An easy access of 2′,3′-dideoxy-3′-α-C-formyl-adenosine and -guanosine analogs via stereoselective CC bond forming radical reaction (original) (raw)
Tetrahedron, 2000
We developed several improved approaches toward 2 H -O-methyl adenosine and guanosine and their N-acyl derivatives. (a) Transglycosylation of N 4 -acetyl-5 H , 3 H -di-O-acetyl-2 H -O-methyl cytidine with N 6 -Bz-adenine provided N 6 -benzoyl-5 H 3 H -di-O-acetyl-2 H -Omethyl adenosine in 50% yield. (b) Regioselective methylation of 2-amino-6-chloro purine riboside with MeI/NaH followed by hydrolysis provided 2 H -O-Me-guanosine in high yield. The same 2 H -O-Me-precursor was transformed into 2 H -O-Me-adenosine in 58% yield. (c) Very efficient transformation of 2,6-diamino-purine riboside into N 2 -isobutyryl (isopropylphenoxyacetyl) 2 H -O-Me-guanosine through methylation of 5 H ,3 H -O-TIPDSi derivative followed by selective N 2 -acylation, deamination and desylilation provided target compounds in 70% combined yield. (d) Mg 2ϩ and Ag ϩ directed methylation of N 1 -Bzl-guanosine proceeded in Ͼ80% yield with ratio of 2 H -O-Me/3 H -O-Me9:1. The same methylation of adenosine with Ag ϩ and Sr 2ϩ acetylacetonates provided 2 H -O-Me-adenosine in 75-80% yield. ᭧
The Journal of Organic Chemistry, 2013
Two α-L-ribo-configured bicyclic nucleic acid modifications, represented by analogues 12 and 13, which are epimeric at C 3 ′ and C 5 ′ have been synthesized using a carbohydrate-based approach to build the bicyclic core structure. An intramolecular L-proline-mediated aldol reaction was employed to generate the cis-configured ring junction of analogue 12 and represents a rare application of this venerable organocatalytic reaction to a carbohydrate system. In the case of analogue 13, where a trans-ring junction was desired, an intermolecular diastereoselective Grignard reaction followed by ring-closing metathesis was used. In order to set the desired stereochemistry at the C 5 ′ positions of both nucleoside targets, a study of diastereoselective Lewis acid mediated allylation reactions on a common bicyclic aldehyde precursor was carried out. Analogue 12 was incorporated in oligonucleotide sequences, and thermal denaturation experiments indicate that it is destabilizing when paired with complementary DNA and RNA. However, this construct shows a significant improvement in nuclease stability relative to a DNA oligonucleotide.
Tetrahedron, 1988
Michael addition reactions of rhe 3'mesuifones 5.6 and 18 with ammonia, primary amines ~~t~~~, ~n~l~.ne~ &Wine methyl ester), secondary 0tnine.r ~~~~~1~'~~ pyrrolidine, piperidine, ~~~ii~~ Md carbon-nucleophiies @c&m ~t~~~~, conirrgate bare of ninome&me nnd pyrrolidin-I-cyclohexene) have been used as means w synthesize new 2; 3 '-di&oxy-2 ',3 '4subs&utedor 2 '-subs&uted nucleosi&s. Most of these nucieophilic addition reactions have given exclusively nans-adducts j7c-j 19d-g & 201 owing w the regiospecific proWnut& of the inremrediary chiral a-sUfony1 cabanion ot C-3'; 0 few of the above re5ction.s huve however produced a mixture of cis-and trans-adducts , although the her is overwhelntingty o major product, upending upon the nature of the 2'-substiiuent and rhe Sype of the 3 '-enestifone [S, 6 or 18j. The Michael ad&% f?, 9,f9,24] have been deprorected at the 5 *-end w produce 2 ',3'-disubstitured-2 ',3'-dideoxy-#-D-nucleosides /84-k, IOa,b,k & 21&g, 22j, 250-c]. Some of the Michael adducts have been C-3 ' desu&onated W produce 5 '-protected-l l J *-dideoxy 2.-s~stit~ed nu~leosides [115-g, 26a,f,g] which are not easily accessible through any other routes. Final& these compounds have been also deproreeted w give nucleosides /lZa-g & 33) in good yields. Cornpout& described herein, with free 5'-hydroxylfwrcdon, ore porenrial inhibitors of rhe HIV-reverse transcriptase promoted c-DNA synthesis. Human I~un~e~ci~ncy Virus (HIV) targets itself to the host's immunological system causing the acquired immune deficiency syndrome (AIDS). As a result, several AIDS-relawt complex including scveml opportunistic infections are initiated in HIV-infected patients causing death. Our efforts to design inhibitors against AIDS virus are based upon the possibilities of targeting suitable synthetic derivatives of nuclcosides to the HIV-specific enzymes. These compounds are intended either to interfere specifIcally with an early event during the HIV replication (e.g. reverse transcriptase) or/and a late event in its life cycle (e.g. proteasejl-Q. Most of the compounds which have turned out to be active against the reverse transcriptase of HIV are 2',3'-dideoxynucleosides and a few 2',3'-dideoxy-3'~substituted (F, N3) nucleoside anaIogue&Q. Synthetic procedures to prepare these compounds and other 2'-or 3'-substituted nucleosides involve one of the following procedures: (i) direct nucleophilic (SN2) displacement of a leaving group lo-17, (ii) nucleophilic ring-opening reactions of 2',3'-@ribo-or lyxoanhydro putine nncleosides or 2',3'-O&w-anhydro pyrimidine nueleosides 18-32, (ii) ring-opening ieaCti0ns of 2X-O-or 2,3'-0-anhydro pyrimidine nucleosides or 8,2,-O-or 8.3'-O-anhydro purine nucleosides33-35, (iv) substitution through the displacement of 2',3'-carboxonium ion36*37, and (v) nuclcphilc addition to appropriately protected 2'-or 3'-keto nucleosides3g-47, or other procedures involving additions and/or rearrangements a-56. me synthesis of the corresponting 2',3'dideoxy-3'-substituted or 2'-substituted nucleosides with an amino substituents [-NHMe,-NMe2,-NHPh,-NHCH2Ph,-Na-aminoacyl,-Na-oligopeptides and other N-substituted cyclic amino derivatives such as piperidino, morpholino, pyrrolidino etc.] can not be prepared by any of the above synthetic procedures 656 without a series of lengthy and labourious transformations. The C-3' ami~&Q and C-3' amid019 substituted nucleosides have been however prepared directly from 2',3'-0-lyvFanhydm pyrimidine nucleosides. HeFein we report that appropziateiy protected 3'-enestdfones of both pyrimidine and purine nucleosides, such as $6 and 18, conveniently undergo Michael addition reactions with ammonia, primary and secondary am&s and with other carbon-nucleophiles to give a variety of 2', 3'-dideoxy-3'-sulfonyl-2'-substituted nucleosides [ 5-f 7a-k + !h,b,k; 6 + Sad + lOa,b; 18 + 19a-g + 24a-c & 201. These derivatives can be easily deprotected at the 5'-end to give corresponding 5'-hydroxy derivatives (8,10,21,X? & 25) which by virtue of their lack of 2' and 3'hydroxyl functions have the potential to block the HIV-specific reverse tmnscriptase promoted cDNA syntbesisl-3. 6705 6706 J.-C. Wtr er al. Alternatively. these compmds have been desulfonated at the C-3' to give the J"-protected 2',3'-dideoxy-2*_substjmted nucleosides (11 & 26) which have been subsequently deprotected at the 5' to give the 2', 3'-dideoxy-2'-substituted nucleosides 12 cpi 33 which also have unique potential to block the ~~~-spccifc reverse msniptae proimt& cafe synthesisl-3. Preparation Of 3'-eneSUlfOne deriVatiVet4 of uridine (5) : The key intermediate, 5'-0-trityl_2',3'_O_anhydro_ lyxofu~nosyl uridine I24 [Tr = trityll was prepared in _ 80 5% yield by an alkaline treamnt of 5'-0_trityl-2',3'~0&nesyl uridine. Compound 1 was then reacted with ~toluenethiolate to give an isomeric mixture of i-(2'-(4-tolue~~io)-~-Dxylofuranosyl)uracil2 & l-(3'-(4-toluenethio)-~-D-atabinofurattosyl)uracil3 in 1:2 ratio. They were separated by standard column chromatography to give the 3'-toluenethio derivative 3 in 55 % yield. Compound 3 was easily oxidized by mchloroperbenzoic acid in dichloromethane at mom temperature to corresponding sulfone 4 in 99 % yield. When a dry pyridine solution of 4 was treated overnight with an excess of methanesulfonyl (= mesyl = MS) chloride at 20 Oc and then at 50 aC for 1 h in presence of water gave a product, which was isolated upon usual work up and c~~to~phy and characterixed as the 3'-enesulfone 5. The 5'-0-trityl gtoup from 5 could be easily deprotected in boiling 80% aqueous acetic acid for 10 mitt to provide the !i'-hydroxy-3'-enesulfone 6 in ca. 'XX yield upon an usual column chromatogmphic purification step. Preparation of N~,N~-dibenzoyl-S'-O~(cl-methoxytrityl)-3"-enesulfone derivative of adenosine (18) : The key intermediate, 2',3'-0-anhydroadenosine 1330 was opened up by a nucleophilic attack with 4-toluenethiolate in hot methanol to give 3'-0-tolylthio derivative 14 as the major product. Compound 14 was fast ~~yls~ylat~ (TM!&Cl in dry pyridine) followed by benzoylation and a hydrolysis step to give compound 15 in 70 % overall yield. Compound 15 was oxidized by m-chloroperbenroic acid in dichloromethane to give the. corresponding 3'-xylotoluenesulfonyl derivative 16 in 93% yield. The 5'-hydroxy group of the sulfone 16 was subsequently protected with 4methoxytrityl {MMTrJ group to give 17 in 92% yield. The !i'-protected sulfone 17 was then treated with mesyl chloride in pyridine solution at 0-4 oC for 24 h. The product that was formed was isolated in 81% yietd and was characterized to be Y-protected-3'enesulfone 18. Clearly, the mesylation of C-2' hydroxyl functions of 4 and 17 gave the corresponding 2'-O-mesylaas as the intermediate which underwent instanteneous base catalyzed cis-@elimination to give the J'-enesulfones 5 and 18. Nucleophitc addition reaction (Michael reaction) to the 3'-enesulfones [S, 6 & 181 : Nucleophilc addition reaction to the electron-deficient double bond constitute the main chemistry of a,&unsaturated sulfones. An extensive series of papers describing such nucleophilic additions of amines, thiolates, alkoxides etc. has been pub&he&g-69. The trans-addition process giving the cis-adduct is the most commonly encountered pathway in allenic-60, propargyllic-60 and a,@enesulfones@. The rn~h~ism of the st~he~c~ pathways of addition of a nucl~phile such as ptoluenesul~de to l-p-tolylsulfonylcyclohexene62 is opposite to that in the l-p-tolylsulfonylcyclopentene63. While, in the formep2, the stereoselective Michael reaction gives the thetmodynamically less stable cis-adduct upon a tram-addition process, but, in the latter63, it is the steric strain in the cis-cyclopentyl system that dictates a &addition process to produce the trans-adduct. Reaction of methylamine with 5 at, RT gave a 5:l mixture of tram-and cis-adducts [7b + 9b]; the latter reaction at 50 oC, however, produced a 1:2 mixture of 7b and 9b, respectively. Reaction of 5 with nitromethane, under the influence of a base, gave corresponding tram-isomer 7k as the major product and the &-isomer 9k as the minor prcduct in 11: 1 ratio. The reaction of 5 with benzylamine at 20 oC was completely stereospecitic giving only the tram-adduct 7d. Similarly, the reactions of 5 with aqueous dimethylamine, pyrrolidine, piperidine, morpholine and glycine methyl ester at 20 oC gave the corresponding tram-adducts [7c,e-i] as the sole ptoduct in moderate to high yields. The reaction of 5 in aqueous ammonia has been studied at different temperatures in o&r to investigate the relative stabilities of the intermediates 27 and 28. It turned out that at 20 Oc, a 21 mixture of tram-versus cis-adduct, 7s & 9n respectively, was isolated; on the other hand, the reaction at 0 Oc produced a 12: 1 mixture while at 75 oC, the distribution of trans-versus cis-product were nspectiveiy 2:3. This shows that the transaddition process giving the cis-adduct is prefered at a higher tempexature while the cis-addition process to give the trnns-adduct is clearly prefered at a lower temperature. The temperatumdependent formation of cis-vetsus tram-adduct was of considerable help in the isolation of pure diastemomer 7j formed in the conjugate addition reaction of the malonate ion with compond 5. In this particular reaction, both diastereomers (rib0 & xyfo) were formed at RT which had almost identical chromatographic properties and consequently caused considerable separation problems in our attempts to isolate a pure diastereomer. It turned out that we could easily circumvent this separation problem by performing the reaction at 0 aC when the pure tram-adduct 7j was only fotmed which was isolated in 66% yield. Reaction of pyrtolidin-l-yl-cyclohexene with the enesulfone 5, upon a hydrolytic work up, gave the C-3' distereospecific tram-adducts 7i(R) and Z(S). *H-NMR data clearly showed that the products 7i(R) and 7i(S) were formed due to the assymmetric...
The Journal of Organic Chemistry
Two α-L-ribo-configured bicyclic nucleic acid modifications, represented by analogues 12 and 13, which are epimeric at C3' and C5' have been synthesized using a carbohydrate-based approach to build the bicyclic core structure. An intramolecular L-proline-mediated aldol reaction was employed to generate the cis-configured ring junction of analogue 12, and represents a rare application of this venerable organocatalytic reaction to a carbohydrate system. In the case of analogue 13, where a trans-ring junction was desired, an intermolecular diastereoselective Grignard reaction followed by ring-closing metathesis was used. In order to set the desired stereochemistry at the C5'-positions of both nucleoside targets, a study of diastereoselective Lewis-acid mediated allylation reactions on a common bicyclic aldehyde precursor was carried out. Analogue 12 was incorporated in oligonucleotide sequences and thermal denaturation experiments indicate that it is destabilizing relative ...
Journal of Medicinal Chemistry, 2005
A series of ring-constrained (N)-methanocarba-5′-uronamide 2,N 6 -disubstituted adenine nucleosides have been synthesized via Mitsunobu condensation of the nucleobase precursor with a pseudosugar ring containing a 5′-ester functionality. Following appropriate functionalization of the adenine ring, the ester group was converted to the 5′-N-methylamide. The compounds, mainly 2-chloro substituted derivatives, were tested in both binding and functional assays at human adenosine receptors (ARs), and many were found to be highly potent and selective A 3 AR agonists. Selected compounds were compared in binding to the rat A 3 AR to assess their viability for testing in rat disease models. The N 6 -(3-chlorobenzyl) and N 6 -(3-bromobenzyl) analogues displayed K i values at the human A 3 AR of 0.29 and 0.38 nM, respectively. Other subnanomolar affinities were observed for the following N 6 derivatives: 2,5-dichlorobenzyl, 5-iodo-2-methoxybenzyl, trans-2phenyl-1-cyclopropyl, and 2,2-diphenylethyl. Selectivity for the human A 3 AR in comparison to the A 1 AR was (fold): the N 6 -(2,2-diphenylethyl) analogue 34 (1900), the N 6 -(2,5dimethoxybenzyl) analogue 26 (1200), the N 6 -(2,5-dichlorobenzyl) and N 6 -(2-phenyl-1cyclopropyl) analogues 20 and 33 (1000), and the N 6 -(3-substituted benzyl) analogues 17, 18, 28, and 29 (700-900). Typically, even greater selectivity ratios were obtained in comparison with the A 2A and A 2B ARs. The (N)-methanocarba-5′-uronamide analogues were full agonists at the A 3 AR, as indicated by the inhibition of forskolin-stimluated adenylate cyclase at a concentration of 10 µM. The N 6 -(2,2-diphenylethyl) derivative was an A 3 AR agonist in the (N)methanocarba-5′-uronamide series, although it was an antagonist in the ribose series. Thus, many of the previously known groups that enhance A 3 AR affinity in the 9-riboside series, including those that reducing intrinsic efficacy, may be adapted to the (N)-methanocarba nucleoside series of full agonists.