Synthesis of enantiomerically pure cyclopropyl carbocyclic nucleosides

Zhao, Yufen; Yang, Te‐Fang; Lee, Migyoung; Chun, Byoung K.; Du, Jinfa; Schinazi, Raymond F.; Lee, Doowon; Newton, M. Gary; Chu, Chung K.

doi:10.1016/s0040-4039(00)73511-8

Cited by 49 publications

(22 citation statements)

References 11 publications

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“…5 By contrast, design and synthesis of analogues comprising a cyclopropane moiety have not produced compounds with antiviral activity despite a significant recent effort. 5,[10][11][12][13][14][15] Guanine analogue 5 of the Z-configuration is a notable exception. 16 The latter compound was designed as a conformationally constrained analogue of acyclovir.…”

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confidence: 99%

“…Thus, the presence of a double bond in cyclic nucleoside analogues such as anti-AIDS drug stavudine 17 (7, d4T, Zerit, Chart 2) or carba analogues neplanocin 5 A (8) and carbovir 5 (9) is a structural feature important for their potent antiviral and (compound 8) antitumor effects. In the acyclic analogue series, introduction of a very rigid allenic moiety as a linker between the heterocyclic base and hydroxymethyl group led to compounds effectively inhibiting the replication of HIV, such as adenallene (10) and cytallene 18,19 (11). Severe conformational constraints imposed by annealing a cyclopropane ring with the cyclopentane moiety of carbocyclic nucleosides in compounds 12 and 13 are also compatible with the potent antiviral effects of these analogues.…”

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confidence: 99%

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(Z)- and (E)-2-((Hydroxymethyl)cyclopropylidene)methyladenine and -guanine. New Nucleoside Analogues with a Broad-Spectrum Antiviral Activity

et al. 1998

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New nucleoside analogues 14-17 based on a methylenecyclopropane structure were synthesized and evaluated for antiviral activity. Reaction of 2,3-dibromopropene (19) with adenine (18) led to bromoalkene 20, which was benzoylated to give N6,N6-dibenzoyl derivative 23. Attempts to convert 20 or 23 to bromocyclopropanes 21 and 22 by reaction with ethyl diazoacetate catalyzed by Rh2(OAc)4 were futile. By contrast, 2,3-dibromopropene (19) afforded smoothly (E)- and (Z)-dibromocyclopropane carboxylic esters 24 + 25. Alkylation of adenine (18) with 24 + 25 gave (E)- and (Z)-bromo derivatives 21 + 22. Base-catalyzed elimination of HBr resulted in the formation of (Z)- and (E)-methylenecyclopropanecarboxylic esters 26 + 27. More convenient one-pot alkylation-elimination of adenine (18) or 2-amino-6-chloropurine (30) with 24 + 25 afforded (Z)- and (E)-methylenecyclopropane derivatives 26 + 27 and 31 + 32. The Z-isomers were always predominant in these mixtures (Z/E approximately 2/1). Reduction of 26 + 27 and 31 + 32 with DIBALH afforded (Z)- and (E)-methylenecyclopropane alcohols 14 + 16 and 33 + 34. The latter were resolved directly by chromatography. Compounds 14 + 16 were converted to N6-(dimethylamino)methylene derivatives 28 and 29 which were separated and deprotected to give 14 and 16. Reaction of 33 and 34 with HCO2H led to guanine analogues 15 and 17. The 1H NMR spectra of the Z-analogues 14 and 15 are consistent with an anti-like conformation of the nucleobases. By contrast, 1H NMR and IR spectra of bromo ester 21 are indicative of syn-conformation of adenine. Several Z-(hydroxymethyl)methylenecyclopropanes exhibited in vitro antiviral activity in micromolar or submicromolar range against human and murine cytomegalovirus (HCMV and MCMV), Epstein-Barr virus (EBV), human herpes virus 6 (HHV-6), varicella zoster virus (VZV), and hepatitis B virus (HBV). Analogues 14, 15, and 33 were the most effective agents against HCMV (IC50 1-2.1, 0.04-2.1, and 0.8-5.6 microM), MCMV (IC50 2.1, 0.3, and 0.3 microM) and EBV in H-1 (IC50 0.2, 0.3, and 0.7 microM) and Daudi cells (IC50 3.2, 5.6, and 1.2 microM). Adenine analogue 14 was active against HBV (IC50 2 microM), VZV (IC50 2.5 microM), and HHV-6 (IC50 14 microM). Synadenol (14) and the E-isomer (16) were substrates of moderate efficiency for adenosine deaminase from calf intestine. The E-isomer 16 was more reactive than Z-isomer 14. The deamination of 14 effectively stopped at 50% conversion. Synadenol (14) was also deaminated by AMP deaminase from aspergillus sp.

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(Z)- and (E)-2-((Hydroxymethyl)cyclopropylidene)methyladenine and -guanine. New Nucleoside Analogues with a Broad-Spectrum Antiviral Activity

et al. 1998

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“…Cyclopropanation of the TBDMS derivative 17 of allylic alcohol 12 is reported to proceed efficiently with ClCH 2 I to yield the silyloxymethylcyclopropane 18, (Scheme 5). 35,36 We examined the deprotection/oxidation sequence from 18 to the carboxylic acid 14. As expected, the silyl group could be easily removed using TBAF (91% yield).…”

Section: Resultsmentioning

confidence: 99%

“…As expected, the silyl group could be easily removed using TBAF (91% yield). The intermediate alcohol 19 was oxidized to 14 with RuO 2 and NaIO 4 in 48% yield 32,35 and with RuCl 3 and NaIO 4 in 62% yield. 37 It occurred to us, however, that the conditions used for the oxidation should also allow for the deprotection of the silyloxy group to the alcohol.…”

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confidence: 99%

Synthesis of a ¹³C labeled N‐cyclopropylamine tetrahydropyridine derivative

Kuttab¹,

Mabic

2002

Labelled Comp Radiopharmac

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SummaryThe synthesis of 1-(2-13 C)-cyclopropyl-4-phenyl-1,2,3,6-tetrahydropyridine (8) is reported. Attempts were first made to prepare labeled cyclopropylamine via a cyclopropanation/Curtius rearrangement sequence, but the yields were too modest to be suitable for the synthesis of a labeled compound. The preparation of 8 was achieved via cyclopropanation of the N-formyl tetrahydropyridine derivative 21 using the Grignard reagent of ethyl bromide and Ti(O-iPr) 4 as a catalyst. The synthesis proceeded in high yield (82%). The method has a wide potential for the synthesis of other cyclopropyl ring labeled and substituted cyclopropyl ring labeled tetrahydropyridine dervatives which can be used in Monoamine Oxidase (MAO) and Cyt P 450 enzymes mechanistic studies.

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“…Cyclopropane derivatives have been found in a wide range of natural and artificial compounds that display important biological activities and in many substances used as starting materials and intermediates in organic synthesis [1][2][3][4][5][6][7][8][9][10]. For example, cyclopropanecarboxylic acids are important starting materials to obtain different compounds such as pyrethrins, pyrethroids, and other industrially valuable compounds [11][12].…”

Section: Introductionmentioning

confidence: 99%

A DFT Study on the Mechanism of Samarium (II)-catalyzed Cyclopropanation Synthesis with α,β -unsaturated Carboxylic Acids, Alcohols and Amides

Zhang¹,

Geng²,

Wang³

et al. 2012

COC

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The mechanisms and regioselectivity of samarium(II)-catalyzed cyclopropanation synthesis with , -unsaturated carboxylic acids, alcohols and amides have been investigated using density functional theory calculations at B3LYP/6-31G(d,p) (LANL2DZ for I and RECPs for Sm) level of theory. Solvent effects on these reactions were explored using calculations that included a polarizable continuum model (PCM) for the solvent (THF). Our calculations suggest that the reaction proceeds through two possible channels: methylene transfer and carbometalation. The results show that the activation energies and mechanisms have larger differences, which have been briefly compared with the different , -unsaturated substrates. The reactions for , -unsaturated carboxylic acids both the carbometalation pathway and the methylene transfer pathway are feasible, while the carbometalation channel occurs more easily. For , -unsaturated alcohols, it is widely favored that the methylene transfer mechanism over carbometalation mechanism, while the energy barriers for , -unsaturated amides are relatively higher of 16.4-23.1 kcal/mol. The computational results are in good explanation with the experimental observations of Concellón, et al. on the cyclopropanation reaction of samarium(II)-catalyzed synthesis based on , -unsaturated substrates.

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Synthesis of enantiomerically pure cyclopropyl carbocyclic nucleosides

Cited by 49 publications

References 11 publications

(Z)- and (E)-2-((Hydroxymethyl)cyclopropylidene)methyladenine and -guanine. New Nucleoside Analogues with a Broad-Spectrum Antiviral Activity

(Z)- and (E)-2-((Hydroxymethyl)cyclopropylidene)methyladenine and -guanine. New Nucleoside Analogues with a Broad-Spectrum Antiviral Activity

Synthesis of a ¹³C labeled N‐cyclopropylamine tetrahydropyridine derivative

A DFT Study on the Mechanism of Samarium (II)-catalyzed Cyclopropanation Synthesis with α,β -unsaturated Carboxylic Acids, Alcohols and Amides

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Synthesis of enantiomerically pure cyclopropyl carbocyclic nucleosides

Cited by 49 publications

References 11 publications

(Z)- and (E)-2-((Hydroxymethyl)cyclopropylidene)methyladenine and -guanine. New Nucleoside Analogues with a Broad-Spectrum Antiviral Activity

(Z)- and (E)-2-((Hydroxymethyl)cyclopropylidene)methyladenine and -guanine. New Nucleoside Analogues with a Broad-Spectrum Antiviral Activity

Synthesis of a 13C labeled N‐cyclopropylamine tetrahydropyridine derivative

A DFT Study on the Mechanism of Samarium (II)-catalyzed Cyclopropanation Synthesis with &#945;,&#946; -unsaturated Carboxylic Acids, Alcohols and Amides

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Synthesis of a ¹³C labeled N‐cyclopropylamine tetrahydropyridine derivative

A DFT Study on the Mechanism of Samarium (II)-catalyzed Cyclopropanation Synthesis with α,β -unsaturated Carboxylic Acids, Alcohols and Amides