Enantioselective Approach to the Synthesis of Cyclohexane Carbocyclic Nucleosides (original) (raw)
Advances in the enantioselective synthesis of carbocyclic nucleosides
Chemical Society Reviews, 2013
Carbocyclic nucleosides are nucleoside analogues in which the furanosidic moiety has been replaced by a carbocycle. Several members of this family have been isolated from natural sources and include a 5-membered ring carbocycle. The aim of this review is to examine critically the different methodologies for the enantioselective construction of 3-to 6-membered rings, with a particular focus on 5-membered rings and their modifications. The procedures for bonding the heterocyclic moiety and the carbohydrate are treated separately. The methods for synthesising the carbocyclic moiety mainly focus on the construction of the cycle, although precise details about the functionalisation are provided in some cases. The selected methods aim to provide an overview of the synthesis of carbocycles related to the synthesis of carbocyclic nucleosides. The methods of synthesis of 5-membered rings are classified into two types: methods in which the cyclopentane ring is formed by ring closing reactions (CQC and C-C formation) and methods that start from preformed 5-membered rings, based mainly on cycloaddition reactions. With respect to the methods of synthesis of 3-, 4-and 6-membered ring carbocyclic nucleosides, a selection of the more relevant enantioselective procedures is presented in a systematic manner.
Enantiodivergent Synthesis of Cyclohexenyl Nucleosides
The Journal of Organic Chemistry, 2009
An enantiodivergent synthesis of several cyclohexenyl nucleosides has been efficiently completed starting from the enantiopure hydrobenzoin-derived monoketal of cyclohex-2-en-1,4-dione, (+)-5. Stereodiversity was accomplished on the base coupling step. This methodology has proved to be useful for the synthesis of enantiopure pyrimidine and purine nucleoside analogues, which anti-HIV activity has been evaluated. (1) (a) Wang, J.; Jin, Y.; Rapp, K. L.; Schinazi, R. F.; Chu, C. K. 9229-9272. (2) Coates, J. A. V.; Inggall, H. J.; Pearson, B. A.; Penn, C. R.; Storer, R.; Williamson, C.; Cameron, J. M. AntiViral Res. 1991, 15, 161-168. (3) Daluge, S. M.; Good, S. S.; Faletto, M. B.; Miller, W. H.; St. Clair, M. H.; Boone, L. R.; Tisdale, M.; Parry, N. R.; Reardon, J. E.; Dornsife, R. E.; Averett, D. R.; Krenitsky, T. A.
Diastereo- and Enantioselective Synthesis of 1′-C-Branched N, O-Nucleosides
Nucleosides Nucleotides & Nucleic Acids - NUCLEOS NUCLEOT NUCLEIC ACIDS, 2003
A synthetic approach towards 1′-C-branched N, O-nucleosides is reported, based on 1,3-dipolar cycloaddition of ethoxycarbonylnitrone. The asymmetric version of the process exploits the presence of a chiral auxiliary at the carbon atom of nitrone and leads to β-D and β-L nucleosides in good yields.
Diastereo- and enantioselective synthesis of N, O-nucleosides
Tetrahedron-asymmetry, 2003
The diastereo-and enantioselective synthesis of aand b-3%-hydroxymethyl-N,O-nucleosides is described, based on the 1,3-dipolar cycloaddition of a N-glycosyl nitrone. Two approaches have been evaluated: the one-step procedure, which uses vinyl nucleobases, showed a better stereoselectivity towards b-nucleosides.
Enantioselective Synthesis of Homo-N-Nucleosides Containing a 1,4-Dioxane Sugar Analog
Molecules, 2008
A dioxane homo-sugar analog, (2S,5S)-and (2R,5S)-5-[(4S)-2,2-dimethyl-1,3dioxolan-4-yl]-2-iodomethyl-1,4-dioxane was prepared from (2R,3R)-dimethyl tartrate, and further elaborated into the corresponding homo-N-nucleoside analogs by its reactions with uracil and adenine, respectively.
Tetrahedron, 2006
Carbocyclic nucleoside analogues remain interesting target molecules having the potential to combine biological activity with greater metabolic stability than their sugar counterparts. This paper describes a rapid and versatile synthetic approach to such compounds based on commercial cyclopentenones (e.g., 1) that has been developed in our laboratory. Carbocyclic nucleosides like 2 0-methylaristeromycin 6 were synthesized in racemic form in 5 steps via key intermediate 4. The procedure was also adapted to the preparation of 4 0-epi-carbocyclic nucleosides using epoxide 17 instead of 4 and employing the same methodology.
Stereocontrolled Syntheses of Carbocyclic C-Nucleosides and Related Compounds
The Journal of Organic Chemistry, 2001
Carbocyclic 9-deazapurine nucleosides (1-4), a spiranic pyrimidone carbocyclic compound (5), and an unusual carbocyclic isonucleoside (6) were prepared as enantiomerically pure compounds via the key intermediates 10 and 21 from 1,4-γ-ribonolactone. The key intermediate 10 was prepared by stereoselective reduction with Bu 3 SnH and then converted to carbocyclic C-ribonucleosides 1, 3, and 4. 2′,3′-Didehydro-2′,3′-dideoxycarbocyclic 9-deazainosine (2) was prepared from a 2′,3′dimesylate 17 by treatment with Li 2 Te followed by an acidic deprotection. The key bicyclic intermediate 21 was prepared from a diol 20 by an intramolecular cyclization using CHI 3-Ph 3 Pimidazole and converted to the spiranic compound 5 and an olefinic nucleoside 6 by the construction of the heterocyclic moiety followed by deprotection.
The Journal of Organic Chemistry, 1996
The development of synthetic routes to carbocyclic nucleoside analogs has attracted considerable attention, due partly to the interesting biological activity of these compounds and also to the persistent challenges associated with constructing substituted 5-membered carbocycles with defined relative and absolute stereochemistry. 3 Particularly noteworthy members of this class of compounds include the naturally-occurring carbocyclic adenosine analog (-)-aristeromycin (1), the biosynthesis 4 and biological activity 5 of which have been subject to recent intensive scrutiny; the related natural product (-)-3′-deoxyaristeromycin (2); 6 (-)-carbovir (3), a selective inhibitor of HIV reverse transcriptase in vitro; 7 and the structurally related (-)-1592U89 succinate (4), which has been reported to have a higher oral bioavailability than carbovir and is currently in clinical trials for the treatment of HIV infection ( ). 8 Our two groups recently uncovered effective catalysts for the highly selective synthesis and manipulation of 5-membered cyclic structures ). Complex 5, generated in situ by the combination of WOCl 4 and 2,6dibromophenol, is a useful and inexpensive catalyst for the ring-closing metathesis (RCM) of acyclic dienes to afford 5-and 6-membered cyclic compounds. 9 The (salen)Cr complex 6 has been identified as a catalyst for the asymmetric ring-opening (ARO) of meso and racemic epoxides by TMSN 3 , 10 with particularly high enantioselectivity displayed for the opening of epoxides fused to 5-membered rings. The sequential application of these two catalytic transformations, along with an intermediary epoxidation reaction, could constitute an efficient method for the conversion of simple dienes to cyclic 1,2amino alcohols wherein a new C-C bond has been constructed and two contiguous stereogenic centers have been established with high relative and absolute control ( ). In this paper, the power of this strategy is illustrated in the efficient synthesis of key intermediates leading to the carbocylic nucleoside analog structures outlined in .
Synthesis of two enantiomerically pure precursors of cyclobutane carbocyclic nucleosides
Tetrahedron: …, 2003
Several bi-functionallized derivatives of cyclobutane have been synthesized by functional-group manipulation starting from (−)-cis-pinonic acid as a common precursor, the configuration of the pre-existing and newly formed stereogenic centers being determined by the configuration of the starting material, commercially available (−)-1S-a-pinene. Final products, (+)-(1S,1%R)-cis-1-[3%-(aminomethyl)-2%,2%-dimethylcyclobutyl]ethanol 5 and (+)-(1S,1%R)-cis-1-[3%-(2¦-aminoethyl)-2%,2%-dimethylcyclobutyl]ethanol 6 are useful as precursors to cyclobutane carbocyclic nucleosides.
The Journal of Organic Chemistry, 2002
The bicyclo[3.1.0]hexane scaffold can lock the conformation of a carbocyclic nucleoside into one of the two antipodal (north or south) conformations typical of conventional nucleosides that normally exist in a rapid, two-state equilibrium in solution. In a recent brief communication, we reported a practical method to access the requisite bicyclo[3.1.0]hexane pseudosugar for the north antipode via an intramolecular olefin-ketocarbene cycloaddition. The most attractive features of this synthesis was that a relatively complex synthon was obtained from simple and inexpensive starting materials and that the resulting racemic mixtures of purine nucleosides could be successfully resolved by adenosine deaminase (ADA) hydrolysis. In this work, we describe the development of a more general, lipase-catalyzed double-acetylation reaction, which could successfully resolve an earlier precursor, 4-(tert-butyldiphenylsilamethoxy)-1-(hydroxymethyl)bicyclo[3.1.0]hexan-2-ol [(()-7], into enantiomerically pure (+)-diacetate 8 and (-)-monoacetate 9. The former diacetate was converted to the conformationally locked (north)-carbocyclic guanosine (+)-17 identical to the one obtained previously by ADA resolution. The present method represents a more general and efficient process applicable to the synthesis of all classes of (north) bicyclo[3.1.0]hexane nucleosides, including pyrimidine analogues. During the lipase-catalyzed resolution, we were able to demonstrate the presence of an unusual acetal-forming reaction that consumed small amounts of the unreactive monoacetate (-)-9. This side reaction was also enzyme-catalyzed and was triggered by the byproduct acetaldehyde generated during the reaction.
Tetrahedron, 2011
An expedient synthesis of 2-deoxy (10) and 3-deoxy (11) cyclohexenyl analogues of 2-deoxy and 3-deoxy-D-ribose sugar from commercially available starting materials is reported. Highly efficient enzymatic resolution of the key compound 10 is described using lipase under hydrolytic conditions. The robust methodology applied here will be useful to synthesize cyclohexenyl nucleosides, which possess potent antiviral activity and are capable of gene silencing via RNAi or antisense applications.
Synthesis of novel carbocyclic nucleosides with a cyclopentenyl ring: Homocarbovir and analogues
Tetrahedron, 1998
Ab~rat't: Several synthetic strategies have been used to prepare Ct:)..cis-4-(aminomethyl)-2-cyclopentenyimethanol (6) from norbornadiene. Amino alchohol 6 has been then used to prepare an homologne of carbovir and its congeners. Alternatively, a synthetic intermediate in the preparation of 6 can be used in a convergent mode to prepare the corresponding adenine and inosine analogues.
Stereoselective synthesis of new bicyclic N, O- iso-homonucleoside analogues
Tetrahedron, 2003
The synthesis of two new bicyclic nucleoside analogues is reported. These compounds are iso-homonucleoside and are synthesised through a 1,3-dipolar cycloaddition of an enantiopure cyclic nitrone to protected allyl acohol and subsequent introduction of thymine by a Mitsunobu reaction. q
Diastereoselective Synthesis of Homo-N,O-nucleosides
ChemInform, 2004
A new class of homo-N,O-nucleosides has been designed, based on the 1,3-dipolar cycloaddition of C-substituted nitrones with allyl nucleobases. The N-methyl-C-ethoxycarbonyl nitrone 1, and the C-a-silyloxymethyl-N-methyl nitrone 7 have been exploited: the stereochemical features of the obtained nucleosides are dependent on the nature of the dipole. The results obtained with DFT calculations fully agree with the experimental results and successfully reproduce the experimentally observed reversal of endo/exo selectivity for nitrones 1 and 7. q