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Total Synthesis of Scholarisine K and Alstolactine A
The first asymmetric total syntheses of scholarisine K and alstolactine A have been accomplished. Our syntheses feature (1) ring closure metathesis and an intramolecular Heck reaction to construct the 1,3-bridged [3,3,1] bicycle (C-D ring), (2) intramolec
Wang, Dan,Hou, Min,Ji, Yue,Gao, Shuanhu
p. 1922 - 1925
(2017)
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Microelectrode Arrays, Dihydroxylation, and the Development of an Orthogonal Safety-Catch Linker
Construction of larger molecular libraries on an addressable microelectrode array requires a method for recovering and characterizing molecules from the surface of any electrode in the array. This method must be orthogonal to the synthetic strategies needed to build the array. We report here a method for achieving this goal that employs the site-selective dihydroxylation reaction of a simple olefin.
Yeh, Nai-Hua,Krueger, Ruby,Moeller, Kevin D.
supporting information
p. 5440 - 5444
(2021/07/26)

Design, Synthesis, and Conformation-Activity Study of Unnatural Bridged Bicyclic Depsipeptides as Highly Potent Hypoxia Inducible Factor-1 Inhibitors and Antitumor Agents
By carrying out structural modifications based on the bicyclic peptide structure of echinomycin, we successfully synthesized various powerful antitumor derivatives. The ring conformation in the obtained compounds was restricted by cross-linking with an unnatural bond. The prepared derivatives were demonstrated to strongly suppress the hypoxia inducible factor (HIF)-1 transcriptional activation and hypoxia induction of HIF-1 protein expression. Particularly, alkene-bridged derivative 12 exhibited remarkably potent cytotoxicity (IC50 = 0.22 nM on the MCF-7 cell line) and HIF-1 inhibition (IC50 = 0.09 nM), which considerably exceeded those of echinomycin. Conformational analyses and molecular modeling studies revealed that the biological activities were enhanced following restriction of the conformation by cross-linking through a metabolically stable and rigid bridge bond. In addition, we proposed a new globular conformation stabilized by intramolecular πstacking that can contribute to the biological effects of bicyclic depsipeptides. The developments presented in the current study serve as a useful guide to expand the chemical space of peptides in drug discovery.
Koike, Kota,Nagano, Masanobu,Ebihara, Masahiro,Hirayama, Tasuku,Tsuji, Mieko,Suga, Hiroaki,Nagasawa, Hideko
p. 4022 - 4046
(2020/06/08)

Divergent Access to Histone Deacetylase Inhibitory Cyclopeptides via a Late-Stage Cyclopropane Ring Cleavage Strategy. Short Synthesis of Chlamydocin
A unified step-economical strategy for accessing histone deacetylase inhibitory peptides is proposed, based on the late-stage installation of multiple zinc-binding functionalities via the cleavage of the strained cyclopropane ring in the common pluripoten
Elek, Gábor Zoltán,Koppel, Kaur,Zubrytski, Dzmitry M.,Konrad, Nele,J?rving, Ivar,Lopp, Margus,Kananovich, Dzmitry G.
supporting information
p. 8473 - 8478
(2019/10/16)

THERAPEUTIC COMPOUNDS AND METHODS OF USE THEREOF
The invention provides a compound as described herein or a pharmaceutically acceptable salt thereof, and compositions containing such compounds and methods for using such compounds and compositions.
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Paragraph 0210

(2019/09/06)

The secondary structure of a heptapeptide containing trifluoromethyl-λ6-tetrafluorosulfanyl substituted amino acids
Site specific introduction of the polar hydrophobic trifluoromethyl-λ6-tetrafluorosulfanyl (CF3SF4) group can effectively control the secondary structure of a heptapeptide, the minimum repeat unit of an α-helix. The struct
Ikeda, Akari,Capellan, Aimée,Welch, John T.
p. 8079 - 8082
(2019/09/19)

THERAPEUTIC COMPOUNDS AND METHODS OF USE THEREOF
The invention provides a compound of formula I: or a pharmaceutically acceptable salt thereof, wherein the variables X, Y1-Y5, R1, R2, R3, R4, and Het have the meaning as described herein, and compositions containing such compounds and methods for using such compounds and compositions.
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Paragraph 0386; 0387; 0388

(2018/04/26)

CALPAIN MODULATORS AND THERAPEUTIC USES THEREOF
Disclosed herein are small molecule calpain modulator compositions, pharmaceutical compositions, the use and preparation thereof. Some embodiments relate to macrocyclic α-keto amide derivatives and their use as therapeutic agents.
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Paragraph 0369

(2018/09/25)

Design, synthesis and biological evaluation of C(4) substituted monobactams as antibacterial agents against multidrug-resistant Gram-negative bacteria
A series of novel pyridone conjugated monobactams with various substituents at the (4) position were synthesized and evaluated for their antibacterial activities against a panel of multidrug-resistant (MDR) Gram-negative bacteria in vitro. Compounds 46d, 54 and 75e displayed good to moderate activities against P. aeruginosa, among which the activity of 75e against P. aeruginosa was comparable to that of BAL30072 under iron limitation condition. Compounds 35, 46d, 54, 56a, 56c and 56d exhibited good to excellent antibacterial activities against E. coli and K. pneumoniae, which were comparable or superior to that of BAL30072. In vitro liver microsomal stability was further evaluated and the results manifested that Compounds 35, 46d and 54 were metabolically stable in human liver microsomes.
Kou, Qunhuan,Wang, Ting,Zou, Feng,Zhang, Shuhua,Chen, Qian,Yang, Yushe
supporting information
p. 98 - 109
(2018/04/05)

Tridentate Directing Groups Stabilize 6-Membered Palladacycles in Catalytic Alkene Hydrofunctionalization
Removable tridentate directing groups inspired by pincer ligands have been designed to stabilize otherwise kinetically and thermodynamically disfavored 6-membered alkyl palladacycle intermediates. This family of directing groups enables regioselective remote hydrocarbofunctionalization of several synthetically useful alkene-containing substrate classes, including 4-pentenoic acids, allylic alcohols, homoallyl amines, and bis-homoallylamines, under Pd(II) catalysis. In conjunction with previous findings, we demonstrate regiodivergent hydrofunctionalization of 3-butenoic acid derivatives to afford either Markovnikov or anti-Markovnikov addition products depending on directing group choice. Preliminary mechanistic and computational data are presented to support the proposed catalytic cycle.
O'Duill, Miriam L.,Matsuura, Rei,Wang, Yanyan,Turnbull, Joshua L.,Gurak, John A.,Gao, De-Wei,Lu, Gang,Liu, Peng,Engle, Keary M.
supporting information
p. 15576 - 15579
(2017/11/14)

High Affinity Agonists of the Neuropeptide y (NPY) Y4 Receptor Derived from the C-Terminal Pentapeptide of Human Pancreatic Polypeptide (hPP): Synthesis, Stereochemical Discrimination, and Radiolabeling
The diastereomeric mixture of d/l-2,7-diaminooctanedioyl-bis(YRLRY-NH2) (BVD-74D, 2) was described in the literature as a high affinity Y4 receptor agonist. Here we report on the synthesis and pharmacological characterization of the pure diastereomers (2R,7R)- and (2S,7S)-2 and a series of homo- and heterodimeric analogues in which octanedioic acid was used as an achiral linker. To investigate the role of the Arg residues, one or two arginines were replaced by Ala. Moreover, Nω-(6-aminohexylaminocarbonyl)Arg was introduced as an arginine replacement (17). (2R,7R)-2 was superior to (2S,7S)-2 in binding and functional cellular assays and equipotent with 17. [3H]Propionylation of one amino group in the linker of (2R,7R)-2 or at the primary amino group in 17 resulted in high affinity Y4R radioligands ([3H]-(2R,7R)-10, [3H]18) with subnanomolar Kd values.
Kuhn, Kilian K.,Ertl, Thomas,Dukorn, Stefanie,Keller, Max,Bernhardt, Günther,Reiser, Oliver,Buschauer, Armin
supporting information
p. 6045 - 6058
(2016/07/26)

METHOD FOR SYNTHESIZING OPTICALLY ACTIVE a-AMINO ACID USING CHIRAL METAL COMPLEX COMPRISING AXIALLY CHIRAL N-(2-ACYLARYL)-2-[5,7-DIHYDRO-6H-DIBENZO[c,e]AZEPIN-6-YL] ACETAMIDE COMPOUND AND AMINO ACID
Objects of the present invention are to provide an industrially applicable method for producing an optically active α-amino acid in high yield and in a highly enantioselective manner, to provide a simple production method of an optically active α,α-disubstituted α-amino acid, and to provide an intermediate useful for the above production methods of an optically active α-amino acid and an optically active α,α-disubstituted α-amino acid. The present invention provides a production method of an optically active α-amino acid or a salt thereof, the production method comprising introducing a substituent into the α carbon in the α-amino acid moiety of a metal complex represented by the following Formula (1): by an alkylation reaction, an aldol reaction, the Michael reaction, or the Mannich reaction, and releasing an optically pure α-amino acid enantiomer or a salt thereof by acid decomposition of the metal complex.
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Paragraph 0339-0346

(2016/05/10)

Ring-closing metathesis based total synthesis of ciliatamides A and B and their structural confirmation
Protecting group dependant ring-closing metathesis based approach to the total synthesis of the revised structures of ciliatamides A and B has been described. The current synthetic strategy utilizes the amino acid as starting material to introduce both the stereogenic centers. However, usage of non-racemizing reagents (EDC·HCl, HATU/NMM); for amide coupling and Grubbs' second generation catalyst for caprolactam ring synthesis makes the present approach more convenient to get the correct conclusion on absolute stereochemistry. Thus, on the basis of similar optical rotation values with the Lindsley's reported data, this synthesis further supported for the actual stereochemistry of both ciliatamides A and B is (R,R).
Avula, Krishnakumari,Mohapatra, Debendra K.
supporting information
p. 1715 - 1717
(2016/04/04)

METHOD FOR SYNTHESIZING OPTICALLY ACTIVE α-AMINO ACID USING CHIRAL METAL COMPLEX COMPRISING AXIALLY CHIRAL N-(2-ACYLARYL)-2-[5,7-DIHYDRO-6H-DIBENZO[c,e]AZEPIN-6-YL]ACETAMIDE COMPOUND AND AMINO ACID
Objects of the present invention are to provide an industrially applicable method for producing an optically active ±-amino acid in high yield and in a highly enantioselective manner, to provide a simple production method of an optically active ±,±-disubstituted ±-amino acid, and to provide an intermediate useful for the above production methods of an optically active ±-amino acid and an optically active ±,±-disubstituted ±-amino acid. The present invention provides a production method of an optically active ±-amino acid or a salt thereof, the production method comprising introducing a substituent into the ± carbon in the ±-amino acid moiety of a metal complex represented by the following Formula (1): by an alkylation reaction, an aldol reaction, the Michael reaction, or the Mannich reaction, and releasing an optically pure ±-amino acid enantiomer or a salt thereof by acid decomposition of the metal complex.
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Paragraph 0561; 0563; 0575; 0586

(2016/11/17)

Insight into Transannular Cyclization Reactions to Synthesize Azabicyclo[X.Y.Z]alkanone Amino Acid Derivatives from 8-, 9-, and 10-Membered Macrocyclic Dipeptide Lactams
An efficient method for synthesizing different functionalized azabicyclo[X.Y.0]alkanone amino acid derivatives has been developed employing electrophilic transannular cyclizations of 8-, 9-, and 10-membered unsaturated macrocycles to form 5,5-, 6,5-, 7,5-, and 6,6-fused bicylic amino acids, respectively. Macrocycles were obtained by a sequence featuring peptide coupling of vinyl-, allyl-, homoallyl-, and homohomoallylglycine building blocks followed by ring-closing metathesis. X-ray crystallographic analyses of the 8-, 9-, and 10-membered macrocyclic lactam starting materials as well as certain bicyclic amino acid products provided insight into their conformational preferences as well as the mechanism for the diastereoselective formation of specific azabicycloalkanone amino acids by way of transannular iodolactamization reactions. (Chemical Equation Presented).
Atmuri, N. D. Prasad,Lubell, William D.
p. 4904 - 4918
(2015/06/02)

Z-selective olefin metathesis on peptides: Investigation of side-chain influence, preorganization, and guidelines in substrate selection
Olefin metathesis has emerged as a promising strategy for modulating the stability and activity of biologically relevant compounds; however, the ability to control olefin geometry in the product remains a challenge. Recent advances in the design of cyclom
Mangold, Shane L.,Oleary, Daniel J.,Grubbs, Robert H.
supporting information
p. 12469 - 12478
(2014/11/07)

Epoxy amino acids produced from allylglycines intramolecularly cyclised to yield four stereoisomers of 4-hydroxyproline derivatives
Derivatives of 2-amino-4-pentenoic acid (allylglycine) were efficiently resolved using Subtilisin or acylase. The side-chain unsaturated bond of the enantiomerically pure amino acid with tert-butoxycarbonyl (Boc) protection was smoothly epoxidized with m-chloroperbenzoic acid. When the Boc protection of the amino group was removed, the amino group intramolecularly attacked the side-chain epoxide, generating compounds with five-membered rings: the 4-hydroxyproline derivatives. Two diastereomeric products were formed through the cyclisation reaction, for example, (2S,4S)-4-hydroxyproline benzyl ester (cis-8) and (2S,4R)-4-hydroxyproline benzyl ester (trans-8) were formed from (2S)-amino acid with a side-chain epoxide. Compound (2S,4S)-4-hydroxyproline benzyl ester (cis-8) was transformed to a lactone (cis-hydroxyproline lactone, 10) with the removal of benzyl alcohol. The cis-conformation was essential for the intramolecular ester exchange reaction; in fact, no lactone formation was observed for the trans isomer (trans-8). The separation of cis-hydroxyproline lactone and the trans-isomeric hydroxyproline benzyl ester was facile and clear, in contrast to the difficult separation of cis- and trans-hydroxyproline derivatives. Thus, two diastereomers of hydroxyproline derivatives for l-hydroxyproline and also for d-hydroxyproline were obtained, i.e., four diastereomers of hydroxyproline derivatives.
Krishnamurthy, Suvratha,Arai, Toru,Nakanishi, Kanae,Nishino, Norikazu
p. 2482 - 2490
(2014/01/06)

Synthesis and self-assembly of NCN-pincer Pd-complex-bound norvalines
The NCN-pincer Pd-complex-bound norvalines Boc-D/L-[PdCl(dpb)]Nva-OMe (1) were synthesized in multigram quantities. The molecular structure and absolute configuration of 1 were unequivocally determined by single-crystal X-ray structure analysis. The robustness of 1 under acidic/basic conditions provides a wide range of N-/C-terminus convertibility based on the related synthetic transformations. Installation of a variety of functional groups into the N-/C-terminus of 1 was readily carried out through N-Boc- or C-methyl ester deprotection and subsequent condensations with carboxylic acids, R 1COOH, or amines, R2NH2, to give the corresponding N-/C-functionalized norvalines R1-D/L-[PdCl(dpb)]Nva- R2 2-9. The dipeptide bearing two Pd units 10 was successfully synthesized through the condensation of C-free 1 with N-free 1. The robustness of these Pd-bound norvalines was adequately demonstrated by the preservation of the optical purity and Pd unit during the synthetic transformations. The lipophilic Pd-bound norvalines L-2, Boc-L-[PdCl(dpb)]Nva-NH-n-C 11H23, and L-4, n-C4H9CO-L- [PdCl(dpb)]Nva-NH-n-C11H23, self-assembled in aromatic solvents to afford supramolecular gels. The assembled structures in a thermodynamically stable single crystal of L-2 and kinetically stable supramolecular aggregates of L-2 were precisely elucidated by cryo-TEM, WAX, SAXS, UV/Vis, IR analyses, and single-crystal X-ray crystallography. An antiparallel β-sheet-type aggregate consisting of an infinite one-dimensional hydrogen-bonding network of amide groups and π-stacking of PdCl(dpb) moieties was observed in the supramolecular gel fiber of L-2, even though discrete dimers are assembled through hydrogen bonding in the thermodynamically stable single crystal of L-2. The disparate DSC profiles of the single crystal and xerogel of L-2 indicate different thermodynamics of the molecular assembly process. Metalated amino acids: A series of NCN-pincer Pd-complex-bound norvaline derivatives was successfully synthesized without loss of the optical purity and Pd unit. Efficient self-assembly properties of these Pd-norvalines were found to afford well-regulated Pd arrays both in the single crystal and in the supramolecular gel. A solvent-dependent configuration control of the Pd array was corroborated by means of single-crystal X-ray crystallography and cryo-TEM analysis. Copyright
Ogata, Kazuki,Sasano, Daisuke,Yokoi, Tomoya,Isozaki, Katsuhiro,Yoshida, Ryota,Takenaka, Toshio,Seike, Hirofumi,Ogawa, Tetsuya,Kurata, Hiroki,Yasuda, Nobuhiro,Takaya, Hikaru,Nakamura, Masaharu
supporting information
p. 12356 - 12375
(2013/09/23)

Synthesis, structure, and function of pcp pincer transition-metal-complex- bound norvaline derivatives
A PCP pincer palladium-complex-bound norvaline, Boc-l-[Pd]Nva-OMe, was synthesized and fully characterized by NMR, FT-ICR-MS, and X-ray crystallography. Selective N- and C-terminus transformations of Boc-l-[Pd]Nva-OMe were performed by conventional deprotection-condensation procedures to afford lipophilic palladium-bound norvaline derivatives without metal detachment. The N-/C-bisfunctionalized palladium-bound norvaline showed self-assembly properties, as evidenced by supramolecular gel formation. The catalytic activity of the supramolecular gel was assessed in the 1,4-conjugate addition of phenylboronic acid.
Takaya, Hikaru,Iwaya, Takashi,Ogata, Kazuki,Isozaki, Katsuhiro,Yokoi, Tomoya,Yoshida, Ryota,Yasuda, Nobuhiro,Seike, Hirofumi,Takenaka, Toshio,Nakamura, Masaharu
supporting information
p. 1910 - 1914
(2013/09/24)

VERSATILE AND STEREOSPECIFIC SYNTHESIS OF GAMMA,DELTA -UNSATURATED AMINO ACIDS BY WITTIG REACTION
The present invention relates to γ,δ-unsaturated a-amino acids of general formula (I). The present invention also provides a versatile process for the stereospecific synthesis of said compounds of formula (I), involving a Wittig reaction. The present invention also relates to intermediate products of general formulae (II) and (III), as shown below, which are involved in the synthesis of compounds (I).
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Page/Page column 48; 49; 58

(2013/03/28)

Stereoselective synthesis of unsaturated and functionalized L-NHBoc amino acids, using wittig reaction under mild phase-transfer conditions
The stereoselective synthesis of a new amino acid phosphonium salt was described by quaternization of melting triphenylphosphine with the β-iodo NHBoc-amino ester, derived from l-aspartic acid. The deprotection of the carboxylic acid function to afford the phosphonium salt with a free carboxylic acid group was achieved by a palladium-catalyzed desallylation reaction. This phosphonium salt was used in the Wittig reaction with aromatic or aliphatic aldehydes and trifluoroacetophenone, under solid-liquid phase-transfer conditions in chlorobenzene and in the presence of K3PO4 as weak base, to afford the corresponding unsaturated amino acids without racemization. Thus, the reaction with substituted aldehydes allows to graft various functionalized groups on the lateral chain of the amino acid, such as trifluoromethyl, cyano, nitro, ferrocenyl, boronato, or azido. In addition, the reaction of the amino acid Wittig reagent with α,β-unsaturated aldehydes leads to amino acids bearing a diene on the lateral chain. Finally, this amino acid phosphonium salt appears to be a new powerful tool for the preparation of unsaturated and non-proteinogenic α-amino acids, directly usable for the synthesis of customized peptides.
Remond, Emmanuelle,Bayardon, Jerome,Ondel-Eymin, Marie-Joelle,Juge, Sylvain
p. 7579 - 7587
(2012/10/29)

A new method of synthesis of 6-substituted piperidine-2,4-diones from homoallylamines
Mono- and dihomoallylamines serve as convenient precursors for the preparation of 6-substituted piperidine-2,4-diones. This transformation is based, on the one hand, on a simple and well-known halocyclocarbamation reaction proceeding by the addition of a
Kuznetsov, Nikolai Yu.,Maleev, Victor I.,Khrustalev, Victor N.,Mkrtchyan, Anna F.,Godovikov, Ivan A.,Strelkova, Tatyana V.,Bubnov, Yuri N.
experimental part
p. 334 - 344
(2012/02/16)

Synthesis and biological evaluation of novel thiocolchicine-podophyllotoxin conjugates
The synthesis and biological evaluation of 9 dimeric compounds obtained by condensation of thiocolchicine and/or podophyllotoxin with 6 different dicarboxylic acids is described. In particular, tubulin assembly assay and immunofluorescence analysis results are reported. The biological data highlighted three compounds as being more active than the others, having a marked ability to inhibit the polymerization of tubulin in vitro and causing significant disruption to the microtubule network in vivo. The spacer unit was found to have a significant effect on biological activity, reinforcing the importance of the design of conjugate compounds to create new biologically active molecules in which the spacer could be useful to improve the solubility and to modulate the efficacy of well known anticancer drugs.
Passarella, Daniele,Peretto, Bruno,Blasco y Yepes, Raul,Cappelletti, Graziella,Cartelli, Daniele,Ronchi, Cristina,Snaith, John,Fontana, Gabriele,Danieli, Bruno,Borlak, Jurgen
experimental part
p. 219 - 226
(2010/04/06)

Progress towards the synthesis of piperazimycin A: synthesis of the non-proteogenic amino acids and elaboration into dipeptides
This Letter describes the synthesis of the five non-proteogenic amino acids required for the total synthesis of piperazimycin A, and synthetic elaboration into multiple dipeptides. Importantly, this Letter details the first example of an elusive piperazic acid-piperazic acid coupling to form this key C5-C14 dipeptide.
Phillip Kennedy,Lindsley, Craig W.
scheme or table
p. 2493 - 2496
(2010/06/14)

PEPTIDE DEFORMYLASE INHIBITORS
The present invention is directed to certain {2-(alkyl)-3-[2-(5-fluoro-4-pyrimidinyl)hydrazino]-3-oxopropyl}hydroxyformamide derivatives, compositions containing them, the use of such compounds in the inhibition of bacterial peptide deformylase (PDF) activity, and in the treatment of bacterial infections. Specifically, the invention is directed to compounds of formula (I), wherein R1, R2 and R3 are defined herein and to pharmaceutically acceptable salts thereof. The compounds of this invention are bacterial peptide deformylase inhibitors and can be useful in the treatment of bacterial infections.
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Page/Page column 129

(2009/06/27)

PTERIDINE DERIVATIVES AS POLO-LIKE KINASE INHIBITORS USEFUL IN THE TREATMENT OF CANCER
Compound of formula (I) are inhibitors of Polo-like kinases (PLKs), and are useful in treatment of cell proliferative diseases: wherein R1 and R2 are hydrogen, or an optionally substituted (C1-C6)alkyl, (C2- Cs
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Page/Page column 50

(2008/12/05)

Synthesis of macrocyclic trypanosomal cysteine protease inhibitors
The importance of cysteine proteases in parasites, compounded with the lack of redundancy compared to their mammalian hosts makes proteases attractive targets for the development of new therapeutic agents. The binding mode of K11002 to cruzain, the major cysteine protease of Trypanosoma cruzi was used in the design of conformationally constrained inhibitors. Vinyl sulfone-containing macrocycles were synthesized via olefin ring-closing metathesis and evaluated against cruzain and the closely related cysteine protease, rhodesain.
Chen, Yen Ting,Lira, Ricardo,Hansell, Elizabeth,McKerrow, James H.,Roush, William R.
scheme or table
p. 5860 - 5863
(2009/05/31)

Synthesis of isotopically labelled amino acids
An efficient approach to the enantioselective synthesis of a series of amino acids from either bromoacetyl bromide or glycine is described using a [2,3]-sigmatropic rearrangement to establish the stereogenic centre at C-2 under mild conditions. Protected allylglycine 5 is a valuable building block to several amino acids e.g. hydrolytic cleavage of the auxiliary in 5 followed by deprotection gave L-allylglycine in 92% yield whilst oxidative cleavage of the terminal alkene followed by deprotection gave L-aspartic acid in 67% yield over the 2 steps. Furthermore alkene 5 may be converted to hydroxy ester 8 which is an intermediate for the synthesis of various amino acids including L-lysine and L-proline. Since the enantiomer of sultam 1 is commercially available, the analogous D-amino acids may be synthesised. This chemistry is readily adapted for the incorporation of isotopic labels for example for the synthesis of [1,2-13C2,15N]-L-homoserine 14. Copyright
Rees, David O.,Bushby, Nick,Harding, John R.,Song, Chuanjun,Willis, Christine L.
p. 399 - 401
(2008/02/08)

MACROCYCLIC SH2 DOMAIN BINDING INHIBITORS
Disclosed are compounds for inhibiting the binding of an SH2 domain-containing protein, for example, a compound of formula (I): FORMULA (I) wherein R1 is a lipophile; R2, in combination with the phenyl ring, is a phenylphosphate mimic group or a protected
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Page/Page column 18

(2010/10/20)

High stereocontrol in the allylation of chiral non-racemic α-alkoxy and α-amino nitrones
The stereocontrolled addition of allylic metals to chiral non-racemic nitrones promoted by the addition of Lewis acids is described. Whereas for α-alkoxy nitrones the stereocontrol depends on the Lewis acid used as an activator, for α-amino nitrones the d
Merino, Pedro,Delso, Ignacio,Mannucci, Vanni,Tejero, Tomas
p. 3311 - 3314
(2007/10/03)

Systematic study of the synthesis of macrocyclic dipeptide β-turn mimics possessing 8-, 9-, and 10- membered rings by ring-closing metathesis
A systematic study was performed to establish general synthesis protocols for forming enantiomerically pure macrocyclic dipeptide lactams. Focusing on macrocycles of 8-, 9-, and 10-membered rings, effective syntheses were achieved by a sequence featuring
Kaul, Ramesh,Surprenant, Simon,Lubell, William D.
p. 3838 - 3844
(2007/10/03)

Convenient access to glutamic acid side chain homologues compatible with solid phase peptide synthesis
(Chemical Equation Presented) Preparation of several side chain length variants of glutamic acid is achieved via olefin cross metathesis of allyl glycine derivatives. The products are suitably protected for direct use in Fmoc solid-phase peptide synthesis, as demonstrated by successful synthesis of test sequences.
Ryan, Shannon J.,Zhang, Yongda,Kennan, Alan J.
p. 4765 - 4767
(2007/10/03)

Locked conformations for proline pyrrolidine ring: Synthesis and conformational analysis of cis- and trans-4-tert-butylprolines
The motional restrictions of the proline pyrrolidine ring allow this secondary amine amino acid to act as a turn inducer in many peptides and proteins. The pyrrolidine ring is known to exhibit two predominant pucker modes (i.e., C-4 (Cγ) exo and endo envelope conformers whose ratio can be controlled by proper substituents in the ring). In nature, the exo puckered 4(R)-hydroxy-L-proline plays a crucial role as a building block in collagen and collagen-like structures. It has been previously concluded that the electronegativity of the 4-cis-substituent increases the endo puckering while the electronegativity of the 4-trans-substituent favors the exo puckering. Here, we have introduced a sterically demanding tert-butyl group at C-4 in trans- and cis-configurations. In the case of trans-substitution, the induced puckering effect on the pyrrolidine ring was studied with X-ray crystallography and 1H NMR spectral simulations. Both cis- and trans-4-tert-butyl groups strongly favor pseudoequatorial orientation, thereby causing opposite puckering effects for the pyrrolidine ring, cis-exo and trans-endo for L-prolines, in contrast to the effects observed in the case of electronegative C-4 substituents. The syntheses and structural analysis are presented for the conformationally constrained 4-tert-butylprolines. The prolines were synthesized from 4-hydroxy-L-proline, substitution with t-BuCuSPhLi being the key transformation. This reaction gave N-Boc-trans-4-tert-butyl-L-proline tert-butyl ester in 94% ee and 57% de. Enantioselectivity was increased to 99.2% ee by crystallization of N-Boc-trans-4-tert-butyl-L-proline in the final step of the synthesis.
Koskinen, Ari M. P.,Helaja, Juho,Kumpulainen, Esa T. T.,Koivisto, Jari,Mansikkamaeki, Heidi,Rissanen, Kari
p. 6447 - 6453
(2007/10/03)

Synthesis of 5/7-, 5/8- And 5/9-bicyclic lactam templates as constraints for external β-turns
The 5/7-, 5/8- and 5/9-bicyclic lactams 3, 17, 5 and 6 have been synthesised as single diastereoisomers by a route involving ring closing olefin metathesis. The X-ray crystal structure of the amino acid hydrochloride 17 has been carried out and compared t
Duggan, Heather M. E.,Hitchcock, Peter B.,Young, Douglas W.
p. 2287 - 2295
(2007/10/03)

NOVEL LACTAMS AND USES THEREOF
This invention relates to novel compounds having formula (I) to their pharmaceutical compositions and to their methods of use. These novel compounds inhibit secretase and thereby inhibit the production of amyloid ? protein, thereby acting to prevent the formation of neurological deposits of amyloid protein. The present invention relates to the treatment of neurological disorders related to amyloid ? - protein production such as Alzheimer's disease.
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Page 42-44

(2010/02/08)

Iminoiodane mediated aziridination of α-allylglycine: Access to a novel rigid arginine derivative and to the natural amino acid enduracididine
The synthesis of fully protected aminodihydrohistidines in optically pure form is described starting from allylglycine derivatives. These compounds represent novel conformationally constrained analogues of arginine, one of them being, in addition, a protected form of the marine natural product, enduracididine. The key step of the strategy is a one-pot copper-catalyzed aziridination of t-butyl (S)-N-(9-phenyl-9H-fluoren-9-yl)allylglycinate ((S)-16) with 2-trimethylsilylethanesulfonamide in the presence of iodosylbenzene.
Sanière, Laurent,Leman, Lo?c,Bourguignon, Jean-Jacques,Dauban, Philippe,Dodd, Robert H.
p. 5889 - 5897
(2007/10/03)

Epothilone derivatives
The present invention relates to epothilone derivatives, having the following formula in which the variables G, W, Q, X, Y, B1, B2, Z1, Z2, and R1-R7are as defined herein, methods for the preparation of the derivatives and intermediates thereof.
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(2008/06/13)

Treatment of parasitic diseases by inhibition of cysteine proteases of the papain superfamily
The present invention relates to compounds and pharmaceutical compositions which inhibit proteases, such as cysteine proteases. In particular, the present invention relates to compounds and pharmaceutical compositions which inhibit cysteine proteases of the papain superfamily. The compounds and pharmaceutical compositions of the present invention are useful for treating diseases, particularly parasitic diseases, which are mediated by such proteases. In particular, the present invention relates to a method of treating malaria by inhibiting the cysteine protease falcipain.
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(2008/06/13)

Hydroboration-Suzuki cross coupling of unsaturated amino acids; the synthesis of pyrimine derivatives
Hydroboration of protected allylglycines with 9-BBN followed by Suzuki cross coupling of the resulting organoboranes proceeded smoothly giving a range of new bis-homophenylalanine and related derivatives in good yields (9 examples, 53-64%). One of the Suzuki coupling products has been elaborated to give the N-Cbz-protected natural product pyrimine. The hydroboration-Suzuki coupling of vinylglycine derivatives was also studied but was less efficient than with the allylglycine derivatives: the best results were obtained using disiamylborane·DMS as the hydroborating agent.
Collier, Philip N,Campbell, Andrew D,Patel, Ian,Taylor, Richard J.K
p. 6117 - 6125
(2007/10/03)

Versatile synthons for optically pure alpha-amino aldehydes and alpha-amino acids: (+)- and (-)-4,5-dialkoxy-2-oxazolidinones.
Both enantiomers of trans-5-benzyloxy-4-methoxy- (BMOx) and trans-4,5-dimethoxy-2-oxazolidinones (DMOx), which are readily accessible from simple 2-oxazolone heterocycles, represent good candidates for a new class of chiral synthons for use in the preparation of optically pure alpha-amino aldehydes and alpha-amino acids, respectively.
Morita,Nagasawa,Yahiro,Matsunaga,Kunieda
p. 897 - 899
(2007/10/03)

A novel application of a Pd(0)-catalyzed nucleophilic substitution reaction to the regio- and stereoselective synthesis of lactam analogues of the epothilone natural products
Several lactam analogues of the epothilones were prepared using a concise semisynthetic approach starting with the unprotected natural products. Highlighted in this strategy is a novel regio- and stereoselective Pd(0)-catalyzed azidation reaction of a macrocyclic lactone. Subsequent reduction and macrolactamization of the resulting azide acid intermediates provided the desired macrolactams in satisfactory overall yields. The entire three-step sequence was streamlined into a 'one-pot' process for the epothilone B-lactam, BMS-247550, which is currently undergoing phase I clinical trials. An initial total synthesis route to prepare the lactam analogue of epothilone C was completed and compared to the more direct semisynthesis approach. All of the lactam analogues were evaluated in vitro and the results are discussed.
Borzilleri,Zheng,Schmidt,Johnson,Kim,DiMarco,Fairchild,Gougoutas,Lee,Long,Vite
p. 8890 - 8897
(2007/10/03)

The direct synthesis of novel enantiomerically pure α-amino acids in protected form via Suzuki cross-coupling
Protected allylglycine has been hydroborated and the intermediate organoborane employed in Suzuki coupling reactions with a number of olefinic, aromatic and heteroaromatic bromides and iodides to produce a range of novel α-amino acids in good, unoptimised yields. (C) 2000 Elsevier Science Ltd.
Collier,Campbell,Patel,Taylor
p. 7115 - 7119
(2007/10/03)

N-substituted 2-amino-4-pentenoic acids for amino acid protection and resolution
N-Substituted 2-amino-4-pentenoic acid derivatives employed for the protection of racemic amino acids were shown to be capable of permitting the chromatographic separation of R and S isomers. When N(α) was disubstituted with benzyl and phenylfluorenyl groups, the racemic amino acids could be separated with facility on open silica gel columns. Further, the optically pure N-protected amino acids so derived could be used for the preparation of misacylated suppressor transfer RNAs. (C) 2000 Elsevier Science Ltd.
Lodder, Michiel,Wang, Bixun,Hecht, Sidney M.
p. 9421 - 9429
(2007/10/03)

1,5-dimethyl-4-phenylimidazolidin-2-one-derived iminic glycinimides: Useful new reagents for practical asymmetric synthesis of α-amino acids
New 1,5-dimethyl-4-phenylimidazolidin-2-one-derived acyclic chiral iminic glycine reagents have been prepared and diastereoselectively alkylated with activated alkyl halides and electrophilic olefins in the presence of lithium chloride under (a) strong bases (LHMDS, KOBu(t)) and low temperature (-78 °C,) conditions; (b) solid-liquid phase-transfer catalysis reaction (LiOH, TBAB, -20 °C) conditions, and (c) in the presence of organic bases (DBU, BEMP, TMG, -20 °C). In the case of dielectrophiles C- and N-alkylation takes place to afford heterocyclic derivatives. Hydrolysis of alkylated products has been carried out (a) in two-step procedures with LiOOH or LiOH followed by acidic hydrolysis or Dowex purification, (b) in one single-step under refluxing water to give the corresponding α-amino acid, (c) in the presence of DBU in methanol to provide N-protected α-amino acids methyl esters, or (d) by a protection-hydrolysis procedure to afford N-Boc-protected α-amino acids. The chiral imidazolidinone has generally been recovered in good yield. This methodology has been shown to be useful for the synthesis of acyclic and heterocyclic (S)- and (R)-α-amino acids.
Guillena,Najera
p. 7310 - 7322
(2007/10/03)

Asymmetric synthesis of α-amino acids by the alkylation of pseudoephedrine glycinamide: Lallylglycine and N-boc-L-allylglycine [Acetamide, 2-amino-N-(2-hydroxy-1-methyl-2-phenylethyl)-N-methyl-, [R- (R,R)]-, 4-Pentenoic acid, 2-amino-, (R)- and 4-Pentenoic acid, 2-[[(1,1-dimethylethoxy)carbonyl]amino]-, (R)-)]
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Myers, Andrew G.,Gleason, James L.,Antoulinakis, Evan G.,Boeckman, Robert K.
p. 57 - 57
(2017/10/06)

Rapid syntheses of 3-amino-5-hydroxymethyl-γ-lactones from L- allylglycine
(3R, 5R) and (3R, 5S) N-protected 3-amino-5-hydroxymethyl-γ-lactones were obtained by one dihydroxylation step from methyl N-protected L- allylglycinate.
Girard, Anne,Greck, Christine,Genet, Jean Pierre
p. 4259 - 4260
(2007/10/03)

Towards a total synthesis of ustiloxins A and B. Stereocontrolled synthesis of (2S,4S,6S)-4-hydroxy-5-phenylsulfinylnorvaline
A short, stereocontrolled synthesis of (2S,4S,6S)-4-hydroxy-5-phenylsulfinylnorvaline (8), an unusual amino acid component of ustiloxins A and B, has been achieved. Stereoselective bromolactonisation of N-Boc-(S)-allylglycine (3) is followed by substitution of the bromide 4a with thiophenol to give the corresponding sulfide 5. Highly stereoselective oxidation of the sulfide 5 gives the corresponding sulfoxide 6a. Removal of the Boc group and lactone ring opening then complete the synthesis of the unusual amino acid.
Hutton, Craig A.,White, Jonathan M.
p. 1643 - 1646
(2007/10/03)

Highly practical methodology for the synthesis of D- and L-α-amino acids, N-protected α-amino acids, and N-methyl-α-amino acids
Full details are provided for an exceedingly practical method to synthesize D- and L-α-amino acids, N-protected α-amino acids, and N-methyl-α-amino acids, employing as a key step the asymmetric alkylation of pseudoephedrine glycinamide (1) or pseudoephedrine sarcosinamide (2). Practical procedures for the synthesis of 1 and 2 from pseudoephedrine and glycine methyl ester or sarcosine methyl ester, respectively, are presented. Optimum protocols for the enolization and subsequent alkylation of 1 and 2 are described. Alkylation reactions of 1 and 2 are found to be quite efficient with a wide range of alkyl halide substrates, and the products are formed with high diastereoselectivity. The products of these alkylation reactions are hydrolyzed efficiently and with little to no racemization simply by heating in water or water-dioxane mixtures. This protocol provides an exceedingly practical method for the preparation of salt-free α-amino acids of high enantiomeric purity. Alternatively, the alkylation products may be hydrolyzed in high yield and with little to no racemization by heating with aqueous sodium hydroxide. The alkaline hydrolyzate can then be treated with an acylating reagent to provide directly highly enantiomerically enriched N-protected derivatives such as N-Boc and N-Fmoc. Key features necessary for the successful execution of these experimental procedures are identified.
Myers, Andrew G.,Gleason, James L.,Yoon, Taeyoung,Kung, Daniel W.
p. 656 - 673
(2007/10/03)

Synthesis of N-protected-α-substituted-glycine racemic esters by zinc-mediated addition of organic halide to glycine cation equivalent
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(2008/06/13)

Use of (S)-N-tert-butoxycarbonylaziridine-2-carboxylate derivatives for α-amino acid synthesis
(S)-tert-Butyl-N-tert-butoxycarbonylaziridine-2-carboxylate and (S)-tert-butyl-N-tert-butoxycarbonylaziridine-2-carboxamide were synthesised and found to react with copper 'catalysed' Grignard reagents to give protected α-amino acids in moderate to good yields.
Baldwin, Jack E.,Farthing, Christopher N.,Russell, Andrew T.,Schofield, Christopher J.,Spivey, Alan C.
p. 3761 - 3764
(2007/10/03)