Synthesis of non glycosidic nucleobase-sugar mimetics - 21/09/10

Doi : 10.1016/j.crci.2009.11.004

Wilfried Hatton ^a,^c, Daniela Arosio ^b,^c, Marco Re ^a, Daniele Giudici ^a, Anna Bernardi ^a,^c, Pierfausto Seneci ^a,^c,^⁎
^a Università degli Studi di Milano, Dipartimento di Chimica Organica e Industriale, Via Venezian 21, 20133 Milano, Italy
^b C.N.R.-Istituto di Scienze e Tecnologie Molecolari (ISTM), Via Fantoli 16/15, 20138 Milano, Italy
^c Centro Interdisciplinare Studi Biomolecolari ed applicazioni Industriali (CISI), Via Fantoli 16/15, 20138 Milano, Italy

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Abstract

Biologically active organic molecules acting as nucleoside mimics are frequently encountered in pharmaceutical research. They are either synthetic heterocycles, which miss the sugar-derived interactions with the active site of the nucleoside-binding protein, or natural products containing a glycosidic linkage, which may cause bioavailability and metabolic stability problems. We report here the concept of synthetic full nucleoside mimics, including both a N-containing nucleobase-like portion and a sugar-like moiety, where the latter consists of 5- and 6-membered carbacycles connected by a more stable and drug-like C-N bond to the nucleobase mimic. Compounds 14, 16 (indolinones), 21 and 23 (benzimidazolones) have been prepared as model compounds.

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Keywords : Epoxide opening, Indolinone, Benzimidazolone, Nucleoside mimic, Heterocycles, Kinases

Plan

Introduction

Results and discussion

Epoxide opening

Synthesis of indolinones 14 and 16

Synthesis of benzimidazolones 21 and 23

Biology

Conclusions

Experimental section

Epoxide opening: general procedure for compound 3

(1S,2S,4S,5S)-dimethyl-4-hydroxy-5-(phenylamino)cyclohexane-1,2-dicarboxylate 6a (Fig. 2. – S1)

(1S,2S,4S,5S)-dimethyl-4-(2-chlorophenylamino)-5-hydroxycyclohexane-1,2-dicarboxylate 6b (Fig. 2. – S2)

(1S,2S,4S,5S)-dimethyl-4-(4-bromophenylamino)-5-hydroxycyclohexane-1,2-dicarboxylate 6c (Fig. 2. – S3)

(1S,2S,4S,5S)-dimethyl-4-(3-fluorophenylamino)-5-hydroxycyclohexane-1,2-dicarboxylate 6d (Fig. 2. – S4)

(1S,2S,4S,5S)-dimethyl-4-(2,3-dimethylphenylamino)-5-hydroxycyclohexane-1,2-dicarboxylate 6e (Fig. 2. – S5)

(1S,2S,4S,5S)-dimethyl-4-(3,5-dimethoxyphenylamino)-5-hydroxycyclohexane-1,2-dicarboxylate 6f (Fig. 2. – S6)

(1S,2S,4S,5S)-dimethyl-4-hydroxy-5-(4-nitrophenylamino)cyclohexane-1,2-dicarboxylate 6g (Fig. 2. – S6)

(1S,2S,4S,5S)-dimethyl-4-hydroxy-5-(pyridin-3-ylamino)cyclohexane-1,2-dicarboxylate 6h (Fig. 2. – S8)

(1S,2S,4S,5S)-dimethyl-4-(tert-butyldimethylsilyloxy)-5-(2-chloro-N-phenylacetamido)cyclohexane-1,2-dicarboxylate 9 (Fig. 2. – S9)

(1S,2S,4S,5S)-dimethyl-4-(tert-butyldimethylsilyloxy)-5-(2-oxoindolin-1-yl)cyclohexane-1,2-dicarboxylate 11 (Fig. 2. – S10)

(1S,2S,4S,5S)-dimethyl-4-(tert-butyldimethylsilyloxy)-5-((E and Z)-3-(4-isopropylbenzylidene)-2-oxoindolin-1-yl)cyclohexane-1,2-dicarboxylate 13

(1S,2S,4S,5S)-dimethyl-4-hydroxy-5-(3-(4-isopropylbenzylidene)-2-oxoindolin-1-yl)cyclohexane-1,2-dicarboxylate 14 (Fig. 2. – S13)

(1S,2S,4S,5S)-dimethyl-4-(tert-butyldimethylsilyloxy)-5-(2-chlorophenylamino)cyclohexane-1,2-dicarboxylate 17 (Fig. 2. – S14)

(1S,2S,4S,5S)-dimethyl-4-(1-(2-chlorophenyl)ureido)-5-hydroxy-cyclohexane-1,2-dicarboxylate 18 (Fig. 2. – S15)

(1S,2S,4S,5S)-dimethyl-4-hydroxy-5-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexane-1,2-dicarboxylate 21 (Fig. 2. – S16)

(±)-(1S,2S,4R,5S)-4-(tert-butyldimethylsilyloxy)-6-oxabicyclo[3.1.0]hexan-2-ol 4 (Fig. 2. – S17)

Epoxide opening: general procedure for compound 4

(±)-(1S,2R,3S,4R)-4-(tert-butyldimethylsilyloxy)-2-(phenylamino)cyclopentane-1,3-diol 7a and (1S,2R,3R,4R)-4-(tert-butyldimethylsilyloxy)-3-(phenylamino)cyclopentane-1,2-diol 8a

(±)-(1S,2S,4R,5S)-4-(tert-butyldimethylsilyloxy)-2-(2-chlorophenyamino)cyclopentane-1,3-diol 7b and (±)-(1S,2R,3R,4R)-4-(tert-butyldimethylsilyloxy)-3-(2-chlorophenylamino)cyclopentane-1,2-diol 8b

(±)-(1S,2R,4S,5R)-2-(4-Bromophenylamino)-4-(tert-butyldimethylsilyloxy)cyclopentane-1,3-diol 7c and (±)-(1S,2R,4S,5R)-3-(4-bromophenylamino)-4-(tert-Butyldimethylsilyloxy) cyclopentane-1,2-diol 8c

8c (Fig. 2. – S23)

(±)-(1S,2R,3S,4R)-4-(tert-butyldimethylsilyloxy)-2-(2,3-dimethylphenylamino)cyclopentane-1,3-diol 7e and (±)-(1S,2R,3R,4R)-4-(tert-butyldimethylsilyloxy)-3-(2,3-dimethylphenylamino)cyclopentane-1,2-diol 8e

(±)-(1S,2R,3S,4R)-4-(tert-butyldimethylsilyloxy)-2-(3,5-dimethoxyphenylamino)cyclopentane-1,3-diol 7f and (±)-(1S,2R,3R,4R)-4-(tert-butyldimethylsilyloxy)-3-(3,5-dimethoxyphenylamino)cyclopentane-1,2-diol 8f

(±)-2-chloro-N-phenyl-N-((1R,2S,3R,5S)-2,3,5-tris(tert-butyldimethylsilyloxy)cyclopentyl) acetamide 10

Silylether intermediate (Fig. 2. – S30)

(±)-1-((1R,2S,3R,5S)-2,3,5-tris(tert-butyldimethylsilyloxy)cyclopentyl) indolin-2-one 12 (Fig. 2. – S32)

(±)-(Z)-3-(4-isopropylbenzylidene)-1-((1R,2S,3R,5S)-2,3,5-tris(tert-butyldimethylsilyloxy)cyclopentyl)indolin-2-one 15Z and (±)-(E)-3-(4-isopropylbenzylidene)-1-((1R,2S,3R,5S)-2,3,5-tris(tert-butyldimethylsilyloxy)cyclopentyl)indolin-2-one 15E

(±)-(Z and E)-3-(4-isopropylbenzylidene)-1-((1R,2S,3R,5S)-2,3,5-trihydroxycyclopentyl)indolin-2-one 16

(±)-2-chloro-N-((1R,2S,3R,5S)-2,3,5-tris(tert-butyldimethylsilyloxy)cyclopentyl)aniline 19 (Fig. 2. – S36)

(±)-2-chloro-N-((1R,2S,3R,5S)-2,3,5-tris(tert-butyldimethylsilyloxy)cyclopentyl)aniline 20

(±)-1-((1R,2S,3R,5S)-2,3,5-tris(tert-butyldimethylsilyloxy)cyclopentyl)1H-benzo[d]imidazol-2(3H)-one 22

(±)-1-((1R,2S,3R,5S)-2,3,5-trihydroxycyclopentyl)1H-benzo[d]imidazol-2(3H)-one 23 (Fig. 2. – S39)

Conflicts of interest

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P. 1284-1300 - octobre 2010 Retour au numéro

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Synthesis of non glycosidic nucleobase-sugar mimetics - 21/09/10

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