Synthesis of l-Deoxyribonucleosides from d-Ribose

Abstract

The preparation of 2-deoxy-l-ribose derivatives or mirror image deoxyribonucleosides (l-deoxyribonucleosides) from d-ribose is reported. Starting from inexpensive d-ribose, an acyclic d-form carbohydrate precursor was synthesized to study a unique carbonyl translocation process. In this novel radical reaction, not only was the configuration of the sugar transformed from the d-form to the l-form, but also deoxygenation at the C(2) position of the sugar was successfully achieved. This is one of the most practical methods for converting a d-sugar to a 2-deoxy-l-sugar in a one-step reaction. To further identify the reaction product, radical reactions followed by treatment with 1,3-propanedithiol and then benzoylation were performed to afford a dithioacetal derivative. The stereochemistry and configuration of the 2-deoxy-l-ribose dithioacetal derivative were confirmed by its X-ray crystal structure. To further apply this methodology, a diethyl thioacetal derivative was formed, followed by selective benzoyl protection, and an NIS-initiated cyclization reaction to give the desired ethyl S-l-2-deoxyriboside, which can be used as a 2-deoxy-l-ribosyl synthon in the formal total synthesis of various l-deoxyribonucleosides, such as l-dT.

From a Carbohydrate Raw Material to an Important Building Block: Cost-Efficient Conversion of d-Fructose into 2-Deoxy-l-ribose

“…Moreover, benzoylation of compound 10 gave the dithioacetal 11 . The spectrometric data for compound 11 were identical with that from a previous report . Eventually, the lipase-catalyzed deprotection of compound 6 gave 2-deoxy- l -ribose as the free sugar.…”

“…The organic layer was dried over MgSO 4 and concentrated to give a crude product, which was purified by flash chromatography with the eluent of EtOAc/hexanes = 15/85 to 25/75 to give the desired product 11 (0.09 g, 95%) as a white solid. [α] 25 D +4.00 ( c = 0.92, CHCl 3 ); [α] 25 D +3.68 ( c = 2.15, CHCl 3 ); IR (neat) 1722 (CO) cm –1 ; 1 H NMR (300 MHz, CDCl 3 ) δ 8.10–7.97 (m, 6H), 7.62–7.50 (m, 3H), 7.49–7.35 (m, 6H), 5.90 (dt, J = 9.0, 3.9 Hz, 1H, H 3 ), 5.81 (dt, J = 6.6, 4.2 Hz, 1H, H 4 ), 4.75 (dd, J = 12.0, 3.9 Hz, 1H, H 5 ), 4.60 (dd, J = 12.0, 6.6 Hz, 1H, H 5′ ), 4.16 (dd, J = 9.0, 5.4 Hz, 1H, H 1 ), 2.92–2.72 (m, 4H, SCH 2 × 2), 2.52–2.30 (m, 2H, H 2 ), 2.13–2.00 (m, 1H, SCH 2 C H 2 ), 1.94–1.77 (m, 1H, SCH 2 C H 2 ); 13 C­{ 1 H} NMR (75 MHz, CDCl 3 ) δ 166.1, 165.5, 165.4, 133.3, 133.1, 129.8, 129.7, 129.6, 129.4, 128.4, 72.2, 70.2, 62.6, 43.1, 36.3, 30.0, 29.7, 25.5. HRMS (ESI + ) m / z calcd for C 29 H 29 O 6 S 2 [M + H] + : 537.1400.…”

“…Compound 6 could also be converted into an acyclic dithioacetal 10 . This dithioacetal derivative 10 could also serve as a l -deoxyribosyl sugar donor for the preparation of various l -deoxyribonucleosides, , such as the antiviral agent l -dT. Moreover, benzoylation of compound 10 gave the dithioacetal 11 .…”

“…A long-term goal in this laboratory is to develop practical synthetic methodologies for the conversion of naturally occurring and inexpensive D-sugars into rare and important L-deoxysugars 11 or L-deoxyribonucleosides. 12 Although we had partial success in developing a carbonyl translocation process 13 to produce L-deoxysugar derivatives from D-sugars, a costefficient synthetic approach for converting a carbohydrate raw material into an important building block would be of considerable value to the pharmaceutical industry. To accomplish this ultimate synthetic challenge, a D-fructose derivative could be transformed to a 3-deoxy-L-fructose analogue using our developed carbonyl translocation process.…”

D-Peptide and D-Protein technology: Recent advances, challenges, and opportunities

“…Construction of the necessary mirror-image oligonucleotides is also a major challenge. Whilst the synthesis of relatively short oligonucleotides is possible from L-xylose or L-arabinose, [23] the resulting oligonucleotides suffer from lower purity. [11][12] With the advent of the high fidelity D-Pfu capable of assembling complex genes, [15] one might argue that this challenge is within reach.…”