- Diazonium ion chemistry: Replacement of H by alkyl at the central carbon accelerates an SN2 substitution reaction
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The rate constants for hydrolysis of diazomethane, diazoethane and 1-diazopropane in aqueous 5% acetonitrile at 25°C and ionic strength 1 M (NaClO4) were measured by stopped-flow spectrophotometry. The pH-rate profile for diazomethane hydrolysis exhibits a pH-independent section in the lower pH range, 8-10, with a downward break at higher pH, as has been reported for slightly different reaction conditions. In the case of diazoethane and 1-diazopropane, the reaction remains pH independent up to pH > 13. General acid catalysis of the hydrolysis reactions of diazomethane and diazoethane were examined in the pH-independent regions. For a limited number of catalysts, the value of Bronsted α was 0.58 for both diazoalkanes. The downward break in the pH rate profile for diazomethane hydrolysis is consistent with what was previously concluded, rate-limiting protonation by H2O in the pH-independent region changing to rate-limiting attack of water on the diazonium ion in the pH-dependent region, the decrease in rate constant with increasing pH being attributed to deprotonation of the diazonium ion by hydroxide ion. The lack of a downward break in the pH-rate profiles for hydrolysis of the diazoethane and 1-diazopropane is attributed specifically to the increase, relative to the methyldiazonium ion, in the rate constant for water attack on the ethyl- and 1-propyldiazonium ions, perhaps by as much as >10 3-fold. Copyright
- Agnew, Tara E.,Kim, Hyun-Joong,Fishbein, James C.
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- Enantiospecific first total synthesis of (6S,7R)-silphiperfolan-6-ol
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Enantiospecific first total synthesis of the angular triquinane sesquiterpene (6S,7R)-silphiperfolan-6-ol has been accomplished, starting from 2-(3-isopropenyl-2-methylene-1-methylcyclopent-1-yl)acetic acid (readily available from (R)-limonene) employing an efficient, regioselective intramolecular rhodium carbenoid insertion into the CH bond of a tertiary methyl group as the key step.
- Srikrishna,Nagaraju, Gopalasetty,Sheth, Vishal M.
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- Terpenic Acids by Cyclopentane Annulation of Exocyclic Dienes. Synthesis of Triquinane Portion of Retigeranic Acid
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Tricyclic ester 5 has been prepared in 13 steps from (+)-pulegone.The key step in the synthesis of 5 involved the condensation of keto ester 15 with ethyl bromocrotonate under Reformatsky conditions to yield lactone 16 as one diastereomer.Either lithium diisopropylamine or 1,8-diazabicycloundec-7-ene was used to effect the elimination to the dienic acid 17, obtained as a mixture of diastereomers in an 80:20 ratio.Conditions were developed for the cyclopropanation of 18 in good isolated yields.The pyrolysis of 19 gave tricyclic ketone 20 in 50 percent yield.The 13C NMR data are provided for all relevant intermediates.The deoxygenation of this ketone provided ester 5.The structural and stereochemical assignments are based on data amassed previously on appropriate model compounds.Potential use of 5 in a convergent synthesis of retigeranic acid (3) is indicated.The concept of generality of this method in the context of total synthesis of other naturally occuring cyclopentene carboxylates is introduced.
- Hudlicky, Tomas,Short, Robert P.
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- General Method of Synthesis of Cyclopentanoid Terpenic Acids. Stereocontrolled Total Syntheses of (+/-)Isocomenic Acid and (+/-)-Epiisocomenic Acid
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(4β,8α)-1α,2,4β-Trimethyl-9α-carboxytricyclo4,8>undec-2-ene (1, isocomenic acid) and (4β,8α)-1α,2,4β-trimethyl-9β-carboxytricyclo4,8>undec-2-ene (28, epiisocomenic acid) were prepared in 10 steps from ester 13.The internal cyclopropanation of exocyclic acrylates and the subsequent vinylcyclopropane-cyclopentene rearrangement were used in an efficient synthesis of a key intermediate, triquinane 23, containing all of the contiguous quarternary centers.The utilization of abnormal Reformatsky reaction of 4-bromocrotonates with keto esters served in the preparation of important precursors to the cyclopentene annulation sequence, the lactone 15, and the dienic acid 19.Hydrogenation of 23 produced the keto ester 25a, which was converted in three steps to either 1 or 28 with complete control of stereochemistry.Carbon-13 data are reported for all intermediates.A total of eight natural products are accessible in a stereocontrolled fashion from keto ester 25a.The generality of this method is thus addressed in the context of system-oriented design of synthesis of cyclopentanoid terpenes.
- Short, Robert P.,Revol, Jean-Marc,Ranu, B. C.,Hudlicky, Tomas
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- Rapid assembly of the salvileucalin B norcaradiene core
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(Chemical Equation Presentation) Preparation of the polycyclic core of the cytotoxic natural product salvileucalin B is described. The key feature of this synthetic strategy is a copper-catalyzed intramolecular arene cyclopropanation to provide the central norcaradiene. These studies lay the foundation for continued investigations toward an enantioselective total synthesis of 1
- Levin, Sergly,Nanl, Roger R.,Relsman, Sarah E.
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- Photochemistry of matrix-isolated diazoethane and methyldiazirine: Ethylidene trapping?
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Photolysis of matrix-isolated diazoethane (1a) at 8 K produces mainly ethene (4a), along with a small amount of 3-methyldiazirine (2a). ESR experiments employing a variety of irradiation conditions matrix media (Ar, N2, Xe) show that triplet ethylidene (3T) is not an observable photoproduct. Similar experiments fail to reveal direct evidence for either singlet or triplet ethylidene by IR or UV-vis spectroscopy. Photolysis of nascent 3-methyldiazirine (2a) also fails to yield ethylidene. Deuterium substitution produces no detectable change in the chemistry. In carbon monoxide-doped matrices, photolysis of 1 generates 3-methyldiazirine (2) and ethene (4) as well as a small amount of methylketene (5). The most plausible interpretation of these results postulates that (i) trapping of incipient singlet ethylidene (3S) by CO competes with the facile hydrogen migration and (ii) intersystem crossing to the triplet does not compete with hydrogen migration.
- Seburg, Randal A.,McMahon, Robert J.
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- 3H-labelled alkyl-nucleotides, -nucleosides and -bases for the immunoanalytical quantification of DNA damage and repair
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Analysis of the formation and repair of structurally modified DNA is of particular interest in the study of carcinogenesis, cancer therapy and aging. The quantification of specific DNA lesions by sensitive immunoanalytical methods requires radiotracers with high specific activity. We describe the synthesis of 3H-labelled adenine-, cytosine-, guanine- and thymine-alkyl derivatives by nucleophilic N- and O-alkylation using alkyl halides and diazoalkanes: 3-alkyl[8-3H]adenine (Alkyl = Me, Et, n-Bu); O6 -alkyl-deoxy[1′,2′-3 H]guanosine (Alkyl = Me, Et, i-Pro, n-Bu); O6-ethyl-deoxyguanosine-5′ -triphosphate ([2-3H-Ethyl]; [8-3H]); O6 -alkyl-9-hydroxyhexyl-[8-3H guanine (Alkyl=Me, Et); 7-ethyl-[8,5′-3H]guanosine-3′,5′-cyclic-phosphate; O2 -and O4-alkyl-[methyl, 1′,2′-3 H]thymidine (Alkyl = Me, Et); the conversion of 3H-labelled thymidine to the corresponding 5-methylcytidine; the synthesis of three different 8-oxoguanine tracers; and the generation of thymidine glycol (5,6-dihydroxy-5,6-dihydro-[methyl-3H]thymidine) from thymidine. All radiotracers were sucessfully employed in competitive radioimmunoassays for the quantification of defined DNA alkylation products in DNA repair analyses. Copyright
- Drosdziok, Wolfgang,Lutze, Catrin,Krueger, Kai,Gluesenkamp, Karl-Heinz,Rajewsky, Manfred F.
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- The substrate dependent competitive formation of cyclobutanones and cyclopentanones in an intramolecular rhodium carbenoid CH insertion reaction: Enantiospecific total synthesis of silphiperfol-6-ene
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The enantiospecific total synthesis of silphiperfol-6-ene has been accomplished starting from the readily available monoterpene (R)-limonene, employing a rhodium carbenoid insertion into the CH bond of a tertiary methyl group. A substrate dependent competitive insertion of the rhodium carbenoid in the γ- and β-CH bonds to form cyclopentanone and cyclobutanones, respectively, has been described.
- Srikrishna, Adusumilli,Nagaraju, Gopalasetty
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- Metal-Free Ring-Expansion Reaction of Six-membered Sulfonylimines with Diazomethanes: An Approach toward Seven-Membered Enesulfonamides
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A new metal-free, ring-expansion reaction of six-membered N-sulfonylimines with unstable diazomethanes, generated in situ from the N-tosylhydrazones, has been developed. This reaction delivers valuable seven-membered enesulfonamides by a Tiffeneau-Demjanov rearrangement and intramolecular proton transfer tautomerization process. Moreover, this ring-expansion reaction can be carried out in a one-pot fashion and scaled up to the gram scale by using aryl aldehydes, without the need to isolate the N-tosylhydrazone. A diazo thing: The title reaction between cyclic N-sulfonylimines and diazo compounds generated in situ from the N-tosylhydrazones is simple and functional-group tolerant. It thus delivers valuable seven-membered sulfonamides in up to 95 % yield. Moreover, this reaction can be carried out in one-pot starting from the aryl aldehydes, without the need to isolate the N-tosylhydrazone (right).
- Xia, An-Jie,Kang, Tai-Ran,He, Long,Chen, Lian-Mei,Li, Wen-Ting,Yang, Jin-Liang,Liu, Quan-Zhong
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supporting information
p. 1441 - 1444
(2016/02/12)
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- Synthetic approaches to the daucane sesquiterpene derivatives employing the intramolecular Buchner cyclisation of α-diazoketones
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The use of the intramolecular Buchner cyclisation of an α-diazoketone as an approach to the synthesis of daucane sesquiterpenes is described; in particular the synthesis of the cis-fused analogue of dihydro CAF-603. The key step in the synthesis is the intramolecular Buchner cyclisation, which provides the bicyclo[5.3.0]decane framework with the required stereochemistry at the quaternary centre generated in the cyclisation. A synthetic route enabling access to an asymmetric synthesis is also outlined.
- Foley, David A.,O'Leary, Patrick,Buckley, N. Rachael,Lawrence, Simon E.,Maguire, Anita R.
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p. 1778 - 1794
(2013/03/13)
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- Design of ciprofloxacin derivatives that inhibit growth of methicillin resistant staphylococcus aureus (MRSA) and methicillin susceptible staphylococcus aureus (MSSA)
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Three derivatives of ciprofloxacin (compound B, C, and D) were constructed utilizing microwave synthesis methodology (compound D) or diazoalkane reaction in nonaqueous solvent (compounds B and C). The final structures of the derivatives featured an ester group in place of the original carboxyl group of the ciprofloxacin. These ester groups contained aliphatic single carbon (compound B), two carbon length (compound C), or three carbon length propyl ester group (compound D). The ester groups strongly affected the molecular properties of the parent ciprofloxacin. As the size of the ester group increased the formula weight, molar volume, and number of rotatable bonds increased. The Log P for these compounds were -0.701, -0.441, -0.065, 0.437 for ciprofloxacin, B, C, and compound D, respectively. Numerical values of dermal permeability coefficient (Kp) increased rapidly as length of the ester carbon chain increased. The immediate consequence of Kp increase is an increased skin penetration rate based on dose and time span of administration. Polar surface area for ciprofloxacin is 74.569 Angstroms2, but decreases to 63.575 Angstroms2 for all three derivatives. All three derivatives of ciprofloxacin showed zero violations of the Rule of 5, indicating these drugs would have favorable bioavailability. Compounds A, B, C, and D were placed into tissue culture with methicillin resistant and susceptible Staphylococcus aureus (MRSA and MSSA, respectively) to determine levels of bacterial growth inhibition. All compounds induced greater than 60 % inhibition of MSSA at concentrations as low as 15.63 micrograms/milliliter. All four compounds induced greater than 80 % inhibition of MRSA at concentratins as low as 15.63 micrograms/milliliter. Development of novel drug designs will benefit the clinical treatment of dangerous infections of MSSA and MRSA.
- Bartzatt, Ronald,Cirillo, Suat L.G.,Cirillo, Jeffrey D.
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experimental part
p. 51 - 56
(2011/12/14)
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- Palladium-catalyzed cyclopropanation of alkenyl silanes by diazoalkanes: Evidence for a Pd0 mechanism
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Alkenyl silanes are efficiently converted to the corresponding silyl cyclopropanes in the presence of a slight excess of diazomethane (2-4 equiv) and a low loading of Pd(OAc)2 (-3 mol%, which corresponds to a turnover frequency of 40000 h-1. Competition experiments revealed that vinyl silanes can be selectively cyclopropanated in the presence of an aliphatic terminal alkene and styrene. The complex [Pd 20(DVTMS)3] (38, DVTMS = divinyltetramethyldisiloxane) proved to be an exceptionally active catalyst for the cyclopropanation reaction, giving complete conversion at -35 °C in 1 min. Intermolecular and intramolecular competition experiments with DVTMS (36), both with Pd(OAc)2 and 38, provided strong evidence for a Pd 0(alkenyl silane)3 resting state. Detailed density functional calculations on the reaction pathways for the cyclopropanation of trimethylvinylsilane and DVTMS by diazomethane with Pd0 corroborated the experimental observations.
- Berthon-Gelloz, Guillaume,Marchant, Melanie,Straub, Bernd F.,Marko, Istvan E.
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supporting information; experimental part
p. 2923 - 2931
(2009/12/01)
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- Enantiospecific synthesis of thaps-8-en-5-ol via stereospecific intramolecular chirality transfer
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Enantiospecific synthesis of thaps-8-en-5-ol, comprising of the carbon framework of a small group of sesquiterpenes containing three contiguous quaternary carbon atoms has been described. (R)-Carvone has been employed as the chiral starting material and a combination of intramolecular alkyation and Criegee fragmentation have been employed for intramolecular stereospecific transfer of the chirality. An intramolecular diazoketone cyclopropanation and regioselective cyclopropane ring cleavage reactions have been employed for the creation of the three requisite contiguous quaternary carbon atoms.
- Srikrishna,Anebouselvy
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p. 449 - 459
(2008/09/20)
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- METHODS, COMPOSITIONS, AND FORMULATIONS FOR PREVENTING OR REDUCING ADVERSE EFFECTS IN A PATIENT
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The present invention provides methods, compositions, formulations, and kits related to acadesine, or a prodrug, analog, or salt thereof, and/or a blood clotting inhibitor for preventing or reducing adverse side effects in a patient. The type of patient that may benefit includes a patient with decreased left ventricular function, a patient with a prior myocardial infarction, a patient undergoing non-vascular surgery, or a fetus during labor and delivery.
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Page/Page column 83-84
(2010/11/24)
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- Stereocontrolled syntheses of the nemorensic acids using 6-diazoheptane-2,5-dione in carbonyl ylide cycloadditions
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Levulinic acid-derived 6-diazoheptane-2,5-dione (9) serves as a common precursor in a formal synthesis of frontalin 19, and in syntheses of cis-nemorensic acid 1, 4-hydroxy-cis-nemorensic acid 2, 3-hydroxy-cis-nemorensic acid 3, and nemorensic acid 4. The key step in these syntheses is the Rh 2(OAc)4-catalyzed tandem carbonyl ylide formation-intermolecular 1,3-dipolar cycloadditions of diazodione 9 with formaldehyde, alkynes or allene, which occur with high regioselectivity. Subsequent oxidative cleavage of the ring originally derived from the cyclic carbonyl ylide intermediate provides a straightforward access to polysubstituted tetrahydrofurans, and in particular an efficient entry to the nemorensic acids. Enantioselective cycloadditions with diazodione 9, using chiral rhodium catalysts, gave cycloadducts in up to 51% ee.
- Hodgson, David M.,Le Strat, Frederic,Avery, Thomas D.,Donohue, Andrew C.,Brueckl, Tobias
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p. 8796 - 8803
(2007/10/03)
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- Sustained-release preparation
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According to a first embodiment, there is provided a sustained-release preparation comprising a water-insoluble or slightly water-soluble polyvalent metal salt of a water-soluble physiologically active substance which is not an endothelin antagonist, and a biodegradable polymer. The sustained-release preparation of the first embodiment is highly efficient in incorporating the water-soluble physiologically active substance and suppresses the initial burst of the water-soluble physiologically active substance. The sustained-release preparation of the present invention is capable of releasing the water-soluble physiologically active substance while retaining its bioactivity after administration in vivo. Furthermore, the water-soluble physiologically active substance in the sustained-release preparation is kept stable for a long period of time, with little loss of bioactivity. According to a second embodiment, there is provided a sustained-release preparation comprising an anti-endothelin substance and a biodegradable polymer. The sustained-release preparation of the present invention sustainedly releases an anti-endothelin substance, serving well in the treatment of endothelin-associated diseases.
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- Asymmetric Wolff rearrangement reactions with α-alkylated-α-diazoketones: Stereoselective synthesis of α-substituted-β-amino acid derivatives
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matrix presented Photoinduced asymmetric Wolff rearrangement reactions were performed with α-amino-α′-melhyl-α′-diazoketones to afford α-methyl-β-amino acid esters with good stereoselectivity. Factors that may influence the stereochemistry were examined, including steric effects and temperature dependence, which had a great impact on the stereochemistry.
- Yang, Hua,Foster, Katherine,Stephenson, Corey R. J.,Brown, William,Roberts, Edward
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p. 2177 - 2179
(2007/10/03)
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- A formal total synthesis of (±)-α-pinguisene and (±)-pinguisenol
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Formal total synthesis of (±)-α-pinguisene and (±)-α-pinguisenol, containing a cis-1,2,6,7-tetramethylbicyclo[4.3.0]-nonane skeleton incorporating two vicinal quaternary carbon atoms and four cis oriented methyl groups on four contiguous carbon atoms, isolated from liverworts is described. Thus, an orthoester Claisen rearrangement of the allyl alcohol 14, obtained from the Hagemann's ester 15, afforded the ene ester 18. Hydrolysis of the ketal and ester moieties transformed the ene ester 18 into keto acid 23. Intramolecular cyclopropanation of the diazo ketone 24 derived from the keto acid 23 afforded a 3:2 mixture of chromatographically separable tricyclic diones 25 and 26. Simultaneous regioselective reductive cyclopropane-ring cleavage and reduction of the cyclohexanone carbonyl in the dione 25 with lithium in liquid ammonia furnished the keto alcohol 27, which on Wolff-Kishner reduction followed by oxidation of the alcohol afforded the bicyclic ketone 11, Schinzer's precusor of pinguisenol 9 and α-pinguisene 10.
- Srikrishna, Adusumilli,Vijaykumar, Dange
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p. 1265 - 1271
(2007/10/03)
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- Stereoselective diazoalkane cycloadditions to chiral 5-alkylidene-1,3- dioxan-4-ones and 3-benzylidene-β-lactones
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Stereoselective 1,3-dipolar cycloaddition of diazoalkanes to (E)-5- alkylidene-1,3-dioxan-4-ones 1 and the (Z)-isomers (Z)-I afforded spiropyrazolines 3 and 10, respectively. The optically active 2-benzylidene- 3-methyl-β-lactone (8) was synthesized from the corresponding 5-benzylidene- 1,3-dioxan-4-one 1f by hydrolysis and recyclization and added diazomethane with opposite stereodifferentiation. Photochemical elimination of nitrogen from spiropyrazolines 3 gave enantiomerically pure spirocyclopropanes 12 that could be further transformed to cyclopropanecarboxylic acids 13 and derivatives 14.
- Bartels, Annett,Jones, Peter G.,Liebscher, Juergen
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p. 1645 - 1654
(2007/10/03)
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- Matrix for sustained-release preparation
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The present invention relates to a matrix for sustained-release preparation comprising an ester formed at a terminal carboxyl group of a straight-chain polyester which essentially consists of an α-hydroxymonocarboxylic acid. The matrix is stable to light, heat, moisture, coloring etc., and is of low toxicity. The sustained-release preparation produced by using the ester of the present invention offers stable drug release over an extended period of time, ensuring sustained stable effect. Furthermore, the sustained-release preparation does not show excess drug release just after administration.
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- Azabicyclic compounds for treating dementia
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A compound of formula (I) useful for treating dementia or a pharmaceutically acceptable salt thereof: STR1 in which one of X and Y represents hydrogen and the other represents Z, where Z is a group in which Q represents a 3-membered divalent residue completing a 5-membered aromatic ring and comprises two or three nitrogen atoms, any amino nitrogen being substituted by a C1-2 alkyl, cyclopropyl or propargyl group, r represents the integer of 2 or 3, s represents an integer of 1 or 2 and t represents 0, with the proviso that when Y is hydrogen s is 1.
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- Degradation and disposal of some antineoplastic drugs
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Bulk quantities and pharmaceutical preparations of the antineoplastic drugs carmustine (BCNU), lomustine (CCNU), chlorozotocin, N-[2-chloroethyl]-N'-[2,6-dioxo-3-piperidinyl]-N-nitrosourea (PCNU), methyl CCNU, mechlorethamine, melphalan, chlorambucil, cyclophosphamide, ifosfamide, uracil mustard, and spiromustine may be degraded using nickel-aluminium alloy in KOH solution. The drugs are completely destroyed and only nonmutagenic reaction mixtures are produced. destruction of cyclophosphamide in tablets requires refluxing in HCl before the nickel-aluminium alloy reduction. Streptozotocin, chlorambucil, and mechlorethamine may be degraded using an excess of saturated bicarbonate solution. The nitrosourea drugs BCNU, CCNU, chlorozotocin, PCNU, methyl CCNU, and streptozotocin were also degraded using hydrogen bromide in glacial acetic acid. The drugs were completely destroyed but some of the reaction mixtures were mutagenic and the products were found to be, in some instances, the corresponding mutagenic, denitrosated compounds.
- Lunn,Sansone,Andrews,Hellwig
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p. 652 - 659
(2007/10/02)
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- Cyclopentene Annulation via Intramolecular Addition of Diazo Ketones to 1,3-Dienes. Applications to the Synthesis of Cyclopentanoid Terpenes
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Initial model studies investigating the utility of a new intramolecular cyclopentene annulation procedure are described as pertaining to the preparation of bicyclooctenones.Several 1-diazo-5,7-octadien-2-ones substituted at the 1-, 7-, or 8-position were decomposed in the presence of Cu(acac)2 to yield stereospecifically the corresponding vinylcyclopropanes 13, 16, 21, 24, and 27.The thermal as well as the rhodium-promoted modes of rearrangement to the appropriate cyclopentenes 14, 17, 22a,b, and 28a,b were studied.Where necessary, diastereomers were separatedand structurally assigned by relying on 13C NMR spectroscopy. 13C NMR data are provided for all new compounds in the bicyclooctane series to serve as an aid in assignments of cyclopentanoid terpenes synthesized by this methodology.The intramolecular cylopropanation-rearrangement sequence of dienic diazo ketones has been shown to provide facile access to bicyclooctanes of the type 14, 17, 22a,b, and 25a,b which are of value as terpene synthons.Enhanced stereoselectivity was observed in the rhodium-promoted cyclopentene rearrangements in favor of the less concave diastereomers (22a, 25a, and 28a).Finally, the sesquiterpene hirsutene (31) was synthesized in 37percent overall yield by this methodology. 13C NMR data for several tricyclo2,6>undecane compounds are also provided.
- Hudlicky, Tomas,Koszyk, Francis J.,Kutchan, Toni M.,Sheth, Jagdish P.
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p. 5020 - 5027
(2007/10/02)
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- Cyclopropanones. Formation of Vinylcyclopropanols and Their Rearrangement to Cyclobutanones
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Vinylcyclopropanols, formed by the addition of vinylmagnesium bromide to the ethyl hemiketal of cyclopropanone, may be converted to cyclobutanone derivatives on reaction with various electrophiles.The ring enlargement of 1-vinyl-2-methylcyclopropanol takes place by preferential migration of the more highly substituted carbon atom.
- Wasserman, Harry H.,Hearn, Michael J.,Cochoy, Robert E.
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p. 2874 - 2880
(2007/10/02)
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