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Synlett 2005(15): 2391-2393  
DOI: 10.1055/s-2005-872658
LETTER
© Georg Thieme Verlag Stuttgart · New York

Asymmetric Synthesis of 4′-Quaternary 2′-Deoxy-3′-epi-β-C-Nucleosides

Dieter Enders*, Antje Hieronymi, André Ridder
Institut für Organische Chemie, RWTH Aachen, Landoltweg 1, 52074 Aachen, Germany
Fax: +49(241)8092127; e-Mail: enders@rwth-aachen.de;
Further Information

Publication History

Received 18 July 2005
Publication Date:
05 August 2005 (online)

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Abstract

An efficient diastereo- and enantioselective synthesis of 4′-quaternary 2′-deoxy-3′-epi-β-C-nucleosides is described employing the RAMP-hydrazone methodology to establish the first stereocentre. Further key steps include diastereoselective nucleophilic 1,2-additions with Grignard and organocerium reagents.

Key words

asymmetric synthesis - nucleoside analogues - hydrazones - organocerium reagents - diastereoselective reduction

12

Typical Procedure for the Grignard Reaction.
In a dried Schlenk flask, equipped with a magnetic stirrer, the ketone 2 was dissolved in abs. THF (10 mL/mmol) under an argon atmosphere. The solution was cooled to -78 °C or -100 °C, respectively, depending on the Grignard reagent employed, which was then slowly added (2.0 equiv). The mixture was allowed to stir while maintaining the temperature constant for 4 h. The reaction was then stopped by addition of sat. aq solution of NH4Cl (5 mL/mmol). After warming up to r.t. the precipitate was dissolved by dilution with H2O. The aqueous phase was extracted with Et2O (50 mL/mmol) and the combined organic layers were washed with brine and dried over MgSO4. Column chromatography (silica gel, Et2O-n-pentane) gave the corresponding alcohols 3a-e as colourless crystals.

13

Typical Procedure for the Cyclisation.
The products 3a-e were dissolved in MeOH (3 mL/mmol) and treated with 3 N methanolic HCl (3 mL/mmol, prepared by mixing one part of aq HCl (12 N) with four parts of MeOH). The reaction was stirred at r.t. until TLC control indicated complete conversion of the starting material. All solvents were evaporated under reduced pressure and the product 4a-e was recrystallised from THF-n-pentane.

14

Typical Procedure for the TBS-Protection.
To a solution of the diols 4a-e in abs. THF (10 mL/mmol) was added pyridine (6.0 equiv), and the mixture was cooled to 0 °C. Slow addition of TBSOTf (3.0 equiv), followed by 4 h of stirring, gave rise to the product. The reaction was quenched with H2O (5 mL/mmol), extracted with Et2O (50 mL/mmol), washed with brine and dried over MgSO4. The products 5a-e were then purified by column chromatography (silica gel, Et2O-n-pentane).

17

Typical Procedure for the 1,2-Addition.
First, CeCl3·7H2O (2.0 equiv), placed in a Schlenk flask, was dried without stirring at 130 °C in vacuo (approx. 0.05 mbar) for 1 h. It was subsequently ground up by stirring under these conditions for an additional hour. After cooling down to r.t. the flask was filled with argon and abs. THF (4 mL/mmol of CeCl3) was added. The suspension was stirred for at least 1 h and then placed in an ultrasound bath for an extra hour. The mixture was then cooled down to -78 °C and the lithium reagent was added dropwise. After 2 h stirring at low temperature a bright yellow colour indicated the formation of the active cerium reagent. The mixture was then cooled down to -105 °C and lactone 5a was added in abs. THF (5 mL/mmol), carefully keeping the temperature below -100 °C. After 30 min, the reaction mixture was allowed to warm up to -99 °C and quenched with H2O (10 mL/mmol). Extraction with CH2Cl2 (100 mL/mmol) followed by treatment with brine and drying over MgSO4 provided the desired products 6a,b, which could be purified by column chromatography (silica gel, Et2O-n-pentane).

19

Typical Procedure for the Reduction According to Evans.
A suspension of Me4NHB(OAc)3 (3.0 equiv) in abs. MeCN (5 mL/mmol) was treated with abs. AcOH (5 mL/mmol) under an argon atmosphere. The resulting solution was cooled down to -30 °C and added to a solution of the hydroxyketone 6a,b in abs. MeCN (2.5 mL/mmol). The reaction was left standing overnight at -26 °C. Quenching the reaction with a solution of 10% Na/K-tartrate in H2O (10 mL/mmol) led to a precipitate, which was dissolved by addition of a sat. aq solution of Na2CO3. The aqueous phase was extracted with Et2O (100 mL/mmol) and the combined organic layers were washed with brine and dried over MgSO4. The cyclised products 7a,b were purified by column chromatography (silica gel, Et2O-n-pentane).

20

Typical Procedure for the Deprotection.
To the TBS ethers 7a,b in CHCl3 at 0 °C was slowly added a 4:1 mixture of TFA and CHCl3. The reaction progress was monitored by TLC. When the reaction was completed the solvent was evaporated under reduced pressure. Traces of TFA were removed by repeated co-evaporation with MeOH. Column chromatography with Et2O on silica gel gave rise to the free β-nucleosides 8a,b.

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(2 R ,3 R ,5 R )-2-(Hydroxymethyl)-2-methyl-5-(1-naphthyl)tetrahydrofuran-3-ol (8b): mp 118 °C. IR (KBr): ν = 3517, 3325, 3047, 2962, 2913, 2862, 1597, 1508, 1435, 1373, 1340, 1283, 1220, 1101, 1055, 1016, 939, 913, 860, 778, 642, 560, 490 cm-1. 1H NMR (400 MHz, CDCl3): δ = 1.57 (s, 3 H, CH 3 ), 2.09 (ddd, 1 H, J = 12.9, 9.3, 6.6 Hz, ArCHCHH), 2.42 (t, 1 H, J = 6.2 Hz, CH2OH), 2.98 (d, 1 H, J = 14.5 Hz, CHOH), 3.02 (ddd, 1 H, J = 12.9, 6.6, 6.3 Hz, ArCHCHH), 3.87 (d, 2 H, J = 6.2 Hz, CH 2 OH), 4.36 (dd, 1 H, J = 14.5, 6.6 Hz, CHOH), 5.67 (dd, 1 H, J = 9.3, 6.3 Hz, ArCH), 7.45-7.99 (m, 7 H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 22.01, 43.67, 66.92, 73.34, 79.74, 83.58, 121.72, 123.06, 125.37, 125.42, 125.90, 127.91, 128.64, 130.46, 133.46, 137.06 ppm. MS (EI): m/z (%) = 115 (5), 127 (9), 128 (25), 129 (9), 141 (19), 142 (9), 152 (11), 153 (24), 154 (18), 155 (31), 156 (9), 165 (12), 166 (10), 167 (24), 170 (9), 183 (5), 184 (5), 209 (75), 210 (11), 227 (52), 228 (8), 258 (100), 259 (17). [α]D 25 +26.3 (c 0.99, CHCl3). Anal. Calcd for C12H16O3: C, 74.39; H, 7.02. Found: C, 74.36; H, 7.19.