A Straightforward Diphenylmethyl Protection Method and Deprotection of Some Pyrimidine Nucleosides

Abstract

Benzhydryl protection of primary and secondary alcohols has been reported previously via reaction with metal alcoholates. Our aim was to find generally useful and very mild conditions for the alcoholic protection and deprotection of nucleosides with the diphenylmethyl group. This was accomplished for some pyrimidine nucleosides using PdCl₂ as the transition metal catalyst, and with optimization yields of 70–90% have been achieved. A lack of solubility of other nucleosides hampers its more general use.

1. Introduction

Nucleoside and nucleotide chemistry generally involves multistep synthesis protocols, where selective and efficient protection and deprotection reactions have always played a central role. The criteria involved in the choice of protecting groups are based on high yielding protection and deprotection steps, chemoselectivity and orthogonality with other protecting and functional groups. For example, various acyl, benzyl, trityl, triethylsilyl [1], and tert-butyldimethylsilyl ethers [2] have found common use for selective protection of primary/secondary alcohols, particularly in carbohydrate and nucleoside/nucleotide chemistry. To our knowledge, only very few specific reviews for nucleoside protection are available [3,4]. For a complete overview of alcohol protecting groups readers may consult Greene and Wuts [5].

Due to their orthogonality regarding deprotection conditions, the 5′-, 3′- and 2′-hydroxyl groups of nucleosides are usually temporarily acylated or converted to either silyl or alkyl ethers for protection, of which the benzyl and trityl groups represent the most popular ethers [6]. The trityl moiety can be readily introduced even on a secondary alcohol under neutral conditions in presence of a hydrogen chloride scavenger like pyridine or triethylamine. In contrast, O-alkylation with a benzyl or diphenyl methyl group generally requires increased activity of the alcohol via deprotonation [7], or activation of the benzyl moiety as a trichloroacetimidate combined with acidic reaction conditions [8]. In some instances, robust protection is mandatory as with a benzyl moiety. The latter however requires hydrogenation conditions for its removal. An alternative protecting strategy therefore is warranted. Hence, we now want to report on metal-catalyzed conditions for protection and deprotection of nucleoside analogues using the diphenylmethyl (DPM) ether group.

Synthesis of DPM ethers using many different strategies has been previously reported, but this protecting group is not very common. As for most benzyl-type ethers, its introduction usually involves nucleophilic substitution of chloro- or bromodiphenylmethane using sodium hydride-generated alkoxides [9]. However, diphenylmethanol in the presence of either a Brønsted acid, Lewis acid, or supported acids likewise has been shown to form DPM ethers. Mechanistically the reaction occurs either via intimate ion-molecule pairs, via solvent separated ion-molecule pairs or via benzhydryl carbocations [10]. A few other methods can nevertheless be found in the literature. These include reagents such as diphenyl-methylphosphate–trifluoroacetic acid [11], diphenylmethyldiazomethane [12,13], or the use of orthoformates [14] at high temperature.

Many other strategies involve metal-catalysed reactions. Ishii, in 2003, reported the first use of Yb(OTf)₃, Sc(OTf)₃ and Hf(OTf)₃ as Lewis acids for the direct reaction of alcohols. Quite interestingly, Ishii found that phenylethanol is in equilibrium with its diether during the reaction with La(OTf)₃ as catalyst [15]. Pale and co-workers reported the use of palladium (II) chloride as a catalyst [16,17]. Later they reported CuBr₂ to be an even better catalyst [18]. Recently, an effective method for the allylation of heteroarenes has also been catalysed by PdCl₂ [19]. Baba and his co-workers reported the use of InCl₃ in the direct substitution of allylic alcohols, benzylic alcohols and benzhydrylic alcohols with nucleophiles. Mechanistic investigation showed that the ether was obtained by the action of In (III) salts [20]. Highly regioselective catalytic amination of Baylis-Hillman adduct with aromatic amines has been promoted by the Lewis acid In(OTf)₃ [21].

As for any benzyl-type ether, deprotection of DPM ethers is mostly achieved under hydrogenation conditions [22], but many other protocols have been reported, including acidolysis [23] and electrolytic reduction [24]. Our research focused on finding a simpler and environmentally acceptable procedure for protection and deprotection of DPM ethers specifically for nucleoside chemistry. We therefore adopted a strategy using transition metals as the catalyst with preference for Pd salts.

2. Results and Discussion

In search for the best catalyst, we allowed thymidine (1) at a scale of 100 mg to react with diphenylmethanol (DPM-OH) in dichloroethane (DCE) in presence of 0.2 equivalents (eq) of various metal salts. Initially, as the rate of reaction was too low at room temperature, we decided to heat the reaction to 85 °C. As shown in Scheme 1, we expected three different products, the mono- and di-O-protected thymidines 3a and 3b, and ether 4, resulting from dimerization of diphenylmethanol. However, using 2.5 eq of DPM-OH and following heating overnight, thymidine 1 was cleanly converted to its protected form 3b in 87% yield with only trace formation of the unwanted ether 4 (Table 1). Likewise formation of benzophenone was not observed. This result indicated that there is complex formation by coordination between the Pd catalyst and diphenylmethanol in which the Lewis acid character of the Pd-complex outbalances the β-elimination pathway (Scheme 2).

Scheme 1. Protection of both hydroxyl groups of thymidine as diphenylmethyl ether.

Scheme 1. Protection of both hydroxyl groups of thymidine as diphenylmethyl ether.

Table 1. Comparison of catalyst effectiveness for formation of bis-benzhydryl thymidine (3b).

Exp.	Catalyst	Recovered 1 (%)	Recovered 2 (%)	Yield 3b (%) a	Yield 4 (%)
1	PdCl2	-	6	87	Trace
2	NiCl2	95	94	2	-
3	CuCl2·2H2O	43	0	55 (24 h)	Trace
4	Pd(OAc)2	10	0	65	-
5	Ni(OAc)2	90	0	0	Trace
6	Cu(OAc)2	32	-	45	Trace

^a Reactions on 100 mg scale were run in refluxing DCE for 16 h with 0.2 eq of the metal catalyst and 2.5 eq of DPM-OH.

Table 1. Comparison of catalyst effectiveness for formation of bis-benzhydryl thymidine (3b).

Exp.	Catalyst	Recovered 1 (%)	Recovered 2 (%)	Yield 3b (%) a	Yield 4 (%)
1	PdCl2	-	6	87	Trace
2	NiCl2	95	94	2	-
3	CuCl2·2H2O	43	0	55 (24 h)	Trace
4	Pd(OAc)2	10	0	65	-
5	Ni(OAc)2	90	0	0	Trace
6	Cu(OAc)2	32	-	45	Trace

^a Reactions on 100 mg scale were run in refluxing DCE for 16 h with 0.2 eq of the metal catalyst and 2.5 eq of DPM-OH.

Scheme 2. Mechanism for diphenylmethyl ether protection.

Scheme 2. Mechanism for diphenylmethyl ether protection.

As we wanted to favor the Lewis acid pathway, we further evaluated catalysts which can form more acidic salt complexes, e.g., nickel being located in the same column as palladium in the Mendeleev periodic table. Unfortunately, when NiCl₂ was used we did not obtain the expected product, and even after 48 h 95% of the starting material was recovered. Reaction in presence of CuCl₂·2H₂O offered the desired product, albeit in low yield. This metal salt screening showed that PdCl₂ was the most effective catalyst for protection of both hydroxyl groups in 1 as their diphenylmethyl ethers, affording almost quantitative yields of the desired product (Table 1).

We also evaluated the effectiveness of metal-catalysed DPM protection in different solvents with thymidine as substrate. As expected, non-polar solvents like dichloroethane, being non-coordinating, proved to be the best and reactions looked very clean on TLC. Formation of diphenylmethanol dimer remained below 5%. On the other hand, polar solvents like DMF led to messy reactions in which the desired product could not be isolated (Table 2). Finally, when carried out on a 2 mmol scale in DCE, 70% of the desired 3b was isolated.

Table 2. Solvent influence on DPM ether formation at either 85 °C or boiling temperature.

Entry	Solvent	Time (h)	Yield 3b (%)
1	DCE	16	87
2	Acetonitrile	48	47
3	THF	48	42
4	Dioxane	16	Degradation
5	DMF	16	Degradation

Table 2. Solvent influence on DPM ether formation at either 85 °C or boiling temperature.

Entry	Solvent	Time (h)	Yield 3b (%)
1	DCE	16	87
2	Acetonitrile	48	47
3	THF	48	42
4	Dioxane	16	Degradation
5	DMF	16	Degradation

Having optimized the conditions for DPM protection for 1, we decided to evaluate this reaction for other nucleosides under similar conditions. Using 2.5 eq of DPM-OH, both 2′-deoxyuridine and 5-fluoro-2′-deoxyuridine reacted cleanly to afford the ethers 6b and 7b in 88% and 85% yield, respectively. Moreover selective protection of the 5′ primary alcohol proved feasible for 2′-deoxynucleosides using only 1.2 eq of DPM-OH with heating at 85 °C, and afforded around 65% for each of the mono-O-alkylated analogues 3a, 6a and 7a (Table 3) with likewise 67% yield for 3a on a 2 mmol scale. Only trace amounts of the bis-diphenylmethyl ether analogues were isolated. Unfortunately, reaction of the ribonucleosides uridine and 5-fluorouridine with 1.2 eq of DPM-OH only afforded a trace of the desired 5′-O-protected nucleoside (Table 3, experiments 7 and 10, respectively). Using 2.5 eq of DPM-OH on both uridine analogues, more than 80% of the bisalkylated derivatives were obtained as a mixture of the 2′,5′- and 3′,5′-O-alkylated conformers (Table 3, experiments 8 and 11, respectively). Finally, per-O-alkylation of ribonucleosides in about 80% yield proved feasible by increasing the incoming DPM-OH ratio to 3.7 eq. This proves much more difficult with the sterically more demanding trityl moieties [25]. Separation of both bis-diphenylmethyl ethers (2′,5′- and 3′,5′-derivative) was cumbersome, but was achieved by using appropriate solvent polarity during column chromatography. The correct position of the diphenylmethyl moiety was determined using 2D-NMR techniques (COSY, HSQC), with the 2′,5′-analogue proving slightly more lipophilic than the 3′,5′-analogue.

As reported before [17], the reaction is believed to occur via formation of the latter benzhydryl carbocation. As shown in Scheme 2, coordination of the hydroxyl oxygen atom to the mild Lewis acid Pd^II is highly likely. Following coordination, there may be transfer of the hydroxyl group to the palladium affording the benzhydryl carbocation.

As shown in Scheme 3, deprotection of synthesized 3′,5′-di-O-benzhydryl-thymidine 3b was successfully achieved by only changing solvent. Following heating of 3b in ethanol at 85 °C with catalytic PdCl₂ (0.2 eq) for 16 h, it was cleanly converted to thymidine.

Table 3. Synthesis of different benzhydryl protected nucleosides.

Entry	Substrate	Eq DPM-OH	Product	Yield (%)
1	thymidine	1.2	5′-O-benzhydryl-thymidine 3a	67
2		2.5	3′,5′-di-O-benzhydryl-thymidine 3b	87
3	2′-deoxyuridine	1.2	5′-O-benzhydryl-2′-deoxyuridine 6a	65
4		2.5	3′,5′-di-O-benzhydryl-2′-deoxyuridine 6b	88
5	5-fluoro-2′-deoxyuridine	1.2	5′-O-benzhydryl-5-fluoro-2′-deoxyuridine 7a	64
6		2.5	3′,5′-di-O-benzhydryl-5-fluoro-2′-deoxyuridine 7b	85
7	uridine	1.2	5′-O-benzhydryl-uridine 8a	Trace
8		2.5	2′,5′-di-O-benzhydryl-uridine 8b	54
			3′,5′-di-O-benzhydryl-uridine 8c	32
9		3.7	2′,3′,5′-tris-O-benzhydryl-uridine 8d	81
10	5-fluorouridine	1.2	5′-O-benzhydryl-5-fluorouridine 9a	Trace
11		2.5	2′,5′-di-O-benzhydryl-5-fluorouridine 9b	59
			3′,5′-di-O-benzhydryl-5-fluorouridine 9c	23
12		3.7	2′,3′,5′-tris-O-benzhydryl-5-fluorouridine 9d	79

Table 3. Synthesis of different benzhydryl protected nucleosides.

Entry	Substrate	Eq DPM-OH	Product	Yield (%)
1	thymidine	1.2	5′-O-benzhydryl-thymidine 3a	67
2		2.5	3′,5′-di-O-benzhydryl-thymidine 3b	87
3	2′-deoxyuridine	1.2	5′-O-benzhydryl-2′-deoxyuridine 6a	65
4		2.5	3′,5′-di-O-benzhydryl-2′-deoxyuridine 6b	88
5	5-fluoro-2′-deoxyuridine	1.2	5′-O-benzhydryl-5-fluoro-2′-deoxyuridine 7a	64
6		2.5	3′,5′-di-O-benzhydryl-5-fluoro-2′-deoxyuridine 7b	85
7	uridine	1.2	5′-O-benzhydryl-uridine 8a	Trace
8		2.5	2′,5′-di-O-benzhydryl-uridine 8b	54
			3′,5′-di-O-benzhydryl-uridine 8c	32
9		3.7	2′,3′,5′-tris-O-benzhydryl-uridine 8d	81
10	5-fluorouridine	1.2	5′-O-benzhydryl-5-fluorouridine 9a	Trace
11		2.5	2′,5′-di-O-benzhydryl-5-fluorouridine 9b	59
			3′,5′-di-O-benzhydryl-5-fluorouridine 9c	23
12		3.7	2′,3′,5′-tris-O-benzhydryl-5-fluorouridine 9d	79

The resulting byproduct ethoxydiphenylmethane 5 was also isolated and characterized by ¹H-NMR showing a singlet at 5.44δ, a quartet at 3.61δ and a triplet at 1.35δ. Deprotection was also attempted using CuBr₂ in catalytic amounts, but even after refluxing for 16 h, presence of the starting material was still observed along with some degraded material (Table 4). The use of CuBr₂ however has been reported before for clean cleavage of bis-(methoxyphenyl)methyl ether moieties [18]. The latter are much more prone to cleavage in agreement with the strongly reduced acid stability of dimethoxytrityl ether in comparison with trityl moieties.

Scheme 3. Deprotection of the DPM ether moiety in refluxing ethanol.

Scheme 3. Deprotection of the DPM ether moiety in refluxing ethanol.

Table 4. Deprotection of DPM ethers in ethanol at 85 °C.

Entry	Catalyst	Time (h)	Yield of 1 (%) a
1	PdCl2	16	85
2	CuBr2	16	43

^a Reaction on 100 mg scale in refluxing ethanol for 16 h with 0.2 eq of metal catalyst.

Table 4. Deprotection of DPM ethers in ethanol at 85 °C.

Entry	Catalyst	Time (h)	Yield of 1 (%) a
1	PdCl2	16	85
2	CuBr2	16	43

^a Reaction on 100 mg scale in refluxing ethanol for 16 h with 0.2 eq of metal catalyst.

As reported before [16], introduction of DPM ether is compatible with the presence of different protecting groups like acyl groups, silyl and benzyl ethers or ester moieties. In our hands, following overnight treatment of 3b with conc. ammonia:MeOH (1:1) or 2M NaOH:dioxane (1:1) no reaction was observed. The compounds likewise proved relatively stable in acidic conditions showing no reaction at RT in 80% acetic acid with overnight treatment, but starting to degrade after heating for 4 h at 80 °C. Finally, a 3% trichloroacetic acid solution in DCE afforded deprotection only after 15 h of reaction, with 50% benzhydryl cleavage after 6 h. Unfortunately, use of the DPM group seems limited to a small series of pyrimidine nucleosides. When evaluating cytidine, adenosine or guanosine nucleosides, the lack of solubility of the starting compounds prevented reaction in DCE while in more polar solvents, degradation was noticed with time. In an attempt to remediate the problem, prior persilylation with bis(trimethylsilyl)acetamide afforded soluble substrates for 2′-deoxycytidine and guanosine, but upon addition of DPM-OH and PdCl₂, rapid precipitation occurred and no alkylated nucleosides could be obtained. Finally, adding small amounts of polar solvents like NMP to improve the solubility in DCE prevented reaction as of likely complexation of the PdCl₂. In conclusion, straightforward introduction and ease of removal of the DPM ether on uridine analogues, promised to make a nice addition to the nucleosidic protecting group repertoire, but unfortunately, the lack of solubility of other nucleosides hampers its general use.

3. Experimental

3.1. General

Reagents and solvents were purchased from commercial suppliers (Acros, Sigma-Aldrich, Bachem, Novabiochem) and used as provided, unless indicated otherwise. All the solvents were of analytical grade and were stored over 4Å molecular sieves. Reactions were carried out in oven-dried glassware under a nitrogen atmosphere with stirring at 85 °C.

¹H and ¹³C-NMR spectra of the compounds dissolved in CDCl₃, MeOD or DMSO-d₆ were recorded on a Bruker UltraShield Avance 300 MHz or 600 MHz spectrometer. The chemical shifts are expressed as δ values in parts per million (ppm), using the residual solvent peaks (CDCl₃: ¹H, 7.26 ppm; ¹³C, 77.16 ppm; MeOD: ¹H, 3.31 ppm; ¹³C, 49.00 ppm) as a reference. Coupling constants are given in Hertz (Hz). The peak patterns are indicated by the following abbreviations: bs = broad singlet, d = doublet, m = multiplet, q = quadruplet, s = singlet and t = triplet. High resolution mass spectra were recorded on a quadrupole time-of-flight mass spectrometer (Q-Tof-2, Micromass, Manchester, UK) equipped with a standard ESI interface; samples were infused in 2-propanol/H2O (1:1) at 3 µL min⁻¹.

For TLC, precoated aluminium sheets were used (Merck, Silica gel 60 F254). The spots were visualized by UV light at 254 nm. Column chromatography was performed on ICN silica gel 60A° 40–60 µM.

3.2. General Procedure for Protection

To a solution of the respective nucleoside (100 mg) and diphenylmethanol in dichloroethane (5 mL/mmol) was added palladium chloride (0.2 eq). The reaction mixture was heated at 85 °C under an argon atmosphere for 16 h or until disappearance of the starting materials as monitored by TLC. The solvent was removed in vacuo and the crude mixture obtained was purified by column chromatography to afford the desired compound.

5′-O-Benzhydryl-thymidine (3a). White solid; TLC (DCM/MeOH 9:1): R_f = 0.70. ¹H-NMR (300 MHz, CDCl₃): δ 8.96 (bs, 1H, NH), 7.55 (s, 1H), 7.54–7.28 (m, 10H), 6.50–6.45 (m, 1H, H-1′), 5.44 (s, 1H, CH), 4.63 (s, 1H), 4.14–4.13 (m, 1H), 3.80–3.76 (m, 1H, H-5′/H-5′′), 3.68–3.63 (m, 1H, H-5′/H-5′′), 2.79 (bs, 1H, OH), 2.46–2.39 (m, 1H, H-2′/H-2′′), 2.36–2.27 (m, 1H, H-2′/H-2′′), 1.41 (s, 3H). ¹³C-NMR (75 MHz, CDCl₃) δ: 163.4, 150.2, 141.2, 141.0, 135.4, 128.4, 127.7, 127.5, 126.6, 126.0, 111.0, 85.8, 84.6, 84.5, 72.5, 68.8, 40.7, 11.4. HRMS calcd for C₂₃H₂₄N₂O₅ [M+Na]⁺: 431.1577; found:431.1576.

3′,5′-di-O-Benzhydryl-thymidine (3b). White solid; TLC (ethyl acetate/hexane 1:1): R_f = 0.70. ¹H-NMR (300 MHz, CDCl₃): δ 9.28 (bs, 1H, NH), 7.50 (s, 1H), 7.49–7.19 (m, 20H), 6.53–6.48 (m, 1H, H-1′), 5.47 (s, 1H, CH), 5.37 (s, 1H, CH), 4.43–4.39 (m, 1H), 4.33–4.30 (m, 1H), 3.77–3.72 (m, 1H, H-5′/H-5′′), 3.53–3.49 (m, 1H, H-5′/H-5′′), 2.62–2.54 (m, 1H, H-2′/H-2′′), 2.24–2.15 (m, 1H, H-2′/H-2′′), 1.42 (s, 3H). ¹³C-NMR (75 MHz, CDCl₃): δ 163.6, 150.2, 141.3, 141.2, 141.1, 141.0, 135.2, 128.4, 128.3, 128.3, 128.2, 127.6, 127.5, 127.5, 126.8, 126.7, 126.5, 126.1, 110.9, 84.8, 84.3, 83.8, 82.1, 77.2, 77.2 68.7, 38.3, 11.4. HRMS calcd for C₃₆H₃₄N₂O₅ [M+H]⁺: 575.2540; found: 575.2540.

5′-O-Benzhydryl-2′-deoxyuridine (6a). White solid; TLC (ethyl acetate/hexane 1:1): R_f = 0.30. ¹H-NMR (600 MHz, CDCl₃): δ 8.35 (bs, 1H, NH), 7.77 (d, 1H, J = 7.8 Hz), 7.36–7.26 (m, 10H), 6.39 (t, 1H, H-1′, J = 6.6 Hz), 5.39 (s, 1H, CH), 5.21–5.19 (m, 1H), 4.64–4.62 (m, 1H), 4.10 (s, 1H), 3.81–3.78 (m, 1H, H-5′/H-5′′), 3.72–3.70 (m, 1H, H-5′/H-5′′), 2.41–2.38 (m, 1H, H-2′/H-2′′), 2.29–2.24 (m, 1H, H-2′/H-2′′), 2.05 (d, 1H, OH, J = 3.6 Hz). ¹³C-NMR (150 MHz, CDCl₃): δ 162.7, 150.0, 141.2, 140.9, 140.3, 128.7, 128.7, 128.1, 128.0, 126.8, 126.7, 102.1, 86.0, 85.1, 85.0, 72.3, 68.9, 59.5, 41.3. HRMS calcd for C₂₂H₂₂N₂O₅ [M+Na]⁺: 417.1421; found: 417.1421.

3′,5′-di-O-Benzhydryl-2′-deoxyuridine (6b). White solid; TLC (ethyl acetate/hexane 1:1): R_f = 0.70. ¹H-NMR (600 MHz, CDCl₃): δ 8.32 (bs, 1H, NH), 7.70 (d, 1H, J =8.4 Hz), 7.36–7.18 (m, 20H), 6.41 (t, 1H, H-1′, J =6.3 Hz), 5.44 (s, 1H, CH), 5.31 (s, 1H, CH), 5.19–5.15 (m, 1H), 4.39–4.36 (m, 1H), 4.31–4.28 (m,1H), 3.77–3.73 (m, 1H, H-5′/H-5′′), 3.57–3.53 (m, 1H, H-5′/H-5′′), 2.56–2.50 (m, 1H, H-2′/H-2′′), 2.16–2.07 (m, 1H, H-2′/H-2′′). ¹³C-NMR (150 MHz, CDCl₃): δ 162.8, 150.0, 141.4, 141.3, 141.2, 140.8, 140.2, 128.7, 128.6, 128.5, 128.0, 127.9, 127.8, 127.1, 127.0, 126.7, 126.6, 102.1, 85.3, 84.9, 84.3, 82.4, 69.0, 38.8. HRMS calcd for C₃₅H₃₂N₂O₅ [M+H]⁺: 561.2383; found: 561.2377.

5′-O-Benzhydryl-5-fluoro-2′-deoxyuridine (7a). White solid; TLC (ethyl acetate/hexane 1:1): R_f = 0.20. ¹H-NMR (300 MHz, CDCl₃): δ 8.39 (bs, 1H, NH), 7.95 (d, 1H, J = 6.3 Hz), 7.37–7.28 (m, 10H), 6.40–6.35 (m, 1H, H-1′), 5.43(s, 1H, CH), 4.64–4.62 (m, 1H), 4.15–4.13 (m, 1H), 3.87–3.82 (m, 1H, H-5′/H-5′′), 3.70–3.66 (m, 1H, H-5′/H-5′′), 2.48–2.40 (m, 1H, H-2′/H-2′′), 2.31–2.22 (m, 1H, H-2′/H-2′′), 1.95 (bs, 1H, OH). ¹³C-NMR (75 MHz, CDCl₃): δ 156.6, 156.4, 148.5, 141.2, 141.0, 140.8, 139.6, 128.8, 128.1, 128.0, 126.8, 126.6, 124.3, 124.1, 86.3, 85.6, 85.3, 72.6, 69.0, 41.3. HRMS calcd for C₂₂H₂₁FN₂O₅ [M+Na]⁺: 435.1327; found: 435.1328.

3′,5′-di-O-Benzhydryl-5-fluoro-2′-deoxyuridine (7b). White solid; TLC (ethyl acetate/hexane 1:1): R_f = 0.70. ¹H-NMR (600 MHz, CDCl₃): δ 8.42 (bs, 1H, NH), 7.86 (d, 1H, J= 6Hz), 7.34–7.15 (m, 20H), 6.37–6.34 (m, 1H, H-1′), 5.40(s, 1H, CH), 5.29 (s, 1H, CH), 4.33–4.28 (m, 2H), 3.75–3.73 (m, 1H, H-5′/H-5′′), 3.48–3.46 (m, 1H, H-5′/H-5′′), 2.56–2.52 (m, 1H, H-2′/H-2′′), 2.09–2.04 (m, 1H, H-2′/H-2′′). ¹³C-NMR (150 MHz, CDCl₃): δ 156.6, 156.4, 141.4, 141.3, 141.2, 140.9, 139.6, 128.7, 128.6, 128.5, 128.5, 128.0, 127.9, 127.8, 127.1, 127.0, 124.3, 124.1, 85.8, 85.1, 84.5, 82.5, 76.8, 69.0, 38.7. HRMS calcd for C₃₅H₃₁FN₂O₅ [M+Na]⁺: 601.2109; found: 601.2098.

2′,5′-di-O-Benzhydryl-uridine (8b). White solid; TLC (ethyl acetate/hexane 1:1): R_f = 0.60. ¹H-NMR (600 MHz, CDCl₃): δ 8.78 (bs, 1H, NH), 7.65 (d, 1H, J = 8.2 Hz), 7.37–7.19 (m, 20H), 6.22 (d, 1H, H-1′, J = 4.2 Hz), 5.80 (s, 1H, CH), 5.37 (s, 1H, CH), 4.93–4.91 (m, 1H), 4.37–4.34 (m, 1H), 4.23–4.21 (m, 1H), 4.15 (t, 1H, J = 4.8 Hz), 3.85–3.83 (m, 1H, H-5′/H-5′′), 3.71–3.69 (m, 1H, H-5′/H-5′′), 2.75 (d, 1H, OH, J = 6 Hz). ¹³C-NMR (150 MHz, CDCl₃): δ 162.7, 149.9, 140.9, 140.6, 140.4, 139.9, 139.6, 128.5, 128.4, 128.3, 127.9, 127.7, 126.9, 126.6, 126.6, 126.4, 101.7, 86.6, 84.8, 83.7, 82.6, 79.5, 69.2, 67.7. HRMS calcd for C₃₅H₃₂N₂O₆ [M+H]⁺: 577.2333; found : 577.2336.

3′,5′-ditri-O-Benzhydryl-uridine (8c). White solid; TLC (ethyl acetate/hexane 1:1): R_f = 0.40. ¹H-NMR (600 MHz, CDCl₃): δ 8.39 (bs, 1H, NH), 7.63 (d, 1H, J = 8.2 Hz), 7.39–7.17 (m, 20H), 6.02 (d, 1H, H-1′, J = 4.2 Hz), 5.52 (s, 1H, CH), 5.26 (s, 1H, CH), 5.13–5.11 (m, 1H), 4.27–4.25 (m, 2H), 4.20–4.17 (m, 1H), 3.72–3.70 (m, 1H, H-5′/H-5′′), 3.41–3.39 (m, 1H, H-5′/H-5′′), 2.95 (d, 1H, OH, J = 7.2 Hz). ¹³C-NMR (150 MHz, CDCl₃): δ 162.4, 150.0, 140.7, 140.4, 140.2, 139.7, 128.5, 128.4, 128.3, 127.9, 127.9, 127.8, 127.6, 126.8, 126.6, 126.4, 126.3, 101.9, 89.0, 84.6, 83.6, 81.5, 75.9, 74.0, 67.8. HRMS calcd for C₃₅H₃₂N₂O₆ [M+H]⁺: 577.2333; found: 577.2330.

2′,3′,5′-tri-O-Benzhydryl-uridine (8d): White solid; TLC (ethyl acetate/hexane 1:1): R_f = 0.80. ¹H-NMR (600 MHz, CDCl₃): δ 8.63 (bs, 1H, NH), 7.63 (d, 1H, J = 8.4 Hz), 7.27–7.03 (m, 30H), 6.23 (d, 1H, H-1′, J = 3 Hz), 5.75(s, 1H, CH), 5.25 (s, 1H, CH), 5.21 (s, 1H, CH), 4.78–4.76 (m, 1H), 4.46 (d, 1H, J = 6 Hz), 4.14 (t, 1H, J = 5.4 Hz), 4.06–4.04 (m, 1H), 3.78–3.76 (m, 1H, H-5′/H-5′′), 3.56–3.54 (m, 1H, H-5′/H-5′′). ¹³C-NMR (150 MHz, CDCl₃): δ 162.5, 149.5, 141.3, 140.7, 140.6, 140.5, 139.6, 128.5, 128.4, 128.3, 128.2, 128.1, 128.0, 127.9, 127.7, 127.6, 127.6, 127.5, 127.4, 127.3, 127.2, 127.1, 126.5, 126.4, 126.4, 126.3, 101.3, 87.4, 84.5, 81.8, 81.8, 77.7, 72.4, 67.0. HRMS calcd for C₄₈H₄₂N₂O₆ [M+H]⁺: 743.3115; found: 743.3107.

2′,5′-di-O-Benzhydryl-5-fluorouridine (9b). White solid; TLC (ethyl acetate/hexane 1:1): R_f = 0.60. ¹H-NMR (600 MHz, CDCl₃): δ 8.61 (bs, 1H, NH), 7.68 (d, 1H, J = 12.6 Hz), 7.36–7.22 (m, 20H), 6.21–6.20 (m, 1H, H-1′), 5.67 (s, 1H, CH), 5.38 (s, 1H, CH), 4.33–4.31 (m, 1H), 4.24–4.22 (m, 1H), 4.17–4.15 (m, 1H), 3.86–3.83 (m, 1H, H-5′/H-5′′), 3.65–3.62 (m, 1H, H-5′/H-5′′), 2.75 (d, 1H, OH, J = 5.4 Hz). ¹³C-NMR (150 MHz, CDCl₃): δ 148.6, 140.9, 140.6, 140.4, 140.3, 139.9, 139.0, 128.5, 128.4, 128.3, 127.9, 127.7, 126.8, 126.6, 126.5, 126.3, 123.5, 123.3, 86.6, 85.2, 83.9, 83.2, 79.4, 69.5, 68.1. HRMS calcd for C₃₅H₃₁FN₂O₆ [M+Na]⁺: 617.2058; found: 617.2062.

3′,5′-ditri-O-Benzhydryl-5-fluorouridine (9c): White solid; TLC (ethyl acetate/hexane 1:1): R_f = 0.40. ¹H-NMR (600 MHz, CDCl₃): δ 8.38 (bs, 1H, NH), 7.78 (d, 1H, J = 7.2 Hz), 7.36–7.16 (m, 20H), 6.02–6.00 (m, 1H, H-1′), 5.50 (s, 1H, CH), 5.27 (s, 1H, CH), 4.25–4.23 (m, 2H), 4.20–4.17 (m, 1H), 3.73–3.70 (m, 1H, H-5′/H-5′′), 3.32–3.30 (m, 1H, H-5′/H-5′′), 2.94 (d, 1H, OH, J = 9.6 Hz). ¹³C-NMR (150 MHz, CDCl₃): δ 156.2, 155.9, 148.5, 141.2, 140.4, 140.3, 140.1, 139.3, 128.5, 128.4, 128.3, 128.0, 127.9, 127.8, 127.6, 126.8, 126.6, 126.5, 126.4, 123.8, 123.5, 89.0, 84.8, 83.8, 81.9, 76.3, 74.1, 67.9. HRMS calcd for C₃₅H₃₁FN₂O₆ [M+Na]⁺: 617.2058; found: 617.2061.

2′,3′,5′-tri-O-Benzhydryl-5-fluorouridine (9d). White solid; TLC (ethyl acetate/hexane 1:1): R_f = 0.80. ¹H-NMR (600 MHz, CDCl₃): δ 8.55 (d, 1H, NH, J = 5.4 Hz), 7.64 (d, 1H, J = 7.2 Hz), 7.37–7.06 (m, 30H), 6.23 (m, 1H, H-1′), 5.60 (s, 1H, CH), 5.34 (s, 1H, CH), 5.23 (s, 1H, CH), 4.43–4.41 (m, 1H), 4.16–4.13 (m, 1H), 4.08–4.05 (m, 1H), 3.79–3.76 (m, 1H, H-5′/H-5′′), 3.46–3.44 (m, 1H, H-5′/H-5′′). ¹³C-NMR (150 MHz, CDCl₃): δ 156.7, 148.6, 141.5, 141.1, 141.0, 140.9, 140.8, 140.6, 139.1, 128.6, 128.5, 128.4, 128.3, 128.0, 127.9, 127.8, 127.7, 127.5, 127.3, 127.2, 127.0, 126.9, 126.8, 126.7, 123.8, 123.5, 87.4, 85.1, 82.7, 82.5, 82.4, 78.3, 73.2.4, 67.9. HRMS calcd for C₄₈H₄₁FN₂O₆ [M+H]⁺: 761.3021; found: 761.3037.

3.3. General Procedure for Deprotection

To a solution of 3′,5′-di-O-benzhydryl-thymidine 3b (100 mg) in ethanol (5 mL/mmol) was added palladium chloride (0.2 eq). The reaction mixture was heated at 85 °C for 16 h until disappearance of the starting material monitoring by TLC. The solvent was removed in vacuo and the crude mixture obtained was purified by column chromatography affording compound 5 and recovered 1 in 85% yield.

Ethoxydiphenylmethane (5). White solid; TLC (ethyl acetate/hexane 1:1): R_f = 0.90. ¹H-NMR (300 MHz, CDCl₃): δ 7.46–7.28 (m, 10H), 5.44 (s,1H), 3.61 (q, 2H, J =6.9 Hz), 1.35 (t, 3H, J =6.9 Hz). ¹³C-NMR (75 MHz, CDCl₃): δ 142.3, 128.1, 127.1, 126.7, 83.2, 64.3, 15.1.

Recovered Thymidine (1). White solid; TLC (DCM/MeOH 9:1): R_f = 0.40. ¹H-NMR (300 MHz, CD₃OD): δ 7.2 (bs, 1H, NH), 6.29 (t, 1H, H-1′, J = 6.6 Hz), 4.43–4.39 (m, 1H), 3.94–3.90 (m, 1H), 3.84–3.71 (m, 2H), 2.27–2.22 (m, 2H), 1.89 (s, 3H, CH₃). ¹³C-NMR (75 MHz, CD₃OD): δ 164.7, 150.6, 136.5, 109.8, 87.1, 84.5, 70.5, 61.1, 39.5, 10.7.

4. Conclusions

A convenient and effective method for the protection of hydroxyl groups of nucleosides as the corresponding diphenylmethyl ether has been developed with the aid of a transition metal catalyst. In addition, only by changing the solvent, the corresponding diphenylmethyl ethers can be deprotected under similar conditions using palladium (II) chloride as catalyst. With both protection and deprotection reactions proceeding under mild conditions and with nice selectivity, this high yielding strategy can be useful for the synthesis of complex nucleosides and nucleotides.