- Chemoenzymatic Synthesis of cis-4-Hydroxy-D-proline
-
Candida antarctica lipase fraction B (CALB) catalyzed the hydrolysis of the (S)-enantiomer of racemic 4-oxo-1,2-pyrrolidinedicarboxylic acid dimethyl ester with high enantioselectivity (> 99.5% ee at 51% conversion). Regioselective hydrogenation of the isolated (R)-4-oxo-1,2-pyrrolidinedicarboxylic acid dimethyl ester produced (2R,4R)-4-hydroxy-1,2-pyrrolidinedicarboxylic acid dimethyl ester in 98% yield, and subsequent hydrolysis of the ester and N-(alkoxycarbonyl) groups produced cis-4-hydroxy-D-proline in 98% yield and 96% de. Diastereomeric mixtures of 4-hydroxy-1,2-pyrrolidinedicarboxylic acid dimethyl esters were also resolved using CALB to produce cis-4-hydroxy-D-proline or trans-4-hydroxy-L-proline in 93 to > 99.5% diastereomeric excess.
- Sigmund, Amy E.,Hong, Wonpyo,Shapiro, Rafael,DiCosimo, Robert
-
-
Read Online
- Spiegelmeric 4R/S-hydroxy/amino-L/D-prolyl collagen peptides: conformation and morphology of self-assembled structures
-
The primary structure of collagen, the major protein in connective tissue of mammals, comprises of repeating triads [(LPro-LHyp-Gly)n, P1, LHyp being 4R-hydroxy-lProline)] in a single strand that adopts left-handed polyproline II type helix. Three such single stranded helices wind around each another and held together by interchain H-bonds to form right-handed triple helix. This manuscript reports on collagen derived from its mirror image triad [(DPro-DHyp-Gly)n, P2, DHyp being 4S-hydroxy-DProline) and its 4-amino analogue (DPro-DAmp-Gly)n P4, DAmp being 4S-amino-DProline that form corresponding spiegelmeric triplexes. The amino L-collagen peptide (LPro-LAmp-Gly)n P3 and its D-analogue P4 show higher thermal stabilities compared to 4-hydroxy-lProline collagen peptides P1 and P2. The enantiomeric peptide pairs show mirror image CD profiles and identical thermal stability, with ionizable 4-amino group in P3 and P4 imparting pH dependent triplex stability. Upon cold mixing of the L- and D-collagen peptides, different morphological nanostructures arise from inter triplex peptide association. When the peptides are hot mixed (annealed), the inter peptide association occurs via interaction of single stranded peptide chains of opposite handedness leading to networked gel formation in P1 and P2, while the charged peptides P3 and P4 show more ordered nanofibers, different from the enantiomerically pure peptides. The nanocomposites of such chiral hybrid peptides may have not only interesting physicomorphology, but also biological properties that need exploration.
- Ganesh, Krishna N,More, Shahaji H
-
-
- INHIBITORS OF CYCLIN DEPENDNT KINASE 7 (CDK7)
-
The present invention provides novel compounds of Formula (I) and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopically labeled derivatives, and compositions thereof. Also provided are methods and kits involving the compounds or compositions for treating or preventing proliferative diseases (e.g., cancers (e.g., leukemia, melanoma, multiple myeloma), benign neoplasms, angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases) in a subject. Treatment of a subject with a proliferative disease using a compound or composition of the invention may inhibit the aberrant activity of cyclin-dependent kinase 7 (CDK7), and therefore, induce cellular apoptosis and/or inhibit transcription in the subject.
- -
-
Paragraph 339
(2018/02/28)
-
- An improved, scalable synthesis of bis-amino acids
-
trans-4-Hydroxy-L-proline derived bis-amino acids are chiral, cyclic building blocks that display two alpha-amino acids that are differentiated from each other with protecting groups. They are assembled into spiroligomers—rigid, shape-programmable spirocyclic oligomers that are both stereochemically and functionally diverse. The synthesis presented here focuses on recent improvements that allow for a convenient, large-scale synthesis of twelve stereochemically pure bis-amino acids from inexpensive trans-4-hydroxy-L-proline. The bis-amino acids differ in stereochemistry as well as the amine protecting group, one of which (para-nitrobenzyl carbamate) has not been previously incorporated into bis-amino acids.
- Cheong, Jae Eun,Pfeiffer, Conrad T.,Northrup, Justin D.,Parker, Matthew F.L.,Schafmeister, Christian E.
-
supporting information
p. 4882 - 4884
(2016/10/24)
-
- A short diastereoselective synthesis of cis-(2S,4S) and cis-(2R,4R)-4-hydroxyprolines
-
A concise synthesis of (2R,4R)-4-hydroxyproline (1) and (2S,4S)-4-hydroxyproline (2) has been developed in enantiomerically pure form from commercially available starting materials with excellent diastereoselectivity. The tightly bound chelation controlled transition state formed during the 5-exo-tet ring closure reaction is assumed to be the origin of high diastereoselectivity.
- Gajare, Vikas S.,Khobare, Sandip R.,Malavika,Rajana, Nagaraju,Venkateswara Rao,Syam Kumar
-
supporting information
p. 3743 - 3746
(2015/06/08)
-
- Rh(II) catalysts with 4-hydroxyproline-derived ligands
-
Three new chiral Rh(II) catalysts with 4-hydroxyproline-derived ligands have been synthesised through a short and efficient synthetic route. The catalysts give good yields and ees in C-H insertion and cyclopropanation reactions, and their properties indicate an all-up reactive conformation of proline- and 4-hydroxyproline-derived Rh(II) catalysts.
- Bonge, Hanne Therese,Kaboli, Massoud,Hansen, Tore
-
scheme or table
p. 5375 - 5377
(2010/11/02)
-
- Prolinol-based nucleoside phosphonic acids: new isosteric conformationally flexible nucleotide analogues
-
trans-4-Hydroxy-l-proline has been used as a starting material for the synthesis of prolinol-based nucleotide analogues with an N-phosphonomethyl moiety attached to the prolinol ring nitrogen atom. The synthetic methodology based on the inversion of configuration at both 1- and 4-position led to all diastereoisomeric O-protected 4-mesyloxyprolinol-N-phosphonates. Alkylation of nucleobases using the synthons in the l-series afforded the nucleotide analogues corresponding to α-l- and β-l-nucleotide. The NMR-based conformational study of these compounds in aqueous solution performed at two different pH values, showing either N-fully protonated or deprotonated forms, revealed the occurrence of the same mostly populated conformer in both cases. All final l-prolinol-based nucleoside phosphonic acids were tested for cytotoxic and antiviral properties, but no significant activity was found.
- Vaněk, Václav,Budě?ínsky, Milo?,Rinnová, Markéta,Rosenberg, Ivan
-
experimental part
p. 862 - 876
(2009/05/09)
-
- Practical syntheses of 4-fluoroprolines
-
4-Fluoroprolines are among the most useful nonnatural amino acids in chemical biology. Here, practical routes are reported for the synthesis of the 2S,4R, 2S,4S, and 2R,4S diastereomers of 4-fluoroproline. Each route starts with (2S,4R)-4-hydroxyproline, which is a prevalent component of collagen and hence readily available, and uses a fluoride salt to install the fluoro group. Hence, the routes provide process-scale access to these useful nonnatural amino acids.
- Chorghade, Mukund S.,Mohapatra, Debendra K.,Sahoo, Gokarneswar,Gurjar, Mukund K.,Mandlecha, Manish V.,Bhoite, Nitin,Moghe, Santosh,Raines, Ronald T.
-
experimental part
p. 781 - 784
(2009/04/04)
-
- 4-Substituted-α,α-diaryl-prolinols improve the enantioselective catalytic epoxidation of α,β-enones
-
To seek novel metal-free organic catalysts for epoxidation with high stereoselectivity, a series of 4-substituted-α,α-diaryl-prolinols were synthesized in four steps from trans-4-hydroxyl-L-proline. These prolinol derivatives catalyzed the asymmetric epoxidation of α,β-enones to give the corresponding chiral epoxides in good yields and high enantioselectivities under mild reaction conditions. Studies of substituent effects on enantioselectivity revealed that steric bulk and electronic effect promoted higher enantioselectivity, and prolinol 8a was found to be the best catalyst until now.
- Li, Yawen,Liu, Xinyuan,Yang, Yingquan,Zhao, Gang
-
p. 288 - 291
(2007/10/03)
-
- Bis (amino acid) molecular scaffolds
-
The present invention provides molecular building blocks of rigid bis(amino acids). The molecular building blocks can be linked together through the formation of rigid diketopiperazine rings, to provide the desired three dimensional structure. Also provided is method of synthesizing macromolecules from the bis (amino acid) building blocks.
- -
-
-
- Ex-chiral pool synthesis and receptor binding studies of 4-substituted prolinol derivatives
-
Starting from natural 4-hydroxyproline, preparation of the four possible stereoisomers of 4-amino- and 4-aminomethyl-substituted prolinol derivatives, respectively, was accomplished by chemo- and regioselective functional group transformations at the 2- and 4-positions of the pyrrolidine moiety. These building blocks were used as valuable precursors for the preparation of new methoxybenzamide derivatives. Dopamine and serotonin binding studies involving the subtypes D1, D2long, D2short, D3 and D4 as well as 5-HT1A and 5-HT2, respectively, displayed interesting structure activity relationships, especially with respect to the absolute and relative configuration of the test compounds. As a complement to the D3 receptor preferring aminomethylpyrrolidine FAUC 21, the (2R,4R)-aminoprolinol derivative ent-24 (FAUC 65) preferentially recognizing the D4 subtype was developed.
- Heindl, Cornelia,Huebner, Harald,Gmeiner, Peter
-
p. 3141 - 3152
(2007/10/03)
-
- Stereoselective synthesis of (1R,4R)-N-acyl-2-oxa-5-aza-bicyclo[2.2.1]heptan-3-ones via mesoionic compounds. An improved synthesis of cis-4-hydroxy-D-proline
-
We report an asymmetric synthesis of (1R,4R)-N-acyl-2-oxa-5-aza-bicyclo[2.2.1]heptan-3-ones, starting from the inexpensive and commercially available trans-4-hydroxy-L-proline and achieved by treating N-acyl-trans-4-hydroxy-L-prolines with acetic anhydride. The formation of intermediate mesoionic compounds may explain the formation of N-acyl-2-oxa-5-aza-bicyclo[2.2.1]heptan-3-ones with (R)-absolute configuration at C(4). Acidic cleavage of these lactones readily affords N-acyl-cis-4-hydroxy-D-prolines or cis-4-hydroxy-D-proline in good yields.
- Dalla Croce, Piero,La Rosa, Concetta
-
p. 197 - 201
(2007/10/03)
-
- A new synthetic method for the preparation of α,β-didehydroamino acid derivatives by means of a wittig-type reaction. Syntheses of (2S, 4S)- and (2R, 4R)-4-hydroxyprolines
-
Ethyl N-Boc- and N-Z-α-tosylglycinates were reacted with a variety of aldehydes in the presence of tributylphosphine and a base to afford the corresponding α,β-didehydroamino acid derivatives with high (Z)-selectivity in good yields. Moreover, ethyl (4S)- and (4R)-2-(N-Boc-amino)-4,5-isopropylidenedioxy-2-pentenoates prepared by the present method were converted to (2S, 4S)- and (2R, 4R)-4-hydroxyprolines, respectively.
- Kimura, Rumi,Nagano, Tanemasa,Kinoshita, Hideki
-
p. 2517 - 2525
(2007/10/03)
-
- Biphenyl derivatives and drug composition
-
A biphenyl derivative represented by the following general formula (1) and a pharmaceutically acceptable salt thereof: [In the formula (1), A represents a single bond, —CH2—, —CO—, —CS— or —SO2—; B represents a single bond or —CH2—; R1represents a hydrogen atom, —OH, —NR11R12(wherein R11and R12each independently represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms), —OCOCH3, or a halogen atom; R2represents a hydrogen atom or R1and R2form a group ═O together; R3represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; provided that in the formula, the absolute configuration of the position a may be either R or S]. The compound of the present invention has considerably high safety and efficacy and is useful as, in particular, a vasopressin receptor antagonist.
- -
-
-
- Pyrrolidine PNA: A Novel Conformationally Restricted PNA Analogue
-
A new conformationally restricted PNA adenine monomer has been synthesized in 13 steps from cis-4-hydroxy-D-proline. A fully modified adenine decamer displayed improved binding affinity toward complementary DNA and RNA oligonucleotides as compared to that of the parent PNA adenine decamer.
- Pueschi, Ask,Tedeschi, Tullia,Nielsen, Peter E.
-
p. 4161 - 4164
(2007/10/03)
-
- Synthesis of DNA-(3')-PNA chimeras with conformationally restricted linkers based on 4-hydroxyproline
-
The synthesis and evaluation of DNA-(3')-PNA chimeras containing rigid linkers based on (R/S)-4-hydroxy-D/L-proline are described. It is shown that installment of the trans-L-linker using the tetrabutylammonium salt of (R)- 4-(4,4'-dimethoxytrityloxy)-N-(thymin-l-yl)acetyl-L-proline (2) leads to a DNA-(3')-PNA chimera which hybridizes efficiently with complementary RNA.
- Verheijen, Jeroen C.,Van Roon, Anne-Marie M.,Van Der Laan, Alexander C.,Van Der Marel, Gijsbert A.,Van Boom, Jacques H.
-
p. 493 - 508
(2007/10/03)
-
- Synthesis and pharmacological activity of 4-amino-5-chloro-2-methoxy-N- [(2S,4S)-1-ethyl-2-hydroxymethyl-4-pyrrolidinyl]benzamide (TKS159) and its optical isomers
-
Of 4-amino-5-chloro-2-methoxy-N-(1-ethyl-2-hydroxymethyl-4- pyrrolidinyl)benzamide, four optical isomers, (2S,4S)-1 (TKS159), (2S,4R)-25, (2R,4S)-26 and (2R,4R)-27, were prepared from optically active 4-amino-1- ethyl-2-hydroxymethylpyrrolidine di-p-toluenesulfonate [(2S,4S)-14, (2S,4R)- 17, (2R,4S)-20 and (2R,4R)-23, respectively]. The requisites, (2S,4S)-14, (2S,4R)-17, (2R,4S)-20 and (2R,4R)-23, were prepared from a commercially available trans-4-hydroxy-L-proline. The absolute configurations of (2S,4S)-1 (TKS159), (2S,4R)-25, (2R,4S)-26 and (2R,4R)-27 were spectroscopically determined. Of the benzamide derivatives, four optical isomers, (2S,4S)-1, (2S,4R)-25, (2R,4S)-26 and (2R,4R)-27, showed a relatively potent affinity for 5-hydroxytryptamine 4 (5-HT4) receptors in a radioligand binding assay ([3H]GR113808). The activities of 25 - 27 were less effective than that of 1 for the gastric emptying of a phenol red semisolid meal in rats. All this suggests that the most potent of the isomers was 4-amino-5-chloro-2-methoxy- N-[(2S,4S)-1-ethyl-2-hydroxymethyl-4-pyrrolidinyl]benzamide (1).
- Yanagi, Toshiharu,Kitajima, Akihiko,Anzai, Kinsei,Kodama, Kazuya,Mizoguchi, Jun-Ichi,Fujiwara, Hiromichi,Sakiyama, Hideyo,Kamoda, Osamu,Kamei, Chiaki
-
p. 1650 - 1654
(2007/10/03)
-
- An improved procedure for the enantioselective synthesis of (+)- and (-)-cis-4-hydroxyprolines and bulgecinines
-
An efficient enantioselective synthesis of both the enantiomers of cis-4-hydroxy-proline and bulgecinine was accomplished starting from synthons 1 or 1'. The improved synthetic route to the aforesaid enantiomerically pure proline derivatives was established via a stereocontrolled double iodocyclization of 3(a,b) or 3'(a,b).
- Graziani, Lucia,Porzi, Gianni,Sandri, Sergio
-
p. 1341 - 1346
(2007/10/03)
-
- Stereoselective synthesis of unnatural aminoacids cis-4-hydroxyproline and bulgecinine
-
A new stereoselective synthesis of both (2R,4R)- and (2S,4S)-4-hydroxy-proline and (+)- and (-)-bulgecinine was performed starting from synthons 1 or 1', respectively. The synthetic route has been established via a novel assisted cleavage of a disubstituted amide in mild conditions and successive stereocontrolled iodocyclization.
- Madau, Alessandra,Porzi, Gianni,Sandri, Sergio
-
p. 825 - 830
(2007/10/03)
-
- Compounds of N-benzoylpyroline
-
Compounds of the general formula (I): STR1 where A, R1, R2, R3, R4, R5 and R6 are defined in the description. Medicinal products.
- -
-
-
- Enantiomerically Pure Pyrrolidine Derivatives from trans-4-Hydroxy-L-proline By Electrochemical Oxidative Decarboxylation and Titanium-Tetrachloride-Mediated reaction with Nucleophiles
-
Preparative electrolysis of N-methoxycarbonyl-O-hydroxyproline 4 in MeOH leads to substitution of the COOH by a MeO group (oxidative decarboxylation).The mixture 5 of the two diastereoisomers (ca. 1:1) thus obtained was reacted in CH2Cl2 with nucleophilic silylated compounds (such as allylsilane, silyl cyanide and 1-phenyl-1-silyloxyethane) or with trimethyl phosphite in the presence of TiCl4 to give 2-allyl-, 2-cyano-, 2-(2-oxo-2-phenylethyl)- and 2-phosphono-substituted hydroxypyrrolidines, respectively, with high diastereoselectivities (>= 90 percent, products 6-12).The configuration of two of the products (6/7 and 8/9) was shown to be cis.
- Renaud, Philippe,Seebach, Dieter
-
p. 1704 - 1710
(2007/10/02)
-
