Phosphine-catalyzed regioselective Michael addition to allenoates

Gandi, Vasudeva Rao; Lü, Yixin

doi:10.1039/c5cc06197k

Cited by 34 publications

(7 citation statements)

References 45 publications

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“…Similarly, a second cyclic species (Cyclo-Redoxin) could be formed from DHA-Redoxin via a thiol–ene-based Michael addition reaction (Scheme ). Because Michael addition can be catalyzed by phosphines, , Cyclo-Redoxin formation could be favored by the presence of the reducing agent TCEP in the incubation mixture. Alternatively, Cyclo-Redoxin could result from nucleophilic attack of the thiol group at C2 of THT + -Redoxin with concomitant elimination of THT.…”

Section: Resultsmentioning

confidence: 99%

The Myeloablative Drug Busulfan Converts Cysteine to Dehydroalanine and Lanthionine in Redoxins

et al. 2016

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The myeloablative agent busulfan (1,4-butane-diol dimethanesulfonate) is an old drug that is used routinely to eliminate cancerous bone marrow prior to hematopoietic stem cell transplant. The myeloablative activity and systemic toxicity of busulfan have been ascribed to its ability to cross-link DNA. In contrast, here we demonstrate that incubation of busulfan with the thiol redox proteins glutaredoxin or thioredoxin at pH 7.4 and 37 °C results in the formation of putative S-tetrahydrothiophenium adducts at their catalytic Cys residues, followed by β-elimination to yield dehydroalanine. Both proteins contain a second Cys, in their catalytic C-X-X-C motif, which reacts with the dehydroalanine, the initial Cys adduct with busulfan, or the S-tetrahydrothiophenium, to form novel intramolecular cross-links. The reactivity of the dehydroalanine (DHA) formed is further demonstrated by adduction with glutathione to yield a lanthionine and by a novel reaction with the reducing agent tris(2-carboxyethyl)phosphine (TCEP), which yields a phosphine adduct via Michael addition to the DHA. Formation of a second quaternary organophosphonium salt via nucleophilic substitution with TCEP on the initial busulfan-protein adduct or on the THT+-Redoxin species is also observed. These results reveal a rich potential for reactions of busulfan with proteins in vitro, and likely in vivo. It is striking that several of the chemically altered protein products retain none of the atoms of busulfan, in contrast to typical drug-protein adducts or traditional protein modification reagents. In particular, the ability of a clinically used drug to convert Cys to dehydrolanine in intact proteins, and its subsequent reaction with biological thiols, is unprecedented.

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Section: Resultsmentioning

confidence: 99%

The Myeloablative Drug Busulfan Converts Cysteine to Dehydroalanine and Lanthionine in Redoxins

et al. 2016

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“…In 2015, Lu and Gandi reported the phosphine-catalyzed Michael addition of cyanoacetates to allenoates (Scheme 155). 225 When arylcyanoacetates were used as substrates, the β -addition adducts with a quaternary center were obtained as the main products, in excellent yields. In contrast, when benzylcyanoacetates were employed as substrates, the β -selectivity was lost and the γ -adducts dominated.…”

Section: Nucleophilic Phosphine Catalysis Of Allenesmentioning

confidence: 99%

Phosphine Organocatalysis

et al. 2018

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The hallmark of nucleophilic phosphine catalysis is the initial nucleophilic addition of a phosphine to an electrophilic starting material, producing a reactive zwitterionic intermediate, generally under mild conditions. In this Review, we classify nucleophilic phosphine catalysis reactions in terms of their electrophilic components. In the majority of cases, these electrophiles possess carbon–carbon multiple bonds: alkenes (section 2), allenes (section 3), alkynes (section 4), and Morita–Baylis–Hillman (MBH) alcohol derivatives (MBHADs; section 5). Within each of these sections, the reactions are compiled based on the nature of the second starting material—nucleophiles, dinucleophiles, electrophiles, and electrophile–nucleophiles. Nucleophilic phosphine catalysis reactions that occur via the initial addition to starting materials that do not possess carbon–carbon multiple bonds are collated in section 6. Although not catalytic in the phosphine, the formation of ylides through the nucleophilic addition of phosphines to carbon–carbon multiple bond–containing compounds is intimately related to the catalysis and is discussed in section 7. Finally, section 8 compiles miscellaneous topics, including annulations of the Hüisgen zwitterion, phosphine-mediated reductions, iminophosphorane organocatalysis, and catalytic variants of classical phosphine oxide–generating reactions.

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“…In an innovative extension of this reaction in 2015, Lu et al. first reported the β‐selective Michael addition of aryl cyanoacetates 2 to allenoates 1 in the presence of PPh 3 to access the desired quaternary carbon center, providing β‐selective Michael adducts 3 a as the major product in high yields (up to 99%) and γ‐adducts 3 b as the minor product (Scheme ) . Notably, the regioselectivity was dependent on the choice of cyanoacetate substituents.…”

Section: Electron‐deficient Allenesmentioning

confidence: 99%

Phosphine‐Catalyzed Reactions with Unsaturated Carbonyl Compounds

Nallapati

Chuang

2018

Asian J Org Chem

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Organophosphines are versatile Lewis basic catalysts that have been confirmed as powerful tools in organic synthesis for the past two decades. The nucleophilic addition of organophosphines to electron-deficient species can be divided into two categories: phosphine-catalyzed and stoichiometric phosphine-mediated transformations. In this focus review, we summarize recent examples of phosphine-catalyzed addition and annulation reactions with allenoates and alkynoates. In addition, we discuss our recent efforts in the development of unusual phosphine-mediated α-addition reactions with enynedioates, enynoates, and oligoynoates and its application in novel functional fullerene derivatives as n-type materials in organic photovoltaics.[a] Dr. Scheme 1. Phosphine-catalyzed Michael addition of arylcyanoacetates to allenoates. 2 3 4 5 6 7 8

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Phosphine-catalyzed regioselective Michael addition to allenoates

Cited by 34 publications

References 45 publications

The Myeloablative Drug Busulfan Converts Cysteine to Dehydroalanine and Lanthionine in Redoxins

The Myeloablative Drug Busulfan Converts Cysteine to Dehydroalanine and Lanthionine in Redoxins

Phosphine Organocatalysis

Phosphine‐Catalyzed Reactions with Unsaturated Carbonyl Compounds

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