Preparation of 4′-benzenesulfonyl-3′-deoxythymidine and its reaction with organoaluminum and organosilicon reagents

Carbohydrate Research 345 (2010) 2616–2622

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Preparation of 40 -benzenesulfonyl-30 -deoxythymidine and its reaction with organoaluminum and organosilicon reagents Hisashi Shimada, Satoshi Kikuchi, Kazuhiro Haraguchi, Hiromichi Tanaka ⇑ School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan

a r t i c l e

i n f o

Article history: Received 29 June 2010 Received in revised form 2 September 2010 Accepted 9 September 2010 Available online 17 September 2010

a b s t r a c t The 40 -benzenesulfonyl derivative of 30 -deoxythymidine was prepared from 30 -deoxythymidine-50 -aldehyde. The 40 -benzenesulfonyl leaving group undergoes a nucleophilic substitution with organoaluminum and organosilicon reagents to furnish a variety of 40 -substituted (Me, Et, i-Bu, trimethylsilylethynyl, CH2CH@CH2, CN, N3) analogues. Ó 2010 Elsevier Ltd. All rights reserved.

Keywords: Benzenesulfonyl-leaving group Nucleophilic substitution Organoaluminum reagent Organosilicon reagent 40 -Substituted 30 -deoxythymidine

1. Introduction

2. Results and discussion

Our recent research interest has been focused on the synthesis of 4 -substituted nucleosides. Two approaches to this class of nucleosides have so far been developed. One is ring-opening of 40 ,50 - or 30 ,40 -epoxysugar nucleosides with organoaluminum or organosilicon reagents,1,2 and the other is nucleophilic substitution of 40 -benzoyloxy3,4 or 40 -benzenesulfonyl5 nucleosides with these reagents. Typical examples for the latter approach carried out in Ref. 5 are shown in Scheme 1. The benzenesulfonyl leaving group at the 40 -position of the thymidine derivative 1 underwent a high yield substitution reaction with complete retention of configuration by reacting with AlMe3 to give 40 -methylthymidine (3). Preparation of 40 -allylthymidine (4) by reacting the a-L-threo-isomer 2 with Me3SiCH2CH@CH2 requires the presence of MeAlCl2 or SnCl4, which acts first as a chlorinating reagent of the 40 -position of 2 and then as a Lewis acid to encourage nucleophilic attack of the silicon reagent. To examine the scope of these substitution reactions, we intended to employ the 40 -benzenesulfonyl derivative of 30 -deoxythymidine as a substrate, to complement published reports for the synthesis of such derivatives: the 40 -cyano,6 40 -azido and 40 -methoxy,7 40 -methyl,8 and 40 -ethynyl9 analogues.

2.1. Preparation of the 40 -benzenesulfonyl derivatives 10D and 10L

0

⇑ Corresponding author. Tel.: +81 3 3784 8186; fax: +81 3 3784 8252. E-mail address: [email protected] (H. Tanaka). 0008-6215/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.carres.2010.09.009

Preparation of the 40 -benzenesulfonyl derivative of 30 -deoxythymidine requires introduction of a benzenesulfenyl group at the 40 -position, which was examined as reported previously5 by reacting the 50 -aldehyde (5)10 with N-(benzenesulfenyl)succinimide in CH2Cl2 in the presence of Et3N. Compound 5 was prepared by oxidation of 30 -deoxythymidine11 with IBX (2-iodoxybenzoic acid).12 Quite different from the previous 40 -sulfenylation of thymidine50 -aldehyde,5 use of Et3N (6 equiv) in the reaction between 5 and N-(benzenesulfenyl)succinimide (2 equiv) in CH2Cl2 (rt, overnight) resulted in only 19% yield of the product (7D/7L = 1:2). Since the aldehyde 5 has the 30 -deoxy structure, it is probable that the H-40 is less acidic than that of thymidine-50 -aldehyde having a 30 -silyloxy substituent. When a secondary amine such as pyrrolidine or Et2NH was present instead of Et3N (in CH3CN, at 50 °C, for 15 min), a higher yield of 7D/7L was obtained (69–72%, 7D/ 7L = 1:2) even with the use of 0.5 equiv of the respective amine. This result suggests that the enamine intermediate 6 is involved in this reaction as depicted in Scheme 2. In fact, when a mixture of 5 and pyrrolidine was heated at 50 °C in CH3CN for 15 min, the 13C NMR spectrum of the evaporated reaction mixture measured in CDCl3 showed the C-50 and C-40 resonances at d 110.75 and d 134.87, respectively, which are consistent with the reported chemical shifts for a uridine-40 ,50 -enamine.13

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O

Me X

Me

NH N

O

O

TBDMSO

AlMe3 for 1 Me3SiCH2CH=CH2/MeAlCl2 for 2

Y

O

O NH O

N

R TBDMSO

TBDMSO 1 X = CH2OTBDMS, Y = SO2Ph

3 R = Me (93% from 1, exclusively)

2 X = SO2Ph, Y = CH2OTBDMS

4 R = allyl (94% from 2, dr 20/1)

Scheme 1. Reaction of 1 with AlMe3 and that of 2 with Me3SiCH2CH@CH2/MeAlCl2.

O

Me H

O

O

N

O

O

Me

NH R2 N

R 2 NH

O NH

O

N

O NH

N SPh

O O

CH3CN, 50 ºC 5

Me X

O

N

O

Y 7 D X = CHO, Y = SPh

6

7 L X = SPh, Y = CHO

Scheme 2. Benzenesulfenylation of 5 by way of the 40 ,50 -enamine intermediate (6).

any precaution. Also, it was found that, in addition to 10D/10L, the reaction mixture contained one product which was assumed to be the aldehyde 11 (Scheme 3) based on its 1H NMR data.14 In this case, we assume that the water contaminating commercial m-CPBA attacks the 40 -position of the protonated 10D/10L to form the incipient 40 -hydroxyl derivative which spontaneously decomposes to give thymine and 11 as shown in Scheme 3.

Compound 7D/7L was treated with NaBH4 to give the alcohol 8D/ 8L (97%, Fig. 1). The hydroxyl group of 8D/8L was then protected with the tert-butyldimethylsilyl (TBDMS) group to give 9D/9L (96%, Fig. 1). The 40 -benzenesulfonyl derivative 10D/10L ( Fig. 1), to be used as a substrate for the reaction with organoaluminum and organosilicon reagents, was prepared in 97% yield by oxidation of 9D/9L with m-CPBA in CH2Cl2. HPLC separation of 10D/10L allowed the isolation of the b-D-isomer 10D and the a-L-isomer 10L. It is worth noting that, to obtain a high yield of 10D/10L, the oxidation of 9D/9L has to be carried out at 30 °C by adding a solution of m-CPBA (2.2 equiv) in CH2Cl2. When the oxidation was carried out at 0 °C by adding m-CPBA in one portion directly to a solution of 9D/9L, an immediate turbidity appeared due to the formation of thymine, which contrasts to the fact that preparation of 1 or 2 (Scheme 1) through m-CPBA oxidation of the corresponding 40 SPh derivative can be performed in CH2Cl2 (0 °C to rt) without

X

NH

O

Our previous studies carried out on the reaction of AlR3 with 40 -benzoyloxy or 40 -benzenesulfonyl derivatives of nucleosides have shown that these substitution reactions, when performed in a nonpolar solvent such as CH2Cl2 or CCl4, proceed mostly with retention of configuration due to the formation of a tight ion pair (SNi mechanism).4b As a matter of course, reaction of the 40 -benzenesulfonyl-30 -deoxythymidine (10D/10L) with AlMe3 follows the above stereochemical trend as shown in Scheme 4. Thus, reaction of the b-D-isomer 10D with AlMe3 (8 equiv) in CH2Cl2 at 0 °C gave exclusively the 40 -methyl derivative 12D resulting from retention of the 40 -configuration. Under the same conditions, reaction of the a-L-isomer 10L also showed a preponderant formation of the retention product 12L, but a significant amount of the inversion product 12D was also formed (12D/12L = 1:2.8). In the reaction of 10L, one would readily interpret the observed decrease of the retention pathway as a consequence of the steric influence of the base moiety. Namely, for the aluminate ([Me3AlOSOPh]) formed from 10L, it may be rather uncomfortable to

8D X = CH2OH, Y = SPh

O

Me

2.2. Reaction of 10D and 10L with organoaluminum reagents

N

O

8L X = SPh, Y = CH2OH 9 D X = CH2OTBDMS, Y = SPh 9 L X = SPh, Y = CH2OTBDMS 10D X = CH2OTBDMS, Y = SO2Ph

Y

10L X = SO2Ph, Y= CH2OTBDMS Figure 1. Structures of 8D, 8L, 9D, 9L, 10D, and 10L.

Me TBDMSO HO+ S Ph O

O

O

Me

NH N

O

TBDMSO H2O

O

O NH N

O

O TBDMS O CH2 C CH2CH2CHO

H O PhSO2 H

thymine

Scheme 3. A possible mechanism for the formation of 11 from the protonated 10D/10L.

11

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O

Me TBDMSO

NH O

N

O

O

Me

S O

AlMe3/CH2Cl2/0 ºC

X

81% yield exclusively 12D

Y

10D

O

O NH N

O

O

Me

AlMe3/CH2Cl2/0 ºC 67% yield 12D/12L = 1/2.8

O

NH

O

S

O

O

N

TBDMSO 10L

12D X = CH2OTBDMS, Y = Me 12L X = Me, Y = CH2OTBDMS Scheme 4. Reactions of 10D and 10L with AlMe3.

In contrast, the reaction of EtAl(C„CSiMe3)2 with 10D gave a complex mixture of products, consisting of the 40 -ethynyl-b-D-isomer 16D and its a-L-isomer 16L (combined yield of 16D plus 16L, 62%; 16D/16L = 3:1), the 40 -ethyl-b-D-isomer 13D and its a-L-isomer 13L (combined yield of 13D plus 13L, 16%; 13D/13L = 7:1), and the elimination products 1716 (8%) and 1817 (trace amount, consisting of two isomers). The yields and ratios were calculated based on 1H NMR spectroscopic analysis of the above mixture by integrating the respective H-6: d 7.06 and 7.11 for 18, d 7.14 for 17, d 7.24 for 13L, d 7.51 for 16D, d 7.63 for 13D, and d 7.68 for 16L. At the present time, it is not clear why the reaction with this particular aluminum reagent proceeded with considerable inversion pathway.

remain on the side it departed (b-face of the furanose ring) due to the presence of the thymine base. It is conceivable, therefore that there is a shift from the initially formed tight ion pair to a loose ion pair, which lowers the extent of the retention pathway. Such an equilibrium shift would be temperature-dependent and this is clearly seen in Table 1, the data of which were obtained from reaction of 10D or 10L with AlMe3 at various reaction temperatures. The results in Scheme 4 are included as entries 3 and 8. Both substrates (10D and 10L) follow the same stereochemical trend that the lower the reaction temperature, the higher the degree of retention of configuration. However, it is apparent that the ion pair derived from 10D is much tighter than that from 10L. As shown in entry 5, even at the refluxing temperature of CH2Cl2, 10D maintained a high degree of retention. Reactions of the 40 -benzenesulfonyl-b-D-substrate 10D with AlEt3, Al(i-Bu)3, and EtAl(C„CSiMe3)2 (ca. 8 equiv each) were also examined in CH2Cl2 at 0 °C, and structures of products are shown in Figure 2. Like the reaction of AlMe3 described above, AlEt3 gave exclusively the 40 -ethyl-b-D-isomer 13D in 72% yield. Similarly, Al(i-Bu)3 gave the retention product 14D (40%) together with 15D15 (34%) resulting from hydride transfer.

2.3. Reaction of 10D/10L with organosilicon reagents Our previous studies have shown that 40 ,50 -epoxy,1a 40 -benzoyloxy,3 and 40 -benzenesulfonyl5 nucleosides undergo nucleophilic attack of organosilicon reagents in the presence of MeAlCl2 or SnCl4. One example5 is shown in Scheme 1. These Lewis acids first serve to introduce a chlorine atom to the 40 -position to give the corresponding 40 -chloro intermediate, and then encourage its nucleophilic substitution with organosilicon reagents. By using the 40 -benzenesulfonyl derivative 10D/10L and SnCl4, reaction with organosilicon reagents was briefly examined, and structures of products are shown in Figure 3. When 10D/10L (10D/10L = 1.0:1.1) was reacted with CH2@CHCH2SiMe3 (10 equiv) in the presence of SnCl4 (4 equiv) in CH2Cl2 at 30 °C for 1 h, the 40 -allyl derivative 19D/19L was obtained in 89% yield with high selectivity for the b-D-isomer (19D/ 19L = 50:1). The depicted stereochemistry of the major product (19D) was determined by NOE experiments: H-50 b/H-6 (2.1%) and H-10 /CH2CH@CH2 (0.6%). In contrast to this, reaction of 10D/10L with Me3SiCN under similar reaction conditions gave the 40 -cyano derivative 20D/20L (81%) with much lower b-D-selectivity (20D/20L = 2:1). Since the separate use of 10D or 10L in this reaction gave similar stereoselectivity

Table 1 Reaction of 10D and 10L with AlMe3 in CH2Cl2 by varying the reaction temperaturea

a b

Entry

Substrate

Temp

Time (h)

Isolated yield (%)

Ratio of 12D/12Lb

1 2 3 4 5 6 7 8 9 10

10D 10D 10D 10D 10D 10L 10L 10L 10L 10L

78 °C 30 °C 0 °C rt Reflux 78 °C 30 °C 0 °C rt Reflux

4.5 1.0 0.5 0.5 0.5 6.0 1.0 0.5 0.5 0.5

82 84 81 61 78 78 76 67 71 78

12D only 12D only 12D only 36:1 14:1 1:7.5 1:3.5 1:2.8 1:2.6 1:1.5

All reactions were carried out by using 8 equiv of AlMe3. The ratio was determined by 1H NMR spectroscopy.

Me TBDMS.O

O

O

Me

NH N

R

O

R

O

O

Me

NH N

O

TBDMS.O

O

O

Me

NH N

O

TBDMS.O

O

TBDMS.O

13D R = Et

13L R = Et

14D R = i-Bu

16L R = C C.SiMe3

17

15D R = H 16D R = C C.SiMe3 Figure 2. Structures of 13D, 13L, 14D, 15D, 16D, 16L, 17, and 18.

18

O NH N

O

H. Shimada et al. / Carbohydrate Research 345 (2010) 2616–2622

19D X = CH2OTBDMS, Y = CH2CH=CH2 Me X

O

O

19L X = CH CH=CH , Y = CH2OTBDMS NH

N

O

2

2

20D X = CH2OTBDMS, Y= CN 20L X = CN, Y = CH2OTBDMS 21D X = CH2OTBDMS, Y = N3

Y

21L X = N3, Y = CH2OTBDMS Figure 3. Structures of 19D, 19L, 20D, 20L, 21D, and 21L.

outcomes [20D/20L = 2:1, 80% yield from 10D; 20D/20L = 1.8:1.0, 91% yield from 10L], there could be a common 40 -chlorinated intermediate involved in both reactions. However, attempted isolation of the supposed 40 -chloro derivative failed, presumably due to the 30 -deoxy structure. The reaction with Me3SiN3 also gave poor stereoselectivity: 21D/21L = 1.9:1.0, combined yield 86%. We are currently investigating why such a big discrepancy was observed in stereoselectivity between the reaction of 10D/10L with CH2@CHCH2SiMe3 and with Me3SiCN (or Me3SiN3). 3. Experimental section 3.1. General 1

H and 13C NMR spectra were recorded either at 400 MHz (JNMGX 400) or at 500 MHz (JNM-LA 500). Chemical shifts are reported relative to Me4Si. Of the two protons at the 20 -, 30 -, and 50 -positions, the one that appears at a higher field is designated like H-20 a, and the other like H-20 b. Mass spectra (MS) and high resolution MS (HRMS) were taken in FAB mode with m-nitrobenzyl alcohol as a matrix on a JNS-SX 102A. UV spectra were measured on a JASCO Ubest-55 spectrophotometer. Column chromatography was carried out on silica gel (Micro Bead Silica Gel PSQ 100B, Fuji Silysia Chemical Ltd). Thin-layer chromatography (TLC) was performed on silica gel (precoated Silica Gel plate F254, Merck). High performance liquid chromatography (HPLC) was carried out on a Shimadzu LC-6AD with a Shim-pack PREP-SIL (H) KIT column (2  25 cm). 3.2. 30 -Deoxythymidine-50 -aldehyde (5) A mixture of 30 -deoxythymidine (1.00 g, 4.42 mmol) and IBX (1.49 g, 5.3 mmol) in CH3CN (15 mL) was refluxed with vigorous stirring for 1 h. The reaction mixture was filtered through a Celite pad. The filtrate was evaporated and the resulting residue was purified by column chromatography (CH2Cl2/acetone = 5:1) to give 5 (960 mg, ca. 97%, foam), which was contaminated with some impurity: 1H NMR (DMSO-d6) d 1.71–2.02 and 2.12–2.32 (4H, each as m, H-20 and H-30 ), 1.78 (3H, d, J = 1.0 Hz, 5-Me), 4.50 (1H, dd, J = 6.1 and 8.3 Hz, H-40 ), 6.07 (1H, t, J = 6.1 Hz, H-10 ), 7.66 (1H, d, J = 1.0 Hz, H-6), 9.65 (1H, d, J = 0.7 Hz, CHO), 11.32 (1H, br, NH); 13 C NMR (DMSO-d6) d 12.38, 25.90, 29.54, 83.14, 86.85, 109.59, 136.79, 150.63, 163.97, 202.45; FAB-MS (m/z) 225 (M++H). FABHRMS (m/z) calcd for C10H12N2O4: 224.080, found: 225.088 (M++H). 3.3. 40 -Benzenesulfenyl-30 -deoxythymidine-50 -aldehyde (7D) and its 40 -epimer (7L) A mixture of 5 (251 mg, 1.12 mmol) and N-(benzenesulfenyl)succinimide (466 mg, 2.24 mmol) in CH3CN (10 mL) was stirred for 5 min at 50 °C under positive pressure of dry Ar. To the resulting solution was added Et2NH (0.06 mL, 0.56 mmol), and stirring was continued for further 30 min at 50 °C. The reaction

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mixture was partitioned between EtOAc and saturated aqueous NH4Cl. The organic layer separated was washed with saturated aqueous NaHCO3. Column chromatography (hexane/EtOAc = 1:1) of the organic layer gave 7D/7L (286 mg, 72%, 7D/7L = 1:2). HPLC separation (hexane/EtOAc = 1:2) gave 7D (tR 10.7 min, foam) and 7L (tR 11.5 min, foam). 3.3.1. Data for 7D 1 H NMR (CDCl3) d 1.92 (3H, d, J = 1.2 Hz, 5-Me), 1.94–2.00 (1H, m, H-20 a), 2.20–2.29 (1H, m, H-30 a), 2.54–2.67 (2H, m, H-20 b and H30 b), 6.55 (1H, dd, J = 6.1 and 6.6 Hz, H-10 ), 7.30–7.39 and 7.51–7.53 (5H, each as m, Ph), 7.36 (1H, d, J = 1.2 Hz, H-6), 8.99 (1H, br, NH), 9.38 (1H, s, CHO); NOE experiments H-10 /SPh (2.7%); 13C NMR (CDCl3) d 12.64, 30.11, 31.79, 86.39, 96.05, 111.73, 128.42, 129.19, 129.58, 135.19, 135.25, 150.20, 163.50, 191.39; FAB-MS (m/z) 333 (M++H). FAB-HRMS (m/z) calcd for C16H16N2O4S: 332.083, found: 333.094 (M++H). 3.3.2. Data for 7L 1 H NMR (CDCl3) d 1.92 (3H, d, J = 1.2 Hz, 5-Me), 2.23–2.33 (2H, m, H-20 a and H-30 a), 2.42–2.48 (1H, m, H-20 b), 2.55–2.59 (1H, m, H30 b), 6.45 (1H, t, J = 5.7 Hz, H-10 ), 7.32–7.38 and 7.50–7.53 (5H, each as m, Ph), 7.80 (1H, d, J = 1.2 Hz, H-6), 8.30 (1H, br, NH), 9.31 (1H, s, CHO); NOE experiments H-10 /CHO (0.5%); 13C NMR (CDCl3) d 12.71, 30.87, 31.32, 88.62, 96.65, 111.44, 128.21, 129.40, 129.63, 134.43, 135.89, 150.10, 163.49, 191.77; FAB-MS (m/z) 333 (M++H). FAB-HRMS (m/z) calcd for C16H16N2O4S: 332.083, found: 333.094 (M++H). 3.4. 40 -Benzenesulfenyl-30 -deoxythymidine (8D) and its 40 -epimer (8L) A solution of 7D/7L (310 mg, 0.90 mmol, 7D/7L = 1:2) in MeOH (30 mL) was treated with NaBH4 (100 mg, 2.6 mmol) at rt for 0.5 h. After evaporation of the solvent, the reaction mixture was partitioned between EtOAc and saturated aqueous NH4Cl. Column chromatography (2% MeOH in CH2Cl2) of the organic layer gave 8D/ 8L (300 mg, 97%, 8D/8L = 1:2). HPLC separation (3% MeOH in CHCl3) gave 8D (tR 10.7 min, foam) and 8L (tR 12.8 min, foam). 3.4.1. Data for 8D UV (MeOH) kmax 262.5 nm (e 12,400), kmin 236.5 nm (e 4300); 1 H NMR (CDCl3) d 1.87 (3H, d, J = 1.2 Hz, 5-Me), 2.04–2.17 and 2.64–2.80 (4H, each as m, H-20 and H-30 ), 2.57 (1H, br, OH), 3.74 (2H, s, H-50 ), 6.51 (1H, dd, J = 4.6 and 7.3 Hz, H-10 ), 7.27 (1H, d, J = 1.2 Hz, H-6), 7.33–7.38 and 7.54–7.57 (5H, each as m, Ph), 8.39 (1H, br, NH); 13C NMR (CDCl3) d 12.38, 30.86, 32.08, 65.18, 85.85, 96.50, 111.25, 128.94, 129.16, 130.04, 136.27, 136.49, 150.07, 163.84; FAB-MS (m/z) 335 (M++H). Anal. Calcd for C16H18N2O4S: C, 57.47; H, 5.43; N, 8.38. Found: C, 57.56; H, 5.41; N, 8.28. 3.4.2. Data for 8L UV (MeOH) kmax 260.5 nm (e 11,300), kmin 236.5 nm (e 4900); 1 H NMR (CDCl3) d 1.95 (3H, d, J = 1.2 Hz, 5-Me), 2.07 (1H, dd, J = 5.9 and 8.3 Hz, OH), 2.18 (1H, ddd, J = 2.7, 8.0, and 13.4 Hz, H30 a), 2.25–2.35 (1H, m, H-20 a), 2.50–2.57 (1H, m, H-20 b), 2.65 (1H, ddd, J = 7.8, 10.7, and 13.4 Hz, H-30 b), 3.57 (1H, dd, J = 8.3 and 12.2 Hz, H-50 a), 3.64 (1H, dd, J = 5.9 and 12.2 Hz, H-50 b), 6.50 (1H, dd, J = 6.6 and 7.8 Hz, H-10 ), 7.31–7.39 and 7.50–7.52 (5H, each as m, Ph), 7.94 (1H, d, J = 1.2 Hz, H-6), 8.44 (1H, br NH); 13C NMR (CDCl3) d 12.57, 31.27, 32.82, 65.80, 87.58, 97.01, 111.75, 128.98, 129.13, 130.32, 134.67, 136.37, 150.82, 163.72; FAB-MS (m/z) 335 (M++H). Anal Calcd for C16H18N2O4S.1/10H2O: C, 57.16; H, 5.46; N, 8.33. Found: C, 57.04; H, 5.42; N, 8.23.

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3.5. 40 -Benzenesulfenyl-50 -O-(tert-butyldimethylsilyl)-30 deoxythymidine (9D) and its 40 -epimer (9L) Compound 8D/8L (8D/8L = 1:2) was silylated in a conventional manner (TBDMSCl/imidazole/DMF) to give 9D/9L (96%, 9D/9L = 1:2, foam) after column chromatography (hexane/EtOAc = 3:1). 3.5.1. Data for 9D UV (MeOH) kmax 262 nm (e 11,700), kmin 237 nm (e 3900); 1H NMR (CDCl3) d 0.05 (6H, s, SiMe2), 0.89 (9H, s, SiBu-t), 1.90 (3H, d, J = 1.2 Hz, 5-Me), 1.93–2.05 and 2.50–2.69 (4H, each as m, H-20 and H-30 ), 3.81 (2H, s, H-50 ), 6.45 (1H, dd, J = 5.6 and 6.6 Hz, H10 ), 7.31–7.36 and 7.53–7.55 (5H, each as m, Ph), 7.43 (1H, d, J = 1.2 Hz, H-6), 9.10 (1H, br, NH); 13C NMR (CDCl3) d 5.41, 5.29, 12.53, 18.45, 25.90, 31.88, 31.90, 67.09, 84.94, 95.81, 111.09, 128.82, 129.02, 130.37, 135.63, 136.08, 150.30, 163.80; FAB-MS (m/z) 449 (M++H). Anal. Calcd for C22H32N2O4SSi: C, 58.90; H, 7.19; N, 6.24. Found: C, 58.70; H, 7.27; N, 6.16. 3.5.2. Data for 9L UV (MeOH) kmax 261 nm (e 11,500), kmin 236.5 nm (e 4300); 1H NMR (CDCl3) d 0.03 and 0.01 (6H, each as s, SiMe2), 0.86 (9H, s, SiBu-t), 1.93 (3H, d, J = 1.2 Hz, 5-Me), 2.07–2.21 and 2.50–2.63 (4H, each as m, H-20 and H-30 ), 2.50–2.63 (2H, m, H-20 b and H-30 b), 3.65 (2H, s, H-50 ), 6.39 (1H, dd, J = 6.1 and 6.6 Hz, H-10 ), 7.30–7.36 and 7.52–7.55 (5H, each as m, Ph), 7.88 (1H, d, J = 1.2 Hz, H-6), 8.94 (1H, br, NH); 13C NMR (CDCl3) d 5.46, 5.22, 12.60, 18.22, 25.78, 31.88, 32.78, 67.03, 88.02, 97.00, 111.12, 128.72, 128.95, 130.97, 134.48, 136.66, 150.41, 163.79 ; FAB-MS (m/z) 449 (M++H). Anal. Calcd for C22H32N2O4SSi: C, 58.90; H, 7.19; N, 6.24. Found: C, 58.99; H, 7.30; N, 6.16. 3.6. 40 -Benzenesulfonyl-50 -O-(tert-butyldimethylsilyl)-30 deoxythymidine (10D) and its 40 -epimer (10L) To a solution of 9D/9L (2.85 g, 6.35 mmol, 9D/9L = 1:2) in CH2Cl2 (30 mL) was added dropwise a CH2Cl2 (20 mL) solution of m-CPBA (70% purity, 3.45 g, 14.0 mmol) at 30 °C. The reaction mixture was stirred for 0.5 h at 30 °C, and then partitioned between EtOAc and saturated aqueous NaHCO3. Column chromatography (hexane/EtOAc = 1:1) of the organic layer gave 10D/10L (2.96 g, 97%, 10D/10L = 1:2). HPLC separation (hexane/EtOAc = 1:1) gave 10D (tR 8.1 min, foam) and 10L (tR 6.7 min, foam). 3.6.1. Data for 10D UV (MeOH) kmax 265.5 nm (e 10,100), kmin 235.5 nm (e 3400); 1 H NMR (CDCl3) d 0.078 and 0.081 (6H, each as s, SiMe2), 0.89 (9H, s, SiBu-t), 1.88 (3H, d, J = 1.2 Hz, 5-Me), 1.96–2.01 (1H, m, H-20 a), 2.51–2.65 (2H, m, H-30 a and H-20 b), 2.75–2.83 (1H, m, H-30 b), 3.67 (1H, d, J = 10.7 Hz, H-50 a), 4.06 (1H, d, J = 10.7 Hz, H-50 b), 6.42 (1H, dd, J = 6.6 and 7.1 Hz, H-10 ), 7.27 (1H, d, J = 1.2 Hz, H-6), 7.58–7.62, 7.69–7.74, and 7.91–7.93 (5H, each as m, Ph), 8.87 (1H, br, NH); NOE experiments H-50 a/H-6 (1.0%); 13C NMR (CDCl3) d 5.48, 5.38, 12.49, 18.39, 25.83, 26.14, 31.31, 63.30, 86.82, 102.18, 111.64, 129.23, 130.13, 134.51, 134.80, 134.92, 149.84, 163.15; FAB-MS (m/z) 481 (M++H). Anal. Calcd for C22H32N2O6SSi: C, 54.97; H, 6.71; N, 5.83. Found: C, 54.95; H, 6.80; N, 5.61. 3.6.2. Data for 10L UV (MeOH) kmax 265.5 nm (e 10,300), kmin 235.5 nm (e 3200); 1 H NMR (CDCl3) d 0.09 and 0.05 (6H, each as s, SiMe2), 0.82 (9H, s, SiBu-t), 2.04 (3H, s, 5-Me), 2.31–2.44, 2.57–2.66, and 2.87–2.94 (4H, each as m, H-20 and H-30 ), 3.46 (1H, d, J = 10.5 Hz, H-50 a), 3.65 (1H, d, J = 10.5 Hz, H-50 b), 6.49 (1H, dd, J = 6.3 and 8.8 Hz, H-10 ), 7.54–7.58, 7.68–7.72, and 7.78–7.80 (5H, each as m,

Ph), 7.95, (1H, s, H-6), 8.89 (1H, br NH); NOE experiments H-50 a/ H-10 (0.6%); 13C NMR (CDCl3) d 5.77, 5.53, 12.68, 18.17, 25.65, 26.55, 30.47, 63.76, 87.13, 102.18, 100.99, 112.14, 129.16, 129.75, 134.41, 135.17, 135.80, 150.44, 163.58; FAB-MS (m/z) 481 (M++H). Anal. Calcd for C22H32N2O6SSi: C, 54.97; H, 6.71; N, 5.83. Found: C, 54.99; H, 6.73; N, 5.68. 3.7. 50 -O-(tert-Butyldimethylsilyl)-30 -deoxy-40 -methylthymidine (12D) and its 40 - epimer (12L): entry 8 in Table 1 as typical procedure for the reaction with AlR3 Under positive pressure of dry Ar, AlMe3 (1.08 M in hexane, 1.55 mL, 1.68 mmol) was added to a solution of 10L (100 mg, 0.21 mmol) in CH2Cl2 (5 mL) at 0 °C. The reaction mixture was stirred for 0.5 h at this temperature. After being quenched with saturated aqueous NH4Cl, the reaction mixture was filtered through a Celite pad. The filtrate was partitioned between CH2Cl2 and saturated aqueous NH4Cl. Column chromatography (hexane/ EtOAc = 3:2) of the organic layer gave 12D/12L (50 mg, 67%, 12D/12L = 1:2.8). HPLC separation (hexane/EtOAc = 2:1) gave 12D (tR 15.8 min, foam) and 12L (tR 14.6 min, foam). 3.7.1. Data for 12D UV (MeOH) kmax 267.5 nm (e 9300), kmin 235 nm (e 2000); 1H NMR (CDCl3) d 0.11 and 0.12 (6H, each as s, SiMe2), 0.94 (9H, s, SiBu-t), 1.22 (3H, s, 40 -Me), 1.74 (1H, ddd, J = 8.3, 8.6, and 12.4 Hz, H-30 a), 1.93 (3H, d, J = 1.2 Hz, 5-Me), 1.98 (1H, dddd, J = 6.8, 8.6, 8.8, and 12.7 Hz, H-20 a), 2.17 (1H, ddd, J = 4.6, 8.8, and 12.4 Hz, H-30 b), 2.41 (1H, dddd, J = 4.6, 6.3, 8.3, and 12.7 Hz, H-20 b), 3.52 (1H, d, J = 11.0 Hz, H-50 a), 3.75 (1H, d, J = 11.0 Hz, H-50 b), 6.15 (1H, dd, J = 6.3 and 6.8 Hz, H-10 ), 7.63 (1H, d, J = 1.2 Hz, H-6), 9.30 (1H, br, NH); NOE experiments H-6/H-50 b (0.8%) and 40 -Me/H-10 (3.0%); 13C NMR (CDCl3) d 4.71, 4.69, 13.21, 19.11, 24.83, 26.11, 32.95, 33.67, 70.01, 85.66, 85.77, 111.11, 136.45, 151.25, 164.76; FAB-MS (m/z) 355 (M++H). Anal. Calcd for C17H30N2O4Si: C, 57.59; H, 8.53; N, 7.90. Found: C, 57.84; H, 8.63; N, 7.85. 3.7.2. Data for 12L UV (MeOH) kmax 268 nm (e 9500), kmin 235 nm (e 2000); 1H NMR (CDCl3) d 0.07 and 0.08 (6H, each as s, SiMe2), 0.91 (9H, s, SiBu-t), 1.37 (3H, s, 40 -Me), 1.73 (1H, ddd, J = 7.1, 9.0, and 12.7 Hz, H-30 a), 1.90–1.99 (1H, m, H-20 a), 1.94 (3H, d, J = 1.2 Hz, 5-Me), 2.17 (1H, ddd, J = 6.3, 8.5, and 12.7 Hz, H-30 b), 2.54 (1H, dddd, J = 6.6, 7.1, 8.5, and 13.4 Hz, H-20 b), 3.44 and 3.52 (1H, d, J = 10.2 Hz, H-50 ), 6.11 (1H, dd, J = 5.4 and 6.6 Hz, H-10 ), 7.24 (1H, d, J = 1.2 Hz, H-6), 9.31 (1H, br, NH); NOE experiments H-10 /H-50 b (0.8%) and H-6/40 -Me (1.9%); 13C NMR (CDCl3) d 5.58, 5.48, 13.29, 18.81, 24.38, 26.43, 32.74, 33.27, 69.94, 86.60, 87.33, 111.05, 135.91, 153.67, 164.67; FAB-MS (m/z) 355 (M++H). Anal. Calcd for C17H30N2O4Si: C, 57.59; H, 8.53; N, 7.90. Found: C, 57.63; H, 8.73; N, 7.89. 3.8. 50 -O-(tert-Butyldimethylsilyl)-30 -deoxy-40 -ethylthymidine (13D) UV (MeOH) kmax 267.5 nm (e 9800), kmin 235 nm (e 2600); 1H NMR (CDCl3) d 0.11 and 0.12 (6H, each as s, SiMe2), 0.94 (3H, t, J = 7.6 Hz, CH2CH3), 0.94 (9H, s, SiBu-t), 1.48–1.61 (2H, m, CH2CH3), 1.83 (1H, ddd, J = 8.0, 9.5, and 11.7 Hz, H-30 a), 1.93 (3H, d, J = 1.2 Hz, 5-Me), 1.94–2.01 (1H, m, H-20 a), 2.07 (1H, ddd, J = 2.7, 8.8, and 11.7 Hz, H-30 b), 2.33–2.40 (1H, m, H-20 b), 3.56 (1H, d, J = 10.7 Hz, H-50 a), 3.74 (1H, d, J = 10.7 Hz, H-50 b), 6.12 (1H, dd, J = 5.9 and 7.6 Hz, H-10 ), 7.65 (1H, d, J = 1.2 Hz, H-6), 9.55 (1H, br, NH); NOE experiments H-6/H-50 a (0.6%), H-6/H-50 b (1.0%), and CH2CH3 /H-10 (1.6%); 13C NMR (CDCl3) d 5.46, 5.43, 7.99,

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12.48, 18.35, 25.88, 30.04, 32.93, 68.32, 85.32, 87.36; 110.48, 135.71, 150.63, 164.17; FAB-MS (m/z) 369 (M++H). Anal. Calcd for C18H32N2O4Si: C, 58.66; H, 8.75; N, 7.60. Found: C, 58.95; H, 8.89; N, 7.59. 3.9. 50 -O-(tert-Butyldimethylsilyl)-30 -deoxy-40 -ethyl-a-L-thymidine (13L) UV (MeOH) kmax 267 nm (e 9900), kmin 234.5 nm (e 2900); 1H NMR (CDCl3) d 0.06 and 0.07 (6H, each as s, SiMe2), 0.90 (9H, s, SiBu-t), 0.98 (3H, t, J = 7.6 Hz, CH2CH3), 1.63–1.90 (4H, m, CH2CH3, H-20 a, and H-30 a), 1.93 (3H, d, J = 1.0 Hz, 5-Me), 2.09 (1H, ddd, J = 6.1, 9.0, and 12.4 Hz, H-30 b), 2.52 (1H, dddd, J = 5.9, 6.6, 9.0, and 12.9 Hz, H-20 b), 3.51 (2H, s, H-50 ), 6.13 (1H, dd, J = 5.9 and 6.1 Hz, H-10 ), 7.23 (1H, d, J = 1.0 Hz, H-6), 9.24 (1H, br, NH); NOE experiments H-50 /H-10 (3.6%) and CH2CH3/H-6 (4.3%); 13C NMR (CDCl3) d 5.61, 5.52, 8.53, 12.70, 18.17, 25.81, 30.22, 32.31, 67.42, 86.02, 87.94, 110.52, 135.35, 150.39, 164.00; FAB-MS (m/z) 369 (M++H). Anal. Calcd for C18H32N2O4Si1/3H2O: C, 57.72; H, 8.79; N, 7.48. Found: C, 57.54; H, 8.79; N, 7.48. 3.10. 40 -Isobutyl-50 -O-(tert-butyldimethylsilyl)-30 -deoxythymidine (14D) UV (MeOH) kmax 267 nm (e 9200), kmin 234.5 nm (e 2000); 1H NMR (CDCl3) d 0.11 and 0.12 (6H, each as s, SiMe2), 0.93 (9H, s, SiBu-t), 0.93–0.95 (6H, m, CH2CHMe2), 1.40 (2H, dd, J = 2.4 and 10.6 Hz, CH2CHMe2), 1.45 (1H, dd, J = 1.6 and 10.6 Hz, CH2CHMe2), 1.69–1.79 (1H, m, CH2CHMe2), 1.82 (1H, ddd, J = 8.0, 9.8, and 12.2 Hz, H-30 a), 1.91 (3H, d, J = 1.2 Hz, 5-Me), 1.94–2.00 (1H, m, H-20 a), 2.12 (1H, ddd, J = 3.4, 8.5, and 12.2 Hz, H-30 b), 2.32–2.39 (1H, m, H-20 a), 3.54 (1H, d, J = 10.7 Hz, H-50 a), 3.76 (1H, d, J = 10.7 Hz, H-50 b), 6.10 (1H, dd, J = 5.6 and 7.6 Hz, H-10 ), 7.65 (1H, d, J = 1.2 Hz, H-6), 8.70 (1H, br, NH); NOE experiments CH2CHMe2/H-10 (2.5%) and H-50 a/H-6 (2.2%); 13C NMR (CDCl3) d 5.40, 12.54, 18.39, 24.16, 24.48, 24.56, 25.92, 32.01, 32.81, 42.37, 68.58, 85.18, 87.52, 110.38, 135.81, 150.49, 163.98; FABMS (m/z) 397 (M++H). Anal. Calcd for C20H36N2O4Si2/5H2O: C, 59.49; H, 9.19; N, 6.94. Found: C, 59.30; H, 9.06; N, 6.67. 3.11. 50 -O-(tert-Butyldimethylsilyl)-30 -deoxy-40 -(trimethylsilyl) ethynylthymidine (16D) and its 40 -epimer (16L) To a solution of HC„CSiMe3 (0.9 mL, 8.2 mmol) in toluene (6 mL) was added BuLi (1.65 M in hexane, 4.8 mL, 8.1 mmol) at 0 °C under positive pressure of dry Ar. The mixture was stirred for 0.5 h, and then reacted with EtAlCl2 (1.04 M in hexane, 3.9 mL, 4.1 mmol) for 0.5 h. Compound 10D (70 mg, 0.16 mmol) was dissolved in CH2Cl2 (5 mL) and reacted with the above prepared EtAl(C„CSiMe3)2 (5 mL, ca. 1.3 mmol) at 0 °C for 2 h. After being quenched with saturated aqueous NH4Cl, the reaction mixture was filtered through a Celite pad. The filtrate was partitioned between CH2Cl2 and saturated aqueous NH4Cl. Column chromatography (hexane/EtOAc = 1:1) of the organic layer gave a mixture of products (56.2 mg, 16D/16L/13D/13L/17/18 = 1.0:0.33:0.29:0.04: 0.17:trace). HPLC purification (hexane/EtOAc = 1:1) of this mixture gave analytically pure 16D (tR 10.1 min) and 16L (tR 9.7 min). 3.11.1. Data for 16D UV (MeOH) kmax 266.5 nm (e 9500), kmin 234 nm (e 1700); 1H NMR (CDCl3) d 0.14 (6H, s, SiMe2), 0.17 (9H, s, C„CSiMe3), 0.94 (9H, s, SiBu-t), 1.91 (3H, d, J = 1.2 Hz, 5-Me), 1.96 (1H, dddd, J = 6.1, 6.6, 8.5, and 12.9 Hz, H-20 a), 2.12 (1H, ddd, J = 6.6, 8.0, and 12.7 Hz, H-30 a), 2.37 (1H, ddd, J = 6.8, 8.5, and 12.7 Hz, H-30 b), 2.56 (1H, dddd, J = 6.3, 6.8, 8.0, and 12.9 Hz, H-20 b), 3.72 (1H, d,

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J = 11.0 Hz, H-50 a), 3.98 (1H, d, J = 11.0 Hz, H-50 b), 6.24 (1H, dd, 6.1 and 6.3 Hz, H-10 ), 7.51 (1H, d, J = 1.2 Hz, H-6), 8.02 (1H, br, NH); NOE experiments H-50 b/H-6 (1.4%); 13C NMR (CDCl3) d 4.88, 4.85, 12.47, 18.40, 25.86, 32.28, 32.57, 67.43, 80.99, 85.18, 90.33, 104.16, 110.55, 135.51, 150.53, 164.13; FAB-MS (m/ z) 437 (M++H). Anal. Calcd for C21H36N2O4Si2: C, 57.76; H, 8.31; N, 6.41. Found: C, 57.80; H, 8.33; N, 6.27. 3.11.2. Data for 16L UV (MeOH) kmax 267.5 nm (e 9000), kmin 234 nm (e 1600); 1H NMR (CDCl3) d 0.07 and 0.08 (6H, each as s, SiMe2), 0.20 (9H, s, C„CSiMe3), 0.90 (9H, s, SiBu-t), 1.95 (3H, d, J = 1.2 Hz, 5-Me), 2.06–2.15 (2H, m, H-20 a and H-30 a), 2.31–2.44 (1H, m, H-30 b), 2.51–2.59 (1H, m, H-20 b), 3.68 (1H, d, J = 10.7 Hz, H-50 a), 3.76 (1H, d, J = 10.7 Hz, H-50 b), 6.15 (1H, d, J = 5.6 Hz, H-10 ), 7.68 (1H, d, J = 1.2 Hz, H-6), 9.80 (1H, br, NH); NOE experiments H-30 b/H-10 (2.5%), H-30 b/H-50 a (1.5%), H-30 b/H-50 b (0.9%); 13C NMR (CDCl3) d 5.47, 5.25, 12.71, 18.27, 25.80, 33.22, 33.36, 67.76, 82.56, 87.86, 91.62, 104.99, 110.31, 136.06, 150.38, 164.11; FAB-MS (m/z) 437 (M++H). Anal. Calcd for C21H36N2O4Si2: C, 57.76; H, 8.31; N, 6.41. Found: C, 57.68; H, 8.32; N, 6.31. 3.12. Compounds 18a and 18b 3.12.1. Data for 18a 1 H NMR (CDCl3) d 0.166 and 0.170 (6H, each as s, SiMe2), 0.94 (9H, s, SiBu-t), 1.92 (3H, d, J = 1.2 Hz, 5-Me), 2.01–2.09 (1H, m, H20 a), 2.42–2.63 (3H, m, H-20 b and H-30 ), 5.68 (1H, dd, J = 1.5 and 1.7 Hz, C@CHOSi), 6.34 (1H, dd, J = 4.4 and 5.9 Hz, H-10 ), 7.11 (1H, d, J = 1.2 Hz, H-6), 8.49 (1H, br, NH); 13C NMR (CDCl3) d 5.39, 5.16, 12.60, 18.48, 23.45, 25.71, 31.37, 86.98, 110.82, 116.83, 134.68, 139.65, 150.52, 163.70; FAB-MS (m/z) 339 (M++H); FABHRMS (m/z) calcd for C16H26N2O4Si: 338.162, found: 339.175 (M++H). 3.12.2. Data for 18b 1 H NMR (CDCl3) d 0.14 (6H, s, SiMe2), 0.94 (9H, s, SiBu-t), 1.93 (3H, d, J = 1.2 Hz, 5-Me), 2.03–2.11, 2,42–2.51, and 2.67–2.75 (4H, each as m, H-20 and H-30 ), 6.28 (1H, dd, J = 4.2 and 6.3 Hz, H-10 ), 6.46 (1H, dd, J = 2.0 and 2.2 Hz, C@CHOSi), 7.06 (1H, d, J = 1.2 Hz, H-6), 8.02 (1H, br, NH); 13C NMR (CDCl3) d 5.36, 5.33, 12.67, 18.20, 22.79, 25.65, 30.63, 86.36, 110.98, 120.45, 134.63, 145.68, 149.86, 163.26; FAB-MS (m/z) 338 (M+); FAB-HRMS (m/z) calcd for C16H26N2O4Si: 338.162, found: 339.175 (M++H). 3.13. 40 -Allyl-50 -O-(tert-butyldimethylsilyl)-30 -deoxythymidine (19D) To a solution of 10D/10L (200 mg, 0.42 mmol, 10D/10L = 1:1.1) in CH2Cl2 (10 mL), were added Me3SiCH2CH@CH2 (0.66 mL, 4.17 mmol) and then SnCl4 (1 M in CH2Cl2, 1.66 mL, 1.66 mmol) at 30 °C under positive pressure of dry Ar. The reaction mixture was stirred at 30 °C for 1 h, and partitioned between CH2Cl2 and saturated aqueous NH4Cl. Column chromatography (hexane/ EtOAc = 2:1) of the organic layer gave 19D/19L (141 mg, 89%, 19D/ 19L = 50:1). 3.13.1. Data for 19D UV (MeOH) kmax 268.5 nm (e 9200), kmin 234.5 nm (e 1900); 1H NMR (CDCl3) d 0.09 and 0.10 (6H, each as s, SiMe2), 0.92 (9H, s, SiBu-t), 1.84–2.03 (2H, m, H-20 a and H-30 a), 1.91 (3H, d, J = 1.2 Hz, 5-Me), 2.04–2.07 (1H, m, H-30 b), 2.22 (1H, dd, J = 7.6 and 13.9 Hz, CH2CH@CH2), 2.29 (1H, dd, J = 6.8 and 13.9 Hz, CH2CH@CH2), 2.33–2.38 (1H, m, H-20 b), 3.53 and 3.72 (2H, each as d, J = 10.7 Hz, H-50 ), 5.08–5.15 (2H, m, CH2CH@CH2), 5.73–5.84

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(1H, m, CH2CH@CH2), 6.11 (1H, dd, J = 5.5 and 6.8 Hz, H-10 ), 7.61 (1H, d, J = 1.2 Hz, H-6), 9.47 (1H, br, NH); 13C NMR (CDCl3) d 5.44, 5.42, 12.51, 18.35, 25.88, 30.30, 32.85, 41.95, 68.59, 85.32, 86.55, 110.55, 119.67, 132.68, 135.64, 164.11; FAB-MS (m/ z) 381 (M++H). Anal. Calcd for C19H32N2O4Si1: C, 59.97; H, 8.48; N, 7.36. Found: C, 59.82; H, 8.52; N, 7.11. 3.14. 50 -O-(tert-Butyldimethylsilyl)-40 -cyano-30 -deoxythymidine (20D) and its 40 - epimer (20L) To a solution of 10D/10L (50 mg, 0.10 mmol, 10D/10L = 1:1.1) in CH2Cl2 (2.5 mL) were added Me3SiCN (0.14 mL, 1.20 mmol) and then SnCl4 (1 M in CH2Cl2, 0.42 mL, 0.42 mmol) at 30 °C under positive pressure of dry Ar. The reaction mixture was stirred at 30 °C for 0.5 h, and partitioned between CH2Cl2 and saturated aqueous NH4Cl. Column chromatography (hexane/EtOAc = 1:1) of the organic layer gave 20D/20L (31 mg, 81%, 20D/20L = 2:1). HPLC separation (hexane/EtOAc = 1:1) gave 20D (tR 9.0 min, foam) and 20L (tR 10.0 min, foam). 3.14.1. Data for 20D IR (neat) 2237 cm1 (CN); UV (MeOH) kmax 263.5 nm (e 9300), kmin 232.5 nm (e 2600); 1H NMR (CDCl3) d 0.147 and 0.148 (6H, each as s, SiMe2), 0.94 (9H, s, SiBu-t), 1.93 (3H, d, J = 1.2 Hz, 5-Me), 2.13 (1H, dddd, J = 5.6, 5.8, 8.8,and 13.2 Hz, H-20 a), 2.40 (1H, ddd, J = 5.8, 8.3, and 13.2 Hz, H-30 a), 2.50 (1H, ddd, J = 7.3, 8.8, and 13.2 Hz, H-30 b), 2.62 (1H, dddd, J = 6.8, 7.3, 8.3, and 13.2 Hz, H-20 b), 3.90 (1H, d, J = 10.9 Hz, H-50 a), 4.04 (1H, d, J = 10.9 Hz, H-50 b), 6.29 (1H, dd, J = 5.6 and 6.8 Hz, H-10 ), 7.23 (1H, d, J = 1.2 Hz, H-6), 9.33 (1H, br, NH); NOE experiment H-50 b/H-6 (0.8%); 13C NMR (CDCl3) d 5.46, 5.40, 12.55, 18.33, 25.75, 30.75, 31.80, 65.92, 80.00, 86.67, 111.44, 111.69, 135.13, 150.13, 163.65; FAB-MS (m/z) 366 (M++H). Anal. Calcd for C17H27N3O4Si: C, 55.86; H, 7.45; N, 11.50. Found: C, 55.85; H, 7.45; N, 11.24.

3.15.1. Data for 21D IR (neat) 2112 cm1 (N3); 1H NMR (CDCl3) d 0.13 (6H, s, SiMe2), 0.93 (9H, SiBu-t), 1.88 (1H, ddd, J = 4.4, 8.5, and 13.2 Hz, H-30 a), 1.92 (3H, d, J = 1.2 Hz, 5-Me), 2.04 (1H, dddd, J = 4.4, 4.6, 9.0, and 13.4 Hz, H-20 a), 2.27 (1H, ddd, J = 8.8, 9.0, and 13.2 Hz, H-30 b), 2.60 (1H, dddd, J = 7.1, 8.5, 8.8, and 13.4 Hz, H-20 b), 3.78 (1H, d, J = 10.9 Hz, H-50 a), 3.98 (1H, d, J = 10.9 Hz, H-50 b), 6.37 (1H, dd, J = 4.6 and 7.1 Hz, H-10 ), 7.36 (1H, d, J = 1.2 Hz, H-6), 9.34 (1H, br, NH); NOE experiment H-50 b/H-6 (1.0%); 13C NMR (CDCl3) d 5.44, 5.40, 12.58, 18.42, 25.83, 31.14, 31.16, 65.66, 86.09, 100.23, 111.15, 135.18, 150.24, 163.79; FAB-MS (m/z) 382 (M++H). FAB-HRMS (m/z) calcd for C16H27N5O4Si: 381.183, found: 382.194 (M++H). 3.15.2. Data for 21L IR (neat) 2108 cm1 (N3); UV (MeOH) kmax 265.5 nm (e 8900), kmin 234 nm (e 2300); 1H NMR (CDCl3) d 0.11 (6H, s, SiMe2), 0.92 (9H, SiBu-t), 1.98 (3H, d, J = 1.2 Hz, 5-Me), 2.05–2.18 (3H, m, H20 a, H-30 a, and H-30 b), 2.44–2.50 (1H, m, H-20 b), 3.81 (1H, d, J = 10.7 Hz, H-50 a), 3.85 (1H, d, J = 10.7 Hz, H-50 b), 6.37 (1H, dd, J = 5.9 and 7.6 Hz, H-10 ), 7.41 (1H, d, J = 1.2 Hz, H-6), 8.93 (1H, br, NH); NOE experiments H-50 a/H-10 (0.6%) and H-10 /H-50 b (0.2%); 13 C NMR (CDCl3) d 5.58, 5.52, 12.73, 18.23, 25.71, 30.30, 32.70, 67.01, 86.74, 99.85, 111.86, 134.96, 150.45, 163.50; FABMS (m/z) 382 (M++H). Anal. Calcd for C16H27N5O4Si: C, 50.37; H, 7.13; N, 18.36. Found: C, 50.63; H, 7.24; N, 18.04. Acknowledgments The financial support from Showa University Research Grant for Young Researchers (to H.S.) is gratefully acknowledged. The authors thank Ms. S. Matsubayashi and Y. Odanaka (Center for Instrumental Analysis, Showa University) for technical assistance with NMR, MS, and elemental analyses. References

3.14.2. Data for 20L IR (neat) 2241 cm1 (CN); UV (MeOH) kmax 264.5 nm (e 10,000), kmin 233 nm (e 3800); 1H NMR (CDCl3) d 0.11 and 0.12 (6H, each as s, SiMe2), 0.92 (9H, s, SiBu-t), 1.98 (3H, s, 5-Me), 2.20 (1H, dddd, J = 7.6, 7.8, 10.7, and 13.2 Hz, H-20 a), 2.41 (1H, ddd, J = 7.3, 10.7, and 13.4 Hz, H-30 a), 2.51 (1H, ddd, J = 2.9, 7.8, and 13.4 Hz, H30 b), 2.61 (1H, dddd, J = 2.9, 5.9, 7.3, and 13.2 Hz, H-20 b), 3.80 (1H, d, J = 10.7 Hz, H-50 a), 3.86 (1H, d, J = 10.7 Hz, H-50 b), 6.28 (1H, dd, J = 5.9 and 7.6 Hz, H-10 ), 7.33 (1H, s, H-6), 9.02 (1H, br, NH); NOE experiments H-10 /H-50 a (0.2%) and H-10 /H-50 b (0.2%); 13 C NMR (CDCl3) d 5.52, 5.41, 12.75, 18.22, 25.69, 31.54, 33.11, 66.32, 80.66, 87.38, 112.12, 119.49, 134.50, 150.29, 163.46; FAB-MS (m/z) 366 (M++H). Anal. Calcd for C17H27N3O4Si: C, 55.86; H, 7.45; N, 11.50. Found: C, 55.92; H, 7.46; N, 11.27. 3.15. 40 -Azido-50 8-O-(tert-butyldimethylsilyl)-30 -deoxythymidine (21D) and its 40 - epimer (21L) To a solution of 10D/10L (50 mg, 0.10 mmol, 10D/10L = 1:1.1) in CH2Cl2 (2.5 mL) were added Me3SiN3 (95% purity, 0.15 mL, 1.08 mmol) and then SnCl4 (1 M in CH2Cl2, 0.42 mL, 0.42 mmol) at 30 °C under positive pressure of dry Ar. The reaction mixture was stirred at 30 °C for 0.5 h, and partitioned between CH2Cl2 and saturated aqueous NH4Cl. Column chromatography (hexane/ EtOAc = 2:1) of the organic layer gave 21D/21L (34 mg, 86%, 21D/21L = 1.9:1). HPLC separation (hexane/EtOAc = 3:2) gave 21D (tR 10.1 min, foam) and 21L (tR 11.1 min, foam).

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