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TitleRien ne se perd, rien ne se crée, tout se transforme.
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Page 1

Rien ne se perd, rien ne se crée, tout se transforme.

- Antoine Lavoisier

Page 2

Members of the Jury

Prof. dr. ir. Guy Smagghe (Chairman)

Department of Crop Protection

Faculty of Bioscience Engineering, Ghent University

Prof. dr. Tom Desmet

Department of Biochemical and Microbial Technology

Faculty of Bioscience Engineering, Ghent University

Prof. dr. ir. Sven Mangelinckx

Department of Sustainable Organic Chemistry & Technology

Faculty of Bioscience Engineering, Ghent University

Prof. dr. Gwilherm Evano

Service de Chimie et Physico-Chimie Organiques

Faculté des Sciences, Université Libre de Bruxelles

Prof. dr. Marc Lecouvey

Laboratoire CSPBAT

UFR de Santé Médecine et Biologie Humaine, Université Paris 13, France

Promoter Prof. dr. ir. Christian Stevens

Department of Sustainable Organic Chemistry and Technology

Faculty of Bioscience Engineering, Ghent University

Dean Prof. dr. ir. Marc Van Meirvenne

Rector Prof. dr. ir. Rik Van de Walle

Page 118

III. Results and Discussion


(Table 29, entry 1). Moreover, separation on column was not successful. Although the

transformation previously never required the use of dried solvent, the reaction was now run in

dry THF. According to 31P NMR, the reaction was finished within 4 hours but 1H NMR showed

that even more uridine acetonide starting material 380 remained (entry 2). Even an excess of
alkynylphosphate 384 was consumed within three hours, while the nucleoside starting material
was still present (entry 3). A change of solvent resulted only in a small improvement (entry 4).

Possibly, an addition-elimination step of hydroxide (as was observed when ethanol addition

product 340 was mixed with Cs2CO3 in methanol, vide supra), yielded the starting material 380

and -ketophosphonate 387 (Scheme 76). Elimination product 388 (the analogue of compound

352, which was produced when serine was added to imidoallenylphosphonate 338, vide supra)
was not observed. The most successful conditions were repeated before the mixture was

purified via reversed phase column chromatography (entry 4). Unfortunately, also in this way

no analytically pure material could be obtained.

Table 29: Screened conditions for the synthesis of uridine acetonide addition product 386.

entry equiv alkyne 384 t (h) solvent 386 (%)a remaining SM 380 (%)b

1 1 6 THFc 77 37

2 1 4 THF 62 45

3 1.5 3 THF 48 32

4 1 2 CH3CNd 70 18

5 1 2 CH3CNd 70 30
a conversion based on 31P NMR b conversion based on 1H NMR c not anhydrous d anhydrous

Page 119

III. Results and Discussion


Scheme 76: Possible formation of -ketophosphonate 387.

5.2.3. Debenzylation of the dibenzyl phosphonate addition product 386

It was then decided to deprotect the nucleoside phosphonate esters first and purify the mixture

at the phosphonic acid stage. Treatment of nucleoside phosphonate 386 with 10 wt% Pd/C
resulted in complete deprotection but three unidentified impurities were also formed (Table

30). Purification by means of preparative TLC (mobile phase: 8:2 iPrOH/water) did not result

in a cleaner product. Moreover, most of the product could not be recovered. Also reversed

phase chromatography proved to be unsuccessful as the product did not show any affinity for

the stationary phase, eluting immediately with 100% water (entry 2).

Table 30: Deprotection and conditions for the attempted purification of

uridine acetonide phosphonic acid aduct 389.

entry purification result

1 pTLC (8/2 iPrOH/H2O) unsuccessful

2 RP chromatography (100% H2O) unsuccessful

3 Wash n-hexane

Wash ethyl acetate

one apolar impurity removed

loss of material in organic phase

4 Recrystallization MeOH unsuccessful

One of the three major impurities could be removed by dissolving the product in water and

extracting the impurity with hexane (entry 3). Washing with ethyl acetate resulted in loss of the

Page 235

Curriculum Vitae


3. International Conference on Phosphorus Boron and Silicon (PBSi 2017), July 3-5,
2017, Paris, France.
Berton, J., Salemi, H., Virieux, D., Stevens, C.
Oral presentation: Synthesis of chiral spiro oxaphospholenes.

Page 236

Curriculum Vitae



1. M. Movsisyan, ‘Benzenesulfonyl chloride: synthesis through mesoreactor technology
and environmental sustainability assessment’ (2012-2013).

2. N. Sevrain, ‘Synthesis of phosphonylated azaheterocycles by gold-induced cyclization’


3. B. Wuyts, ‘Esterification of fermentation products’ (2013).

4. S. Gilles, ‘Studie van fosfono-allenen als toetreding tot azaheterocyclische fosfonaten’

5. J. Mariën, ‘Synthese van gefosfonyleerde oxazolidinonen en oxazolonen via goud-
gemedieerde ringsluiting’ (2013-2014).

6. H. Mahjoub, ‘Synthesis of 3,5-diphosphonylpyridines’ (2014 and 2015).

7. P. Naert, ‘Ionic liquid driven esterification of aqueous fermentation product’ (2014-

8. B. Withoeck, ‘Synthese van gefosfonyleerde -lactamen via Kharasch reactie’ (2016).

9. G. Saborit i Canals, ‘Synthesis of phosphonylated -lactams’ (2016).

10. D. Vanavermaete, ‘Fosmidomycine-geïnspireerde zoektocht naar anti-

malariamiddelen’ (2016-2017).

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