SYNTHETIC APPLICATIONS OF ARYL H-PHOSPHONATES IN ...

S242 SYNTHETIC APPLICATIONS OF ARYL H-PHOSPHONATES IN NUCLEOTIDE CHEMISTRY J. CIESLAKa, J. JANKOWSKAa, A. KERSb, I. KERSb, A. SOBKOWSKAa, M. SOBKOWSKIa, J. STAWINSKIb and A. KRASZEWSKIa,* a

Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14, 61-704 Poznan, Poland b Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, S-106 91, Stockholm, Sweden

Aryl nucleoside H-phosphonate diesters were found to be versatile synthetic intermediates for the preparation of various functionalized alkyl nucleoside H-phosphonates, dinucleoside H-phosphonates, and nucleoside H-phosphonamidates.

The synthetic methodology employing H-phosphonate intermediates becomes at present a well established approach for the preparation of nucleotides, oligonucleotides, and a variety of other phosphorus-containing natural products and their analogues. It involves synthesis of stable, easily accessible H-phosphonate monoesters, which upon activation with condensing agents in the presence of a hydroxylic component can be transformed to the corresponding H-phosphonate diesters1,2. The latter ones can be further converted via oxidation under various reaction conditions to the derivatives containing unmodified3 or modified4–6 phosphate moiety. The coupling agent commonly used for the activation of H-phosphonate monoesters is pivaloyl chloride1,2. It produces the mixed phosphono-acyl anhydrides, which in the reactions with nucleophiles, e.g. alcohols, afford H-phosphonate diesters with high chemoselectivity. Reactivity of the above type of mixed anhydrides is governed by an electron-withdrawing effect of an acyl group (which makes the phosphorus centre more electrophilic) and by a steric hindrance around the carbonyl centre, which secures the chemoselectivity of the substitution (P vs C=O). There are, however, several disadvantages of using a methodology based on condensing agents. The first one is that a condensing agent, in spite of a steric hindrance around its electrophilic centre, may react with a hydroxylic component and/or with a product of the condensation. In the instance of H-phosphonate derivatives, these side reactions, O-acylation or P-acylation, are heavily suppressed, but they may occur to some extent when a large excess of a condensing agent is used (e.g., during solid phase synthesis of oligonucleotides). The second important factor which may limit efficiency of the coupling reaction is the formation of diacyl phosphites7 during the course of activation of H-phosphonate monoesters. These intermediates are less reactive than the corresponding phosphono-acyl anhydrides, but their formation may lead finally to side Special Issue

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S243 products, i.e. phosphite triesters. However, the use of other type of activators, e.g. di(pentafluorophenyl) carbonate8, was claimed to suppress most of side reactions during solid phase synthesis of oligonucleotides. As a part of our studies in H-phosphonate chemistry we have been searching for another way to limit the occurrence of possible side reactions during H-phosphonate diester formation. We assumed that certain type of H-phosphonate derivatives with only one electrophilic centre located on phosphorus might offer some advantages over the bis-centre active species produced from H-phosphonate monoesters and a condensing agent. We have previously found that H-phosphonate diesters with two or one aryloxy group bound to phosphorus are reactive enough to undergo readily transesterification9 with amino alcohols forming exclusively aminoalkyl nucleoside H-phosphonate diesters. These considerations prompted us to assess aryl nucleoside H-phosphonate diesters as potential substrates for the synthesis of various nucleoside H-phosphonate derivatives.

RESULTS AND DISCUSSION

Aryl nucleoside H-phosphonates are easily accessible in a direct coupling of nucleoside H-phosphonates and an appropriate phenol. Their reactivity towards different type of nucleophiles was investigated in a few selected reactions (Scheme 1). Aryl H-phosphonate diesters differ in their reactivity depending on the electronic structure of the aromatic moiety. Among various investigated substituted phenol derivatives (2,4,6-trimethylphenyl, 4-methylphenyl, phenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 4nitrophenyl, 2,4,6-trichlorophenyl) those obtained from H-phosphonate monoesters and 2,4,6-trichlorophenol possessed properties most suitable for our purpose. Below, we give a short account of some synthetic applications of these in situ produced intermediates. The reactions of 2,4,6-trichlorophenyl nucleoside H-phosphonate 5 with alcohols. Transesterification of aryl nucleoside H-phosphonate 5 in methylene dichloride–pyridine (9 : 1, v/v) with 3 molar equiv. of primary (e.g., ethanol), secondary (e.g., isopropyl alcohol), or tertiary alcohols (e.g., t-butanol) was followed by 31P NMR spectroscopy. All reactions proceeded readily towards the corresponding alkyl nucleoside H-phosphonate diesters of type 6 and the only difference observed was in the rate of formation of the products 6. Thus, in the instance of ethanol the reaction went to completion in less than 3 min, for isopropanol, in ca 5 min, and for tert-butanol, in ca 8 min. These differences reflect apparently changes in steric hindrance of the alkyl substituents and indicate also that the reaction proceeds most likely via SN2(P) mechanism. The reactions of 2,4,6-trichlorophenyl nucleoside H-phosphonate 5 with 5′-OH nucleosides. The aryl nucleoside H-phosphonate diester 5 (1.5 molar equiv.) in the reaction with 3′-O,N4-dibenzoylcytidine afforded in less than three minutes the Collect. Czech. Chem. Commun. (Vol. 61) (1996)

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S244 corresponding 3′–5′ dinucleoside H-phosphonate diester of type 7 as the sole nucleotidic product. The reactions of 2,4,6-trichlorophenyl nucleoside H-phosphonate 5 with diols. 1,3Propanediol and its higher homologues (up to 1,8-octanediol) (3 molar equiv.) during transesterification of 5 produced cleanly linear hydroxyalkyl nucleoside H-phosphonate diesters of type 8. The reactions of 2,4,6-trichlorophenyl nucleoside H-phosphonate 5 with amines. The aminolysis of 5 with various primary (e.g., n-butyl-, isopropyl and tert-butyl-) and secondary (e.g. N-butyl-N-methyl-, N,N-dibutyl-) amines (7–9 molar equiv.) occurred readily (completion in less than 3 min) and cleanly to produce the corresponding nucleoside H-phosphonamidates of type 9. The reactions of 2,4,6-trichlorophenyl nucleoside H-phosphonate 5 with amino alcohols. In the reactions with amino alcohols (e.g., 2-aminoethanol, 3-aminopropanol, 4-aminobutanol, 5-aminohexanol), the aryl nucleoside H-phosphonate 5 afforded in less than three minutes exclusively the corresponding aminoalkyl nucleoside H-phosphonate diesters of type 10.

SCHEME 1 Ar 2,4,6-trichlorophenyl; B heterocyclic base; Bz benzoyl; dmt 4,4′-O-dimethoxytrityl; Py pyridine; Pv pivaloyl; NEP 5,5-dimethyl-2-oxo-1,3,2-dioxaphosphinate-2-yl

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S245 In conclusion, the easily accessible aryl nucleoside H-phosphonate diesters 5 appeared to be useful substrates for the synthesis of various types of phosphonic acid derivatives. The main advantages of this synthetic approach to phosphonic acid derivatives are: (i) elimination of a condensing agent, (ii) mild reaction conditions, (iii) possibility to modulate reactivity of the phosphorus centre in 5 by changing the aryl moiety, and (iv) since aryl H-phosphonates 5 possess only one electrophilic centre, the substitution reactions occur readily and with a complete chemoselectivity. We believe that these features can make the approach via aryl H-phosphonate intermediates a convenient and general route for the preparation of various phosphorus-containing natural products and their analogues. We are indebted to Professor M. Wiewiorowski and to Professor P. J. Garegg for their interest and helpful discussions. Financial support from the State Committee for Scientific Research, Republic of Poland [2 P303 145 07], the Swedish Natural Science Research Council, and the Swedish Research Council for Engineering Sciences is gratefully acknowledged.

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