Carbocyclic nucleosides synthesis

Wang J, Jin Y, Rapp KL, Schinazi RF, Chu CK (2007) D- and L-2, 3 -didehydro-2, 3 -dideoxy-3 -fluoro-carbocyclic nucleosides synthesis, anti-HIV activity and mechanism of resistance. J Med Chem 50 1828-1839... 

The Tsuji-Trost reaction, more commonly applied to carbocyclic nucleoside synthesis, has been used in the synthesis of famciclovir 21 (Scheme 5) <2000T4589>. Reaction of 2-amino-6-chloropurine with allylic carbonate 22 in the presence of Pd2DBA3 and bis(diphenylphosphino)ethane (DPPE) gave a 1 1 ratio of 23 to 24 after 1 h (DBA = dibenzylideneacetone). However, a ratio of >95 5 in favor of the thermodynamically favored N-9 isomer 23 was subsequently obtained upon further stirring, highlighting the reversibility of the reaction in this specific instance. 

Park, K.H. et al. Enantioselective Synthesis of (IR,4S)-I-Amino-4-(hydroxy-methyl)-2-cyclopentene, a Precursor for Carbocyclic Nucleoside Synthesis. 2.4 1994 [165]... 

Brothwick, A. D., Evans, D. N., Kirk, B. E., et al. (1990) Fluoro carbocyclic nucleosides synthesis and antiviral activity of 2 -and 6 -(luoro carbocyclic pyrimidine nucleosides including carbocyclic l-(2-deoxy-2-fluoro-P-d-arabinofuranosyl)-5-methyluracil and carbocyclic l-(2 -deoxy-2-fluoro-P-d-arabinofuranosyl)5-iodouracil. J. Med. Chem., 33, 179-186. 

The previously described 7-deazapurine carbocyclic nucleoside synthesis (see Scheme 1) indicated that the most efficient route to 22 would be via reaction of the protected chiral amine 23 with the dimethylacetal of 2-(2-amino-4,6-dichloropyrimidin-S yl)acetaldehyde followed by ring closure, hydrolysis and dqirotection. A review of the literature revealed two enantioselective routes to cyclobutyl derivatives that had been used in the chiral synthesis of carbocyclic oxetanocins and could be employed for preparing a precursor to 23. In one case, however, the initial step involved a [2-i-2]-cycloaddition reaction of not easily obtainable reagents in the presence of a chiral titanium compound as... 

A new short synthesis of the Ohno lactone 106, a useful building block for carbocyclic nucleosides, has been described, proceeding in 54% overall yield from the cycloadduct of cyclopentadiene and acrylic acid. Also rqwrted is a large-scale route to the racemic synthon 107, which can be resolved enzymically and used for carbocyclic nucleoside synthesis. Indeed,... 

New developments in the selective synthesis of cyclopentyl carbocyclic nucleosides 98T9229. 

Azabicyclo[2.2.1]hept-5-en-3-one, a bicyclic y-lactam, is an intermediate for the synthesis of antiviral carbocyclic nucleosides (Figure 6.41). This compound was resolved using a cloned lactamase in an industrial-scale process [106,107]. 

The resulting derivatives (269) can be considered as strategically important intermediates in the synthesis of glycosidase inhibitors and carbocyclic nucleosides (150). A new approach to the stereoselective synthesis of the piperidine ring with the use of [4+ 2] [3+ 2]-cycloaddition from specially prepared substrates is also very interesting (431)b, c. In the context of this problem, the conditions for the formation of systems containing quaternary vicinal stereocenters were found. 

D-Ribonolactone is a convenient source of chiral cyclopentenones, acyclic structures, and oxacyclic systems, useful intermediates for the synthesis of biologically important molecules. Cyclopentenones derived from ribono-lactone have been employed for the synthesis of prostanoids and carbocyclic nucleosides. The cyclopentenone 280 was synthesized (265) from 2,3-0-cyclohexylidene-D-ribono-1,4-lactone (16b) by a threestep synthesis that involves successive periodate oxidation, glycosylation of the lactol with 2-propanol to give 279, and treatment of 279 with lithium dimethyl methyl-phosphonate. The enantiomer of 280 was prepared from D-mannose by converting it to the corresponding lactone, which was selectively protected at HO-2, HO-3 by acetalization. Likewise, the isopropylidene derivative 282 was obtained (266) via the intermediate unsaturated lactone 281, prepared from 16a. Reduction of 281 with di-tert-butoxy lithium aluminum hydride, followed by mesylation, gave 282. 

Taylor, S.J.C., Sutherland, A.G., Lee, C., Wisdom, R., Thomas, S., Roberts, S.M. and Evans, C., Chemoenzymatic synthesis of (—)-carhovir utilizing a whole cell catalysed resolution of 2-azabicyclo[2.2.1 ]hept-5-en-3-one. J. Chem. Soc. Chem. Commun., 1990, 1120-1121 Evans, C.T., Roberts, S.M., Shoheru, K.A. and Sutherland, A.G., Potential use of carbocyclic nucleosides for the treatment of AIDS chemo-enzymatic syntheses of the enantiomers of carbovir. J. Chem. Soc. Perkin Trans. 1,1992, 589-592. 

A cyclic ring sulfite (with an -O-SO-0- ring in a carbocyclic nucleoside) was oxidised by RuClj/aq. Na(lO )/CCl -CH3CN/0°C as a synthon for the convergent synthesis of carbocyclic nucleosides (Fig. 5.17) [116]. 

A number of workers have described the synthesis and cycloaddition reactions of oxazoline nitrone dipoles, (e.g., 361 and 362, Scheme 1.80) (413 17). A homochiral oxazoline nitrone derived from camphor has been used to great effect by Langlois and co-workers (418,419), from which they have prepared a number of natural targets through enantioselective cycloaddition reactions, including the antiviral carbocyclic nucleoside analogue (+)-carbovir (48) (Fig. 1.1, Section 1.3). 

In conjunction with this, Jeong reported the cycloadditions of bis(allyl) and bis(homoallyl) acetals of alkynals leading to bicyclic lactols. Smaltz extended its utility to the synthesis of carbocyclic nucleoside by coupling with nucleophilic substitution of a 7r-allylic palladium complex (Equation (46)). ... 

Synthesis of Amino/Hydroxy Substituted Cyclopentanes and a Carbocyclic Nucleoside... 

In 1988 Koizumi et al. reported the first sulfoxide used as a chiral synthetic equivalent of dimethyl acetylene dicarboxylate [86a]. The synthesis of dimethyl (R)s-2-(10-isobornylsulfmyl) maleate (88), its reaction with cyclopentadiene catalyzed by ZnCl2, and the further transformation of the major adduct 89 into a half-ester 90 (which had been used as the starting material for the synthesis of carbocyclic nucleosides (-)-aristeromycin and (-)-neplanomicin) are described (Scheme 46). 

A unique member of the seven carbon carbaketose family, namely hept-2-uloseptanosylamine 342, was assembled by Mandal [78,79] during a remarkable total synthesis of chiral carbocyclic nucleosides from D-glucose. Here, a diastereoselective intramolecular nitrone cycloaddition reaction was the decisive move to install the carbaseptanose ring system (Scheme 56). 

Crimmins, M.T. New Developments in Enantioselective Synthesis of Cyclopentyl Carbocyclic Nucleosides. 1998 [2d]... 

Agrofoglio, L. et al. Synthesis of a New Exocyclic Amino Carbocyclic Nucleoside with Potential Antiviral Activity. 2.4 1993 [103]... 

Boyer, S.J. et al. Carbocyclic Nucleoside Analogs. I. Concise Enantioselec-tive Synthesis of Functionalized Cyclopentanes and Formal Total Synthesis of Aristeromycin. 2.4 1997 [109]... 

Gallos, J.K. et al. Facile Synthesis of Enantiomerically Pure Carbafuranoses Precursors of Carbocyclic Nucleosides. 2.1 2001 [120]... 

Martinez, L.E. et al. Highly Efficient and Enantioselective Synthesis of Carbocyclic Nucleoside Analogs Using Selective Early Transition Metal Catalysis. 2.4 1996 [148]... 

Maycock, C D. et al. An Application of Quinic Acid to the Synthesis of Cyclic Homochiral Molecules A Common Route to Some Interesting Carbocyclic Nucleoside Precursor. 2.4 1993 [151]... 

An interesting application of a chiral nitroso dienophile combined with the conversion of the primarily generated 1,2-oxazine into a cyclopentene derivative has been carried out by Miller et al. and is directed towards the synthesis of carbocyclic nucleoside analoga such as 4-28 [353 -355]. The alanine derived dienophile 4-23 cycloadded to cyclopentadiene giving two diastereomeric, however easily separable adducts 4-24 and 4-25. The N-0 bond of 4-24 was then reduc-... 

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. 

V. E. Marquez, M. Lim, M. S. Khan, and B. Kaskar, (4R,5R)-(-)-3-(Benzyloxymethyl)-4,5-0-iso-propylidene-2-cyclopentenone-4,5-diol. An optically active a-, /1-unsaturated cyclopentenone for the synthesis of neplanocin A and other cyclopentene carbocyclic nucleosides, Nucleic Acid Chem., 4(1991)27-35. 

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