The Use of Diethyl Azodicarboxylate and Triphenylphosphine in Synthesis and Transformation of Natural Products

Mitsunobu, Oyo

doi:10.1055/s-1981-29317

Cited by 4,404 publications

(1,876 citation statements)

References 16 publications

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“…Compound 13 was used as a common intermediate in the synthesis of nisoxetine derivatives 8 and 10. The coupling product 15 was obtained by the Mitsunobu reaction [25] of commercially available 3-bromo-2-hydroxypyridine 14 with 13. Initial attempts to remove the Boc protecting group of 15 using TFA resulted in the cleavage of the pyridyl ether.…”

Section: Chemistrymentioning

confidence: 99%

(R)-N-Methyl-3-(3-125I-pyridin-2-yloxy)-3-phenylpropan-1-amine: a novel probe for norepinephrine transporters

Balagopal¹,

Kung²,

Lieberman³

et al. 2008

Nuclear Medicine and Biology

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Alterations in the serotonin and norepinephrine neuronal functions have been observed in patients with major depression. Several antidepressants bind to both serotonin transporters (SERT) and norepinephrine transporters (NET). The ability to image NET in the human brain would be a useful step toward understanding how alterations in NET relate to disease. In this study, we report the synthesis and characterization of a new series of derivatives of iodo-nisoxetine (INXT), a known radioiodinated probe. The most promising, (R)-N-methyl-3-(3-iodopyridin-2-yloxy)-3-phenylpropylamine (PYINXT) 9, displayed a high and saturable binding to NET with a K d value of 0.53 ± 0.03 nM. Biodistribution studies of [ 125 I]PYINXT in rats showed moderate initial brain uptake (0.54 %dose/organ at 2 min) with a relatively fast washout from the brain (0.16 %dose/organ at 2 hr) as compared to [ 125 I]INXT, 7. The hypothalamus (a NET rich region) to striatum (a region devoid of NET) ratio was found to be 2.14 at 4 hr post i.v. injection. The preliminary results suggest that this improved iodinated ligand, when labeled with 123 I, may be useful for mapping NET binding sites with SPECT in the living human brain.

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Section: Chemistrymentioning

confidence: 99%

(R)-N-Methyl-3-(3-125I-pyridin-2-yloxy)-3-phenylpropan-1-amine: a novel probe for norepinephrine transporters

Balagopal¹,

Kung²,

Lieberman³

et al. 2008

Nuclear Medicine and Biology

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“…Compound 34 was then converted into diyne 36 as the substrate for the envisaged ring-closing alkyne metathesis (RCAM) via the corresponding triflate. [11,14] Since attempted conversion of the diastereomeric alcohol 35 into diyne 36 under Yamaguchi conditions [17] led to the concomitant isomerization of the (Z)-configured a,b-unsaturated carboxylic acid 9 with formation of the thermodynamically more stable (E)-configured ester 37, [18] the secondary hydroxy group of 35 was inverted by means of a Mitsunobu reaction/saponification sequence, [19] thereby ensuring convergence of the assembly line. Cyclization of 36 by ringclosing alkyne metathesis (RCAM) [20,21] proceeded smoothly, affording cyclo- Ar= 3, activated in situ with CH 2 Cl 2 , as previously described by our group, [22] was used as the catalyst (Scheme 5); in striking contrast, attempted cyclization with the aid of the Schrock alkylidyne [(tBuO) 3 W CCMe 3 ] (41) [23] met with failure, thus attesting to the superior functional group compatibility of the molybdenum-based system.…”

Section: Introductionmentioning

confidence: 99%

Latrunculin Analogues with Improved Biological Profiles by “Diverted Total Synthesis”: Preparation, Evaluation, and Computational Analysis

Fürstner

Kirk

Fenster

et al. 2006

Chemistry A European J

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Deliberate digression from the blueprint of the total syntheses of latrunculin A (1) and latrunculin B (2) reported in the accompanying paper allowed for the preparation of a focused library of “latrunculin‐like” compounds, in which all characteristic structural elements of these macrolides were subject to pertinent molecular editing. Although all previously reported derivatives of 1 and 2 were essentially devoid of any actin‐binding capacity, the synthetic compounds presented herein remain fully functional. One of the designer molecules with a relaxed macrocyclic backbone, that is compound 44, even surpasses latrunculin B in its effect on actin while being much easier to prepare. This favorable result highlights the power of “diverted total synthesis” as compared to the much more widely practiced chemical modification of a given lead compound by conventional functional group interconversion. A computational study was carried out to rationalize the observed effects. The analysis of the structure of the binding site occupied by the individual ligands on the G‐actin host shows that latrunculin A and 44 both have similar hydrogen‐bond network strengths and present similar ligand distortion. In contrast, the H‐bond network is weaker for latrunculin B and the distortion of the ligand from its optimum geometry is larger. From this, one may expect that the binding ability follows the order 1 ≥ 44 > 2, which is in accord with the experimental data. Furthermore, the biological results provide detailed insights into structure/activity relationships characteristic for the latrunculin family. Thus, it is demonstrated that the highly conserved thiazolidinone ring of the natural products can be replaced by an oxazolidinone moiety, and that inversion of the configuration at C16 (latrunculin B numbering) is also well accommodated. From a purely chemical perspective, this study attests to the maturity of ring‐closing alkyne metathesis (RCAM) catalyzed by a molybdenum alkylidyne complex generated in situ, which constitutes a valuable tool for advanced organic synthesis and natural product chemistry.

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“…We speculated that this failure might be due to the competitive cyclization between N-3 and C-5′ of the activated species as we observed consumption of the alcohol with formation of an extremely polar product. 16 Installation of a Boc-carbamate at N 6 of the adenine served to attenuate the nucleophilicity of N-3 and suppress this undesired reaction. Succesful Mitsunobu coupling to afford 19 was achieved by addition of DIAD via syringe pump to a stirring solution of the β-ketosulfonamide 12, N 6 -Boc-adenosine 18 and TPP at 0 °C (Scheme 2).…”

mentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of β-Ketosulfonamide Adenylation Inhibitors as Potential Antitubercular Agents

et al. 2006

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The antitubercular nucleoside antibiotics 1 and 2 were recently described that inhibit the adenylateforming enzyme MbtA and disrupt biosynthesis of the virulence-conferring siderophore known as mycobactin in M. tuberculosis. Herein, we report efforts to refine this inhibitor scaffold by replacing the labile acylsulfamate linkage (highlighted) with the more chemically robust β-ketosulfonamide linkage of 3 and 4.Mycobacterium tuberuculosis, the etiological agent of tuberculosis (TB), is the leading bacterial cause of infectious disease mortality. 1 The development of M. tuberculosis strains which are resistant to all of the current front-line antitubercular drugs has prompted worldwide efforts to discover new antibiotics to treat this notorious pathogen. Iron acquisition is an essential process for M. tuberculosis as well as almost all other microorganisms. 2 However, this essential micronutrient is highly sequestered in a mammalian host. Bacteria have evolved a variety of mechanisms to obtain this vital nutrient, but the most common mechanism involves the synthesis of small-molecule iron chelators, termed siderophores. 3 M. tuberculosis produces a pair of related peptidic siderophores known as mycobactin-T 8 and carboxymycobactins 9 that vary by the appended lipid residue and will hereafter be refered to collectively as the mycobactins (Figure 1). 4 The critical role of the mycobactins for growth and virulence of M. tuberculosis is supported by substantial in vitro and in vivo evidence. 5 Therefore inhibition of mycobactin biosynthesis 6 or antagonism of mycobactin function 7 represents an attractive strategy for the development of a new class of antitubercular agents.The biosynthesis of the mycobactins is initiated by MbtA, an adenylate forming enzyme, which activates salicylic acid 5 at the expense of ATP to form salicyladenylate 6 that remains tightly aldri015@umn.edu. Supporting Information Available: Experimental procedures, compound characterization data and 1 H and 13 C NMR of compounds reported herein, details of the [ 32 P]PPi-ATP exchange assay to determine K app I values, molecular modeling, and growth inhibition assay of M. tuberculosis H37Rv under iron-deficient conditions.

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The Use of Diethyl Azodicarboxylate and Triphenylphosphine in Synthesis and Transformation of Natural Products

Cited by 4,404 publications

References 16 publications

(R)-N-Methyl-3-(3-125I-pyridin-2-yloxy)-3-phenylpropan-1-amine: a novel probe for norepinephrine transporters

(R)-N-Methyl-3-(3-125I-pyridin-2-yloxy)-3-phenylpropan-1-amine: a novel probe for norepinephrine transporters

Latrunculin Analogues with Improved Biological Profiles by “Diverted Total Synthesis”: Preparation, Evaluation, and Computational Analysis

Design, Synthesis, and Biological Evaluation of β-Ketosulfonamide Adenylation Inhibitors as Potential Antitubercular Agents

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