Phenylsulfanylation of 3′,4′-unsaturated adenosine employing thiophenol-N-iodosuccinimide leads to 4′-phenylsulfanylcordycepin: Synthesis of 4′-substituted cordycepins on the basis of substitution of the phenylsulfanyl leaving group

Article abstract of DOI:10.1021/jo201246y

Upon reaction of the 3′,4′-unsaturated adenosine derivative 2 with N-iodosuccinimide (NIS) and thiophenol, an unexpected electrophilic hydrophenylsulfanylation proceeded to provide 4′-phenylsulfanylcordycepin 7 in 79% yield with the ratio 7a/7b = 6.6/1. A study of the reaction mechanism revealed that hydrogen iodide (HI) generated from NIS and PhSH acted as an active species. On the basis of a deuterium experiment using PhSD, initial protonation occurred at the β face of the double bond to furnish the β-π complex III, which underwent anti addition of PhSH as a major pathway. Nucleophilic substitution of N⁶-pivaloylated 9 with various alcohols in the presence of N-bromosuccinimide (NBS) gave the respective 4′-α-alkoxycordycepins 15a-21a as the major stereoisomers. Use of DAST in place of an alcohol gave the 4′-α-fluoro analogue 23a stereoselectively. Radical-mediated carbon-carbon bond construction was also applicable to 7, giving 4′-α-allylcordycepin (24a) and 4′-α-cyanoethylcordycepin (25) derivatives.

Full text of DOI:10.1021/jo201246y

Article
pubs.acs.org/joc
Phenylsulfanylation of 3′,4′-Unsaturated Adenosine Employing
Thiophenol-N-Iodosuccinimide Leads to 4′-
Phenylsulfanylcordycepin: Synthesis of 4′-Substituted Cordycepins
on the Basis of Substitution of the Phenylsulfanyl Leaving Group
Yutaka Kubota,* Mariko Ehara, Kazuhiro Haraguchi,* and Hiromichi Tanaka
School of Pharmacy, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan
S
* Supporting Information
ABSTRACT: Upon reaction of the 3′,4′-unsaturated adeno-
sine derivative 2 with N-iodosuccinimide (NIS) and
thiophenol, an unexpected electrophilic hydrophenylsulfanyla-
tion proceeded to provide 4′-phenylsulfanylcordycepin 7 in
79% yield with the ratio 7a/7b = 6.6/1. A study of the reaction
mechanism revealed that hydrogen iodide (HI) generated
from NIS and PhSH acted as an active species. On the basis of
a deuterium experiment using PhSD, initial protonation occurred at the β face of the double bond to furnish the β-π complex III,
which underwent anti addition of PhSH as a major pathway. Nucleophilic substitution of N6-pivaloylated 9 with various alcohols
in the presence of N-bromosuccinimide (NBS) gave the respective 4′-α-alkoxycordycepins 15a−21a as the major stereoisomers.
Use of DAST in place of an alcohol gave the 4′-α-fluoro analogue 23a stereoselectively. Radical-mediated carbon−carbon bond
construction was also applicable to 7, giving 4′-α-allylcordycepin (24a) and 4′-α-cyanoethylcordycepin (25) derivatives.
Scheme 1. Synthesis of 4′-Carbon-Substituted Cordycepin
from 2
INTRODUCTION
■
The nucleoside antibiotic cordycepin (1; Figure 1) has been
reported to possess biological effects on RNA biosynthesis,1
Figure 1. Structure of cordycepin (1).
methyl transferase,2 and purine biosynthesis.3 These facts have
stimulated the synthesis of numerous analogues with the aim of
discovering chemotherapeutically viable compounds;4 however,
reported modifications at its sugar moiety have been quite
limited.5 In the course of our ongoing research on the synthetic
chemistry of unsaturated sugar nucleosides,6 we have recently
reported the iodobenzoyloxylation of the 3′,4′-unsaturated
adenosine derivative 2 utilizing N-iodosuccinimide (NIS) and
benzoic acid (Scheme 1).7 Radical-mediated deiodination of the
resulting adduct 3 furnished 4′-benzoyloxycordycepin (4),
which served as a useful precursor for the synthesis of the
novel 4′-carbon-substituted analogues 5 by nucleophilic
substitution of the benzoyloxy leaving group with organosilicon
or organoaluminum reagents.8
fluoride,10 and C-glycoside11 through activation of the phenyl-
sulfanyl group under neutral conditions. We envisioned that the
versatility of the phenylsulfanyl substituent as a leaving group
would enable the synthesis of novel 4′-substituted derivatives of
cordycepin by substitution reactions of the phenylsulfanyl
group. In accord with the synthetic route visualized in Scheme
Phenylthioglycosides have been utilized as stable and useful
Received: June 17, 2011
Published: September 27, 2011
glycosyl donors for the synthesis of O-glycoside,9 glycosyl
© 2011 American Chemical Society
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1, we have attempted to prepare 6 by reaction of 2 with NIS-
thiophenol (PhSH) (Figure 2). Unexpectedly, instead of the
(entry 3), which supports the proposed reaction mechanism
shown in Scheme 2.
This reaction did not occur when PhSNa was used instead of
PhSH or when DMAP was added to the reaction medium.
These facts led us to postulate the reaction mechanism depicted
in Scheme 2. Thus, hydrogen iodide would be generated from 2
PhSH plus NIS. In support of this PhSSPh generated
accompanied by HI could be confirmed on the basis of 13C
NMR of the reaction mixture of PhSH and NIS. Next, HI
protonates the N1 nitrogen group to form incipient
intermediate I (entries 3 and 5 in Table 1). If 1 equiv more
of HI is present, I is then transformed to the oxonium ion II
through protonation of the 3′,4′-double bond. Finally, II
undergoes nucleophilic attack by PhSH to furnish 7. If the
reaction mechanism is correct, an N6-acylated substrate would
give the desired product by using only 1 equiv of NIS because
the amide nitrogen does not have sufficient basic character. As
anticipated, when N6-pivaloylated 8 was subjected to reaction
with 6 equiv of PhSH in the presence of NIS (1 equiv), the
desired product 9 was obtained as a diastereomeric mixture in
33% yield (Figure 3). It deserves additional comment that
reactions utilizing NBS and NCS instead of NIS gave a complex
mixture of products.
To see if the addition reaction proceeds in an anti or syn
fashion, PhSD was used as the nucleophile instead of PhSH
(Scheme 3). PhSD (deuteration degree 93%) was prepared
from the reaction of PhSH and D2O by the literature
procedure.14 To avoid deuterium exchange between PhSD
and 6-NH2, the N,N-dimethylamino 3′,4′-unsaturated adenosine
derivative 10 was used as the substrate. Compound 10 was
prepared from N,N-dimethyladenosine15 according to the
published procedure.12 The four stereoisomers 11 (β-anti-
adduct), 12 (β-syn-adduct), 13 (α-anti-adduct), and 14 (α-syn-
adduct) were obtained in 77% combined isolated yield from the
reaction under the conditions shown in entry 4 in Table 1. By
comparison of the integration of H-1′ and H-3′ of 11−14 in the
1H NMR spectrum of the mixture, the isomeric ratio was found
to be as follows: 11/12/13/14 = 26/3.3/1.0/4.0. On the basis
of the ratio 11 + 12/13 + 14, β-π complex III was found to be
formed predominantly over α-π complex V (III/V = 29.3/5.0).
This stereochemical outcome was quite unexpected, since the
iodobenzoyloxylation shown in Scheme 1 (2 → 3) proceeded
through an α-iodonium ion as an intermediate. At the moment,
we have no reasonable explanation for the reversed stereo-
chemistry of the incoming electrophile. Concomitant formation
of the β-syn adduct 12 and α-syn-adduct 14 indicates that III
and V exist as an equilibrium mixture with the carboxonium
ions IV and VI, respectively. These ions underwent preferential
attack from their α-face due to the presence of the adenine base
(11 vs 12 and 13 vs 14).
Figure 2. Structures of compounds 6 and 7a,b.
desired 6, the reaction gave the 4′-phenylsulfanylcordycepin
derivatives 7a,b lacking an iodo substituent at the 3′-position.
Since this novel hydrosulfanylation reaction of 2 would
constitute a more efficient route to 4′-substituted cordycepin,
we intended to optimize the reaction conditions and clarify the
reaction mechanism. In this paper, we will describe these results
and demonstrate the scope of 7 for the synthesis of novel 4′-
substituted analogues of cordycepin.
RESULTS AND DISCUSSION
■
When 212 was reacted with NIS (3 equiv) and PhSH (3 equiv)
in CH2Cl2 at room temperature for 3 min, a mixture of the β-D
isomer 7a and its 4′-epimer 7b was obtained in 62% combined
yield (7a/7b = 2.3/1). Compounds 7a,b could be separated by
HPLC (hexane/ethyl acetate 1/2). The depicted structures of
1
7a,b were determined on the basis of their H NMR spectrum,
in which signals of H-3′a and H-3′b were observed as doublets
of doublets at 2.15 and 2.85 ppm for 7a and 2.34 and 2.69 ppm
for 7b.13 Assignment of H-3′a/H-3′b and determination of the
stereochemistry at the 4′-position were performed on the basis
of NOE experiments: H-5′/H-8 (0.4%), H-2′/H-5′ (0.5%), H-
5′/H-3′b (1.6%), H-1′/H-3′a (1.7%), and H-1′/H-Ph (2.2%) for
7a; H-1′/H-5′b (1.7%), H-1′/H-3′b (3.7%), H-3′b/H-5′b
(1.5%), H-3′a/H-8 (1.7%), and H-3′a/H-Ph (2.2%) for 7b.
To optimize the reaction conditions, we have varied the
amount of these reagents, and the results are summarized in
Table 1, which includes the result in the case of 3 equiv of each
a
Table 1. Reaction of 2 with NIS-PhSH
amt of NIS
(equiv)
amt of PhSH
(equiv)
combined yield of ratio 7a/
b
entry
7 (%)
7b
1
2
3
4
5
3
3
3
2
1
3
62
trace
71
79
0
2.3/1
1.5
6
6.6/1
6.6/1
6
6
a
This reaction was carried out by reacting 2 with NIS and PhSH in
b
CH2Cl2 at room temperature for 3 min. These ratios were
1
With the 4′-phenylsulfanyl cordycepin derivative 7 in hand,
we next examined the synthesis of 4′-alkoxy analogues. Initially,
7 was reacted with MeOH in the presence of NBS. In this case,
8-brominated products having methoxy groups at the 4′-
position were formed as byproducts. To avoid this side
reaction, N6-pivaloylated 9 was used for this alkoxylation.16
Thus, when 9 was treated with NBS (1.5 equiv) in MeOH, a
mixture of diastereomers of 4′-methoxy derivatives was
obtained (Scheme 4 and entry 1 in Table 2). Due to partial
depivaloylation during the reaction, the crude reaction mixture
was treated with NH3/MeOH to give a mixture of 15a and 15b
in 93% combined yield (15a/15b = 1.6/1). The analytically
pure sample could be obtained by HPLC separation (CHCl3/
determined by H NMR spectroscopy.
reagent in entry 1. Initially, the amount of PhSH decreased to
1.5 equiv, which resulted in retarding the reaction (entry 2),
whereas 6 equiv of PhSH improved the isolated yield (71%)
and gave the ratio of 7a/7b (6.6/1) shown in entry 3. Next, the
effect of varying the amount of NIS was examined. As shown in
entry 4, NIS could be decreased to 2 equiv to give 7a,b in 79%
yield with the same diastereoselectivity, whereas no reaction
was observed in the case of 1 equiv of NIS. As can be seen from
the above results, the required molar ratio of PhSH/NIS is 2/1
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Scheme 2. Plausible Reaction Pathway for the Formation of 7
alcohols without loss of efficiency, as shown in entries 2−7 in
Table 2.
As can be seen by the ratio of isomers, the major
diastereomers were the β-D nucleosides 15a−21a. We assumed
that steric shielding by the N6-pivaloyladenine moiety would be
a determinant for the observed β-D-selectivity. In fact, we
observed the trend that formation of the β-D isomer became
more favorable upon increasing the bulkiness of the alcohol
employed.
Figure 3. Structures of compounds 8 and 9.
By reacting 9 with DAST/NBS in CH2Cl2, the 4′-fluoro
analogues 23a,b could be synthesized in 54% yield as a mixture
of diastereomers (23a/23b = 2.4/1) after deprotection of the
N6-pivaloyl group of 22 by treatment of the crude mixture with
NH3/MeOH (Scheme 5).
MeOH = 60/1). The depicted structures of 15a,b were
confirmed on the basis of NOE experiment: H-8/H-5′b (0.3%)
and H-1′/OCH3-4′ (0.7%) for 15a; H-8/OCH3 (2.8%) and H-
1′/H-5′b (0.9%) for 15b. In addition to higher primary alcohols,
this reaction can also be applied to secondary and tertiary
Scheme 3. Reaction of 10 with NIS-PhSD
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Scheme 4. Reaction of 9 with ROH in the Presence of NBS
a
Table 2. Synthesis of 4′-Alkoxycordycepin
combined yield
(%)
ratio of
b
entry
alcohol
products (R)
isomers
1
2
3
4
5
6
7
MeOH
EtOH
15a + 15b (Me)
16a + 16b (Et)
17a + 17b (n-Pr)
93
86
1.6/1
1.5/1
1.9/1
2.0/1
1.8/1
2.3/1
2.6/1
n-PrOH
99
n-BuOH 18a + 18b (n-Bu)
98
i-PrOH
i-BuOH
t-BuOH
19a + 19b (i-Pr)
20a + 20b (i-Bu)
21a + 21b (t-Bu)
91
100
88
Figure 4. Structures of compounds 24a,b and 25.
a
The reaction was carried out in the presence of N-bromosuccinimide
CONCLUSION
■
b
(1.5 equiv) in ROH at room temperature for 45 min. These ratios
were determined by H NMR spectroscopy.
In conclusion, we have developed a novel method for the
synthesis of 4′-substituted cordycepin analogues by substitution
of a phenylsulfanyl leaving group. Synthesis of 4′-phenylsulfanyl
cordycepin 7 was carried out through a novel electrophilic
hydrophenylsulfanylation reaction of the 3′,4′-unsaturated
adenosine derivative 2 employing a NIS-PhSH system. A
study of the reaction mechanism revealed that hydrogen iodide
(HI) generated from NIS and PhSH acted as an active species.
On the basis of a deuterium experiment using PhSD, initial
protonation of the double bond occurred at the β face to
furnish β-π complex III, which underwent anti addition of
PhSH as a major pathway. Reaction of N6-pivaloylated 9 with
various alcohols in the presence of NBS gave the 4′-alkoxy
analogues 15−21 with preferential formation of the β-D isomer.
4′-Fluorocordycepin 23 could also be prepared using DAST as
a fluoride source. Furthermore, radical-mediated allylation and
cyanoethylation of 7 gave 4′-allylcordycepin (24) and 4′-
cyanoethylcordycepin (25) derivatives, respectively.
1
Scheme 5. Reaction of 9 with DAST in the Presence of NBS
EXPERIMENTAL SECTION
■
NMR spectra were recorded either at 400 MHz or at 500 MHz.
Chemical shifts are reported relative to Me4Si. Mass spectra (MS)
were taken in FAB mode with m-nitrobenzyl alcohol as a matrix.
Column chromatography was carried out on silica gel. Thin-layer
chromatography (TLC) was performed on silica gel F254 plates. When
necessary, analytical samples were purified by high-performance liquid
chromatography (HPLC) with a Shim-Pack PREP-SIL (H) KIT
column (2 × 25 cm).
Finally, introduction of a carbon substituent was examined.
We have already reported that reaction of the 1′-phenylsulfanyl-
2′-deoxyuridine derivative with Bu3SnCH2CHCH2 in the
presence of AIBN under reflux conditions gave the 1′-allyl-2′-
deoxyuridine derivative.17 Utilizing this procedure, 24a (β-D
isomer) was obtained in 7% yield. In contrast, 24a could be
obtained in 83% yield along with its epimer 24b by carrying out
the allylation under photochemical conditions initiated with
(Bu3Sn)2 at room temperature (24a/24b = 3.8/1) (Figure 4).
In addition to the above radical substitution reaction, a radical
addition reaction could be also carried out by using acrylonitrile
as a radical acceptor in the presence of Bu3SnH and AIBN
under reflux conditions to give the 4′-cyanoethyl derivative 25
in 49% yield.18
2′,5′-Bis-O-(tert-butyldimethylsilyl)-4′-phenylsulfanylcordy-
cepin (7a) and 9-[2,5-Bis-O-(tert-butyldimethylsilyl)-3-deoxy-4-
phenylsulfanyl-α-L-lyxofuranosyl]adenine (7b). To a CH2Cl2
(5.0 mL) solution of 2 (300 mg, 0.63 mmol) and NIS (283 mg,
1.26 mmol) was added PhSH (0.39 mL, 3.77 mmol), and the mixture
was stirred at room temperature for 3 min. After quenching with Et3N
(0.88 mL, 6.28 mmol), the reaction mixture was partitioned between
AcOEt and saturated aqueous Na2S2O3. The organic layer was washed
with saturated aqueous NaHCO3. Silica gel column chromatography
(hexane/AcOEt = 1/2) of the organic layer gave a mixture of 7a and
7b as a pale yellow foam (293 mg, 79%: 7a/7b = 6.6/1). HPLC
separation (hexane/AcOEt = 1/2) gave analytically pure 7a (tR = 7.8
min, foam) and 7b (tR = 12.2 min, foam).
Physical Data for 7a: UV (MeOH) λmax 259 nm (ε 17 600), λmin
1
234 nm (ε 4300); H NMR (CDCl3) δ −0.24, −0.13, 0.04, and 0.05
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(12H, each as s), 0.77 and 0.92 (18H, each as s), 2.15 (1H, dd, J = 7.3
and 13.2 Hz), 2.85 (1H, dd, J = 7.8 and 13.2 Hz), 3.68 (2H, s), 4.75
(1H, ddd, J = 6.3, 7.3, and 7.8 Hz), 5.70 (2H, br), 6.20 (1H, d, J = 6.3
Hz), 7.27−7.34 and 7.57−7.60 (5H, each as m), 8.07 (1H, s), 8.38
(1H, s); 13C NMR (CDCl3) δ −5.5, −5.33, −5.26, −5.2, 17.8, 18.4,
25.5, 25.9, 41.8, 68.1, 75.7, 88.9, 93.8, 119.7, 128.7, 128.9, 130.9, 135.8,
139.1, 150.3, 153.2, 155.3; NOE (CDCl3) H-5′/H-8 (0.4%), H-5′/H-
3′b (δ 2.85) (1.6%), H-1′/H-3′a (δ 2.15 ppm) (1.7%), H-2′/H-3′b
(10.1%), H-2′/H-5′ (0.5%), H-1′/H-Ph (2.2%); FAB-MS (m/z) 588
(M+ + H). Anal. Calcd for C28H45N5O3SSi2: C, 57.20; H, 7.71; N,
11.91. Found: C, 57.19; H, 7.82; N, 11.82.
Physical Data for 7b: UV (MeOH) λmax 259 nm (ε 17 800), λmin
234 nm (ε 5300); 1H NMR (CDCl3) δ −0.11, −0.03, −0.02, and 0.01
(12H, each as s), 0.81 and 0.91 (18H, each as s), 2.34 (1H, dd, J = 6.6
and 13.8 Hz), 2.69 (1H, dd, J = 6.6 and 13.8 Hz), 3.66 and 3.79 (2H,
each as d, Jgem = 10.6 Hz), 4.87 (1H, dt, J = 4.4 and 6.6 Hz), 5.76 (2H,
br, 6-NH2), 6.15 (1H, d, J = 4.4 Hz), 7.25−7.35 and 7.51−7.53 (5H,
each as m), 8.33 (1H, s), 8.36 (1H, s); 13C NMR (CDCl3) δ −5.5,
−5.3, −5.11, −5.09, 17.8, 18.2, 25.6, 25.8, 40.8, 66.2, 76.4, 91.3, 97.1,
119.7, 128.8, 130.8, 135.2, 139.6, 150.2, 153.2, 155.3; NOE (CDCl3)
H-5′b (δ 3.79)/H-1′ (1.7%), H-1′/H-3′b (δ 2.69) (3.7%), H-3′b/H-5′b
(1.5%), H-2′/H-3′a (δ 2.34) (4.2%), H-3′a/H-8 (1.7%), H-3′a/H-Ph
(2.2%); FAB-MS (m/z ) 588 (M+ + H). Anal. Calcd for
C28H45N5O3SSi2: C, 57.20; H, 7.71; N, 11.91. Found: C, 57.21; H,
7.69; N, 12.06.
Reaction of 8 with PhSH in the Presence of NIS: Formation
of 9a,b. To a CH2Cl2 (6.3 mL) solution of 8 (460 mg, 0.82 mmol)
and NIS (184 mg, 0.82 mmol) was added PhSH (0.51 mL, 4.92
mmol) and the mixture was stirred at room temperature for 3 min.
The reaction mixture was partitioned between AcOEt and saturated
aqueous Na2S2O3. The organic layer was washed with saturated
aqueous NaHCO3. Silica gel column chromatography (hexane/AcOEt
= 3/1) of the organic layer gave a mixture of 9a and 9b as a pale yellow
foam (184 mg, 33%: 9a/9b = 6.2/1).
9-[2,5-Bis-O-(tert-butyldimethylsilyl)-3-deoxy-β-D-glycero-
pent-3-enofuranosyl]-N6-dimethyladenine (10). Compound 10
was prepared from N,N-dimethyladenosine15 in 30% overall yield by
four steps according to the published procedure.12
d, J = 10.6 Hz), 3.76 (1H, d, J = 10.6 Hz), 4.82 (1H, ddd, J = 4.4, 6.3,
and 6.6 Hz), 6.19 (1H, d, J = 4.4 Hz), 7.24−7.33 and 7.51−7.53 (5H,
each as m), 8.33 (1H, s), 8.34 (1H, s); 13C NMR (CDCl3) δ −5.5,
−5.3, −5.13, −5.08, 17.9, 18.2, 25.6, 25.8, 38.5, 41.9, 66.0, 76.6, 91.2,
97.1, 120.1, 128.7, 128.7, 131.0, 135.1, 137.2, 150.7, 152.6, 154.9; NOE
(CDCl3): H-1′/H-5′b (δ 3.76) (1.8%), H-1′/H-3′b (δ 2.67) (4.1%), H-
3′b/H-5′b (1.5%), H-8/H-3′a (δ 2.32) (0.2%); FAB-HRMS (m/z)
calcd for C30H50N5O3SSi2 616.3173, found 616.3151 (M+ + H).
Reaction of 10 with PhSD/NIS: Preparation of 11−14.
Compounds 11−14 (191 mg, β-D/α-L = 6.2/1) were obtained in 77%
yield from 10 (200 mg, 0.40 mmol) as described for the synthesis of 7.
The ratio 11/12/13/14 (=26/3.3/1.0/4.0) was calculated as shown in
Table 3.
Table 3
chem shift (ppm)
integration
assigned proton
2.13
2.32
2.67
2.86
6.19
6.24
5.04
0.51
0.85
1.75
1.00
5.61
H-3′a (β-D isomer)
H-3′a (α-L isomer)
H-3′b (α-L isomer)
H-3′b (β-D isomer)
H-1′ (α-L isomer)
H-1′ (β-D isomer)
a
11/12/13/14 = (5.6 1− 1.75)/(1.00 − 0.51)/(1.00 − 0.85)/(5.61 −
5.04).
2′,5′-Bis-O-(tert-butyldimethylsilyl)-4′-phenylsulfanyl-N 6-
pivaloylcordycepin (9a) and 9-[2,5-Bis-O-(tert-butyldimethyl-
silyl)-3-deoxy-4-phenylsulfanyl-α-L-lyxofuranosyl]-N6-pivaloy-
ladenine (9b). A CH2Cl2 (20 mL) solution of a mixture of 7a and 7b
(1.89 g, 3.21 mmol, β-D/α-L = 9/1), pivaloyl chloride (0.48 mL, 3.86
mmol), and i-Pr2NEt (0.84 mL, 4.82 mmol) was stirred at room
temperature for 3 h. The reaction mixture was partitioned between
CH2Cl2 and saturated aqueous NaHCO3. Silica gel column
chromatography (hexane/AcOEt = 3/1) of the organic layer gave 9
(1.92 g, 89%, β-D/α-L = 9/1) as a foam. HPLC separation (hexane/
AcOEt = 2/1) gave analytically pure 9a (tR = 6.8 min, foam) and 9b
(tR = 8.7 min, foam).
Physical Data for 10: UV (MeOH) λmax 274 nm (ε 18 400), λmin
1
Physical Data for 9a: UV (MeOH) λmax 260 nm (ε 16 900), λmin
238 nm (ε 2600); H NMR (CDCl3) δ 0.04, 0.07, 0.09, and 0.10
1
235 nm (ε 5500); H NMR (CDCl3) δ −0.27, −0.13, 0.04, and 0.05
(12H, each as s), 0.88 and 0.91 (18H, each as s), 3.52 (6H, br), 4.24
and 4.29 (2H, each as d, J = 14.8 Hz), 5.17 (1H, d, J = 0.9 Hz), 5.24
(1H, dd, J = 0.9 and 1.9 Hz), 6.44 (1H, d, J = 1.9 Hz), 7.73 (1H, s),
8.36 (1H, s); 13C NMR (CDCl3) δ −5.43, −5.41, −4.6, −4.5, 18.0,
18.3, 25.7, 25.8, 38.5, 58.6, 80.1, 91.6, 99.4, 119.9, 135.2, 150.2, 152.8,
154.9, 161.9; FAB-MS (m/z) 506 (M+ + H). Anal. Calcd for
C24H43N5O3Si2: C, 56.99; H, 8.57; N, 13.85. Found: C, 56.83; H, 8.61;
N, 13.61.
(12H, each as s), 0.76 and 0.91 (18H, each as s), 1.41 (9H, s), 2.16
(1H, dd, J = 7.5 and 13.2 Hz), 2.86 (1H, dd, J = 8.0 and 13.2 Hz), 3.65
and 3.69 (2H, each as d, J = 10.9 Hz), 4.76 (1H, ddd, J = 6.3, 7.5, and
8.0 Hz), 6.23 (1H, d, J = 6.3 Hz), 7.27−7.36 and 7.56−7.59 (5H, each
as m), 8.21 (1H, s), 8.49 (1H, br), 8.78 (1H, s); 13C NMR (CDCl3) δ
−5.5, −5.34, −5.25, −5.1, 17.8 18.3, 25.4, 25.9, 27.4, 40.5, 41.8, 68.0,
75.5, 88.8, 93.8, 122.7, 128.7, 129.0, 130.6, 135.8, 141.1, 149.5, 151.9,
152.9, 175.6; FAB-MS (m/z) 673 (M+ + H). Anal. Calcd for
C33H53N5O4SSi2: C, 58.98; H, 7.95; N, 10.42. Found: C, 58.82; H,
8.07; N, 10.42.
Deuterium Exchange Experiment. Undeuterated compounds
(661 mg, β-D/α-L = 6.9/1) were obtained in 75% yield from 10 (725
mg, 1.43 mmol) as described for the synthesis of 7.
Physical Data for 2′,5′-Bis-O-(tert-butyldimethylsilyl)-N6-dimeth-
yl-4′-phenylsulfanylcordycepin (β-D Isomer): UV (MeOH) λmax 272
Physical Data for 9b: UV (MeOH) λmax 260 nm (ε 16 900), λmin
1
235 nm (ε 5500); H NMR (CDCl3) δ −0.12, −0.04, 0.02, and 0.01
1
nm (ε 22 800), λmin 237 nm (ε 6300); H NMR (CDCl3) δ −0.23,
(12H, each as s), 0.81 and 0.91 (18H, each as s), 1.42 (9H, s), 2.33
(1H, dd, J = 6.6 and 13.9 Hz), 2.71 (1H, dd, J = 6.3 and 13.9 Hz), 3.65
and 3.79 (2H, each as d, J = 10.6 Hz), 4.85 (1H, ddd, J = 4.4, 6.3, and
6.6 Hz), 6.22 (1H, d, J = 4.4 Hz), 7.25−7.35 and 7.50−7.53 (5H, each
as m), 8.48 (1H, br), 8.59 (1H, s), 8.75 (1H, s); 13C NMR (CDCl3) δ
−5.5, −5.3, −5.1, −5.0, 17.8, 18.2, 25.6, 25.8, 27.4, 40.5, 40.7, 66.0,
76.5, 91.6, 97.3, 122.9, 128.8, 128.9, 130.7, 135.1, 141.9, 149.4, 151.8,
152.8, 175.7; FAB-MS (m/z) 672 (M+ + H). Anal. Calcd for
C33H53N5O4SSi2: C, 58.98; H, 7.95; N, 10.42. Found: C, 58.97; H,
8.07; N, 10.48.
−0.12, 0.02, and 0.03 (12H, each as s), 0.77 and 0.91 (18H, each as s),
2.13 (1H, dd, J = 7.4 and 13.2 Hz), 2.86 (1H, dd, J = 7.8 and 13.2 Hz),
3.52 (6H, br), 3.64 (1H, d, J = 10.8 Hz), 3.67 (1H, d, J = 10.8 Hz),
4.76 (1H, ddd, J = 6.7, 7.4, and 7.8 Hz), 6.24 (1H, d, J = 6.7 Hz),
7.24−7.60 (5H, m), 7.92 (1H, s), 8.36 (1H, s); 13C NMR (CDCl3) δ
−5.5, −5.3, −5.24, −5.21, 17.8, 18.3, 25.5, 25.9, 38.5, 41.8, 67.9, 75.1,
88.2, 93.3, 120.2, 128.6, 128.8, 131.0, 135.8, 136.5, 150.9, 152.6, 154.9;
NOE (CDCl3): H-Ph/H-1′ (2.3%), H-1′/H-3′a (δ 2.13) (4.1%), H-3′b
(δ 2.86)/H-8 (0.4%); FAB-MS (m/z) 616 (M+ + H). Anal. Calcd for
C30H49N5O3SSi2: C, 58.50; H, 8.02; N, 11.37. Found: C, 58.49; H,
8.08; N, 11.10.
2′,5′-Bis-O-(tert-butyldimethylsilyl)-4′-methoxycordycepin
(15a) and 9-[2,5-Bis-O-(tert-butyldimethylsilyl)-3-deoxy-4-me-
thoxy-α-L-lyxofuranosyl]adenine (15b). Compound 9 (150 mg,
0.223 mmol, 9a/9b = 9/1) and NBS (60 mg, 0.335 mmol) were
dissolved in MeOH (3.0 mL), and the reaction mixture was stirred at
room temperature for 45 min. Evaporation of the resulting solution
was followed by washing with AcOEt and saturated aqueous Na2S2O3.
Physical Data for 9-[2,5-Bis-O-(tert-butyldimethylsilyl)-3-deoxy-
4-phenylsulfanyl-α-L-lyxofuranosyl]-N6-dimethyladenine (α-L Iso-
mer): 1H NMR (CDCl3) δ −0.10, −0.05, −0.03, and 0.00 (12H,
each as s), 0.81 and 0.90 (18H, each as s), 2.32 (1H, dd, J = 6.6 and
13.8 Hz), 2.67 (1H, dd, J = 6.3 and 13.8 Hz), 3.54 (6H, br), 3.63 (1H,
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The organic layer was evaporated, and the residue was treated with
NH3/MeOH (ca. 30 mL) at 0 °C for 24 h. Evaporation of the solvent
followed by column chromatography (hexane/AcOEt = 1/5) of the
residue gave 15a,b (105 mg, 93%, β-D/α-L = 1.6/1) as a foam. HPLC
separation (CHCl3/MeOH = 60/1) gave analytically pure β-D isomer
(tR = 6.6 min, foam) and α-L isomer (tR = 8.2 min, foam).
Physical Data for 17a: UV (MeOH) λmax 259 nm (ε 14 600), λmin
228 nm (ε 2200); H NMR (CDCl3) δ −0.23, −0.14, 0.15, and 0.16
1
(12H, each as s), 0.77 (9H, s), 0.95 (3H, t, J = 7.3 Hz), 0.97 (9H, s),
1.59 (2H, hex, J = 7.3 Hz), 2.20 (1H, dd, J = 7.6 and 13.4 Hz), 2.60
(1H, dd, J = 7.8 and 13.4 Hz), 3.54−3.65 (2H, m), 3.65 (1H, d, J =
10.4 Hz), 3.81 (1H, d, J = 10.4 Hz), 4.66 (1H, ddd, J = 5.9, 7.6, and 7.8
Hz), 5.92 (2H, br), 6.16 (1H, d, J = 5.9 Hz), 8.12 (1H, s), 8.36 (1H,
s); 13C NMR (CDCl3) δ −5.4, −5.34, −5.30, −5.27, 10.6, 17.8, 18.4,
23.3, 25.5, 26.0, 39.7, 63.8, 66.6, 77.0, 89.5, 108.9, 119.5, 138.8, 150.1,
153.1, 155.4; NOE (CDCl3): H-5′b (δ 3.81)/H-8 (1.1%), H-1′/4′-
OCH2 (1.4%); FAB-MS (m/z) 538 (M+ + H). Anal. Calcd for
C25H47N5O4Si2: C, 55.83; H, 8.81; N, 13.02. Found: C, 55.91; H, 9.01;
N, 13.02.
Physical Data for 15a: UV (MeOH) λmax 260 nm (ε 14 200), λmin
1
228 nm (ε 1100); H NMR (CDCl3) δ −0.23, −0.13, 0.14, and 0.16
(12H, each as s), 0.77 and 0.97 (18H, each as s), 2.20 (1H, dd, J = 7.8
and 13.7 Hz), 2.61 (1H, dd, J = 7.8 and 13.7 Hz), 3.43 (3H, s), 3.65
(1H, d, J = 10.2 Hz), 3.80 (1H, d, J = 10.2 Hz), 4.73 (1H, dt, J = 5.8
and 7.8 Hz), 6.13 (2H, br), 6.15 (1H, d, J = 5.8 Hz), 8.16 (1H, s), 8.36
(1H, s); 13C NMR (CDCl3) δ −5.44, −5.35, −5.30, −5.25, 17.8, 18.4,
25.5, 26.0, 39.2, 49.7, 66.2, 76.7, 89.5, 109.0, 119.6, 138.8, 150.1, 153.1,
155.6; NOE (CDCl3): H-5′b (3.80 ppm)/H-8 (0.5%), H-1′/4′-OMe
(0.9%); FAB-MS (m/z ) 510 (M+ + H). Anal. Calcd for
C23H43N5O4Si2: C, 54.19; H, 8.50; N, 13.74. Found: C, 53.89; H,
8.63; N, 13.51.
Physical Data for 17b: UV (MeOH) λmax 259 nm (ε 15 400), λmin
1
228 nm (ε 3100); H NMR (CDCl3) δ −0.03, 0.01, 0.10, and 0.11
(12H, each as s), 0.85 (9H, s), 0.93 (3H, t, J = 7.3 Hz), 0.94 (9H, s),
1.62 (2H, ddq, J = 6.8, 7.1, and 7.3 Hz), 2.31 (1H, dd, J = 6.3 and 13.9
Hz), 2.40 (1H, dd, J = 5.1 and 13.9 Hz), 3.54 (1H, dt, J = 6.8 and 8.8
Hz), 3.60 (1H, dt, J = 7.1 and 8.8 Hz), 3.75 (1H, d, J = 10.7 Hz), 3.89
(1H, d, J = 10.7 Hz), 4.88 (1H, ddd, J = 3.2, 5.1, and 6.3 Hz), 6.01
(2H, br), 6.08 (1H, d, J = 3.2 Hz), 8.12 (1H, s), 8.35 (1H, s); 13C
NMR (CDCl3) δ −5.5, −5.4, −5.1, −5.0, 10.7, 17.8, 18.2, 23.1, 25.6,
25.8, 41.2, 63.98, 64.03, 76.1, 91.1, 110.9, 119.8, 139.3, 149.9, 153.0,
155.5; NOE (CDCl3) H-8/4′-OCH2 (1.2%); FAB-MS (m/z) 538 (M+
+ H). Anal. Calcd for C25H47N5O4Si2: C, 55.83; H, 8.81; N, 13.02.
Found: C, 55.91; H, 8.99; N, 13.12.
Physical Data for 15b: UV (MeOH) λmax 260 nm (ε 14 800), λmin
228 nm (ε 1800); 1H NMR (CDCl3) δ −0.06, −0.01, 0.11 (12H, each
as s), 0.83 and 0.94 (18H, each as s), 2.33 (1H, dd, J = 6.6 and 13.7
Hz), 2.38 (1H, dd, J = 5.9 and 13.7 Hz), 3.38 (3H, s), 3.72 (1H, d, J =
10.7 Hz), 3.88 (1H, d, J = 10.7 Hz), 4.94 (1H, ddd, J = 3.7, 5.9, and 6.6
Hz), 5.59 (2H, br), 6.09 (1H, d, J = 3.7 Hz), 8.07 (1H, s), 8.37 (1H,
s); 13C NMR (CDCl3) δ −5.5, −5.3, −5.1, −5.0, 17.8, 18.2, 25.6, 25.8,
41.5, 49.9, 63.3, 76.2, 91.0, 110.7, 119.8, 139.3, 150.1, 153.1, 155.4;
NOE (CDCl3): H-5′a (δ 3.72)/H-1′ (0.9%), H-8/4′-OMe (2.8%);
FAB-MS (m/z) 510 (M+ + H). Anal. Calcd for C23H43N5O4Si2: C,
54.19; H, 8.50; N, 13.74. Found: C, 54.30; H, 8.71; N, 13.72.
2′,5′-Bis-O-(tert-butyldimethylsilyl)-4′-ethoxycordycepin
(16a) and 9-[2,5-Bis-O-(tert-butyldimethylsilyl)-3-deoxy-4-
ethoxy-α-L-lyxofuranosyl]adenine (16b). Compounds 16a and
16b were prepared as described above for 15 by starting from an
EtOH (3.0 mL) solution of 9 (9a/9b = 9/1, 150 mg, 0.223 mmol) and
NBS (60 mg, 0.335 mmol). HPLC separation (CHCl3/MeOH = 60/
1) of the reaction mixture (16a/16b = 1.5/1, 86% yield) gave
analytically pure 16a (tR = 6.2 min, foam) and 16b (tR = 7.3 min,
foam).
4′-Butyloxy-2′,5′-bis-O-(tert-butyldimethylsilyl)cordycepin
(18a) and 9-[4-Butyloxy-2,5-bis-O-(tert-butyldimethylsilyl)-3-
deoxy-α-L-lyxofuranosyl]adenine (18b). Compounds 18a and
18b were prepared as described above for 15 starting from an n-
butanol (3.0 mL) solution of 9 (9a/9b = 9/1, 150 mg, 0.223 mmol)
and NBS (60 mg, 0.335 mmol). HPLC separation (CHCl3/MeOH =
80/1) of the reaction mixture (18a/18b = 2.0/1.0, 98%) gave
analytically pure 18a (tR = 6.5 min, foam) and 18b (tR = 7.5 min,
foam).
Physical Data for 18a: UV (MeOH) λmax 259 nm (ε 14 700), λmin
1
228 nm (ε 2300); H NMR (CDCl3) δ −0.23, −0.14, 0.14, and 0.16
(12H, each as s), 0.77 (9H, s), 0.92 (3H, t, J = 7.3 Hz), 0.97 (9H, s),
1.35−1.44 (2H, m), 1.52−1.59 (2H, m), 2.20 (1H, dd, J = 7.6 and 13.4
Hz), 2.60 (1H, dd, J = 7.8 and 13.4 Hz), 3.57−3.71 (3H, m), 3.80
(1H, d, J = 10.5 Hz), 4.66 (1H, ddd, J = 5.9, 7.6, and 7.8 Hz), 5.92
(2H, br), 6.15 (1H, d, J = 5.9 Hz), 8.18 (1H, s), 8.36 (1H, s); 13C
NMR (CDCl3) δ −5.4, −5.34, −5.30, −5.27, 13.9, 17.8, 18.4, 19.3,
25.5, 26.0, 32.1, 39.7, 66.6, 77.0, 89.5, 108.9, 119.6, 138.8, 150.1, 153.1,
155.4; NOE (CDCl3) H-1′/4′-OCH2 (1.6%), H-5′b (δ 3.80)/H-8
(0.5%); FAB-MS (m/z ) 552 (M+ + H). Anal. Calcd for
C26H49N5O4Si2: C, 56.59; H, 8.95; N, 12.69. Found: C, 56.73; H,
9.21; N, 12.77.
Physical Data for 16a: UV (MeOH) λmax 260 nm (ε 14 200), λmin
228 nm (ε 1100); H NMR (CDCl3) δ −0.24, −0.14, 0.15, and 0.16
1
(12H, each as s), 0.77 and 0.97 (18H, each as s), 1.22 (3H, t, J = 6.9
Hz), 2.21 (1H, dd, J = 7.8 and 13.4 Hz), 2.60 (1H, dd, J = 8.0 and 13.4
Hz), 3.64−3.82 (4H, m), 4.67 (1H, ddd, J = 5.9, 7.8, and 8.0 Hz), 5.79
(2H, br), 6.15 (1H, d, J = 5.9 Hz), 8.18 (1H, s), 8.36 (1H, s); 13C
NMR (CDCl3) δ −5.4, −5.33, −5.30, −5.25, 15.6, 17.8, 25.5, 26.0,
39.7, 57.7, 66.6, 76.9, 89.4, 108.9, 119.6, 138.8, 150.2, 153.1, 155.4;
NOE (CDCl3): H-1′/4′-OCH2 (0.9%); FAB-MS (m/z) 524 (M+ +
H). Anal. Calcd for C24H45N5O4Si2: C, 55.03; H, 8.66; N, 13.37.
Found: C, 55.14; H, 8.82; N, 13.34.
Physical Data for 18b: UV (MeOH) λmax 260 nm (ε 14 400), λmin
Physical Data for 16b: UV (MeOH) λmax 260 nm (ε 14 400), λmin
1
1
228 nm (ε 2300); H NMR (CDCl3) δ −0.02, 0.02, 0.10, and 0.11
227 nm (ε 1800); H NMR (CDCl3) δ −0.03, 0.01, 0.10, and 0.11
(12H, each as s), 0.85 (9H, s), 0.92 (3H, t, J = 7.6 Hz), 0.94 (9H, s),
1.33−1.43 (2H, m), 1.55−1.62 (2H, m), 2.30 (1H, dd, J = 6.5 and 13.9
Hz), 2.40 (1H, dd, J = 4.9 and 13.9 Hz), 3.58 (1H, dt, J = 6.8 and 8.8
Hz), 3.65 (1H, dt, J = 7.1 and 8.8 Hz), 3.75 (1H, d, J = 10.7 Hz), 3.89
(1H, d, J = 10.7 Hz), 4.87 (1H, ddd, J = 3.2, 4.9, and 6.5 Hz), 6.06
(2H, br), 6.08 (1H, d, J = 3.2 Hz), 8.12 (1H, s), 8.35 (1H, s); 13C
NMR (CDCl3) δ −5.5, −5.4, −5.1, −5.0, 13.9, 17.8, 18.2, 19.4, 25.6,
25.8, 31.9, 41.2, 62.2, 64.0, 76.1, 91.1, 110.9, 119.8, 139.3, 149.9, 153.0,
155.5; NOE (CDCl3) H-8/4′-OCH2 (1.0%), H-1′/H-5′a (δ 3.75)
(0.7%); FAB-MS (m/z ) 552 (M+ + H). Anal. Calcd for
C26H49N5O4Si2: C, 56.59; H, 8.95; N, 12.69. Found: C, 56.64; H,
9.11; N, 12.72.
2′,5′-Bis-O-(tert-butyldimethylsilyl)-4′-isopropyloxycordyce-
pin (19a) and 9-[2,5-Bis-O-(tert-butyldimethylsilyl)-3-deoxy-4-
isopropyloxy-α-L-lyxofuranosyl]adenine (19b). Compounds 19a
and 19b were prepared as described above for 15 by starting from an
isopropyl alcohol (3.0 mL) solution of 9 (9a/9b = 9/1, 150 mg, 0.223
mmol) and NBS (60 mg, 0.335 mmol). HPLC separation (CHCl3/
MeOH = 80/1) of the reaction mixture (19a/19b = 1.8/1, 91%) gave
(12H, each as s), 0.85 and 0.93 (18H, each as s), 1.23 (3H, t, J = 7.1
Hz), 2.31 (1H, dd, J = 6.5 and 13.9 Hz), 2.39 (1H, dd, J = 5.1 and 13.9
Hz), 3.60−3.75 (2H, m), 3.74 (1H, d, J = 10.7 Hz), 3.89 (1H, d, J =
10.7 Hz), 4.89 (1H, ddd, J = 3.4, 5.1, and 6.5 Hz), 5.85 (2H, br), 6.08
(1H, d, J = 3.4 Hz), 8.13 (1H, s), 8,36 (1H, s); 13C NMR (CDCl3) δ
−5.5, −5.3, −5.1, −5.0, 15.4, 17.8, 18.2, 25.6, 41.4, 57.9, 64.0, 76.2,
91.1, 110.9, 119.8, 139.3, 149.9, 153.1, 155.4; NOE (CDCl3): H-5′a (δ
3.74)/H-1′ (0.3%), H-8/4′-OCH2 (0.9%); FAB-MS (m/z) 524 (M+ +
H). Anal. Calcd for C24H45N5O4Si2: C, 55.03; H, 8.66; N, 13.37.
Found: C, 54.83; H, 8.59; N, 13.39.
2′,5′-Bis-O-(tert-butyldimethylsilyl)-4′-propyloxycordycepin
(17a) and 9-[2,5-Bis-O-(tert-butyldimethylsilyl)-3-deoxy-4-pro-
pyloxy-α-L-lyxofuranosyl]adenine (17b). Compounds 17a and
17b were prepared as described above for 15 by starting from a
propanol (3.0 mL) solution of 9 (9a/9b = 9/1, 150 mg, 0.223 mmol)
and NBS (60 mg, 0.335 mmol). HPLC separation (CHCl3/MeOH =
70/1) of the reaction mixture (17a/17b = 9/1, 150 mg, 0.223 mmol)
gave analytically pure 17a (tR = 6.6 min, foam) and 17b (tR = 7.8 min,
foam).
8715
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analytically pure 19a (tR = 7.0 min, foam) and 19b (tR = 8.7 min,
foam).
separation (CHCl3/MeOH = 80/1) of the reaction mixture (21a/21b
= 2.6/1, 88%) gave analytically pure 21a (tR = 6.9 min, foam) and 21b
(tR = 8.5 min, foam).
Physical Data for 19a: UV (MeOH) λmax 259 nm (ε 14 600), λmin
1
228 nm (ε 2100); H NMR (CDCl3) δ −0.23, −0.14, 0.15, and 0.17
Physical Data for 21a: UV (MeOH) λmax 260 nm (ε 15 000), λmin
1
(12H, each as s), 0.77 and 0.97 (18H, each as s), 1.18 and 1.22 (6H,
each as d, J = 6.1 Hz), 2.15 (1H, dd, J = 7.8 and 13.4 Hz), 2.63 (1H,
dd, J = 7.8 and 13.4 Hz), 3.62 (1H, d, J = 10.2 Hz), 3.79 (1H, d, J =
10.2 Hz), 4.18 (1H, sept, J = 7.1 Hz), 4.63 (1H, dt, J = 5.9 and 7.8
Hz), 5.92 (2H, br), 6.18 (1H, d, J = 5.9 Hz), 8.20 (1H, s), 8.36 (1H,
s); 13C NMR (CDCl3) δ −5.4, −5.33, −5.29, −5.25, 17.8, 18.4, 24.6,
24.6, 25.5, 26.0, 41.0, 65.7, 66.8, 77.0, 89.4, 109.4, 119.6, 138.8, 150.2,
153.1, 155.4; NOE (CDCl3) H-8/H-5′b (δ 3.79) (0.4%), H-1′/4′-
OCH (4.6%); FAB-MS (m/z) 538 (M+ + H). Anal. Calcd for
C25H47N5O4Si2: C, 55.83; H, 8.81; N, 13.02. Found: C, 55.87; H, 9.00;
N, 13.11.
228 nm (ε 2300); H NMR (CDCl3) δ −0.21, −0.13, 0.15, and 0.17
(12H, each as s), 0.78 and 0.98 (18H, each as s), 1.36 (9H, s), 2.19
(1H, dd, J = 7.6 and 13.0 Hz), 2.70 (1H, dd, J = 7.6 and 13.0 Hz), 3.57
(1H, d, J = 10.1 Hz), 3.94 (1H, d, J = 10.1 Hz), 4.56 (1H, dt, J = 5.5
and 7.6 Hz), 6.03 (2H, br), 6.23 (1H, d, J = 5.5 Hz), 8.24 (1H, s), 8.37
(1H, s); 13C NMR (CDCl3) δ −5.4, −5.31, −5.25, −5.2, 17.8, 18.5,
25.5, 26.0, 31.0, 44.3, 68.1, 76.1, 77.2, 89.4, 109.9, 119.5, 138.8, 150.1,
153.1, 155.5; NOE (CDCl3) H-1′/4′-O-tBu (4.6%), H-8/H-5′b (δ
3.94) (0.8%); FAB-MS (m/z) 552 (M+ + H). Anal. Calcd for
C26H49N5O4Si2: C, 56.59; H, 8.95; N, 12.69. Found: C, 56.61; H, 9.17;
N, 12.84.
Physical Data for 21b: UV (MeOH) λmax 260 nm (ε 14 600), λmin
228 nm (ε 1100); H NMR (CDCl3) δ −0.04, 0.02, 0.10, and 0.12
Physical Data for 19b: UV (MeOH) λmax 260 nm (ε 14 900), λmin
228 nm (ε 2200); H NMR (CDCl3) δ −0.02, 0.02, 0.11, and 0.12
1
1
(12H, each as s), 0.84 and 0.95 (18H, each as s), 1.29 (9H, s), 2.31
(1H, dd, J = 6.6 and 13.7 Hz), 2.47 (1H, dd, J = 5.1 and 13.7 Hz), 3.83
(1H, d, J = 10.7 Hz), 3.93 (1H, d, J = 10.7 Hz), 4.78 (1H, ddd, J = 3.4,
5.1, and 6.6 Hz), 5.95 (2H, br), 6.23 (1H, d, J = 3.4 Hz), 8.25 (1H, s),
8.37 (1H, s); 13C NMR (CDCl3) δ −5.31, −5.26, −5.0, −4.9, 17.9,
18.2, 25.7, 25.9, 31.1, 44.2, 66.0, 76.1, 76.4, 91.0, 112.4, 119.6, 139.6,
150.1, 153.1, 155.4; NOE (CDCl3) H-1′/H-5′a (δ 3.83) (1.2%); FAB-
MS (m/z) 552 (M+ + H). Anal. Calcd for C26H49N5O4Si2: C, 56.59;
H, 8.95; N, 12.69. Found: C, 56.49; H, 9.16; N, 12.75.
2′,5′-Bis-O-(tert-butyldimethylsilyl)-4′-fluorocordycepin
(23a) and 9-[2,5-Bis-O-(tert-butyldimethylsilyl)-3-deoxy-4-fluo-
ro-α-L-lyxofuranosyl]adenine (23b). To a CH2Cl2 (6.0 mL)
solution of a mixture of 9 (100 mg, 0.15 mmol, 9a/9b = 8.2/1) and
NBS (39.2 mg, 0.22 mmol) was added DAST (0.059 mL, 0.45 mmol)
at 0 °C under an Ar atmosphere. The reaction mixture was stirred at
room temperature for 30 min and quenched with saturated aqueous
NaHCO3. The organic phase was washed with water, dried over
Na2SO4, and concentrated under reduced pressure. Silica gel column
chromatography (hexane/AcOEt = 6/1) of the residue afforded 22a,b
(65.8 mg, 75%, 22a/22b = 2.4/1) as a foam. Compound 22 was
treated with NH3/MeOH (ca. 50 mL) at 0 °C for 48 h. The reaction
mixture was evaporated to dryness, and silica gel column
chromatography (hexane/AcOEt = 3/1) of the residue gave 23
(85.4 mg, 95%) as a foam. HPLC separation (CHCl3/MeOH = 80/1)
gave analytically pure 23a (tR = 7.5 min, foam) and 23b (tR = 8.8 min,
foam). Stereochemistry at the 4′-position of 23b was determined by
NOE measurments of its 2′,5′-diacetate.
(12H, each as s), 0.85 and 0.94 (18H, each as s), 1.14 and 1.18 (6H,
each as d, J = 7.1 Hz), 2.29 (1H, dd, J = 6.6 and 14.0 Hz), 2.42 (1H,
dd, J = 4.6 and 14.0 Hz), 3.76 (1H, d, J = 10.7 Hz), 3.89 (1H, d, J =
10.7 Hz), 4.21 (1H, sept, J = 7.1 Hz), 4.82 (1H, ddd, J = 3.2, 4.6, and
6.6 Hz), 5.59 (2H, br), 6.07 (1H, d, J = 3.2 Hz), 8.19 (1H, s), 8.35
(1H, s); 13C NMR (CDCl3) δ −5.5, −5.4, −5.01, −4.97, 17.9, 18.2,
24.2, 24.3, 25.7, 25.8, 41.6, 64.7, 66.1, 75.6, 91.1, 111.4, 119.8, 139.8,
149.9, 153.0, 155.3; NOE (CDCl3) H-8/4′-OCH(CH3)2 (4.4%), H-1′/
H-5′a (δ 3.76) (1.0%); FAB-MS (m/z) 538 (M+ + H). Anal. Calcd for
C25H47N5O4Si2: C, 55.83; H, 8.81; N, 13.02. Found: C, 55.80; H, 9.08;
N, 12.91.
2′,5′-Bis-O-(tert-butyldimethylsilyl)-4′-isobutyloxycordyce-
pin (20a) and 9-[2,5-Bis-O-(tert-butyldimethylsilyl)-3-deoxy-4-
isobutyloxy-α-L-lyxofuranosyl]adenine (20b). Compounds 20a
and 20b were prepared as described above for 15, by starting from an
isobutyl alcohol (3.0 mL) solution of 9 (9a/9b = 9/1, 150 mg, 0.223
mmol) and NBS (60 mg, 0.335 mmol). HPLC separation (CHCl3/
MeOH = 80/1) of the reaction mixture (20a/20b = 2.3/1, 100%) gave
analytically pure 20a (tR = 6.7 min, foam) and 20b (tR = 7.9 min,
foam).
Physical Data for 20a: UV (MeOH) λmax 260 nm (ε 14 800), λmin
1
228 nm (ε 2200); H NMR (CDCl3) δ −0.23, −0.15, 0.15, and 0.16
(12H, each as s), 0.77 (9H, s), 0.92 and 0.94 (6H, each as d, J = 6.6
Hz), 0.97 (9H, s), 1.82 (1H, tsept, J = 6.6 Hz), 2.20 (1H, dd, J = 7.6
and 13.4 Hz), 2.61 (1H, dd, J = 8.0 and 13.4 Hz), 3.37 (1H, dd, J = 6.6
and 8.7 Hz), 3.65 (1H, d, J = 10.2 Hz), 3.81 (1H, d, J = 10.2 Hz), 4.44
(1H, dd, J = 6.6 and 8.7 Hz), 4.64 (1H, ddd, J = 5.6, 7.6, and 8.0 Hz),
5.82 (2H, br), 6.15 (1H, d, J = 5.6 Hz), 8.19 (1H, s), 8.36 (1H, s); 13
C
Physical Data for 23a: UV (MeOH) λmax 259 nm (ε 14 500), λmin
1
226 nm (ε 2200); H NMR (CDCl3) δ −0.01, 0.00, 0.10, and 0.11
NMR (CDCl3) δ −5.4, −5.32, −5.29, −5.26, 17.9, 18.4, 19.35, 19.41,
25.5, 26.0, 28.8, 39.7, 66.5, 68.7, 77.2, 89.6, 109.0, 119.6, 138.8, 150.1,
153.1, 155.4; NOE (CDCl3) H-1′/4′-OCH2 (4.6%); FAB-MS (m/z)
552 (M+ + H). Anal. Calcd for C26H49N5O4Si2: C, 56.59; H, 8.95; N,
12.69. Found: C, 56.68; H, 9.21; N, 12.89.
(12H, each as s), 0.85 and 0.92 (18H, each as s), 2.23 (1H, ddd, J =
3.4, 14.4, and 17.8 Hz), 2.89 (1H, ddd, J = 6.8, 14.4, and 25.1 Hz),
3.79 (1H, dd, J = 3.7 and 10.7 Hz), 3.88 (1H, dd, J = 7.3 and 10.7 Hz),
4.80 (1H, ddd, J = 3.2, 3.4, and 6.8 Hz), 5.83 (1H, br s), 6.30 (1H, dd,
J = 1.2 and 3.2 Hz), 8.06 (1H, s), 8.34 (1H, s); 13C NMR (CDCl3) δ
−5.5, −5.4, −5.1, −5.0, 17.8, 18.4, 25.5, 25.9, 39.8, 40.1, 63.9, 64.4,
75.7, 92.7, 119.4, 120.0, 121.6, 138.8, 149.6, 153.2, 155.4; NOE
(CDCl3) H-8/H-3′b (δ 2.89) (2.0%), H-1′/H-3′a (δ 2.23) (1.8%);
FAB-MS (m/z) 498 (M+ + H). Anal. Calcd for C22H40FN5O3Si2: C,
53.09; H, 8.10; N, 14.07. Found: C, 53.02; H, 8.17; N, 13.89.
Physical Data for 20b: UV (MeOH) λmax 260 nm (ε 14 300), λmin
1
227 nm (ε 900); H NMR (CDCl3) δ −0.02, 0.02, 0.10, and 0.11
(12H, each as s), 0.85 (9H, s), 0.92 (3H, d, J = 6.6 Hz), 0.93 (9H, s),
0.94 (3H, d, J = 6.6 Hz), 1.82 (1H, ddsept, J = 6.6 Hz), 2.20 (1H, dd, J
= 6.3 and 13.9 Hz), 2.61 (1H, dd, J = 4.9 and 13.9 Hz), 3.37 and 3.44
(2H, each as dd, J = 6.6 and 8.3 Hz), 3.65 (1H, d, J = 10.6 Hz), 3.81
(1H, d, J = 10.6 Hz), 4.64 (1H, ddd, J = 3.4, 4.9, and 6.3 Hz), 5.83
(2H, br), 6.15 (1H, d, J = 3.2 Hz), 8.19 (1H, s), 8.36 (1H, s); 13C
NMR (CDCl3) δ −5.5, −5.4, −5.1, −5.0, 17.9, 18.2, 19.5, 25.6, 25.8,
28.7, 41.0, 64.0, 68.9, 76.1, 91.2, 110.9, 119.9, 139.4, 149.9, 153.0,
155.4; NOE (CDCl3) H-8/4′-OCH2CH (1.6%), H-1′/H-5′a (δ 3.65)
(1.0%); FAB-MS (m/z ) 552 (M+ + H). Anal. Calcd for
C26H49N5O4Si2: C, 56.59; H, 8.95; N, 12.69. Found: C, 56.64; H,
9.19; N, 12.48.
Physical Data for 23b: UV (MeOH) λmax 259 nm (ε 14 800), λmin
1
227 nm (ε 2500); H NMR (CDCl3) δ −0.12, −0.05, 0.09, and 0.10
(12H, each as s), 0.80 and 0.91 (18H, each as s), 2.48 (1H, ddd, J =
7.1, 13.6, and 26.3 Hz), 2.51 (1H, ddd, J = 7.1, 13.6, and 26.6 Hz),
3.75−3.85 (2H, m), 5.01 (1H, dt J = 4.6 and 7.1 Hz), 5.95 (2H, br),
6.16 (1H, dd, J = 4.6 and 6.1 Hz), 8.06 (1H, s), 8.36 (1H, s); 13C
NMR (CDCl3) δ −5.41, −5.35, −5.21, −5.16, 17.8, 18.3, 25.5, 25.8,
40.7, 49.9, 64.4, 64.8, 75.8, 91.4, 119.6, 120.1, 122.4, 138.6, 138.6,
150.1, 153.3, 155.5; NOE (CDCl3) H-1′/H-3′a (δ 2.50) (1.0%), H-2′/
H-3′b (δ 3.06) (5.9%), H-3′a/H-5′a (δ 4.34) (2.5%); FAB-MS (m/z)
498 (M+ + H). Anal. Calcd for C22H40FN5O3Si2: C, 53.09; H, 8.10; N,
14.07. Found: C, 53.41; H, 8.28; N, 14.04.
4′-tert-Butoxy-2′,5′-bis-O-(tert-butyldimethylsilyl)-
cordycepin (21a) and 9-[4-tert-Butoxy-2,5-bis-O-(tert-butyldi-
methylsilyl)-3-deoxy-α-L-lyxofuranosyl]adenine (21b). Com-
pounds 21a and 21b were prepared as described above for 15, by
starting from a tert-butyl alcohol (3.0 mL) solution of 9 (9a/9b = 9/1,
150 mg, 0.223 mmol) and NBS (60 mg, 0.335 mmol). HPLC
4′-Allyl-2′,5′-bis-O-(tert-butyldimethylsilyl)cordycepin
(24a)7 and 9-[4-Allyl-2,5-bis-O-(tert-butyldimethylsilyl)-3-
8716
dx.doi.org/10.1021/jo201246y|J. Org. Chem. 2011, 76, 8710−8717

The Journal of Organic Chemistry
Article
deoxy-α-L-lyxofuranosyl]adenine (24b). A benzene (5.0 mL)
solution of a mixture of 7 (200 mg, 0.34 mmol, 7a/7b = 6.1/1),
allyltributylstannane (0.31 mL, 1.02 mmol), and bis(tributylstannane)
(0.09 mL, 0.17 mmol) was irradiated with a high-pressure mercury
lamp at room temperature for 30 min. Silica gel column
chromatography (hexane/AcOEt = 4/1) of the reaction mixture
afforded 24a,b (146.4 mg, 83%, 24a /24b = 3.8/1) as a foam.
Physical Data for 24b: UV (MeOH) λmax 259 nm (ε 15 000), λmin
Tetrahedron Lett. 1992, 33, 4129. (d) Kumamoto, H.; Hayakawa, H.;
Tanaka, H.; Shindoh, S.; Kato, K.; Miyasaka, T.; Endo, K.; Machida,
H.; Matsuda, A. Nucleosides Nucleotides 1998, 17, 15.
(5) (a) Koole, L. H.; Buck, M. H.; Bazin, H.; Chattopadhyaya, J.
Tetrahedron 1987, 43, 2989. (b) Bazin, H.; Chattopadhyaya, J. J. Chem.
Scr. 1986, 26, 13.
(6) Haraguchi, K.; Itoh, Y.; Tanaka, H. J. Synth. Org. Chem., Jpn.
2003, 61, 974.
(7) Kubota, Y.; Kunikata, M.; Ishizaki, N.; Haraguchi, K.; Odanaka,
Y.; Tanaka, H. Tetrahedron 2008, 64, 2391.
(8) Kubota, Y.; Kunikata, M.; Haraguchi, K.; Tanaka, H. J. Org.
Chem. 2009, 74, 3402.
(9) Nicolaou, K. C.; Seitz, S. P.; Papahatjis, D. P. J. Am. Chem. Soc.
1983, 105, 2430.
(10) Nicolaou, K. C.; Dolle, R. E.; Papahatjis, D. P.; Randall, J. L. J.
Am. Chem. Soc. 1984, 106, 4189.
1
228 nm (ε 2400); H NMR (CDCl3) δ −0.13, −0.04, 0.09, and 0.10
(12H, each as s), 0.81 and 0.94 (18H, each as s), 2.48 (1H, dd, J = 5.5
and 13.3 Hz), 2.51 (1H, dd, J = 7.0 and 13.3 Hz), 3.48 (2H, d, J = 3.4
Hz), 3.75−3.85 (2H, m), 4.97−5.17 (3H, m), 5.79 (2H, br), 5.84−
5.98 (2H, m), 7.93 (1H, s), 8.35 (1H, s); 13C NMR (CDCl3) δ −5.43,
−5.37, −5.1, 17.8, 18.2, 25.6, 25.9, 38.8, 41.4, 67.6, 75.6, 87.0, 91.6,
118.8, 120.3, 133.5, 139.4, 149.8, 152.9; NOE (CDCl3) H-3′a (δ
2.48)/H-5′ (3.7%), H-3′b (δ 2.51)/−CH2CHCH2 (3.1%); FAB-MS
(m/z) 520 (M+ + H). Anal. Calcd for C25H45N5O3Si2: C, 57.76; H,
8.73; N, 13.47. Found: C, 57.39; H, 8.82; N, 13.67.
(11) Keck, G. E.; Enholm, E. J.; Yates, J. B.; Wiley, M. R. Tetrahedron
1985, 41, 4079.
2′,5′-Bis-O-(tert-butyldimethylsilyl)-4′-cyanoethylcordyce-
pin (25). To a toluene (5.0 mL) solution of a mixture of 7 (200 mg,
0.34 mmol) and acrylonitrile (0.11 mL, 1.70 mmol) was added
dropwise Bu3SnH (0.10 mL, 0.37 mmol) and AIBN (31 mg, 0.19
mmol) dissolved in toluene (5.0 mL) over 1 h under a positive
pressure of dry Ar, and the solution was refluxed. The reaction mixture
was stirred for 3 h. Silica gel column chromatography (hexane/AcOEt
= 1/3) of the reaction mixture afforded 25 (88.3 mg, 49%) as a foam.
Physical Data for 25: 1H NMR (CDCl3) δ −0.09, −0.04, 0.09, and
0.11 (12H, each as s), 0.83 and 0.92 (18H, each as s), 1.91 (1H, dd, J =
5.4 and 13.1 Hz), 2.10 (1H, ddd, J = 6.6, 9.3, and 14.1 Hz), 2.21 (1H,
ddd, J = 6.1, 9.3, and 14.1 Hz), 2.45−2.56 (2H, m), 2.60 (1H, dd, J =
6.8 and 13.1 Hz), 3.55 (1H, d, J = 10.5 Hz), 3.81 (1H, d, J = 10.5 Hz),
5.08 (1H, ddd, J = 4.1, 5.4, and 6.8 Hz), 5.93 (1H, d, J = 4.1 Hz), 6.07
(2H, br), 8.04 (1H, s), 8.33 (1H, s); 13C NMR (CDCl3) δ −5.4, −5.1,
−5.0, 12.0, 17.7, 18.2, 25.5, 25.8, 32.9, 40.3, 67.3, 76.0, 86.3, 91.7,
119.7, 120.0, 139.4, 149.5, 152.8, 155.5; NOE (CDCl3) H-8/H-5′b (δ
3.81) (0.3%), H-2′/H-5′b (1.0%); FAB-HRMS (m/z) calcd for
C25H45N6O3Si2 533.3092, found 533.3114 (M+ + H).
(12) Kubota, Y.; Haraguchi, K.; Kunikata, M.; Hayashi, M.; Ohkawa,
M.; Tanaka, H. J. Org. Chem. 2006, 71, 1099.
(13) Of the two protons at the 3′-position, the one that appears at a
higher field is designated as H-3′a and the other as H-3′b. This is also
applicable to H-5′.
(14) Shono, T; Matsumura, Y.; Tsubata, K. Chem. Lett. 1979, 1051.
(15) Rife, J. P.; Cheng, C. S.; Moore, P. B.; Strobel, S. A. Nucleosides
Nucleotides 1998, 17, 2281.
(16) Compound 9 could be prepared from 7 in 89% yield.
(17) Kumamoto, H.; Murasaki, M.; Haraguchi, K.; Anamura, A.;
Tanaka, H. J. Org. Chem. 2002, 67, 6124−6130.
1
(18) Although a diastereomer of 25 was confirmed by H NMR
spectra of the reaction mixture, it could not be separated from other
unknown products by HPLC.
ASSOCIATED CONTENT
■
S
* Supporting Information
Figures giving 1H and 13C NMR spectra of all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Tel: +81 3 3784 8187. Fax: +81 3 3784 8252. E-mail: y-
kubota@pharm.showa-u.ac.jp; harakazu@pharm.showa-u.ac.jp.
■
ACKNOWLEDGMENTS
■
Financial support from the Japan Society for the Promotion of
Science (KAKENHI No. 23790141 to Y.K. and No. 21590123
to K.H.) is gratefully acknowledged. We are grateful to Miss Y.
Odanaka and Mrs. T. Matsubayashi (Center for Instrumental
Analysis, Showa University) for technical assistance with NMR,
MS, and elemental analyses.
REFERENCES
■
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8717
dx.doi.org/10.1021/jo201246y|J. Org. Chem. 2011, 76, 8710−8717