- Efficient stereodivergent synthesis of erythro- and threo-sphingosines: Unprecedented reversal of the stereochemistry in the addition
-
A convenient diastereoselective synthesis of D-erythro- and L-threo-sphingosine derivatives is described. L-Serine-derived aldehyde (Garner's aldehyde) (2) was treated with 1-alkenyl-zirconocene chlorides (3) in the presence of ZnBr2 in THF to give the natural erythro-(anti-) isomers with high diastereoselectivity (anti/syn=12-20:1). In contrast, reaction of 2 with 1-alkenyl-ethyl-zinc, prepared from 3 and Et2Zn, in CH2Cl2 gave the unnatural threo-(syn-) isomers predominantly (anti/syn=1:12-15).
- Murakami, Teiichi,Furusawa, Kiyotaka
-
-
Read Online
- Efficient synthesis of a configurationally stable L-serinal derivative
-
An efficient synthesis of a configurationally stable L-serinal derivative 8 was achieved using an N-hydroxymethyl group in about 50% overall yield in four steps from L-serine. Not more than 1% racemization was observed during the preparation of 8. Its enantiomeric integrity was maintained for at least 15 days at room temperature, and it was stable on silica gel. The orthogonal protective groups of 8 would make it a useful chiral synthon.
- Yoo, Dongwon,Seok Oh, Joon,Lee, Dong-Whal,Kim, Young Gyu
-
-
Read Online
- A stereodivergent route to four stereoisomeric 3′- acetoxycyclopentenylglycine derivatives
-
A short and efficient synthetic route to four stereoisomeric 3-acetoxycyclopentenylglycine derivatives from l-serine has been developed. The method features a stereoselective conjugate addition and ring-closing metathesis as key steps. Georg Thieme Verlag Stuttgart · New York.
- Kundu, Indranil,Maitra, Ratnava,Jana, Manoranjan,Chattopadhyay, Shital K.
-
-
Read Online
- Generating Stereodiversity: Diastereoselective Fluorination and Highly Diastereoselective Epimerization of α-Amino Acid Building Blocks
-
Diastereoselective fluorination of N-Boc (R)- and (S)-2,2-dimethyl-4-((arylsulfonyl)methyl)oxazolidines and a previously unknown diastereoselective epimerization at the fluorine-bearing carbon atom α to the sulfone was realized. Diastereoselectivities of both reactions were excellent for benzothiazolyl sulfones, allowing access to two enantiomerically pure diastereomers from one chiral precursor. To demonstrate synthetic utility, the benzothiazolyl sulfones were converted to diastereomerically pure (S,S)- and (R,S)-benzyl sulfones via sulfinate salts and to amino acids. To understand the diastereoselectivities, DFT analysis was performed.
- Wei, Wei,Khangarot, Rama Kanwar,Stahl, Lothar,Veresmortean, Cristina,Pradhan, Padmanava,Yang, Lijia,Zajc, Barbara
-
p. 3574 - 3578
(2018/06/26)
-
- MACROCYCLIC BROAD SPECTRUM ANTIBIOTICS
-
Provided herein are antibacterial compounds, wherein the compounds in some embodiments have broad spectrum bioactivity. In various embodiments, the compounds act by inhibition of bacterial type 1 signal peptidase (SpsB), an essential protein in bacteria. Pharmaceutical compositions and methods for treatment using the compounds described herein are also provided.
- -
-
-
- Design, synthesis and structure-activity relationship studies of a novel focused library of 2,3,4-substituted oxazolidines with antiproliferative activity against cancer cell lines
-
In the present work we describe the synthesis and antiproliferative evaluation of a focused library of 30 novel oxazolidines designed by modification of N-substituent, by ring variation, by alkyl variation or by extension of the structure. It was noted that carbamate and N,O-aminal groups were essential for activity. In general, replacement of the phenyl ring with pyridinyl was not tolerated. However, the introduction of a second phenyl ring with an appropriate spacer at the 3- or 4-position of the first phenyl ring generally enhanced the cytotoxic profile. Among all the prepared compounds, 24 was the most potent compound found in this class, being active on four of five cancer cell lines and it was 5-fold and 10-fold more potent than the lead compounds against HL60 and JURKAT cells, respectively. In addition, it showed relevant activity against MCF-7 and HCT-116 cells, which were resistant to lead. Moreover, 24 showed little antiproliferative activity against VERO, indicating low toxicity to normal cells. Thus, this compound has the potential to be developed as an anticancer agent.
- Andrade, Saulo F.,Oliveira, Bárbara G.,Pereira, Larissa C.,Ramos, Jonas P.,Joaquim, Angélica R.,Steppe, Martin,Souza-Fagundes, Elaine M.,Alves, Ricardo J.
-
-
- OXADIAZOLE MODULATORS OF S1P METHODS OF MAKING AND USING
-
The invention is directed to Compounds of Formula (I): wherein each variable is defined herein, as well as methods of making and using the compounds as agonists of S1P1 and/or S1P5 for instance for treating graft versus host disease and autoimmune diseases.
- -
-
Paragraph 0118
(2017/01/23)
-
- THIADIAZOLE MODULATORS OF S1P AND METHODS OF MAKING AND USING
-
The invention is directed to compounds of the formula: wherein each of the variables are defined herein, as well as methods of making and using the compounds as agonists of S1P1 and/or S1P5 for instance treating an autoimmune disease.
- -
-
Paragraph 0114
(2017/01/26)
-
- Docking model of the nicotinic acetylcholine receptor and nitromethylene neonicotinoid derivatives with a longer chiral substituent and their biological activities
-
In the present study, nitromethylene neonicotinoid derivatives possessing substituents that contain a sulfur atom, oxygen atom or aromatic ring at position 5 on the imidazolidine ring were synthesized to evaluate their affinity for the nicotinic acetylcholine receptor (nAChR) and their insecticidal activity against adult female houseflies. Comparing the receptor affinity of the alkylated derivative with the receptor affinity of compounds possessing either ether or thioether groups revealed that conversion of the carbon atom to a sulfur atom did not influence the receptor affinity, whereas conversion to an oxygen atom was disadvantageous for the receptor affinity. The receptor affinity of compounds possessing a benzyl or phenyl group was lower than that of the unsubstituted compound. Analysis of the three-dimensional quantitative structure-activity relationship using comparative molecular field analysis demonstrated that steric hindrance of the receptor should exist around the C3 of an n-butyl group attached at position 5 on the imidazolidine ring. A docking study of the nAChR-ligand model suggested that the ligand-binding region expands as the length of the substituent increases by brushing against the amino acids that form the binding region. The insecticidal activity of the compounds was positively correlated with the receptor affinity by considering log P and the number of heteroatoms, including sulfur and oxygen atoms, in the substituents, suggesting that the insecticidal activity is influenced by the receptor affinity, hydrophobicity, and metabolic stability of the compounds.
- Nagaoka, Hikaru,Nishiwaki, Hisashi,Kubo, Takuya,Akamatsu, Miki,Yamauchi, Satoshi,Shuto, Yoshihiro
-
p. 759 - 769
(2015/02/19)
-
- Synthesis of a novel series of 2,3,4-trisubstituted oxazolidines designed by isosteric replacement or rigidification of the structure and cytotoxic evaluation
-
We have previously reported on a study of the structure-activity relationship in a series of 2,3,4-substituted oxazolidines recently discovered by our group varying the substituent at the ring or stereochemistry of the oxazolidine ring. We discovered the cytotoxic and pro-apoptotic potential of compounds 1 and 2 with good selectivity against cancer cell lines. In the present study we describe the synthesis and cytotoxic evaluation against cancer cell lines (HL60, JURKAT, MDA-MB-231 and LNCaP) of a series of oxazolidines designed by isosteric replacement or rigidification of the oxymethylene spacer of compounds 1 and 2. Alkenes 3 and 4 retained the activity against MDA-MB-231 cells and they were more active on HL60, JURKAT and LNCaP cells. Considering LNCaP cells, E-isomer 4 was at least 7 times and about 3 times more potent than lead 1 and Z-isomer 3, respectively. Compound 4 exerted significant activity against LNCaP with IC50 in the low micromolar range (11 μM) without affecting VERO cells and PBMC proliferation (IC50 > 100 μM) indicating its low toxicity to normal cells.
- Andrade, Saulo F.,Teixeira, Claudia S.,Ramos, Jonas P.,Lopes, Marcela S.,Pdua, Rodrigo M.,Oliveira, Mnica C.,Souza-Fagundes, Elaine M.,Alves, Ricardo J.
-
p. 1693 - 1699
(2014/12/11)
-
- Synthesis of novel 2,3,4-trisubstituted-oxazolidine derivatives and in Vitro cytotoxic evaluation
-
We have previously reported the discovery of cytotoxic and pro-Apoptotic hit compound 1,1-dimethylethyl (S)- 2,2-dimethyl-4-[(3-nitrophenoxy)methyl]-3- oxazolidinecarboxylate 1 against leukemia cells. In the present work we describe the synthesis of 25 derivatives of this hit varying the substituent at ring or stereochemistry of the oxazolidine ring and evaluated them against human cancer cells lines. Six compounds exerted significant activity against HL60 promyelocytic leukemia cells with IC50 in low micromolar range (4-18 μM) and three compounds displayed activity against MDA-MB231 breast cancer cells (25-37 μM). In vitro cytotoxicity on normal cells PBMC (human peripheral blood mononuclear cells) was also evaluated. Compounds 7e (p-NO2, S) and 7m (p-COOCH3, S) showed good antiproliferative activity against HL60 (4 and 5 μM) and MDA-MB231 (37 and 25 μM) without affecting lymphocyte proliferation in PBMC, indicating low toxicity to normal cells. Besides, compound 7e induced DNA fragmentation on about 100% of HL60 cells at 50 μM. In this case, it was more potent than 7m and lead 1. This indicated that compound 7e has a great pro-Apoptotic potential.
- Andrade, Saulo F.,Campos, Edmar F.S.,Teixeira, Claudia S.,Bandeira, Cristiano C.,Lavorato, Stefania N.,Romeiro, Nelilma C.,Bertollo, Caryne M.,Oliveira, M?nica C.,Souza-Fagundes, Elaine M.,Alves, Ricardo J.
-
p. 609 - 618
(2014/11/07)
-
- Transformation of d-serine to highly functionalized cyclohexenecarboxylates in study of oseltamivir synthesis
-
In an attempted synthesis of oseltamivir, D-serine was used to prepare (R)-Garner aldehyde, which reacted with vinylzinc reagent to give an alcohol product predominating in the (1′R,4S)-isomer. After the alcohol was protected as p-methoxybenzyl ether, the N,O-acetal was hydrolyzed and oxidized to an aldehyde, which underwent Reformatsky-type reaction with ethyl α-(bromomethyl)acrylate by promotion of indium to give an addition product readily for ring-closure metathesis to afford 3-alkoxy-4-amido-5-hydroxy-1- cyclohexenecarboxylates. After activation of the 5-hydroxy group as methanesulfonate, an attempted substitution reaction with sodium azide gave unexpectedly a cyclic carbamate via an intramolecular nucleophilic attack of the 4-tert-butoxycarbamate group.
- Lai, Joshua,Fang, Jim-Min
-
scheme or table
p. 426 - 435
(2012/08/07)
-
- Enantioselective synthesis of Garner's aldehyde by asymmetric hydroformylation
-
Both enantiomers of Garner's aldehyde (3) are prepared from the same alkene 4 by catalytic asymmetric hydroformylation.
- Clemens, Alexander J. L.,Burke, Steven D.
-
experimental part
p. 2983 - 2985
(2012/06/01)
-
- Discovery of cytotoxic and pro-apoptotic compounds against leukemia cells: Tert-butyl-4-[(3-nitrophenoxy) methyl]-2,2-dimethyloxazolidine-3-carboxylate
-
Aims: We evaluated biological activity in leukemia cells lines of R and S enantiomers of tert-butyl 4-[(3-nitrophenoxy)-methyl]-2,2-dimethyloxazolidine-3- carboxylate (BNDC). Main methods: Cytotoxic activity was assessed by MTT assay. Flow cytometry assays were used to determined DNA fragmentation (Propidium Iodide-PI staining) and phosphatidylserine exposure (Annexin-V and PI staining). DNA condensation was evaluated by fluorescence microscopy using double-staining in leukemia cells (Hoechst and PI). Caspase activities were measured using Z-VAD-FMK, a non-selective caspase inhibitor, by flow cytometry and Z-DEVD-AMC, a selective caspase-3 substrate, by fluorescence spectrometry. Key findings: Both enantiomers displayed cytotoxic activity against leukemia cell lines (HL60, HL60.Bcl-2, HL60.Bcl-XL and Jurkat) with low toxicity against human peripheral blood mononuclear cell - PBMC based on IC50 values. In HL60 cell lines, compounds induce exposure of phosphatidylserine and DNA fragmentation, which could be blocked by pretreatment of cells with Z-VAD-FMK. Confirming this observation, both enantiomers induced caspase-3 activation. Additional analysis revealed an increased percentage of apoptotic cells (defined as those with fragmented nuclei and condensed chromatin) after treatment with compounds. Significance: Taken together, the results indicate that BNDC compounds exhibited cytotoxic and pro-apoptotic activities and have a potential for developing a new class of anticancer drugs.
- Pinto, Mauro C.X.,Dias, Danielle F.,Del Puerto, Helen L.,Martins, Almir S.,Teixeira-Carvalho, Andréa,Martins-Filho, Olindo A.,Badet, Bernard,Durand, Philippe,Alves, Ricardo J.,Souza-Fagundes, Elaine M.
-
experimental part
p. 786 - 794
(2012/06/04)
-
- Orthogonally protected glycerols and 2-aminodiols: Useful building blocks in heterocyclic chemistry
-
The efficient synthesis of orthogonally protected glycerols, 2-aminopropane-1,3-diols and 2-aminobutane-1,4-diols that can constitute useful tools in heterocyclic chemistry, is reported. These interesting tri-functionalized small synthons were easily prepared from serine or aspartic acid. In addition, these substrates can be readily transformed into their iodide derivatives in very good yields. ARKAT USA, Inc.
- Ollivier, Anthony,Goubert, Marlene,Tursun, Ahmatjan,Canet, Isabelle,Sinibaldia, Marie-Eve
-
experimental part
p. 108 - 126
(2010/10/03)
-
- Design, synthesis and in vitro evaluation on glucosamine-6P synthase of aromatic analogs of 2-aminohexitols-6P
-
The aminosugars are very important structural components of bacterial and fungi cell walls. Glucosamine-6-phosphate synthase (GlmS), which catalyses the first step of the aminosugar biosynthetic pathway i.e. the formation of D-glucosamine-6-phosphate from
- Dias, Danielle F.,Roux, Ce?line,Durand, Philippe,Iorga, Bogdan,Badet-Denisot, Marie A.,Badet, Bernard,Alves, Ricardo J.
-
scheme or table
p. 680 - 685
(2010/11/03)
-
- OXIM DERIVATIVES AS HSP90 INHIBITORS
-
The invention relates to HSP90 inhibiting compounds consisting of the formula: (I) wherein the variables are as defined herein. The invention also relates to pharmaceutical compositions, kits and articles of manufacture comprising such compounds; methods and intermediates useful for making the compounds; and methods of using said compounds.
- -
-
Page/Page column 215
(2009/09/05)
-
- Optimization of 1H-tetrazole-1-alkanenitriles as potent orally bioavailable growth hormone secretagogues
-
1H-Tetrazole-1-alkanenitrile SR-9g exhibits a >10-fold in vivo potency enhancement over the lead nitrile 1 and has acceptable oral bioavailability in rats and dogs. An enantiospecific synthesis of 1H-tetrazole-1-alkanenitrile nitriles 9 has been developed.
- Hernandez, Andres S.,Swartz, Stephen G.,Slusarchyk, Dorothy,Yan, Mujing,Seethala, R. Krishna,Sleph, Paul,Grover, Gary,Dickinson, Kenneth,Giupponi, Leah,Harper, Timothy W.,Humphreys, W. Griffith,Longhi, Daniel A.,Flynn, Neil,Murphy, Brian J.,Gordon, David A.,Biller, Scott A.,Robl, Jeffrey A.,Tino, Joseph A.
-
p. 2067 - 2072
(2008/12/21)
-
- Regioselective cleavage of the bis-benzylidene acetal of D-mannitol under oxidative and reductive conditions: A new approach to C2-symmetric chiral ligands
-
A highly regioselective oxidative cleavage of 1,3:4,6-di-O-benzylidene-d- mannitol was carried out using NBS and the resultant product was readily converted to the C2-symmetric chiral ligand, (R,R)-3,4-dihydroxy-1,5- hexadiene. On the other hand, reductive cleavage of 1,3:4,6-di-O-benzylidene-d- mannitol was achieved in a highly regioselective manner using BF 3?OEt2 and Et3SiH to give a highly functionalized benzyl ether, which was converted to a synthetically useful C2-symmetric bis-amino alcohol derivative.
- Aravind, Appu,Mohanty, Subhendu K.,Pratap, T. Veerabhadra,Baskaran, Sundarababu
-
p. 2965 - 2968
(2007/10/03)
-
- Synthesis of 3-Aminochroman Derivatives by Radical Cyclization
-
(Equation presented) Enantiomerically pure 5-acetyl-3-amino-3,4-dihydro-2H- 1-benzopyran and methyl 3-amino-3,4-dihydro-2H-1-benzopyran-5-carboxylate were successfully synthesized starting from D- or L-serine. The formation of the benzopyran ring involved a radical cyclization step. The enantiomeric purities of the final aminochroman derivatives were determined by capillary electrophoresis using β-cyclodextrins as a chiral selector.
- Pave, Gregoire,Usse-Versluys, Stephanie,Viaud-Massuard, Marie-Claude,Guillaumet, Gerald
-
p. 4253 - 4256
(2007/10/03)
-
- Selective reduction of aldehydes via BINOL-Zr complex
-
An easily assembled catalyst from (±)-BINOL (1,1′-bi-naphthol) and Zr(OiPr)4·iPrOH selectively reduces aldehydes at room temperature. Ketones remain intact under these conditions. A catalytic amount of BINOL-Zr complex in the presence of 2-propanol also effectively reduces a variety of chiral and achiral aldehydes.
- Lorca, Miguel,Kuhn, Dan,Kurosu, Michio
-
p. 6243 - 6246
(2007/10/03)
-
- Convenient procedures for the synthesis of N-BOC-D-serinal acetonide from L-serine
-
Two straightforward synthetic routes for the preparation of enantiomerically pure N-BOC-D-serinal acetonide (enantiomer of Garner's aldehyde) starting from naturally occurring L-serine are described.
- Avenoza,Cativiela,Corzana,Peregrina,Zurbano
-
p. 1146 - 1150
(2007/10/03)
-
- Grignard reactions to chiral oxazolidine aldehydes
-
Modest to high levels of asymmetric induction are observed with Grignard additions to Garner type aldehydes. The resultant secondary alcohols are important precursors of chiral building blocks for asymmetric synthesis and we have demonstrated that they can be readily converted into their respective γ-hydroxy-β-amino alcohols and β-hydroxyamino acids. Additionally, aryloxy ethers, important components of many natural products, can be obtained from these precursors.
- Williams, Lorenzo,Zhang, Zhongda,Shao, Feng,Carroll, Patrick J.,Joullie, Madeleine M.
-
p. 11673 - 11694
(2007/10/03)
-
- Asymmetric allylboration of 2-N,3-O-isopropylidene-N-Boc-L-serinal: Diastereoselective synthesis of the calicheamicin γ1(I) amino sugar
-
Syntheses of the calicheamicin amino sugar 6 and its erythro diastereomer 7 have been completed by a sequence involving the asymmetric allylboration of N-Boc-serinal acetonide L-8 with the tartrate ester modified allylboronates (R,R)-9 and (S,S)-9, respectively. The reaction of (R,R)-9 and L-8 in toluene provides 14 with 89:11 selectivity, whereas the reaction of (S,S)-9 with L-8 in Et2O provides the diastereomer 15 with 90:10 selectivity. It is shown that the relatively modest diastereoselectivity of these double asymmetric reactions is compromised by the low enantiomeric purity of 8 (86-87% ee), and data are provided indicating that these reactions should be highly diastereoselective (≥95:5 in each case) if performed with enantiomerically pure aldehyde. The two diastereomeric homoallylic alcohols, 14 and 15, are easily elaborated into the targeted amino sugars 6 and 7 via the acetamide-substituted pyranosides 22 and 26. Methyl pyranosides 22a and 22e were shown to adopt preferentially the unexpected conformations B and D, with axial acetamide substituents, in nonpolar solvents, while the expected conformations A and C were strongly favored in d6-DMSO because of hydrogen bonding interactions with the solvent. The syntheses of 6 and 7 reported herein are expected to facilitate the design and synthesis of analogs of the calicheamicin aryl tetrasaccharide 3, which should prove useful in further analysis and applications of oligosaccharides as DNA binders.
- Roush,Hunt
-
p. 798 - 806
(2007/10/02)
-
- SYNTHESIS OF ACYCLIC ANALOGUES OF KAINOIDS AND NEUROEXCITATORY ACTIVITY
-
Four configurational isomers of 3-benzylglutamic acid, acyclic analogues of kainoids were synthesized to examine their structure-activity relationship.
- Yanagida, Miwa,Hashimoto, Kimiko,Ishida, Michiko,Shinozaki, Haruhiko,Shirahama, Haruhisa
-
p. 3799 - 3802
(2007/10/02)
-
- The Synthesis and Configurational Stability of Differentially Protected β-Hydroxy-β-amino Aldehydes
-
Syntheses of 1,1-dimethylethyl (S)-4-formyl-2,2-dimethyl-3-oxazolidinecarboxylate (5) and 1,1-dimethylethyl (4S-trans)-4-formyl-2,2,5-trimethyl-3-oxazolidinecarboxylate (6) from commercially available serine and threonine derivatives are described.The method involves selective reduction of the corresponding oxazolidine esters 3 and 4 using diisobutylaluminum hydride at low temperature.These differentially protected β-hydroxy-α-amino aldehydes are also shown to be produced in 93-95 percent enantiomeric excess (via NMR and HPLC analysis of the Mosher esterderivatives 8 and epi-8)-thus making them useful as chiral, nonracemic synthons for asymmetric synthesis.
- Garner, Philip,Park, Jung Min
-
p. 2361 - 2364
(2007/10/02)
-