Synthesis of Enantiomerically Pure 4-Substituted Glutamic Acids and Prolines: General Aldol Reaction of Pyroglutamate Lactam Lithium Enolate Mediated by Et2O.cntdot.BF3

Ezquerra, J.; Pedregal, Concepciòn; Yruretagoyena, B.; Rubio, Alberto Pérez; Carreño, M. Carmen; Escribano, Ana; Ruano, José Luis Garcı́a

doi:10.1021/jo00114a054

Cited by 59 publications

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“…This latter compound was hydrolyzed and deprotected to give 16 as a single diastereoisomer. The attribution of the 2S,4S configuration to this product was made on the basis of comparison with analogous reactions described in the literature, [25] and confirmed by NMR mono-and bidimensional NOE experiments on compound 21, that showed a cis relationship between the two hydrogen atoms in the positions C-2 and C-4.…”

Section: Synthesis Of Monatin Analoguessupporting

confidence: 63%

Monatin, Its Stereoisomers and Derivatives: Modeling the Sweet Taste Chemoreception Mechanism

et al. 2005

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The sweet natural compound monatin 1 has two stereogenic centers, and the 2S,4S absolute configuration has been attributed previously to the natural isomer. Among the four stereoisomers of monatin, three of them, particularly the 2R,4R isomer, tastes intensely sweet. The conformations of the four compounds have been studied by means of molecular modelling techniques. Both the diastereoisomeric forms show strong intramolecular hydrogen bonds which involve different functional groups and give rise to two different minimum energy conformations. The tertiary alcohol group in monatin seems to be indirectly involved in the generation of the taste, acting as an important contraint in generating the active conformation. The most important glucophores have

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Section: Synthesis Of Monatin Analoguessupporting

confidence: 63%

Monatin, Its Stereoisomers and Derivatives: Modeling the Sweet Taste Chemoreception Mechanism

et al. 2005

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“…The Boc protective group in 13 was replaced by a Cbz to obtain 14 for achieving better stereo-selectivity in subsequent steps. The stereochemistry of the benzyl group in 13 and 14 was confirmed by two-dimensional (2D) Nuclear Overhauser Effect (NOE) data of 14 (Supporting Information) and was found to be same as that in the previous report 25. The carbonyl group in 14 was selectively reduced, followed by acetylation and introduction of a syn -allyl group at the C-5 position via the N -acyl iminium ion chemistry to afford compound 15 26.…”

supporting

confidence: 65%

“…Briefly, compound 13 was prepared from the commercially available pyroglutamate ester 12 25. The Boc protective group in 13 was replaced by a Cbz to obtain 14 for achieving better stereo-selectivity in subsequent steps.…”

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confidence: 99%

Design, Synthesis, and Evaluation of Potent, Nonpeptidic Mimetics of Second Mitochondria-Derived Activator of Caspases

et al. 2009

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A series of new Smac mimetics have been designed, synthesized and evaluated. The most potent compound 10 binds to XIAP, cIAP-1 and cIAP-2 BIR3 proteins with K i values of 3.9, 0.37 and 0.25 nM, respectively. Compound 10 antagonizes XIAP in a cell-free functional assay and induces rapid cIAP-1 degradation in cancer cells. Compound 10 inhibits cell growth in the MDA-MB-231 cancer cell line with an IC 50 value of 8.9 nM.Apoptosis is a critical cell process in normal development and homeostasis of multicellular organisms to eliminate unwanted or damaged cells. Evasion of apoptosis is now recognized as a hallmark of all cancers. 1-2 Targeting key apoptosis regulators with a goal to promote apoptosis in cancer cells is a new strategy for anticancer drug design. [3][4] Inhibitor of apoptosis proteins (IAPs) a are a class of key apoptosis regulators. 5,6 Among them, cellular IAP-1 (cIAP-1) and cIAP-2 play a critical role in regulation of tumor necrosis factor (TNF) receptor-mediated apoptosis, 7 and X-linked IAP (XIAP) is a central regulator of both death-receptor-mediated and mitochondria-mediated apoptosis pathways. 8 XIAP inhibits apoptosis through direct binding to and inhibition of three cysteine proteases, an initiator caspase-9 and the two effectors caspase-3 and -7. 5,6 XIAP contains three Baculoviral IAP Repeats (BIR) domains. While the third BIR domain (BIR3) of XIAP selectively targets caspase-9, the BIR2 domain, together with the immediate preceding linker, inhibits both caspase-3 and caspase-7. 6,8 Since these caspases play a critical role in the execution of apoptosis, XIAP functions as an efficient inhibitor of apoptosis. 6,8 Accordingly, these IAP proteins, especially XIAP, are considered as promising cancer therapeutic targets. [8][9] Smac (Second Mitochondria-derived Activator of Caspases) is a potent pro-apoptotic protein and an endogenous antagonist of IAP proteins. 10,11 Previous studies have firmly established that Smac interacts with XIAP and cIAP-1/2 proteins via its AVPI tetra-peptide motif. 15 Smac, in its dimeric form, interacts with both BIR2 and BIR3 domains in XIAP and effectively removes the inhibition of XIAP to not only caspase-9 but also caspase-3/-7.In the last few years, intense research efforts have been devoted to the design and development of small molecules to mimic the AVPI binding motif as antagonists of IAP proteins and as a new class of anticancer drugs. 4,[16][17][18][19][20][21][22][23] These small molecules are called Smac mimetics. To date, two different types of Smac mimetics have been reported, namely monovalent and bivalent Smac mimetics ( Figure 1). 4,[16][17][18][19][20][21][22][23] Monovalent Smac mimetics such as 1-4 are designed to mimic a single AVPI binding motif, [16][17][18][19] whereas the bivalent compounds, such as 5 and 6, contain mimetics of two AVPI binding motifs tethered together through a linker. 4,[20][21][22][23] Bivalent Smac mimetics can achieve much higher affinities to XIAP and can be much more potent than the corresponding monovalent Sma...

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“…Fortunately,t he addition of BF 3 ·OEt 2 to the reactionm ixture allowedt he aldol reaction to proceed, affording 21 as as ingle diastereomer in high yield. [16] This reaction is rather unusuali ni ts combined use of both as trong Scheme1.Key strategic elements of our approach to exiguaquinol presented as aretrosynthetic analysis.…”

mentioning

confidence: 95%

“…Fortunately, the addition of BF 3 ·OEt 2 to the reaction mixture allowed the aldol reaction to proceed, affording 21 as a single diastereomer in high yield. [16] This reaction is rather unusual in its combined use of both a strong Lewis acid and a lithium enolate to promote an aldol addition. The aldol adduct was then protected, the sulfides were each oxidized to the corresponding sulfoxides, and subsequent thermal elimination afforded diene 22 .…”

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confidence: 99%

A Synthesis of Exiguaquinol Dessulfate

Schwarzwalder

Scott

Vanderwal

2016

Chemistry A European J

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A concise and stereoselective synthesis of exiguaquinol dessulfate is described. Sequential application of a Diels–Alder cycloaddition, a desymmetrizing aldol addition, and a reductive Heck cyclization established most of the architecture of exiguaquinol, and a carefully choreographed introduction of the polar substituents afforded the title compound; unfortunately, naphthoquinol sulfation could not be achieved to deliver exiguaquinol. Our hypothesis regarding the configurational preference of the N-acyl hemiaminal, which was based upon an analysis of internal hydrogen-bonding interactions with polar functional groups, was proven correct. Unfortunately, the title compound did not demonstrate any bactericidal activity against H. pylori cultures. A desymmetrization strategy led to the synthesis of a congener of exiguaquinol, an inhibitor of the H. pylori MurI enzyme and a potential antibiotic. The pentacyclic architecture was accessed via convergent Diels–Alder and aldol additions, followed by a reductive Heck cyclization to forge the vicinal quaternary stereogenic centers.

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Synthesis of Enantiomerically Pure 4-Substituted Glutamic Acids and Prolines: General Aldol Reaction of Pyroglutamate Lactam Lithium Enolate Mediated by Et2O.cntdot.BF3

Cited by 59 publications

References 0 publications

Monatin, Its Stereoisomers and Derivatives: Modeling the Sweet Taste Chemoreception Mechanism

Monatin, Its Stereoisomers and Derivatives: Modeling the Sweet Taste Chemoreception Mechanism

Design, Synthesis, and Evaluation of Potent, Nonpeptidic Mimetics of Second Mitochondria-Derived Activator of Caspases

A Synthesis of Exiguaquinol Dessulfate

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