- Divergent asymmetric total synthesis of all four pestalotin diastereomers from (R)-glycidol
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All four chiral pestalotin diastereomers were synthesized in a straightforward and divergent manner from common (R)-glycidol. Catalytic asymmetric Mukaiyama aldol reactions of readily-available bis(TMSO)diene (Chan’s diene) with (S)-2-benzyloxyhexanal der
- Moriyama, Mizuki,Nakata, Kohei,Fujiwara, Tetsuya,Tanabe, Yoo
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- Synthesis and Characterization of the Selective, Reversible PKCβ Inhibitor (9 S)-9-[(Dimethylamino)methyl]-6,7,10,11-tetrahydro-9 H,18 H-5,21:12,17-dimethenodibenzo[ e,k]pyrrolo[3,4- h][1,4,13]oxadiazacyclohexadecine-18,20(19 H)-dione, Ruboxistaurin (LY333531)
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The demonstrated role of PKCβ in mediating amphetamine-stimulated dopamine efflux, which regulates amphetamine-induced dopamine transporter trafficking and activity, has promoted the research use of the selective, reversible PKCβ inhibitor (9S)-9-[(dimethylamino)methyl]-6,7,10,11-tetrahydro-9H,18H-5,21:12,17-dimethenodibenzo[e,k]pyrrolo[3,4-h][1,4,13]oxadiazacyclohexadecine-18,20(19H)-dione, ruboxistaurin. Despite the interest in development of ruboxistaurin as the mesylate monohydrate (Arxxant) for the treatment of diabetic retinopathy, macular edema, and nephoropathy, several crucial details in physicochemical characterization were erroneous or missing. This report describes the synthesis and full characterization of ruboxistaurin free base (as a monohydrate), including X-ray crystallography to confirm the absolute configuration, and of the mesylate salt, isolated as a hydrate containing 1.5 mol of water per mole.
- Lewin, Anita H.,Brieaddy, Larry,Deschamps, Jeffrey R.,Imler, Gregory H.,Mascarella, S. Wayne,Reddy, P. Anantha,Carroll, F. Ivy
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p. 246 - 251
(2018/09/25)
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- Diastereoselective Desymmetrization of p-Quinamines through Regioselective Ring Opening of Epoxides and Aziridines
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A highly diastereoselective desymmetrization of p-quinamines via regioselective ring opening of epoxides and aziridines under mild conditions has been developed. A chairlike six-membered transition state with minimized 1,3-diaxial interactions explains the relative stereoselectivity of the cyclization reaction. This transition-metal free [3 + 3] annulation reaction provides rapid access to fused bicyclic morpholines and piperazines with a tetrasubstituted carbon center in high yields. In addition, it also allows the synthesis of enantioenriched products by using easily accessible chiral nonracemic epoxides and aziridines.
- Jadhav, Sandip B.,Chegondi, Rambabu
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supporting information
p. 10115 - 10119
(2019/12/24)
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- Prepartion method of itraconazole
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The invention discloses a preparation method of itraconazole. Raceme-glycidol which is cheap and easy to obtain is adopted as raw materials, hydroxyls at the two ends are protected by trityl and benzyl and then esterified by 2,4-dichlorobenzene formyl chloride, then, a silylation Grignard addition reaction and a beta-silicyl alcohol elimination reaction are adopted for reducing carbonyl into carbon-carbon double bonds, iodine is adopted for performing an olefin addition reaction and a stereoselectivity ring-closure reaction, triazole replacement and debenzylation are performed, and tosyl is introduced to obtain a compound 9; the compound and a compound 10 are subjected to a condensastion reaction to obtain itraconazole; the overall synthesis process is small in pollution, easy to process, few in by-product, high in reaction selectivity and purity, environmentally friendly, low in production cost and suitable for industrial production; the defects that in the prior art, the selectivity is poor, multiple by-products are produced, the yield is low, and expensive catalysts and reagents with large environmental pollution are avoided are avoided.
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Paragraph 0043; 0044; 0045; 0046
(2017/04/29)
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- Modular synthesis of dihydroxyacetone monoalkyl ethers and isosteric 1-hydroxy-2-alkanones
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Straightforward methods for the efficient, systematic preparation of libraries of the title compound classes have been evaluated. A general and efficient modular route to dihydroxyacetone monoethers was developed based on trityl glycidol, which, through epoxide opening, oxidation, and deprotection, provided variously alkylated ethers by three routine operations in good overall yields (eight examples, 24-59 %). The preparation of structurally related 1-hydroxyalkanones depends on the availability of the most economic starting materials and on their physicochemical properties. Thus, the most practical one-step approaches consisted of the sec-selective oxidation of short-chain 1,2-diols (≤ C6) using NaOCl, and the direct ketohydroxylation of 1-alkenes (≥ C6) using buffered stoichiometric KMnO4 or catalytic RuO4 with reoxidation by oxone, for which mostly good overall yields were achieved on a multigram scale (nine examples, 15-78 %).
- Güclü, Deniz,Rale, Madhura,Fessner, Wolf-Dieter
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supporting information
p. 2960 - 2964
(2015/04/27)
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- Synthesis of a structural analogue of the repeating unit from streptococcus pneumoniae 19F capsular polysaccharide based on the cross-metathesis- selenocyclization reaction sequence
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Pseudo-oligosaccharides have attracted much interest as scaffolds for the synthesis of sugar mimics endowed with very similar biological properties but structurally and synthetically simpler than their natural counterparts. Herein, the synthesis of pseudo-oligosaccharides using the cross-metathesis reaction between distinct sugar-olefins followed by intramolecular selenocyclization of the obtained heterodimer as key steps is first investigated. This methodology has been then applied to the preparation of structural analogues of the trisaccharide repeating unit from Streptococcus pneumoniae 19F. The inhibition abilities of the synthetic molecules were evaluated by a competitive ELISA assay using a rabbit polyclonal anti-19F serum.
- Ronchi, Paolo,Scarponi, Catalina,Salvi, Matteo,Fallarini, Silvia,Polito, Laura,Caneva, Enrico,Bagnoli, Luana,Lay, Luigi
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p. 5172 - 5183
(2013/07/26)
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- Chiral nanoporous metal-metallosalen frameworks for hydrolytic kinetic resolution of epoxides
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Chiral nanoporous metal-organic frameworks are constructed by using dicarboxyl-functionalized chiral Ni(salen) and Co(salen) ligands. The Co(salen)-based framework is shown to be an efficient and recyclable heterogeneous catalyst for hydrolytic kinetic resolution (HKR) of racemic epoxides with up to 99.5% ee. The MOF structure brings Co(salen) units into a highly dense arrangement and close proximity that enhances bimetallic cooperative interactions, leading to improved catalytic activity and enantioselectivity in HKR compared with its homogeneous analogues, especially at low catalyst/substrate ratios.
- Zhu, Chengfeng,Yuan, Guozan,Chen, Xu,Yang, Zhiwei,Cui, Yong
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supporting information; experimental part
p. 8058 - 8061
(2012/07/14)
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- A straightforward approach to substituted 2-(hydroxymethyl)-2,3- dihydrofuro[2,3- b ]pyridines and 3-hydroxy-3,4-dihydro-2 H -pyrano[2,3- b ]pyridines
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An efficient route to 2-(hydroxymethyl)-2,3-dihydrofuro[2,3-b]pyridines and 3-hydroxy-3,4-dihydro-2H-pyrano[2,3-b]pyridines is reported. The strategy is based on an intramolecular inverse electron demand Diels-Alder reaction starting from 1,2,4-triazines.
- Hajbi, Youssef,Suzenet, Franck,Khouili, Mostafa,Lazar, Said,Guillaumet, Gerald
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experimental part
p. 1349 - 1355
(2010/07/02)
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- AMINOALCOHOL LIPIDOIDS AND USES THEREOF
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Aminoalcohol lipidoids are prepared by reacting an amine with an epoxide-terminated compound are described. Methods of preparing aminoalcohol lipidoids from commercially available starting materials are also provided. Aminoalcohol lipidoids may be prepare
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Page/Page column 163
(2010/06/11)
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- Synthetic studies towards the total synthesis of providencin
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A synthetic approach to assemble the uncommon furylcyclobutane substructure in providencin has been developed starting from a commercially available cyclobutane precursor. Georg Thieme Verlag Stuttgart.
- Schweizer, Eliane,Gaich, Tanja,Brecker, Lothar,Mulzer, Johann
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p. 3807 - 3814
(2008/09/18)
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- Enantioselective incorporation of carbon dioxide into epoxides catalyzed by optically active cobalt(II) complexes
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The enantioselective chemical fixation of CO2 into an epoxide was developed using an optically active ketoimi-natocobalt(II) complex as a chiral Lewis acid. In the presence of a catalytic amount of the cobalt complex and amine base, enantioselective CO2 fixation with an epoxide proceeded with kinetic resolution to afford the corresponding carbonate along with unreacted epoxide, both of which were optically active. To improve their enantioselectivities, the ligand structures of the cobalt complexes and amine bases were examined. Thus, the optimized catalytic system was successfully applied to various epoxides to obtain the corresponding optically active cyclic carbonates and to recover epoxides with good-to-high enantioselectivities.
- Yamada, Wataru,Kitaichi, Yasunori,Tanaka, Hirotaka,Kojima, Tomohide,Sato, Mitsuo,Ikeno, Taketo,Yamada, Tohru
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experimental part
p. 1391 - 1401
(2009/06/20)
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- Lipase-mediated resolution of 3-hydroxy-4-trityloxybutanenitrile: synthesis of 2-amino alcohols, oxazolidinones and GABOB
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Lipase-mediated kinetic resolution of 3-hydroxy-4-trityloxybutanenitrile gave the (S)-alcohol and (R)-acetate in good yields and high enantioselectivities. The resolution using Pseudomonas cepacia lipase (Burkholderia cepacia) immobilized on modified cera
- Kamal, Ahmed,Khanna, G.B. Ramesh,Krishnaji,Ramu
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p. 1281 - 1289
(2007/10/03)
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- CIDOFOVIR PEPTIDE CONJUGATES AS PRODRUGS
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Cidofovir-based compounds having an amino acid, dipeptide or tripeptide attached to a cidofovir or cyclic cidofovir framework. The compounds show enhanced oral bioavailability and increased binding to the PepT1 transporter. The present invention also provides compositions and methods for treating virus infections, and a method of preparing cidofovir.
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Page/Page column 11; figure 3
(2008/06/13)
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- Total synthesis of the microtubule stabilizing antitumor agent laulimalide and some nonnatural analogues: The power of sharpless' asymmetric epoxidation
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Three different routes are described for the synthesis of deoxylaulimalide (3), which is the immediate precursor of the marine sponge metabolite laulimalide (1). These routes mainly differ with respect to their ring closing step. Thus, route 1 uses a Still-Gennari olefination, route 2 a Yamaguchi lactonization, and route 3 an intramolecular allylsilane-aldehyde addition for establishing the macrocyclic structure. The unprotected deoxy derivative 3 was subjected to Sharpless' asymmetric epoxidation (SAE). With (R,R)-tartrate the 16,17-epoxide laulimalide (1) is formed selectively, whereas (S,S)-tartrate generates the 21,22-epoxide 142. This demonstrates the high reagent control involved in the SAE process, which in this case is used to achieve high stereo- and regioselectivity. Laulimalide and some derivatives thereof have been tested with respect to antitumor activity and compared to standard compounds paclitaxel and epothilone B.
- Ahmed, Anjum,Hoegenauer, E. Kate,Enev, Valentin S.,Hanbauer, Martin,Kaehlig, Hanspeter,Ohler, Elisabeth,Mulzer, Johann
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p. 3026 - 3042
(2007/10/03)
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- Chromogenic compound
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This application relates to a novel compound of formula I, as defined herein, processes and intermediates for its preparation and the use of the compound of formula I as a substrate for a pharmaceutical screen.
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- Cyclization strategies for the synthesis of macrocyclic bisindolylmaleimides
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Three new approaches to the synthesis of macrocyclic bisindolylmaleimides 1-4 have been identified. Two strategies afford 8, the penultimate intermediate for the synthesis of 1-4, in 73% and 32% yield by intramolecular cyclization of 31 and 40, respectively. The optimum synthesis of 1 was achieved in nine steps and 15% yield by intramolecular formation of the macrocycle and maleimide in one step by reaction of the sodium indolate of 12 with methyl indole-3-glyoxylate 47. The mechanism of this reaction has been elucidated, using the trityl-protected derivative, to involve initial formation of the tricarbonyl imide 48, followed by irreversible alkylation of the indole nitrogen to generate the 17-membered macrocycle 49. Cyclization of 49 to hydroxymaleimide 50 and subsequent dehydration afforded 8a. This approach eliminated the problem of dimerization observed in the intramolecular cyclization reactions.
- Faul,Krumrich
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p. 2024 - 2033
(2007/10/03)
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- Synthesis of the C15-C27 fragment of the antitumor agent laulimalide
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A stereocontrolled synthesis of the C15-C27 fragment of laulimalide is described. Key features are a divergent-convergent synthesis from (R)-glycidol, an interesting formation of a trisubstituted double bond via ring closing metathesis with Grubbs' ruthen
- Dorling,Ohler,Mulzer
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p. 6323 - 6326
(2007/10/03)
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- Synthesis and Absolute Configuration of a Novel Aminoglycoglycerolipid, Species-Specific Major Immunodeterminant of Mycoplasma fermentans
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In order to determine the absolute configuration of a novel aminoglycoglycerolipid isolated from Mycoplasma fermentans, the possible two diastereomers were stereoselectively synthesized by using (S)- and (R)-glycidols as the key building block. Their 1H-1H-cosy spectra compared with those of the natural product allowed us to determine the absolute configuration of the glycolipid. - Keywords: amino-alcohols; glycolipids; immunodeficiency; phospholipids; phosphoramidites
- Nishida, Yoshihiro,Takamori, Yusuke,Ohrui, Hiroshi,Ishizuka, Ineo,Matsuda, Kazuhiro,Kobayashi, Kazukiyo
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p. 2371 - 2374
(2007/10/03)
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- Formulations and methods for generating active cytofectin: polynucleotide transfection complexes
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In the generation of cytofectin:polynucleotide complexes for transfection of cells, formulations, counterions, and reaction conditions for maximizing the transfection include using a cationic amine compound that has the general structure: STR1 wherein Rs
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- Polyfunctional cationic cytofectins, formulations and methods for generating active cytofectin: polynucleotide transfection complexes
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Amine containing compounds and their use in the generation of cytofectin:polynucleotide complexes for transfection of cells, formulations, counterions, and reaction conditions for maximizing the transfection include using cationic amine compounds that hav
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- Macrocyclic bisindolylmaleimides: Synthesis by inter- and intramolecular alkylation
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Macrocyclic bisindolylmaleimides 1-4 have been identified as competitive reversible inhibitors of PKC β1 and β2 and are being advanced to the clinic for evaluation as a treatment of retinopathy associated with diabetic complications. Highly convergent and stereoselective syntheses of 1-4 have been developed. The key synthetic step involves intermolecular alkylation of symmetrical bisindolylmaleimide 9 with chiral bisalkylating agent 8c and is amenable to the preparation of multikilogram quantities of these compounds. The synthetic sequence to 1, the most active the compound, proceeds in 11 steps and 26% overall yield (> 98% ee) from (R)-1-chloro-2,3-propanediol. No chromatographic purifications are required throughout the process and the final product is isolated in >97% purity after crystallization from DMF/MeOH. Synthesis of 1-4 by intramolecular alkylation proved less efficient, requiring 17 steps and affording 1-4 in lower overall yields of 6.0-8.5%.
- Faul, Margaret M.,Winneroski, Leonard L.,Krumrich, Christine A.,Sullivan, Kevin A.,Gillig, James R.,Neel, David A.,Rito, Christopher J.,Jirousek, Michael R.
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p. 1961 - 1973
(2007/10/03)
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- A Practical Synthesis of (S)-HPMPC
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Synthesis of the title nucleotide was accomplished in high yield starting from (S)-tritylglycidol (5) and N-benzoylcytosine (9).
- Brodfuehrer, Paul R.,Howell, Henry G.,Sapino, Chester Jr.,Vemishetti, Purushotham
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p. 3243 - 3246
(2007/10/02)
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- Synthesis and Biological Activity of Acyclic Analogues of Nojirimycin
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A series of acyclic compounds has been prepared which comprises compounds that mimic key structural elements of nojirimycin 1 and 1-deoxynojirimycin 2, both of which are highly effective glucosidase inhibitors, in order to ascertain if similar biological
- Fowler, Paul A.,Haines, Alan H.,Taylor, Richard J. K.,Chrystal, Ewan J. T.,Gravestock, Michael B.
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p. 2229 - 2236
(2007/10/02)
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- Insight into Rh(I)-catalyzed cyclization of 6-octen-1-als with a chiral protecting group
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Rh(I)(Wilkinson)[ClRh(PPh3)3]-catalyzed cyclization of 6-octen-als with a chiral protecting group at the C2-position afforded only cis-cyclohexanol derivatives, and in the case of C4-position yielded a mixture of cis and trans cyclohexanol. These findings were remakably different from the case of the C3-position, in which the trans cyclohexanol derivative was obtained. Wilkinson's complex acts as [ClRh(PPh3)3] a Lewis acid, and this bulkier Lewis acid affords higher diastereoselectivity. Rh(I)-catalyzed cyclization of 6-octen-1-al derivatives is not affected by chiral ligands.
- Koga,Funakoshi,Matsuda,Sakai
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p. 1857 - 1868
(2007/10/02)
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