- Enantioselective total synthesis of (+)-amabiline
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The first total synthesis of (+)-amabiline, an unsaturated pyrrolizidine alkaloid from Cynoglossum amabile, is reported. This convergent, enantioselective synthesis proceeds in 15 steps (10-step longest linear sequence) in 6.2% overall yield and features
- Senter, Timothy J.,Fadeyi, Olugbeminiyi O.,Lindsley, Craig W.
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- Synthesis of the Dipeptide Hydroxyethylene Isostere of Leu-Val, a Transition State Mimic for the Control of Enzyme Function
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Dipeptide isosteres have recently begun to attract attention because of their ability to mimic the transition states of proteolytic enzymes or to alter or enhance the function of regulatory peptides.We have developed a general approach that may be used to prepare a diverse array of dipeptide hydroxyethylene isosteres.As an example we have prepared a mimic of Leu-Val, the cleavage site of the enzyme renin.The sequence begins with leucinal 8. which is converted to the aldehyde 15ct by addition of vinylmagnesium bromide to form an allylic alcohol.This is converted to the acetonide, ozonized, and equilibrated to give the trans aldehyde 15t as the primary product.A Wadsworth-Emmons olefination fallowed by hydrogenation affords the ester 30 as a mixture of isomers.Hydrolysis of the acetonide and purification gives the desired lactone 26β in 23percent overall yield from BOC-leucinol.
- Wuts, Peter G. M.,Putt, Sterling R.,Ritter, Allen R.
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- Total synthesis of a novel 2-thiabicyclo[3.2.0]heptan-6-one analogue of penicillin N
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A route has been developed which allows synthesis of novel cyclobutanone analogues of penicillin. This is illustrated by the synthesis of (1R,4R,5R,5′R,7S)-(1b) and (1S,4S,5S,5′R,7R)-7-[5′ -amino-5′-carboxy]pentanamido]-2-thiabicyclo[3.2.0] heptan-6-one-4-carboxylate (1a), an analogue of penicillin N. The key steps in the synthesis were the formation of the bicyclic structure via a [2+2] cycloaddition and the introduction of nitrogen at C7 via an intramolecular nitrene insertion.
- Ferguson, Amanda C.,Adlington, Robert M.,Martyres, Domnic H.,Rutledge, Peter J.,Cowley, Andrew,Baldwin, Jack E.
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- Synthesis and olfactoric activity of side-chain modified β-santalol analogues
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Three osmophoric points have been postulated to be necessary for the sandalwood scent of β-santalol derivatives. One of these points, close to the hydroxyl group, is highly specific on the stereochemistry and, in particular, on the molecular shape. The ro
- Buchbauer, Gerhard,Sunara, Aneta,Weiss-Greiler, Petra,Wolschann, Peter
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- Design, Synthesis, and Biological Evaluation of Novel Pyrimido[4,5-b]indole Derivatives against Gram-Negative Multidrug-Resistant Pathogens
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Due to the poor permeability across Gram-negative bacterial membranes and the troublesome bacterial efflux mechanism, only a few GyrB/ParE inhibitors with potent activity against Gram-negative pathogens have been reported. Among them, pyrimido[4,5-b]indol
- Kong, Qidi,Pan, Wei,Xu, Heng,Xue, Yaru,Guo, Bin,Meng, Xin,Luo, Cheng,Wang, Ting,Zhang, Shuhua,Yang, Yushe
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supporting information
p. 8644 - 8665
(2021/06/28)
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- P2X4 RECEPTOR MODULATING COMPOUNDS
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Provided herein are P2X4 receptor modulating compounds, methods of their synthesis, pharmaceutical compositions comprising the compounds, and methods of their use. The compounds provided herein are useful for the treatment, prevention, and/or management of various disorders, including but not limited to, chronic pain, neuropathy, inflammatory diseases and central nervous system disorders.
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Paragraph 00256
(2015/06/25)
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- A Total synthesis of aliskiren starting from D-Tartrate diester
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A formal total synthesis of aliskiren was accomplished. A key in our synthesis was to use the symmetric ciscisoid-Cis-Bis-Lactone 3' as a precursor, which was prepared from D-tartrate diester. Appending the end groups and functional group transformations completed the synthesis.
- Kim, Ji Hei,Ko, Soo Y.
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p. 3777 - 3781
(2014/01/17)
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- Investigation on lewis acid mediated diels-alder reactions of 2-phosphono-2-alkenoates. Application to total synthesis of (±)-α- alasken-8-one via reductive alkylation of resulting adduct
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(Chemical Equation Presented) The Lewis acid mediated Diels-Alder reactions of three 2-phosphono-2-alkenoates including triethyl 2-phosphonoacrylate (1), triethyl 2-phosphonobut-2-enoate (2), and ethyl 2-(diethoxyphosphono)-3- methylbut-2-enoate (3) have been investigated. Of several Lewis acids tested, tin(IV) chloride was shown to be the most effective at enhancing the regio- and stereoselectivity of the reactions of 1 with the electron-rich dienes to result in the formation of the single regio- and/or stereoisomers in good yields. Bearing the β methyl group(s), 2 displayedmuch less reactivity than 1 while 3 was completely unreactive under the study's conditions. Throughout the investigation, we found that the cycloadditions of 2, especially of the Z-isomer, could be efficiently induced by using zinc chloride at elevated temperatures. Furthermore, a lithium naphthalenide (LN)-induced reductive alkylation process was applied to the resulting Diels-Alder adducts 4 to allow the phosphono group at the quaternary carbon centers to be replaced by various alkyl groups to afford the alkyl-substituted esters 12, therefore practically turning 1 and 2 into the useful synthetic equivalents of the corresponding 2-alkyl 2-alkenoates that usually display poor Diels-Alder reactivity. Application of this combined operation has facilitated the total synthesis of the sesquiterpene natural product α-alasken-8-one (8) in racemic form.
- Liao, Chuan-Cheng,Zhu, Jia-Liang
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body text
p. 7873 - 7884
(2010/01/16)
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- CHEMICAL COMPOUNDS
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The present invention relates to novel compounds with a variety of therapeutic uses, more particularly novel naphthalene compounds that are particularly useful for selective estrogen receptor modulation.
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Page/Page column 119
(2010/02/15)
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- Absolute configuration and synthesis of β- and δ-lactones present in the pheromone system of the giant white butterfly Idea leuconoe
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Males of the giant white butterfly Idea leuconoe release a complex mixture of compounds during courtship. Besides alkaloids, aromatics, terpenoids and hydrocarbons, several lactones have been identified in the pheromone bouquet. Two simple stereoselective methods to create the lactones in good enantiomeric excesses have been developed. The generation of the stereocenters of the β-lactones la and lb is based on a controlled C-C coupling by a Horner-Wadsworth-Emmons approach, followed by asymmetric dihydroxylation, whereas the synthesis of the δ-lactone 3b uses an enantioselective hydrogenation of a dioxoalkanoate precursor. The absolute configurations of the natural lactones 1a, 1b and 3b were determined by gas chromatography on a chiral stationary phase. Both 1a and 1b are of (S,S) configuration, suggesting their biosynthetic origin from (-)-viridifloric acid (7a) or (-)norviridifloric acid (7b), respectively. In contrast, natural 3b is a mixture of all enantiomers, in which the (5S,7S) enantiomer dominates. Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002.
- Stritzke, Katja,Schulz, Stefan,Nishida, Ritsuo
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p. 3884 - 3892
(2007/10/03)
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- Exploration of Neutral Endopeptidase Active Site by a Series of New Thiol-Containing Inhibitors
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With the aim of characterizing the active site of the neutral endopeptidase and especially its putative S1 subsite, two series of new thiol inhibitors designed to interact with the S1, S'1, and S'2 subsites of the enzyme have been synthesized.These molecules correspond to the general formula HSCH(R1)CH(R2)CONHCH(R3)COOH (series I) and HSCH(R1)CH(R2)CONHCH(R3)CONHCH(R4)COOH (series II).Due to the synthetic pathway used, these inhibitors were obtained as mixtures of four stereoisomers.HPLC separation of the stereoisomers of 17 HSCHCH(CH2Ph)CONHCH(CH3)COOH allowed the stereochemical dependence of the inhibitory potency to be determined.The most active isomer 17b (IC50 = 3.6 nM) is assumed to have the S,S,S stereochemistry as deduced from both NMR and HPLC data.Although none of the inhibitors obtained were significantly more active than thiorphan, HSCH2CH(CH2Ph)CONHCH2COOH (IC50 = 4 nM), which interacts only with the S'1 and S'2 subsites of NEP, their enhanced hydrophobicity is expected to improve their pharmacokinetic properties.All these compounds displayed low affinities for ACE (IC50S > 1 μM).The determination of the IC50S of two inhibitors of series II for NEP and for a mutated enzyme in which Arg102 was replaced by Glu102 allowed their mode of binding to the active site of NEP to be characterized.The R2 and R3 chains fit the S'1-S'2 subsites, while the R4 group is probably located outside the active site.Taken together these results indicate that the R1 chain of these inhibitors creates no additional stabilizing interactions with the active site of NEP.Two hypotheses may account for this: there is no hydrophophobic S1 subsite in NEP or the inhibitors have structures which are too constrained for optimized interactions with the active site.
- Gomez-Monterrey, Isabel,Turcaud, Serge,Lucas, Evelyne,Bruetschy, Luce,Roques, Bernard P.,Fournie-Zaluski, Marie-Claude
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- Reaction of Diethyl Phosphorochloridite with Enolates: A General Method for Synthesis of β-Keto Phosphonates and α-Phosphono Esters through C-P Bond Formation
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The reaction of ketone enolates with diethyl phosphorochloridite, followed by air oxidation of the intermediate reaction products, has proven to be a general and convenient method for preparation of β-keto phosphonates.Fourteen β-keto phosphonates have been prepared by this method, in an average yield greater than 60percent.This procedure also appears to be applicable to preparation of both α-phosphono aldehydes and α-phosphono esters.Although special precautions may be necessary to avoid aldol condensation during formation of aldehyde enolates, in two cases it was shown that the resulting enolates react readily with diethyl chlorophosphite.Finally, a set of five ethyl esters was converted to α-phosphono esters by this method.Yields of the α-phosphono esters are influenced by steric hindrance at the enolate carbon, but the average yield for this series was ca. 70percent.Because this synthetic method relies upon an electrophilic phosphorus reagent for formation of the C-P bond, it is complementary to the traditional Arbuzov synthesis.On the basis of the 21 examples presented here, it appears to be more widely applicable.
- Lee, Koo,Wiemer, David F.
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p. 5556 - 5560
(2007/10/02)
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- 5-Substituted amino-4-hydroxy-pentenoic acid derivatives and their use
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A 5-substituted amino-4-hydroxy-pentenoic acid or its salt represented by the formula: wherein each of R1 and R2 which may be the same or different is a hydrogen atom, a lower alkyl group, an aralkyl group, a lower alkoxycarbonyl group, an aryloxycarbonyl group, an aralkyloxycarbonyl group or a lower alkanoyl group which may be substituted by from one to three substituents selected from the group consisting of an amino group, a hydroxyl group, a carboxyl group, an aryloxy group, an aralkyloxycarbonylamino group, a lower alkoxycarbonylamino group and a group (wherein each of X1 and X2 which may be the same or different is a hydrogen atom, a lower alkyl group, an aryl group or an aralkyl group, or X1 and X2 form together with the adjacent nitrogen atom a 5- or 6-membered heterocyclic group which may further contain a hetero atom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom) and which may further contain a double bond in its carbon chain, each of R3, R4 and R6 which may be the same or different is a hydrogen atom, a lower alkyl group, a cycloalkyl group, a cycloalkylalkyl group, an aryl group, an aralkyl group or a residue of an acidic, neutral or basic amino acid, R5 is a hydrogen atom or a lower alkyl group, R7 is a hydrogen atom, a lower alkyl, cycloalkyl, cycloalkylalkyl or aralkyl group which may be substituted by one or two hydroxyl groups or a residue of an acidic, neutral or basic amino acid, R8 is a hydroxyl group, a -OY group (wherein Y is a lower alkyl group, an aryl group, an aralkyl group, a lower alkoxyalkyl group, a lower alkanoyloxyalkyl group, a lower alkoxycarbonyloxyalkyl group, or a 1-phthalidyl group) or a group (wherein each of Y1 and Y2 which may be the same or different is a hydrogen atom, a lower alkyl group, an aryl group, an aralkyl group or a cycloalkyl group, or Y1 and Y2 form together with the adjacent nitrogen atom a 5- or 6-membered heterocyclic group which may further contain a hetero atom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom), and each of n and m which may be the same or different is 0 or 1.
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