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

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.

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

References

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2a For an overview see: Perspectives in Nucleoside and Nucleic Acid Chemistry   Kisakürek MV. Rosemeyer H. VHCA; Zürich: 2000. 

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2c For a review on thio nucleosides see: Yokoyama M. Synthesis  2000,  1637 

3 Summerer D. Marx A. Angew. Chem. Int. Ed.  2001,  40:  3693 ; Angew. Chem. 2001, 113, 3806

4a Nomura M. Shuto S. Tanaka M. Sasaki T. Mori S. Shigeta S. Matsuda A. J. Med. Chem.  1999,  42:  2901 

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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).

15 Chamberlin AR. Dezube M. Reich SH. Sall DJ. J. Am. Chem. Soc.  1989,  111:  6247 

16 Imamoto T. Tawarayama Y. Sugiura Y. Mita T. Hatanaka Y. Yokoyama M. J. Org. Chem.  1984,  49:  3904 

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).

18 Evans DA. Chapman KT. Carreira EM. J. Am. Chem. Soc.  1988,  110:  3560 

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.

21

(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.