel synthetic pathways were developed, adapted from standard peptide chemistry, to produce the 2-aminomethylpyrrolidine (pyrr) ligand and its derivatives with differing arrangements of methyl substituents at the exocyclic amine sites. The crystal structure of [PtCl2(R-dimepyrr)] (R-dimepyrr = N,N-dimethyl-2(R)-aminomethylpyrrolidine) is reported and the five-membered ligand ring has been shown to be in an envelope conformation. Cytotoxicity studies were carried out on the ovarian cancer A2780 tumour cell line and its cisplatin-resistant variant, A2780cisR. Remarkably good activity was seen for several of the drugs when compared to cisplatin despite the addition of substantial steric bulk to the amine groups, and there was a lack of cross-resistance with cisplatin seen for some compounds.
- Diakos, Connie I.,Zhang, Mei,Beale, Philip J.,Fenton, Ronald R.,Hambley, Trevor W.
-
experimental part
p. 2807 - 2814
(2009/10/10)
-
- N-urethane-protected amino alkyl isothiocyanates: Synthesis, isolation, characterization, and application to the synthesis of thioureidopeptides
-
(Chemical Equation Presented) Synthetically useful N-Fmoc amino-alkyl isothiocyanates have been described, starting from protected amino acids. These compounds have been synthesized in excellent yields by thiocarbonylation of the monoprotected 1,2-diamines with CS2/TEA/p-TsCl, isolated as stable solids, and completely characterized. The procedure has been extended to the synthesis of amino alkyl isothiocyanates from Boc- and Z-protected amino acids as well. The utility of these isothiocyanates for peptidomimetics synthesis has been demonstrated by employing them in the preparation of a series of dithioureidopeptide esters. Boc-Gly-OH and Boc-Phe-OH derived isothiocyanates 9a and 9c have been obtained as single crystals and their structures solved through X-ray diffraction. They belong to the orthorhombic crystal system, and have a single molecule in the asymmetric unit (Z′ = 1). 9a crystallizes in the centrosymmetric space group Pbca, while 9c crystallizes in the noncentrosymmetric space group P212121.
- Sureshbabu, Vommina V.,Naik, Shankar A.,Hemantha,Narendra,Das, Ushati,Guru Row, Tayur N.
-
supporting information; experimental part
p. 5260 - 5266
(2009/12/06)
-
- Peptide deformylase inhibitors of Mycobacterium tuberculosis: Synthesis, structural investigations, and biological results
-
Bacterial peptide deformylase (PDF) belongs to a subfamily of metalloproteases catalyzing the removal of the N-terminal formyl group from newly synthesized proteins. We report the synthesis and biological activity of highly potent inhibitors of Mycobacterium tuberculosis (Mtb) PDF enzyme as well as the first X-ray crystal structure of Mtb PDF. Structure-activity relationship and crystallographic data clarified the structural requirements for high enzyme potency and cell based potency. Activities against single and multi-drug-resistant Mtb strains are also reported.
- Pichota, Arkadius,Duraiswamy, Jeyaraj,Yin, Zheng,Keller, Thomas H.,Alam, Jenefer,Liung, Sarah,Lee, Gladys,Ding, Mei,Wang, Gang,Chan, Wai Ling,Schreiber, Mark,Ma, Ida,Beer, David,Ngew, Xinyi,Mukherjee, Kakoli,Nanjundappa, Mahesh,Teo, Jeanette W.P.,Thayalan, Pamela,Yap, Amelia,Dick, Thomas,Meng, Wuyi,Xu, Mei,Koehn, James,Pan, Shi-Hao,Clark, Kirk,Xie, Xiaoling,Shoen, Carolyn,Cynamon, Michael
-
scheme or table
p. 6568 - 6572
(2009/09/30)
-
- PDF INHIBITORS
-
The invention relates to novel compounds that are inhibitors of peptidyl deformylase (PDF). The compounds are useful as antimicrobials and antibiotics. The compounds of the invention display selective inhibition of peptidyl deformylase versus other metalloproteinases such as MMPs. Methods of preparation and uses of the compounds are also disclosed.
- -
-
Page/Page column 32
(2010/11/28)
-
- Modular syntheses of oxazolinylamine ligands and characterization of group 10 metal complexes
-
The syntheses of aminoalkyloxazoline and pyrrolidinyloxazoline ligands, each of which bear a pair of chiral centres, by both known and new routes are reported. Variable temperature NMR studies show that the known stepwise syntheses of the pyrrolidinyl compounds are not complicated by epimerization; however, coordination of one of the aminoalkyl derivatives to Pt(II) under conditions of prolonged heating to 80°C does give mixtures of diastereomeric N,N′-chelated complexes that result from inversion of the chiral centre associated with the aminoalkyl fragment. A new synthesis of pyrrolidinyloxazoline ligands that involves the Zn-catalyzed cyclization of Cbz-protected 2-cyanopyrrolidine and β-amino alcohols is also reported. This procedure offers the advantages of economy, shorter time, and fewer purification steps over the previously reported synthesis. In addition, the crystal structure of an enantiopure Pd(II) complex of an N.N′-chelated pyrrolidinyloxazoline is disclosed. This compound has a pseudo-C2 axis of symmetry, which may make it suitable for asymmetric catalytic applications.
- Caputo, Christine A.,Carneiro, Florentino D S.,Jennings, Michael C.,Jones, Nathan D.
-
-
- PEPTIDE DEFORMYLASE INHIBITORS
-
Novel PDF inhibitors of formulas (I) and (II), pharmaceutical compositions thereof and methods for their use in the treatment of bacterial infections are described.
- -
-
Page/Page column 14; 24
(2010/11/27)
-
- Practical synthesis of (S)-pyrrolidin-2-yl-1H-tetrazole, incorporating efficient protecting group removal by flow-reactor hydrogenolysis
-
A practical, safe, high-yielding and efficient synthesis of (S)-pyrrolidin-2-yl-1H-tetrazole has been developed, which avoids the generation of ammonium azide in the cyclisation step and the use of a 9:1 acetic acid-water mixture as the solvent in the hydrogenation. The previously extended hydrogenolysis reaction time (three days) is now reduced to hours through the use of an H-Cube (a continuous-flow reactor employing a mixed hydrogen-liquid flow stream). Georg Thieme Verlag Stuttgart.
- Franckevi?ius, Vilius,Knudsen, Kristian Rahbek,Ladlow, Mark,Longbottom, Deborah A.,Ley, Steven V.
-
p. 889 - 892
(2007/10/03)
-
- 5-(Pyrrolidine-2-yl)tetrazole: Rationale for the increased reactivity of the tetrazole analogue of proline in organocatalyzed aldol reactions
-
5-[(2S)-Pyrrolidine-2-yl]-1H-tetrazole (1), i.e. the tetrazolic acid analogue of proline, has been found to be significant more reactive than L-proline (2) in various organocatalyzed reactions. In the organocatalyzed direct asymmetric aldol reaction, acetone was reacted with aromatic and aliphatic aldehydes to afford the resulting β-hydroxy ketones in good yields and moderate to high enantiomeric excesses. The increased reactivity of 1, as compared to 2, has been rationalized through a combined computational and NMR spectroscopic study. It was found that catalyst 2 was almost completely engaged in oxazolidinone formation with the aldehyde whereas 1 did not take part in such parasitic equilibrium. This finding, together with the improved solubility of the tetrazole analogue, is proposed to account for the observed reactivity. Wiley-VCH Verlag GmbH & Co. KGaA, 2005.
- Hartikka, Antti,Arvidsson, Per I.
-
p. 4287 - 4295
(2007/10/03)
-
- Organocatalysis with proline derivatives: Improved catalysts for the asymmetric Mannich, nitro-Michael and aldol reactions
-
Tetrazole and acylsulfonamide organocatalysts derived from proline have been synthesised and applied to the asymmetric Mannich, nitro-Michael and aldol reactions to give results that are superior to the proline-catalysed counterpart.
- Cobb, Alexander J. A.,Shaw, David M.,Longbottom, Deborah A.,Gold, Johan B.,Ley, Steven V.
-
-
- VLA-4 INHIBITOR
-
A compound which selectively inhibits bonding between a ligand and α4β1 integrin (VLA-4); a process for producing the compound; and a medicine containing the compound. The compound is one represented by, e.g., the formula (I) or a salt thereof. Also provided is a preventive and/or therapeutic agent which contains the compound or salt as a major component and is effective against diseases attributable to cell adhesion, such as, e.g., inflammatory reaction, autoimmune disease, cancer metastasis, bronchial asthma, nasal obstruction, diabetes, arthritis, psoriasis, multiple sclerosis, inflammatory intestinal disease, and rejection reaction in transplantation. (In the formula, Y1 represents arylene, etc.; V1 represents aryl, etc.; and R11 to R14 each represents H, OH, halogeno, etc.)
- -
-
Page/Page column 240-241
(2010/02/15)
-
- Rational design of asymmetric organocatalysts - Increased reactivity and solvent scope with a tetrazolic acid
-
Replacement of the carboxylic acid functionality in the widely used organocatalyst proline with a tetrazolic acid leads to a catalyst with increased reactivity and solvent scope, as demonstrated in the direct catalytic asymmetric aldol reaction.
- Hartikka, Antti,Arvidsson, Per I.
-
p. 1831 - 1834
(2007/10/03)
-
- 5-Pyrrolidin-2-yltetrazole: A New, Catalytic, More Soluble Alternative to Proline in an Organocatalytic Asymmetric Mannich-type Reaction
-
A Mannich-type addition of ketones to N-PMP protected α-imino ethyl glyoxalate is catalyzed by a new proline analogue, 5-pyrrolidin-2-yltetrazole 1. The new organocatalyst has significant advantage over its parent in that it can be used in non-polar solvents without loss of enantioselectivity.
- Cobb, Alexander J. A.,Shaw, David M.,Ley, Steven V.
-
p. 558 - 560
(2007/10/03)
-
- Synthesis of functionalised oxazoles and bis-oxazoles
-
A new method for the synthesis of oxazoles, and in particular chiral non-racemic oxazoles derived from amino acids, has been developed. Thus, rhodium(II) catalysed reaction of diazocarbonyl compounds 6 and 11 in the presence of amides 8 and 10 results in regioselective insertion of the carbenoid into the amide N-H bond with formation of the β-carbonyl amides 9 and 12. Cyclodehydration of amides 9 and 12 using triphenylphosphine-iodine-triethylamine gives functionalised oxazoles 7 and 13. The oxazoles 13c and 13f were converted into the bis-oxazoles 17a and 17b by a second rhodium(II) catalysed regioselective N-H insertion reaction on the amides 15, followed by cyclodehydration.
- Bagley, Mark C.,Buck, Richard T.,Hind, S. Lucy,Moody, Christopher J.
-
p. 591 - 600
(2007/10/03)
-
- Catalytic epoxidation of unfunctionalized alkenes by dinuclear nickel(II) complexes
-
The synthesis, crystal and molecular structure and catalytic activity in epoxidation reactions of new dinuclear nickel(II)-complexes, octahedral μ-diacetato-μ-[2,6-bis[N-2-2'-pyridylethyl)formimidoyl]phenolato]bis nickel(II)·perchlorate·methanol (6) and square planar (μ-hydroxo-μ-[2,6-bis[N-((S)-1-benzyl-2-yl-pyrrolidine)formimidoyl]p henolato]bisnickel(II)·bisperchlorate (7), are described. For the preparation of 7 a new 5-step route for homochiral bisamine (S)-benzyl-2-aminomethyl-pyrrolidine (19) was developed starting from (S)-proline. Epoxidation of unfunctionalized alkenes with sodium hypochlorite and tert-butyl hydroperoxide as terminal oxidants was effectively catalyzed with bisnickel(II)-complexes 6 and 7, and a turnover of 165 was reached using trans-β-methylstyrene (34). The epoxidations probably proceed via a radical intermediate (such as OCl·) and no enantioselectivity is obtained under phase transfer conditions. In epoxidation reactions employing tert-butyl hydroperoxide as terminal oxidant a turnover of 43 was obtained with trans-stilbene (30) as substrate. Unexpectedly in the case of styrene (29) 1,2-bis-(tert-butylperoxy)ethylbenzene (59) was isolated as the major product.
- Rispens, Minze T.,Gelling, Onko Jan,De Vries, Andre H.M.,Meetsma, Auke,Van Bolhuis, Fre,Feringa, Ben L.
-
p. 3521 - 3546
(2007/10/03)
-
- Synthesis, antitumor activity, and nephrotoxicity of the optical isomers of 2-aminomethylpyrrolidine(1,1-cyclobutane-dicarboxylato) platinum(II)
-
The optical isomers of 2-aminomethylpyrrolidine(1,1-cyclobutane-dicarboxylato)platinum(II) (DWA2114, 1), which has potent antitumor activity against various tumors, were synthesized. They were examined for antitumor activity against Colon 26 carcinoma in a sc-iv system, and changes in urinary protein and sugar levels in drug-treated mice were used as an index of nephrotoxicity. In their effect on tumors, (+)-(S)-2-aminomethylpyrrolidine(1,1-cyclobutanedicarboxylato) platinum(II) (6b) was more potent than the enantiomer 6a in that the effective dose of 6b was smaller than that of 6a; but, both drugs exhibited potent antitumor activity. On the other hand, a distinct difference between 6a and 6b was shown in their nephrotoxicity. Isomer 6b induced a great increase in urinary protein and sugar levels in mice, whereas 6a caused no increase in these levels.
- Morikawa,Honda,Endoh -i.,Matsumoto,Akamatsu -i.,Mitsui,Koizumi
-
p. 837 - 842
(2007/10/02)
-
- N-heterocyclic platinum complexes
-
Novel platinum complexes represented by the formula: STR1 wherein A is alkylene having carbon atoms of from 1 to 3; R1, R2, R3 and R4 are the same or different and are hydrogen or alkyl having carbon atoms of from 1 to 4; X and Y are independently a halogen atom, or combined together to form STR2 and l, m and n are independently 0 or 1, and a process for preparing the same are disclosed. These platinum complexes have high antitumor activity and low toxicity, and are easily soluble in water. Therefore, they are very useful as an antitumor agent.
- -
-
-
- Electrochemical Decarboxylation of L-Threonine and Oligopeptide Derivatives with Formation of N-Acyl-N,O-acetals: Preparation of Oligopeptides with Amide or Phosphonate C-Terminus
-
Derivatives of α-amino acids with two stereogenic centers (cf.L-threonine) and di-, tri- and tetrapeptides are electrolyzed in MeOH or AcOH, with formation of N-acyl-N,O-acetals (1b - 15b, 20b), in an anodic oxidative substitution of the COOH by an OR group.The amine ends of the oligopeptides may be benzyloxycarbonyl(Z)- or (tert-butoxy)carbonyl(Boc)-protected.With unprotected dipeptides, an electrolytic decarboxylative cyclization to imidazolidinones (18c, 19c) may also occur (in H2O/NH4OAc).The electrolyses are carried out in simple flasks with cooling jackets ('undivided cell'), using constant current conditions and anodes of Pt or glassy C.The electrolyte is generated in situ by adding 10 - 20 mol-percent of a tertiary amine.Mild acidic hydrolysis of electrolysis products thus obtained may lead to amino-acid amides or peptide amides (10c, 11c, 12c, 17c) with one amino acid less than the starting material.The N,O-acetals from L-threonine and the oligopeptides also react with organometallic nucleophiles such as Grignard compounds (->21 - 26, 29), with formation of products in which the original COOH group has been replaced by alkyl or allyl (sometimes even with moderate stereoselectivity).By treatment of the peptide-derived (open-chain) N,O-acetals with trialkyl or triaryl phosphites/TiCl4, the RO group is replaced by a phosphodiester group in a (non-diastereoselective) Michaelis-Arbuzov-type reaction (1d, 1e, 2d - 9d, 5e).Thus, the two-step sequence of electrolysis and phosphonation converts an oligopeptide derivative to an analogue with a phosphonic-acid end group.The diastereoisomeric N-protected dimethyl and diethyl dipeptidephosphonates (also prepared from the corresponding diaryl esters by Ti(OR)4-mediated transesterification) could be separated by preparative HPLC (SiO2, Lichrosorb Si 60, 10 μm); the dextrorotatory isomers of 1d - 3d were assigned L,D-, the laevorotatory ones L,L-configuration by hydrolysis to and identification of the known amino and aminophosphonic acids.The results described demonstrate a new simple route leading, from a give oligopeptide, to pure peptide analogues of known configuration.
- Seebach, Dieter,Charczuk, Roland,Gerber, Christian,Renaud, Philippe,Berner, Heinz,Schneider, Helmut
-
p. 401 - 425
(2007/10/02)
-
- Dichlorotris(dimethylamino)phosphorane as a Dehydratisation Reagent for the Preparation of N-Protected Amino Acid Amides
-
Besides for the synthesis of peptides and activated esters dichlorotris(dimethylamino)phosphorane (2) now proved to be an excellent reagent for the preparation of N-protected amino acid amides.
- Appel, Rolf,Hiester, Ernst
-
p. 2037 - 2040
(2007/10/02)
-