- Synthesis of a Mexican bean beetle azamacrolide allomone via a novel lactam to lactone ring expansion
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The Mexican bean beetle (Epilachna varivestis) defensive secretion azamacrolide 1 has been synthesized via the novel ring expansion of N-hydroxyethyl lactam 12, which was prepared in seven steps from cyclooctanone (6).
- Gribble, Gordon W.,Silva, Richard A.
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- Synthetic Entry to Polyfunctionalized Molecules through the [3+2]-Cycloaddition of Thiocarbonyl Ylides
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Here we present a comprehensive study on the [3+2]-cycloaddition of thiocarbonyl ylides with a wide variety of alkenes and alkynes. The obtained dihydro- and tetrahydrothiophene products serve as exceptionally versatile intermediates providing access to thiophenes, dienes, dendralenes, and vic-quarternary carbon centers. The use of high-pressure conditions enables thermally unstable, sterically encumbered or moderately reactive substrates to undergo the cycloaddition under mild conditions, thereby increasing the yield by up to 58percent. In addition, we showcase its utility by the formal syntheses of the pharmaceuticals NGB 4420 and tenilapine.
- Habiger, Christoph,Haut, Franz-Lucas,Korber, Johannes Nepomuk,Müller, Thomas,Magauer, Thomas,Mayer, Peter,Speck, Klaus,Wurst, Klaus
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supporting information
(2019/09/06)
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- Synthesis of Cyclic Peptide Mimetics by the Successive Ring Expansion of Lactams
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A successive ring-expansion protocol is reported that enables the controlled insertion of natural and non-natural amino acid fragments into lactams. Amino acids can be installed into macrocycles via an operationally simple and scalable iterative procedure, without the need for high dilution. This method is expected to be of broad utility, especially for the synthesis of medicinally important cyclic peptide mimetics.
- Stephens, Thomas C.,Lodi, Mahendar,Steer, Andrew M.,Lin, Yun,Gill, Matthew T.,Unsworth, William P.
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supporting information
p. 13314 - 13318
(2017/10/05)
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- The profound effect of the ring size in the electrocyclic opening of cyclobutene-fused bicyclic systems
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Fused cyclobutenes, prepared by the photocycloaddition of propargyl alcohols to cyclic anhydride chromophores, undergo facile thermochemical ring opening to fused γ-lactones. The size of the fused ring profoundly influences the temperature that is required to facilitate the ring opening (from 50°C to 180°C) and the nature of the product that is formed. Our studies provide new insights into the mechanistic course of these reactions and have been extended to facilitate the preparation of lactams fused to medium-sized rings.
- Ralph, Michael J.,Harrowven, David C.,Gaulier, Steven,Ng, Sean,Booker-Milburn, Kevin I.
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supporting information
p. 1527 - 1531
(2015/01/30)
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- Structure-activity relationship for the first-in-class clinical steroid sulfatase inhibitor Irosustat (STX64, BN83495)
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Structure-activity relationship studies were conducted on Irosustat (STX64, BN83495), the first steroid sulfatase (STS) inhibitor to enter diverse clinical trials for patients with advanced hormone-dependent cancer. The size of its aliphatic ring was expanded; its sulfamate group was N,N-dimethylated, relocated to another position and flanked by an adjacent methoxy group; and series of quinolin-2(1H)-one and quinoline derivatives of Irosustat were explored. The STS inhibitory activities of the synthesised compounds were assessed in a preparation of JEG-3 cells. Stepwise enlargement of the aliphatic ring from 7 to 11 members increases potency, although a further increase in ring size is detrimental. The best STS inhibitors invitro had IC50 values between 0.015 and 0.025nM. Other modifications made to Irosustat were found to either abolish or significantly weaken its activity. An azomethine adduct of Irosustat with N,N-dimethylformamide (DMF) was isolated, and crystal structures of Irosustat and this adduct were determined. Docking studies were conducted to explore the potential interactions between compounds and the active site of STS, and suggest a sulfamoyl group transfer to formylglycine75 during the inactivation mechanism.
- Woo, L.W. Lawrence,Ganeshapillai, Dharshini,Thomas, Mark P.,Sutcliffe, Oliver B.,Malini, Bindu,Mahon, Mary F.,Purohit, Atul,Potter, Barry V.L.
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experimental part
p. 2019 - 2034
(2012/07/03)
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- Total synthesis, molecular editing and evaluation of a tripyrrolic natural product: The case of "butylcycloheptylprodigiosin"
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Conflicting reports are found in the literature on whether the ortho-pyrrolophane derivative 6, which has been named " butylcycloheptylprodigiosin" even though it is a cyclononane derivative, is a natural product or merely a mis-assigned structure. This dispute has now been resolved by an unambiguous total synthesis of this complex alkaloid which confirms the initial structure assignment. The chosen approach is largely catalysis-based, featuring the first application of a "Narasaka-Heck" reaction in natural product chemistry. This palladium-catalyzed transformation allows the unsaturated oxime ester 26 to be converted into the bicyclic dihydropyrrole 27. Other notable reactions of the reported approach to 6 are a regioselective Tsuji-Trost reaction of the doubly allylic acetate 21 with methyl acetoacetate. a base-induced aromatization of 27 to the corresponding pyrrole 28. a chemoselective oxidation of the benzylic methyl group in 33 with cerium ammonium nitrate in a biphasic reaction medium that does not affect the labile pyrrole nucleus, and a Suzuki cross-coupling for the completion of the heterocyclic domain. Diversification in the latter step leads to a set of analogues that differ from the natural product in the terminal (hetero)arene ring. This structural modification results in complete loss of the very pronounced ability of the parent compound 6 to induce oxidative cleavage in double stranded DNA in the presence of Cu11. Several cyclononane-, cyclononene- and cyclononadiene derivatives prepared en route to 6 have been characterized by crystal structure analysis, allowing the conformational behavior of nine-membered carbocycles to be studied.
- Fuerstner, Alois,Radkowski, Karin,Peters, Hartwig,Seidel, Guenter,Wirtz, Conny,Mynott, Richard,Lehmann, Christian W.
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p. 1929 - 1945
(2008/02/03)
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- CERTAIN MACROCYCLIC LACTAM DERIVATIVES
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The invention relates to macrocyclic lactam derivatives of formula I STR1 wherein R is hydrogen or acyl; m is an integer from 4 to 9 inclusive; n is 1 or 2; p is zero, 1 or 2; X is--CONH--or--NHCO--; Y is S, O or CH 2 ; R 1 is--COOH; or R 1 is STR2 in which R 2 is hydrogen, lower alkyl, aryl-lower alkyl, amino-lower alkyl, hydroxy-lower alkyl, acyloxy-lower alkyl, lower alkoxy-lower alkyl, mercapto-lower alkyl, lower alkyl-(thio, sulfinyl or sulfonyl)-lower alkyl, or carboxy-lower alkyl, R 3 is hydrogen or lower alkyl, and q is zero or an integer from 1 to 5 inclusive; or R 1 is STR3 in which R 4 is hydrogen, lower alkyl, lower alkoxy, hydroxy or acyloxy, and r is 1 or 2; or R 1 is STR4 in which s is 1 or 2; or R 1 is STR5 in which R 5 and R 6 independently represent hydrogen, lower alkyl, C 5-or C 6-cycloalkyl, (hydroxy-, acyloxy or lower alkoxy-) lower alkyl, carbocyclic or heterocyclic monocyclic aryl, or (hydroxy-, acyloxy-or alkoxy-) lower alkyloxy-lower alkyl; or R 5 and R 6 together with the nitrogen to which they are attached represent pyrrolidino, piperidino, morpholino, piperazino or N-alkylpiperazino; and macrocyclic sulfur and oxygen containing lactam ring isomers in which a CH 2 group of (CH 2) m in formula I is replaced by O or S, and Y represents CH 2 ; and pharmaceutically acceptable prodrug esters of any above said compound with a free carboxyl group; and pharmaceutically acceptable salts of any said compounds with a free acid or basic salt forming group; pharmaceutical compositions comprising said compounds; methods for the preparation of said compounds and for the preparation of intermediates; and methods of treating disorders in mammals which are responsive to the inhibition of neutral endopeptidases by administration of said compounds to mammals in need of such treatment.
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- Design and synthesis of an orally active macrocyclic neutral endopeptidase 24.11 inhibitor
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A potent macrocyclic inhibitor of neutral endopeptidase (NEP) 24.11 was designed using a computer model of the active site of thermolysin. This 10- membered ring lactam represents a general mimic for any hydrophobic dipeptide in which the two amino acid side chains bind to an enzyme in a contiguous orientation. The parent 10-membered ring lactam was synthesized and exhibited excellent potency as an NEP 24.11 inhibitor (IC50 = 3 nM). In order to improve oral bioavailability, various functionality was attached to the macrocycle. These modifications lead to CGS 25155, an orally active NEP 24.11 inhibitor that slows down the degradation of the cardiac hormone atrial natriuretic factor, producing a lowering of blood pressure in the DOCA-salt rat model of hypertension.
- MacPherson,Bayburt,Capparelli,Bohacek,Clarke,Ghai,Sakane,Berry,Peppard,Trapani
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p. 3821 - 3828
(2007/10/02)
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- Synthesis of Medium and Large Rings, XVI: Boat-shaped Arenes - Synthesis, Structure, and Properties of Paracyclophanes and (1,4)Naphthalinophanes
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A preparative synthesis of the compounds 2, 5, 7, and 11 starting from cyclononanone is described.Key steps are the conversion of 5,6,7,8,9,10-hexahydro-4H-cyclononafuran to the β,β'-heptanooxepines 1, which can be desoxygenated.The NMR spectra of the new cyclophanes are discussed in detail.The deformation angles α of the boat-shaped heptano-bridged benzene rings were determined for 5 and 11 by X-ray analysis.Values between 13.6 degree and 15.9 degree are found.In several respects heptano-bridged ansa compounds are interesting borderline cases: The oxepines 9 and 15 probably exist in a valence tautomeric equilibrium with the corresponding cyclophane oxides 10 and 16.The bis(acetoxymethyl)paracyclophane 2c still adds chlorine under mild conditions. 12 does not exist as β-naphthol but as "non-enolized" ketone.
- Hunger, Juergen,Wolff, Christian,Tochtermann, Werner,Peters, Eva-Maria,Peters, Karl,Schnering, Hans Georg von
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p. 2698 - 2722
(2007/10/02)
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