Asymmetrische Synthese chiraler Phosphorverbindungen durch destruktiv‐Oxidation von P(III)‐Verbindungen mittels chiraler Oxaziridine

Verfürth, Uwe; Ugi, Ivar

doi:10.1002/cber.19911240725

Cited by 13 publications

(6 citation statements)

References 40 publications

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“…To overcome these problems, a different synthetic pathway to the key nucleoside aryl phosphite intermediate was reported by Jiang et al based on P(III) substitution. 213 Using d4T and AZT as models, this three-component Arbuzov reaction 214 is initiated by reacting the nucleoside with phosphorodichloridate (1 equiv), t- BuOH, and triethylamine to yield the corresponding nucleoside aryl phosphate 416 (Scheme 122 ). These conditions afforded the nucleoside aryl phosphite cleanly and in high yield (86% for the p -methoxy phenol derivative).…”

Section: Nucleoside Monophosphate Prodrugsmentioning

confidence: 99%

Synthesis of Nucleoside Phosphate and Phosphonate Prodrugs

et al. 2014

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Section: Nucleoside Monophosphate Prodrugsmentioning

confidence: 99%

Synthesis of Nucleoside Phosphate and Phosphonate Prodrugs

et al. 2014

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“…On the other hand, despite the complementarities existing between camphor- and fenchone-derived chirality transfers, C(10)-substituted fenchones have not been obtained, nor probed. This is due to the fact that enantiopure 10-fenchonesulfonic acid (the fenchone analogue of 6 and, therefore, the potential key starting material for other C(10)-substituted fenchones) is not commercially available …”

Section: Introductionmentioning

confidence: 99%

C(10)-Substituted Camphors and Fenchones by Electrophilic Treatment of 2-Methylenenorbornan-1-ols: Enantiospecificity, Scope, and Limitations

et al. 2003

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Valuable chiral sources of C(10)-substituted camphors and C(10)-substituted fenchones can be straightforwardly obtained by treatment of an appropriate, easily obtainable, camphor- or fenchone-derived 2-methylenenorbornan-1-ol with an electrophilic reagent. The process takes place via a tandem regioselective carbon-carbon double-bond addition/stereocontrolled Wagner-Meerwein rearrangement. A complete study of the enantiospecificity, scope, and limitations of this process, as well as about the role played by the hydroxyl group attached at the C(1) bridgehead position of the starting 2-methylenenorbornan-1-ols, has been realized. The feasibility of the described methodology has been exemplified by the highly efficient enantiospecific preparation of several interesting C(10)-halogen-, C(10)-O-, C(10)-S-, C(10)-Se-, or C(10)-C-substituted camphors and fenchones.

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“…Here, we have developed an improved and cheaper procedure for synthesis of aryl phosphoramidates of nucleosides. We attempted the following procedure: three-component reaction of aryl phosphorodichloride 15 at -5 °C with one equivalent of nucleoside (AZT or d4T) and one equivalent of tert-butyl alcohol yielded nucleoside aryl H-phosphonate in about 86% yield ( 31 P NMR determination) while small amount of dinucleoside phosphite ( 31 P NMR: d = ca. 9.50 ppm, 2-7%) and the other unknown phosphate side product ( 31 P NMR: d = ca.…”

mentioning

confidence: 99%

One-Pot Synthesis of Aryl Phosphoramidate Derivatives of AZT/d4T as Anti-HIV Prodrugs

Jiang¹,

Guo²,

Fu³

et al. 2005

Synlett

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S y n t h e s i s o f A r y l P h o s p h o r a m i d a t e D e r i v a t i v e s o f A Z T / d 4 TAbstract: Arbuzov reaction of aryl phosphorodichloridite with mixture of one equivalent of AZT or d4T and one equivalent of tertbutyl alcohol led to the corresponding AZT/d4T aryl H-phosphonate diesters, and the following reaction of the H-phosphonate diesters with amino acid methyl esters in the presence of N-chlorosuccinimide (NCS) produced membrane-soluble anti-HIV prodrugs AZT/d4T aryl phosphoramidate derivatives in good yields. Some dideoxynucleosides (ddNs) including 3¢-azido-2¢,3¢-dideoxythymidine (AZT, zidovudine) 1 and 2¢,3¢-dideoxy-2¢,3¢-didehydrothymidine (d4T, stavudine) 2 have emerged as efficient drugs against human immunodeficiency virus (HIV), 3 and the anti-retroviral effects of these compounds involve their conversion, through cellular enzymes, to the corresponding 5¢-triphosphates (ddNTPs) which interact with HIV-associated reverse transcriptase. Specifically, the first phosphorylation step for d4T is the rate-limiting step, whereas for AZT phosphorylation to the nucleoside 5¢-diphosphate is the slowest step in the phosphorylation pathway. 4 However, in many cases the unnatural ddNs have poor affinity for nucleoside kinases, 5 one possibility to improve the efficiency of ddNs could be to bypass the phosphorylation steps. Unfortunately, these polar nucleotides are not able to cross the cell membrane efficiently, 6 and they are readily dephosphorylated in extracellar fluids and on cell surfaces by nonspecific phosphohydrolases. 7 Hence, the strategies of temporarily masking or reducing the phosphate negative charges of nucleoside 5¢-monophosphates (NMPs) with neutral substituents to prodrugs are used, these prodrugs would be freed to the corresponding NMPs once inside the cell. McGuigan et al. have developed the phosphoramidate diester prodrugs of 2¢,3¢-dideoxy-2¢,3¢-didehydroadenosine (d4A), 2¢,3¢-dideoxyadenosine (ddA) 8a and d4T, 8b-d which exhibited greatly enhanced activity against HIV compared to their parent nucleoside analogues in vitro, and full activity was retained in kinase-deficient cell lines. 8 So the development of nucleoside prodrugs capable of undergoing intracellular activation to the corresponding nucleotides has become an area of intense interest. 9 Recently, we have developed the methods for synthesis of the nucleoside phosphporamidate monoesters using nucleoside di-, triphosphates 10,11 or fluorenylmethyl nucleoside 5¢-H-phosphonates 12 as starting materials. The typical synthesis of the nucleoside phosphoramidate diesters is from sequential reactions of phosphoryl chloride with phenol or p-substituted phenol, amino acid methyl ester and nucleoside, 13 however, the intermediates aryl chlorophosphoramidates are of low reactivity, the following reaction with nucleosides usually needs a long reaction time, and sometimes yields are very low. Here, we would like to report a new method for synthesis of aryl phosphoramidate derivatives.Atherton-Todd reaction is a convenient and effic...

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Asymmetrische Synthese chiraler Phosphorverbindungen durch destruktiv‐Oxidation von P(III)‐Verbindungen mittels chiraler Oxaziridine

Cited by 13 publications

References 40 publications

Synthesis of Nucleoside Phosphate and Phosphonate Prodrugs

Synthesis of Nucleoside Phosphate and Phosphonate Prodrugs

C(10)-Substituted Camphors and Fenchones by Electrophilic Treatment of 2-Methylenenorbornan-1-ols: Enantiospecificity, Scope, and Limitations

One-Pot Synthesis of Aryl Phosphoramidate Derivatives of AZT/d4T as Anti-HIV Prodrugs

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