Mitsunobu purines

In another purine library synthesis, Schultz and co-workers attached a 6-aminomethylaniline side chain to the PAL linker1718 via reductive amina-tion (Scheme 5). Alkylation at the 9-position was achieved using Mitsunobu conditions and an SwAr reaction was used to functionalize the 2-position with amines. The final cleavage of the aniline was achieved using 90%... 

An oxidizing agent. Useful for the dealkylation of amines and the conversion of pyrimidines to purines. It is most often associated with triphenylphosphine (TPP) in the Mitsunobu reaction. Examples ... 

Schultz and co-workers31 also described the preparation of a 2,6,9-trisubstituted purine library. A preformed 2-fluoro-6-(4-aminobenzylamino) purine was reductively aminated onto the BAL linker 12. Mitsunobu chemistry was employed to alkylate the C9 position on the support-bound intermediate (Scheme 4). Subsequently, SNAr chemistry was used to incorporate amines at C6. The newly introduced primary and secondary amines bear diverse functional groups and the Mitsunobu reaction allows for incorporation of primary and secondary alcohols lacking acidic hydrogens. The support-bound product 13 was cleaved with 90% TFA/10% H20 to give a library with HPLC purities ranging between 51 and 85%. 

The reaction sequence starts by anchoring 2,6-dichloropurine onto the sohd-phase PAT, -amine at the more reactive C6 position with exclusive regioselectivity. A multitude of PAL-amine resins 59 can be prepared ahead by reductive amination of commercial (4-formyl-3,5-dimethoxyphe-noxy)-methylpolystyrene. The N9 position of the purine (60) may be modified by Mitsunobu alkylation. The final derivatization step involves a palladium-catalyzed cross-coupling reaction in position 2. This reaction... 

Mitsunobu Reaction for Endocyclic N9-Alkylation on Purine Scaffold (60) (Fig. 10).15 This is described later in the section dedicated to Mitsunobu reactions. 

Mitsunobu Reaction for Exocyclic N2-Alkylation on a Purine Scaffold (Fig. 16).47 2,6-Di-tert-butyl-4-methylpyridine (1.54 g, 7.5 mmol, 0.3 M) is added to freshly distilled CH2C12 (25 ml) at 0° under N2. To this solution is added trifluoroacetic anhydride (706 pi, 5.0 mmol, 0.2 M) and the mixture is stirred for 5-10 min. The solution is then transferred to the resin 83 and the flask is vortexed and vented several times to relieve pressure. The flask is shaken for 6-12 h after which the solvent is removed and the resin washed with dry CH2C12 (5 x 25 ml) with vortexing between each rinse. The resulting resin 84 is dried. 

The reaction of an epoxide containing molecule with a nucleophile is typically an excellent manner in which to open the epoxide ring. A recent synthesis of carbocyclic nucleoside analogues provides an excellent example of reaction conditions that epoxides can sometimes withstand <07T5050>. Treatment of epoxide 18 with chloropurine under Mitsunobu conditions provides a good yield of epoxy purine derivative 19. This derivative was then converted to adenine derivative 20 by ester hydrolysis and subsequent chloride displacement with cyclopropylamine. 

Cyclic phosphonate analogues of PMEA (36) have been obtained after stereoselective cyclisation of an acyclic phosphonyl intermediate to the phos-phonyltetrahydrofuran nucleoside derivative. A series of cyclopropylphos-phonate analogues (37) has been synthesised stereoselectively via intramolecular epoxide opening reaction of y,5-epoxyalkanephosphonates with subsequent Mitsunobu coupling reaction to purine bases. Acyclic phosphonate derivatives of thymine (38-43) have been prepared and evaluated as multisubstrate analogue inhibitors of Escherichia coli thymidine phosphor-... 

The Mitsunobu reaction has been used previously to prepare 5 -0-acylnucle-osides and nucleoside 5 -phosphates [111, 112]. With purine nucleosides, the approach failed (< 1 % yields) in the preparation of 5 -phosphates, the main product being N3,5"-cyclonucleosides resulting from an intramolecular nucleophilic attack by a purine ring nitrogen atom on the 5 -carbon atom. The predominant formation of the purine cyclonucleosides was attributed to electrostatic interactions between the phosphorus cation and the purine base which brought the reaction sites (5 and 3-N) close enough to favor cyclization [113]. 

A new class of iso-4 -thionucleosides 171, with the base moiety at the 2 position, was synthesized from D-glucose by the couphng of l,4-anhydro-4-tliio-D-arabinitol 168 with purine and pyrimidine bases using the Mitsunobu reaction. The reaction gave predominantly p isomers 170 a p 1 6), when acetonitrile was used as solvent. The reaction proceed via competition between a direct Sn2 reaction and an episulfonium intermediate 169. 

The iso-4 -thiopurine and pyrimidine L-nucleosides 211 were synthesized from 1,4-thio-L-arabinitol (151) via 3-fluoro derivative 209, which was transformed into 210 by a Mitsunobu reaction. Coupling of 210 with purine and pyrimidine bases by the Mitsunobu reaction, followed by deprotection, gave the desired 211. 

A series of novel 3 -thiacarbocyclic nucleosides 240, carrying purine and pyrimidine bases, have been prepared from D-glucose. The key steps were the treatment of dimesylate 237 with Na2S, inversion at C-4 by the Mitsunobu reaction (BzOH, PhsP, and DEAD), and coupling of mesylate 239 with the nucleoside base in the presence of potassium carbonate, followed by deprotection. None of these nucleoside were active against HIV-1. 

Many anti-viral compounds are analogues of the natural nucleic acid nucleosides such as adenosine 225. This example 226, known as (5, 5 )-iso-ddA (dda stands for di-deoxy-adenosine), has a severely modified sugar 227 but the purine, adenine 228, is unaltered. The purine is attached to C-2 instead of C-1 making the molecule more stable and two of the OH groups have been removed. Coupling adenine to the modified sugar 227 needs a Mitsunobu process.42... 

The syntheses of the adenine (239) and guanine (240) derivatives, both with anti-herpes virus activity, have been carried out through Mitsunobu reactions between appropriately protected purines and diethyl (3-hydroxy-2-propynyl)phOvSphonate it was... 

The oxorhenium(V) complex 80 has been prepared from 2, 3 -diamino-2, 3 -dideoxyadenosine, and exists as a 2 1 mixture of syn- and an/i-isomers. Both were inhibitors of purine-specific ribonuclease, with the 57/i-isomer being more effective. " The same group has described a route to 3, 5 -diamino-3, 5 -dideoxy-adenosine (82) from the /> xo-epoxide 81 (Vol. 25, p. 251-2), as outlined in Scheme 10. The Mitsunobu inversion using benzyl alcohol as nucleophile is noteworthy, and proved superior to other strategies. An oxorhenium(V) complex was also formed from 82." Thymidine can be converted into the anhydronucleo-side 83 by two successive Mitsunobu reactions, and 83 was converted into the aminoderivative 84 of AZT, and some phosphoramidates were produced from 84." Some 5 -deoxy-5 -sulfonylamido derivatives of AZT have also been produced by successive displacements at 0-5 and 0-3 by nitrogen nucleophiles." ... 

Conformationally-locked C-nucleosides such as 147 have been reported from Imanishi s laboratory. These were prepared by formation of the C-T-O bond in Mitsunobu reactions, the necessary diols being formed by stereoselective addition of Grignard derivatives of the heterocycles to an aldehyde. Use of lithiated heterocycles gave substantially more of the other epimers of the diols, thus permitting access to the a-anomers after Mitsunobu reaction. The oxazole 147 and the compound without the phenyl group were incorporated into oUgonuc-leotides, and the triplex-forming ability of the these towards a purine sequence of duplex DNA was studied. ... 

The Mitsunobu reaction of achiral and chiral 3,4-dihydro-2H-l,5-benzoxathiepin-3-ol with aminopurines proceeded via a complete inversion of the stereogenic center of the secondary alcohol giving alkylated purines linked to a homochiral six-membered ring (14ITA22425). 

A special subclass of amine formation reaction is the coupling of alcohols with purines to form nucleoside derivatives. The application of the Mitsunobu reaction in this context is sufficiently expansive to warrant a mini-review in its own right, but due to space constraints only a limited number of recent examples are shown below (195 - 198). "" The reader is referred to the references for additional information. Additional examples using iV -benzoylthymine, adenine, deazapurine, 6-azauracil, and 3-benzoyluracir have been reported in the literature as well. The preparation of racemic isonucleosides via the Mitsunobu reaction is also known. 

The Mitsunobu reaction, using dibenzyl phosphate or benzyl methylphosphonate as nucleophile, can be used to convert 2, 3 -0-isopropylidene purine nucleosides... 

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