Nucleophilic substitution at the 4′-position of nucleosides: New access to a promising anti-HIV agent 2′,3′-didehydro-3′-deoxy- 4′-ethynylthymidine

Article abstract of DOI:10.1021/jo060194m

For the synthesis of 2′,3′-didehydro-3′-deoxy-4′- ethynylthymidine (8: 4′-Ed4T), a recently reported promising anti-HIV agent, a new approach was developed. Since treatment of 1-(2,5-dideoxy-β-L- glyceropent-4-enofuranosyl)thymine with Pb(OBz)₄

Full text of DOI:10.1021/jo060194m

Nucleophilic Substitution at the 4′-Position of Nucleosides:
New Access to a Promising Anti-HIV Agent
2′,3′-Didehydro-3′-deoxy-4′-ethynylthymidine
Kazuhiro Haraguchi,* Masanori Sumino, and Hiromichi Tanaka
School of Pharmaceutical Sciences, Showa UniVersity, 1-5-8 Hatanodai, Shinagawa-ku,
Tokyo 142-8555, Japan
harakazu@pharm.showa-u.ac.jp
ReceiVed January 29, 2006
For the synthesis of 2′,3′-didehydro-3′-deoxy-4′-ethynylthymidine (8: 4′-Ed4T), a recently reported
promising anti-HIV agent, a new approach was developed. Since treatment of 1-(2,5-dideoxy-â-L-glycero-
pent-4-enofuranosyl)thymine with Pb(OBz)4 allowed the introduction of the 4′-benzoyloxy leaving group,
nucleophilic substitution at the 4′-position became feasible for the first time. Thus, reaction between the
4′-benzoyloxy derivative (14) and Me3SiCtCAl(Et)Cl as a nucleophile led to the isolation of the desired
4′-“down”-ethynyl derivative (18) stereoselectively in 62% yield. As an application of this approach,
other 4′-substituted nucleosides, such as the 4′-allyl (24a) and 4′-cyano (26a) derivatives, were synthesized
using organosilicon reagents. In these instances, pretreatment of 14 with MeAlCl2 was necessary.
Introduction
of these 4′-carbon-substituted nucleosides has mostly relied on
manipulations of the 4′-hydroxymethyl derivative of nucleosides
or sugars that can be prepared by the well-known aldol-
Cannizzaro reaction of the corresponding aldehyde,4,5 although
several other newer synthetic methods for this class of nucleo-
sides are also available.6
With the aim of developing a new synthetic method for this
class of nucleosides with a wider scope, we have already carried
out ring-opening of 4′,5′-epoxynucleosides with organosilicon7
or organoaluminum8 reagents. One example is shown in Scheme
1 for the preparation of the 4′-methyl, 4′-vinyl, and 4′-ethynyl
analogues of 1-(2-deoxy-â-D-threo-pentofuranosyl)thymine. Thus,
oxidation of the 4′,5′-unsaturated derivative 39 with an acetone
Nucleosides constitute an important class of biologically
active compounds, especially as antiviral and antitumor agents.1
Recently, their 4′-carbon-substituted analogues have attracted
much attention due to the reported potent anti-HIV activity of
4′-cyanothymidine (1)2 and 4′-ethynylthymidine (2).3 Synthesis
(4) Nomura, M.; Shuto, S.; Tanaka, M.; Sasaki, T.; Mori, S.; Shigeta,
S.; Matsuda, A. J. Med. Chem. 1999, 42, 2901.
(5) Ohrui, H.; Kohgo, S.; Kitano, K.; Sakata, S.; Kodama, E.; Yoshimura,
K.; Matsuoka, M.; Shigeta, S.; Mitsuya, H. J. Med. Chem. 2000, 43, 4516.
(6) For an excellent review dealing with the synthesis and anti-HIV
activity of 4′-C-substituted nucleosides, see: Hayakawa, H.; Kohgo, S.;
Kitano, K.; Ashida, N.; Kodama, E.; Mitsuya, H.; Ohrui, H. AntiViral Chem.
Chemother. 2004, 15, 169.
(7) Haraguchi, K.; Takeda, S.; Tanaka, H. Org. Lett. 2003, 5, 1399.
(8) Haraguchi, K.; Takeda, S.; Tanaka, H.; Nitanda, T.; Baba, M.;
Dutschman, G. E.; Cheng, Y.-C. Bioorg. Med. Chem. Lett. 2003, 13, 3775.
(1) For a review, see: Nucleosides and Nucleotides as Antitumor and
AntiViral Agents; Chu, C. K., Baker, D. C., Eds.; Plenum Press: New York,
1993.
(2) O-Yang, C.; Wu, H. Y.; Fraser-Smith, E. B.; Walker, K. A. M.
Tetrahedron Lett. 1992, 33, 37.
(3) Kodama, E.; Kohgo, S.; Kitano, K.; Machida, H.; Gatanda, H.;
Shigeta, S.; Matsuoka, M.; Ohrui, H.; Mitsuya, H. Antimicrob. Agents
Chemother. 2001, 45, 1539.
10.1021/jo060194m CCC: $33.50 © 2006 American Chemical Society
Published on Web 05/11/2006
J. Org. Chem. 2006, 71, 4433-4438
4433

Haraguchi et al.
SCHEME 1
SCHEME 2
SCHEME 3
solution of dimethyldioxirane (DMDO) gave the epoxide 4,
which was then reacted with organoaluminum reagents (R3Al)
to furnish the 4′-carbon-substituted products (5-7).8
During this study, 2′,3′-didehydro-3′-deoxy-4′-ethynylthymi-
dine (8: 4′-Ed4T), prepared from 7 by a series of conventional
complex mixture of products due to concomitant occurrence of
other reaction pathways such as substitution of hydrogen at the
allylic position, skeletal rearrangement, double bond migration,
and C-C bond cleavage.12 Nevertheless, some successful
examples have been reported in the case of electron-rich olefins
such as enol ethers,13,14 since the initial step of the diacetox-
ylation is considered to be electrophilic in nature.
We first thought that reaction of Pb(OAc)4 with the conju-
gated diene 915 (Scheme 2) would allow regioselective vicinal
diacetoxylation to give the 4′-acetoxy-d4T derivative 10 due to
the presence of an enol ether structure and that this reaction,
when combined with subsequent nucleophilic 4′-ethynylation,
might constitute the most straightforward route to 4′-Ed4T (8).
Upon reacting Pb(OAc)4 (1.5 equiv) with 9 prepared by the
published procedure16 in toluene at room temperature for 5 h,
two products (10 and 11) were detected by TLC analysis
(hexane/EtOAc ) 1/2: 10, Rf 0.2; 11, Rf 0.38). Although silica
gel column chromatography allowed the isolation and structural
confirmation of these products (10, ca. 35%; 11, 50%), the 4′-
acetoxy derivative 10 appeared to be too unstable for further
reaction, liberating 11 during evaporation of the solvent or even
on standing at room temperature. This fact led us to examine
diacyloxylation of the previously employed 4′,5′-unsaturated
derivative (3).8
reactions, was found to be more potent against HIV than the
parent compound stavudine (d4T) and much less toxic to various
cells and also to mitochondrial DNA synthesis.10 This compound
has several additional advantages as a promising anti-HIV
agent: (1) it is a better substrate for human thymidine kinase
than d4T, (2) it is very much resistant to catabolism by
thymidine phosphorylase, and (3) its activity enhances in the
presence of a major mutation K103N, a known resistant
mutation for some non-nucleoside reverse transcriptase inhibi-
tors.10,11
To further evaluate 4′-Ed4T (8) in animal studies, we were
in need of an alternative synthetic method suitable for its large
scale preparation, since the route shown in Scheme 1 is frustrated
by inaccessibility of a highly concentrated acetone solution of
DMDO. One apparent means of settling this problem is to
introduce a leaving group to the 4′-position and execute
nucleophilic ethynylation. However, to the best of our knowl-
edge, there have been no precedents available for the introduc-
tion of a leaving group to the 4′-position of nucleosides. These
situations led us to carry out the present study. In this paper,
we demonstrate that the reaction between 1-(2,5-dideoxy-â-L-
glycero-pent-4-enofuranosyl)thymine and Pb(OCOR)4 allows
introduction of an acyloxy leaving group to the 4′-position, and
that nucleophilic ethynylation of the resulting 4′-acyloxy deriva-
tive with an organoaluminum reagent enabled us to prepare the
title compound (8) in a fairly large scale. Introduction of allyl
and cyano groups was also examined briefly by the use of
organosilicon reagents.
When the reaction of 3 with Pb(OAc)4 was carried out under
similar reaction conditions to those employed for 9, the
4′-acetoxy derivative 12a was obtained (Scheme 3),17 but the
yield was only 28%. The main product in this reaction was
devoid of UV absorption, and its FAB-MS [m/z 289 (M+
H)] and H NMR [δ 9.71 (1H, t, J ) 1.3 Hz, CHO)] spectra
suggested the depicted aldehyde structure 13a (60%).
+
1
It is conceivable that acidic reaction media encourages
protonation to the 4′-acetoxy group of 12, which renders attack
of a nucleophile (acetate anion?) to its carbonyl group feasible.
On the basis of this assumption, the diacetoxylation was re-
Results and Discussion
(12) Mihailovic, M. L.; Cekovic, Z.; Lorenc, L. In Organic Syntheses
by Oxidation with Metal Compound; Mijs, W. J., De Jonge, C. R. H. I.,
Eds.; Plenum Press: New York and London, 1986; pp 741-815.
(13) Criegee, R.; Dimroth, P.; Noll, K.; Simon, R.; Weis, C. Chem.
Ber.1957, 90, 1070.
Diacyloxylation of 4′,5′-Unsaturated Thymine Nucleosides.
Although vicinal diacetoxylation of olefins with Pb(OAc)4 has
been known for a long time, this reaction usually leads to a
(14) Mu¨ller, R.; Plieninger, H. Chem. Ber. 1959, 92, 3009.
(15) For an example of the reaction of conjugated dienes with Pb(OAc)4,
see: Uemura, S.; Tabata, A.; Okano, M. Chem. Commun. 1970, 1630.
(16) Verheyden, J. P. H.; Moffatt, J. G. J. Org. Chem. 1974, 39, 3573.
(17) The depicted stereochemistry of 12a was determined by NOE
experiment: H-5′b/H-6 (1.7%). Of the two protons at the 5′-position, the
one that appears at a higher field is designated as H-5′a, and the other as
H-5′b, throughout the text and Experimental Section.
(9) For the preparation of 3 and 19, see Supporting Information.
(10) Dutschman, G. E.; Grill, S. P.; Gullen, E. A.; Haraguchi, K.; Takeda,
S.; Tanaka, H.; Baba, M.; Cheng, Y.-C. Antimicrob. Agents Chemother.
2004, 48, 1640.
(11) Nitanda, T.; Wang, X.; Kumamoto, H.; Haraguchi, K.; Tanaka, H.;
Cheng, Y.-C.; Baba, M. Antimicrob. Agents Chemother. 2005, 49, 3355.
4434 J. Org. Chem., Vol. 71, No. 12, 2006

Synthesis of 4′-Ed4T by Nucleophilic Substitution
SCHEME 4
SCHEME 5
examined by adding bases. After several attempts (imidazole
and collidine), the presence of i-Pr2NEt (1.5 equiv) was found
to prevent the formation of 13a completely, but the yield of 12
(32%, 12a/12b ) 1/0.4) remained unchanged.
Yukawa and Sasaki briefly reported that,18 although Pb(OAc)4
did not work for vicinal diacetoxylation of styrene, use of lead
tetracarboxylate prepared from higher carboxylic acids gave
styrene glycol dicarboxylates. When Pb(OBz)4 (1.5 equiv),
prepared from Pb(OAc)4 and benzoic acid,19 was reacted with
3 in the presence of i-Pr2NEt (1.5 equiv) in toluene at room
temperature for 14 h, the 4′-benzoyloxy derivative 14 was
obtained in 71% yield (14a/14b ) 1/0.8) without forming the
aldehyde 13b. After HPLC separation, the stereochemistry of
14a and 14b was confirmed by their NOE experiments: 14a,
H-5′b/H-6 (3.4%) and H-5′a/H-6 (1.4%); 14b, H-5′b/H-3′
(0.7%).
SCHEME 6
of 16 was not high, formation of the spiro derivative 15 was
suppressed to a trace amount.
Reaction of the 4′-Benzoyloxy Derivative (14) with Or-
ganoaluminum Reagents. Reaction of the 4′-benzoyloxy
derivative (14) with a commercially available hexane solution
of Me3Al was first carried out as a model experiment. As shown
in Scheme 4, three isomeric products [m/z 475 (M+ + H)] were
formed upon reacting 14 with 4.0 equiv of Me3Al. The minor
product was the expected 4′-methyl derivative 16a (15%),20
which underwent debenzoylation by treatment with NaOMe in
MeOH. Silica gel column chromatography gave other two
products as a mixture of two diastereomers (76%, 15a/15b )
1/1). Their spiro structure was assumed based on the fact that
they did not undergo debenzoylation with NaOMe in MeOH.
HPLC separation of the mixture followed by NOE experiment21
led us to propose the depicted 4′-configuration for both
diastereomers.
On the other hand, when 14 was reacted with a hexane
solution of MeAlCl2 (4.0 equiv) in CH2Cl2 for 2 h at 0 °C
(Scheme 5), the 4′-methyl derivative was not detected, but
instead two isomeric 4′-chlorinated products (17a, 53%; 17b,
14%)22 were formed. These compounds are rather unstable
(decomposed during TLC analysis), but they can be isolated
by HPLC. Independent treatment of the isolated 17a or 17b
with MeAlCl2 in CH2Cl2 again resulted in a mixture of both
compounds, showing that they are interconvertible in the
presence of MeAlCl2. It was found that further treatment of the
above reaction mixture containing 17 with Me3Al (6.0 equiv,
at room temperature for 23 h) gave the 4′-methyl derivatives
(16a, 14%; 16b, 19%) in one-pot manner. Although the yield
With these experimental results in hand, introduction of an
ethynyl group to the 4′-position of 14 was investigated. One-
pot treatment of 14 with MeAlCl2 followed by triethynylalu-
minum, previously employed for epoxide ring-opening,8 did not
allow the introduction of an ethynyl group. On the other hand,
the use of ethyl[trimethylsilyl(ethynyl)]aluminum chloride Me3-
SiCtCAl(Et)Cl23 in this one-pot reaction, in place of triethyn-
ylaluminum, furnished the 4′-ethynyl derivative 18 as a single
isomer in 51% yield.24 During this ethynylation reaction of 14,
we noticed that the ethynylaluminum reagent itself was capable
of chlorinating 14, and that the 4′-ethynylation gradually took
place afterward. Thus, when 14 was reacted with 8.0 equiv of
Me3SiCtCAl(Et)Cl in CH2Cl2 at room temperature overnight
(Scheme 6), 18 was formed stereoselectively and isolated in
62% yield by silica gel column chromatography. This ethyn-
ylation can be performed in several-10 g scale. To ascertain
that both isomers of the 4′-chloro intermediate (17) lead to the
formation of 18, the reaction of Me3SiCtCAl(Et)Cl with the
two isomers was independently carried out. As a result, both
17a and 17b gave 18 exclusively in 71% and 50% yields,
respectively.
It is not clear why 17 furnished the desired 4′-R-ethynyl
derivative 18 exclusively while it gave two isomeric 4′-methyl
derivatives (16a and 16b, Scheme 5) upon reacting with Me3-
Al.25 However, it is certainly true that the 3′-â-O-TBDMS group
had played an important role in the above ethynylation, since
the 4′-benzoyloxy derivative 199 with the opposite 3′-configu-
(18) Yukawa, Y.; Sakai, M. Bull. Chem. Soc. Jpn. 1963, 36, 761.
(19) For the preparation of Pb(OBz)4, see: Bachman, G. B.; Wittmann,
J. W. J. Org. Chem. 1963, 28, 65.
(20) The depicted stereochemistry of 16a was determined by NOE
experiment: H-6/H-5′a (1.8%), H-6/H-5′b (3.6%), H-1′/CH3-4′ (1.4%), and
H-3′/CH3-4′ (3.6%).
(21) NOE data for 15a (less polar) and 15b (more polar) are as follows:
15a, H-5′a/H-6 (2.5%); 15b, H-5′b/H-6 (3.3%).
(22) NOE data for 17a and 17b are as follows: 17a, H-5′b/H-6 (1.3%)
and H-5′a/H-6 (1.1%); 17b, H-3′/H-5′a (1.4%).
(23) This reagent has been successfully used for the introduction of the
trimethylsilylethynyl group to the anomeric position of uracil nucleoside,
see: Itoh, Y.; Haraguchi, K.; Tanaka, H.; Gen, E.; Miyasaka, T. J. Org.
Chem. 1995, 60, 656.
(24) The depicted stereochemistry of 18 was determined by NOE
experiment: H-5′a,b/H-6 (6.5%).
(25) The bulkiness of aluminum reagent working in this reaction is
certainly one important determinant for the observed stereochemical
outcome, but it is difficult to know its actual structure.
J. Org. Chem, Vol. 71, No. 12, 2006 4435

Haraguchi et al.
SCHEME 7
amined by using organosilicon reagents. As shown in Scheme
9, when allyltrimethylsilane (5 equiv) was reacted with 14 in
the presence of SnCl4 (3 equiv) in CH2Cl2, many products were
formed, from which the spiro derivative 23 (14%, obtained as
a single isomer, stereochemistry of the newly formed ketal
carbon is not known) and the two isomeric 4′-allyl derivatives
(24a, 9.4%; 24b, 14%) were isolated. The observed formation
of the spiro derivative (23) in a considerable amount was
certainly reminiscent of the reaction with Me3Al shown in
Scheme 4.
SCHEME 8
We, therefore, pretreated 17 with MeAlCl2 (5.0 equiv) and
then reacted with allyltrimethylsilane (6.0 equiv) in a one-pot
manner. This reaction suppressed the formation of 23 to a trace
amount and gave stereoselectively the 4′-R-allyl derivative 24a
(31%) and its 5′-O-debenzoylated product 25 (11%) without
forming 24b. In contrast to this, the 4′-cyanation carried out
under similar reaction conditions by using cyanotrimethylsilane
produced the 4′-R-cyano (26a, 29%) as well as the 4′-â-cyano
(26b, 23%) derivatives.
SCHEME 9
Conclusion
As an alternative method for the synthesis of 4′-Ed4T (8), a
nucleophilic substitution approach was investigated. The first
step, introduction of a leaving group to the 4′-position, was
accomplished by vicinal diacyloxylation of the 4′,5′-unsaturated
thymine-nucleoside 3 with Pb(OBz)4 in the presence of i-Pr2-
NEt. The formation of the 4′-benzoloxy derivative (14) in this
reaction constitutes the first example of the introduction of a
leaving group to the 4′-position of nucleosides.
Nucleophilic ethynylation of the 4′-benzoyloxy group of 14
was successfully carried out by using Me3SiCtCAl(Et)Cl as a
nucleophile to give the desired 4′-“down”-ethynyl derivative
18 exclusively. It was found that this ethynylation proceeds
through the 4′-chloro intermediate (17), and the presence of the
3′-O-silyl group of 14 is crucial for the stereochemical outcome.
Allylation and cyanation of 14 were also examined briefly
by using allyltrimethylsilane and cyanotrimethylsilane, respec-
tively. In these instances, pretreatment of 14 with MeAlCl2 was
necessary.
ration gave solely the 4′-â-ethynylated product 2026 in 31% yield
(Scheme 7).
Preparation of 4′-Ed4T (8). The above-prepared 18 was
converted to 4′-Ed4T (8) by a conventional reaction sequence
(Scheme 8). Thus, desilylation of 18 with Bu4NF in THF gave
the 3′-hydroxy derivative 21 (97%), which was sulfonylated with
(CF3SO2)O in the presence of pyridine in THF. The resulting
3′-triflate 22 was not isolated, instead extracted with CHCl3,
and subjected to â-elimination with DBN/CH3CN. Removal of
the 5′-O-benzoyl group was carried out in a one-pot manner by
adding MeOH to the elimination mixture. This procedure
allowed preparation of the title compound 4′-Ed4T (8) in 69%
overall yield from 21.
Experimental Section
Reaction of Pb(OBz)4 with 3 in the Presence of i-Pr2NEt:
Preparation of 1-[5-O-Benzoyl-4-benzoyloxy-3-O-(tert-butyldi-
methylsilyl)-2-deoxy-â-D-threo-pentofuranosyl]thymine (14a) and
1-[5-O-Benzoyl-4-benzoyloxy-3-O-(tert-butyldimethylsilyl)-2-
deoxy-r-L-erythro-pentofuranosyl]thymine (14b). To a toluene
(70 mL) solution of 3 (3.98 g, 11.76 mmol) were added i-Pr2NEt
(5.1 mL, 29.4 mmol) and Pb(OBz)4 (20.33 g, 29.4 mmol) at 0 °C
under Ar atmosphere. The mixture was stirred at room temperature
for 4 h, quenched with saturated aq NaHCO3, and filtered through
a Celite pad. The filtrate was partitioned between CHCl3/saturated
aq NaHCO3. Column chromatography (hexane/EtOAc ) 3/1) of
the organic layer gave a mixture of 14a and 14b (4.84 g, 71%,
Synthesis of the 4′-Allyl and 4′-Cyano Derivatives. To
demonstrate the utility of the 4′-benzoyloxy derivative (14),
preparation of other 4′-carbon-substituted analogues was ex-
(26) The depicted stereochemistry of 20 was determined by its NOE
data [tert-butyl/H-5′a,b (0.3%); SiMe3/H-6 (0.8%)] as well as by the fact
that its H-5′ resonance appeared as a singlet.
4436 J. Org. Chem., Vol. 71, No. 12, 2006

Synthesis of 4′-Ed4T by Nucleophilic Substitution
14a/14b ) 1/0.8). Compounds 14a (foam, tR 13.7 min) and 14b
(foam, tR 15.2 min) were separated by HPLC (CH2Cl2/EtOAc )
5/1).
The reaction mixture was quenched with saturated aq NaHCO3
and filtered through a Celite pad. The filtrate was partitioned
between CH2Cl2/saturated aq NaHCO3. Column chromatography
(hexane/EtOAc ) 5/1-3/1) of the organic layer followed by
separation by HPLC (hexane/EtOAc ) 11/9) gave 16a (syrup, 11.6
mg, 11%, tR 15.8 min) and 16b (syrup, 15.3 mg, 19%, tR 12.5 min).
Physical data for 16b: UV (MeOH) λmax 267 nm (ꢀ 11100),
Physical data for 14a: UV (MeOH) λmax 266 nm (ꢀ 11600), λmin
250 nm (ꢀ 9300); 1H NMR (CDCl3) δ 0.15 and 0.20 (6H, each as
s), 0.93 (9H, s), 1.91 (3H, d, J ) 1.0 Hz), 1.98 (1H, dt, J ) 8.2
and 2.8 Hz), 2.94-3.01 (1H, m), 4.95 (1H, t, J ) 2.8 Hz), 5.11
(1H, d, J ) 12.0 Hz), 5.19 (1H, d, J ) 12.0 Hz), 6.65 (1H, dd,
J ) 8.2 and 3.0 Hz), 7.35 (2H, dd, J ) 10.7 and 4.9 Hz), 7.45-
7.54 (3H, m), 7.61 (2H, ddd, J ) 10.5, 5.8, and 2.1 Hz), 7.93 (2H,
dd, J ) 8.3 and 1.1 Hz), 8.03 (2H, dd, J ) 8.3 and 1.1 Hz), 8.57
(1H, br); 13C NMR (CDCl3) δ -5.0, -4.9, 12.5, 17.9, 25.6, 39.9,
62.0, 74.2, 85.4, 111.5, 111.9, 128.4, 128.6, 129.4, 129.5, 129.6,
129.8, 133.2, 133.7, 135.9, 150.2, 163.4, 164.6, 165.7. FAB-MS
(m/z) 581 [M + H]+. Anal. Calcd for C30H36N2O8Si: C, 62.05; H,
6.25; N, 4.82. Found: C, 62.00; H, 6.26; N, 4.75.
λ
min 247 nm (ꢀ 6900); 1H NMR (CDCl3) δ 0.07 and 0.11 (6H, each
as s), 0.90 (9H, s), 1.51 (3H, s), 1.94 (3H, d, J ) 1.2 Hz), 2.01
(1H, dd, J ) 15.0 and 2.7 Hz), 2.94 (1H, ddd, J ) 15.0, 7.8, and
5.7 Hz), 4.18 (1H, d, J ) 11.5 Hz), 4.24-4.29 (2H, m), 6.34 (1H,
dd, J ) 7.8 and 2.7 Hz), 7.46-7.50 (2H, m), 7.60-7.62 (2H, m),
8.02-8.05 (2H, m), 8.52 (1H, br); 13C NMR (CDCl3) δ -5.1, -4.9,
12.6, 18.0, 18.7, 25.6, 68.0, 73.3, 84.9, 88.2, 110.4, 128.6, 129.4,
129.6, 130.1, 133.5, 136.4, 150.2, 163.5, 166.0. FAB-MS [M +
H]+ 475 (M+ + H). Anal. Calcd for C24H34N2O6Si: C, 60.73; H,
7.22; N, 5.90. Found: C, 61.01; H, 7.36; N, 5.64.
Physical data for 14b: UV (MeOH) λmax 268 nm (ꢀ 10800),
1-[5-O-Benzoyl-3-O-(tert-butyldimethylsilyl)-2-deoxy-4-C-(tri-
methylsilyl)ethynyl-â-D-threo-pentofuranosyl]thymine (18). To
a toluene (15 mL)/hexane (100 mL) solution of TMSCtCAl(Et)-
Cl23 (68.88 mmol) was added a CH2Cl2 (45 mL) solution of 14
(5.0 g, 8.61 mmol) at 0 °C under Ar atmosphere. The mixture was
stirred at room temperature overnight, quenched with saturated aq
NaHCO3, and filtered through a Celite pad. The filtrate was
partitioned between CHCl3/saturated aq NaHCO3. Column chro-
matography (hexane/EtOAc ) 3/1) of the organic layer gave 18
(foam, 3.0 g, 62%): UV (MeOH) λmax 266 nm (ꢀ 10900), λmin 247
λ
min 251 nm (ꢀ 8300); 1H NMR (CDCl3) δ 0.02 and 0.06 (6H, each
as s), 0.75 (9H, s), 1.69 (3H, d, J ) 0.7 Hz), 2.33-2.40 (1H, m),
2.76-2.82 (1H, m), 4.73 (1H, t, J ) 6.6 Hz), 4.91 (1H, d, J )
11.7 Hz), 5.08 (1H, d, J ) 11.7 Hz), 6.35 (1H, t, J ) 6.3 Hz),
7.45-7.52 (4H, m), 7.58-7.66 (3H, m), 8.02-8.04 (2H, m), 8.10-
8.13 (2H, m), 8.53 (1H, br); 13C NMR (CDCl3) δ -5.3, -4.8, 12.3,
17.7, 25.4, 39.0, 63.3, 72.1, 84.1, 109.0, 111.0, 128.6, 128.7, 129.3,
129.7, 129.8, 129.8, 133.5, 135.6, 150.2, 163.4, 163.9, 165.6. FAB-
MS (m/z) 581 [M + H]+. Anal. Calcd for C30H36N2O8Si: C, 62.05;
H, 6.25; N, 4.82. Found: C, 62.05; H, 6.28; N, 4.77.
1
nm (ꢀ 6000); H NMR (CDCl3) δ 0.09 and 0.13 (6H, each as s),
Reaction of 14 with MeAlCl2: Formation of 1-[5-O-Benzoyl-
3-O-(tert-butyldimethylsilyl)-4-chloro-2-deoxy-â-D-threo-pento-
furanosyl]thymine (17a) and 1-[5-O-Benzoyl-3-O-(tert-butyldi-
methylsilyl)-4-chloro-2-deoxy-r-L-erythro-pentofuranosyl]thymine
(17b). To a CH2Cl2 (7 mL) solution of 14 (300 mg, 0.52 mmol)
was added MeAlCl2 (1.0 M hexane solution, 2.6 mL, 2.6 mmol) at
0 °C under Ar atmosphere. The mixture was stirred for 2 h at 0
°C, quenched with saturated aq NaHCO3, and filtered through a
Celite pad. The filtrate was partitioned between CH2Cl2/saturated
aq NaHCO3. HPLC purification (hexane/EtOAc ) 7/3) of the
organic layer gave 17a (foam, 135 mg, 53%, tR 11 min) and 17b
(foam, 35 mg, 14%, tR 13 min).
0.12 (9H, s), 0.89 (9H, s), 1.90 (3H, d, J ) 1.2 Hz), 1.95 (1H, ddd,
J ) 2.8, 1.2, and 14.6 Hz), 3.01 (1H, ddd, J ) 8.2, 5.2, and 14.6
Hz), 4.50 (1H, dd, J ) 1.2 and 5.2 Hz), 4.64 (1H, d, J ) 10.8 Hz),
4.68 (1H, d, J ) 10.8 Hz), 6.40 (1H, dd, J ) 2.8 and 8.2 Hz),
7.44-7.48, 7.57-7.61, and 8.07-8.10 (6H, each as m), 8.24 (1H,
br); 13C NMR (CDCl3) δ -5.2, -4.9, 0.5, 12.5, 17.9, 18.0, 25.5,
25.57, 25.6. 41.5, 64.8, 76.4, 83.2, 84.4, 93.3, 101.1, 110.8, 128.29,
128.35, 128.37, 129.5, 129.72, 129.7, 133.2, 136.2, 150.4, 163.8,
166.0. FAB-MS [M + H]+ 557 (M+ + H). Anal. Calcd for
C29H36N2O6Si: C, 60.40; H, 7.24; N, 5.03. Found: C, 60.36; H,
7.38; N, 4.79.
1-[5-O-Benzoyl-3-O-(tert-butyldimethylsilyl)-2-deoxy-4-C-(tri-
methylsilyl)ethynyl-r-L-threo-pentofuranosyl]thymine (20). This
compound was obtained in 31% yield (foam, 30 mg) from 19 (100
mg, 0.17 mmmol) by the procedure described above for the
preparation of 18. Physical data for 20: UV (MeOH) λmax 228 nm
Physical data for 17a: 1H NMR (CDCl3) δ 0.12 (6H, s), 0.90
(9H, s), 1.87 (1H, t, J ) 2.9 Hz), 1.91 (3H, d, J ) 1.4 Hz), 3.17-
3.24 (1H, m), 4.72 (1H, d, J ) 5.1 Hz), 4.77 (1H, d, J ) 12.0 Hz),
4.85 (1H, d, J ) 12.0 Hz), 6.70 (1H, dd, J ) 8.8 and 2.9 Hz),
7.45-7.52 (3H, m), 7.59-7.61 (1H, m), 8.07-8.10 (2H, m), 8.82
(1H, br); 13C NMR (CDCl3) δ -5.2, -4.9, 12.4, 17.8, 25.5, 39.1,
1
(ꢀ 15100) and 267 nm (ꢀ 10700), λmin 247 nm (ꢀ 6800); H NMR
(CDCl3) δ 0.11, 0.13, and 0.14 (15H, each as s), 0.91 (9H, s), 1.96
(3H, d, J ) 1.0 Hz), 2.36-2.42 (1H, m), 2.49 (1H, ddd, J ) 13.5,
5.7, and 2.0 Hz), 4.58 (2H, s), 4.57-4.59 (1H, m), 6.46 (1H, dd,
J ) 8.0 and 5.7 Hz), 7.46 (2H, t), 7.57-7.60 (1H, m), 7.67 (1H, d,
J ) 1.0 Hz), 8.07 (2H, dd, J ) 8.3 and 1.2 Hz), 8.74 (1H, br, NH);
13C NMR (CDCl3) δ -5.1, -4.7, -0.41, -0.03, 12.8, 17.9, 25.6,
41.5, 65.0, 83.3, 86.6, 94.6, 102.8, 110.9, 128.4, 129.7, 129.9, 133.1,
135.8, 150.1, 163.6, 165.8. FAB-MS (m/z) 557 [M + H]+. Anal.
Calcd for C29H36N2O6Si: C, 60.40; H, 7.24; N, 5.03. Found: C,
60.53; H, 7.35; N. 4.99.
65.0, 78.6, 85.5, 108.7, 112.0, 128.4, 129.2, 129.7, 133.4, 135.6,
-
150.4, 163.8, 165.6. FAB-MS (m/z) 459 (M+
35Cl). High-
resolution FAB-MS (m/z) calcd for C23H32ClN2O6Si: 495.1718
[M + H]+. Found: 495.1740.
Physical data for 17b: 1H NMR (CDCl3) δ 0.11 (6H, s), 0.92
(9H, s), 1.97 (3H, d, J ) 1.2 Hz), 2.32-2.36 (1H, m), 2.62-2.68
(1H, m), 4.51 (1H, d, J ) 12.2 Hz), 4.60 (1H, dd, J ) 10.9 and 6.5
Hz), 4.92 (1H, d, J ) 12.2 Hz), 6.38 (1H, dd, J ) 9.5 and 6.1 Hz),
7.46-7.50 (3H, m), 7.58-7.64 (1H, m), 7.71 (1H, d, J ) 1.2 Hz),
8.01-8.03 (2H, m), 8.30 (1H, br); 13C NMR (CDCl3) δ -5.1, -4.7,
12.7, 17.9, 25.5, 25.5, 25.6, 36.5, 63.9, 71.0, 83.6, 108.9, 112.1,
128.6, 129.0, 129.7, 133.6, 135.5, 150.5, 163.3, 165.2. FAB-MS
(m/z) 459 (M+ - 35Cl). High-resolution FAB-MS [M + H]+ calcd
1-[5-O-Benzoyl-2-deoxy-4-C-ethynyl-â-D-threo-pentofurano-
syl]thymine (21). To a THF (17 mL) solution of 18 (2.99 g, 5.368
mmol) was added Bu4NF·3H2O (2.81 g, 10.74 mmol) at 0 °C, and
the mixture was stirred for 1.5 h. Evaporation of the solvent
followed by column chromatography (2% MeOH in CH2Cl2) of
the residue gave 21 (foam, 1.93 g, 97%): UV (MeOH) λmax 266
nm (ꢀ 10000), λmin 247 nm (ꢀ 6500); 1H NMR (CDCl3, after addition
of D2O) δ 1.94 (3H, d, J ) 1.2 Hz), 2.15 (1H, dd, J ) 15.0 and
3.2 Hz), 2.60 (1H, s), 3.01 (1H, ddd, J ) 15.0, 9.0, and 5.2 Hz),
4.34 (1H, d, J ) 5.2 Hz), 4.40 (1H, d, J ) 11.2 Hz), 4.96 (1H, d,
J ) 11.2 Hz), 6.34 (1H, d, J ) 9.0 and 3.2 Hz), 7.46-7.51, 7.61-
7.65, and 8.09-8.11 (5H, each as m), 7.70 (1H, d, J ) 1.2 Hz),
8.47 (1H, br); 13C NMR (CDCl3) δ 12.5, 38.8, 63.4, 74.6, 76.4,
80.0, 82.3, 84.9, 111.5, 128.4, 128.6, 129.0, 130.0, 130.1, 133.3,
-
for C23H32N2O6Si: 460.2030 (M+ Cl + H). Found: 460.2004.
Reaction of 14 with MeAlCl2 Followed by Me3Al in a One-
Pot Manner: Formation of 16a and 1-[5-O-Benzoyl-3-O-(tert-
butyldimethylsilyl)-2-deoxy-4-C-methyl-r-L-erythro-pentofuran-
osyl]thymine (16b). To a CH2Cl2 (5 mL) solution of 14 (100 mg,
0.17 mmol) was added MeAlCl2 (1.0 M hexane solution, 0.86 mL,
0.86 mmol) at 0 °C under Ar atmosphere. After the mixture was
stirred for 2 h at 0 °C, Me3Al (1 M hexane solution, 1.03 mL, 1.03
mmol) was added, and it was kept stirring at room temperature for
20 h.
J. Org. Chem, Vol. 71, No. 12, 2006 4437

Haraguchi et al.
133.8, 137.9, 150.6, 163.7, 167.4. FAB-MS (m/z) 371 [M + H]+.
Anal. Calcd for C19H19N2O6: C, 61.62; H, 4.90; N, 7.56. Found:
C, 61.31; H, 4.88; N, 7.35.
with allyltrimethylsilane (0.20 mL, 1.72 mmol) at room temperature
for 16 h. The reaction mixture was partitioned between CHCl3/
saturated aq NaHCO3. Preparative TLC (hexane/EtOAc ) 1/1) of
the organic layer gave 24a (15.3 mg, 31%) and 25 (4.5 mg, 11%,
syrup).
2′,3′-Didehydro-3′-deoxy-4′-C-ethynylthymidine (8: 4′-Ed4T).
To a THF (50 mL) solution of 21 (5.0 g, 13.5 mmol) were added
pyridine (8.1 mL, 101.3 mmol) and (CF3SO2)2O (7.5 mL, 44.6
mmol) at 0 °C under Ar atmosphere. The reaction mixture was
stirred at room temperature overnight and then partitioned between
CHCl3/H2O. The organic layer containing 22 was dried (Na2SO4)
and evaporated. The resulting syrup was dissolved in CH3CN (20
mL) and reacted with DBN (5.0 mL, 40.5 mmol) at room
temperature for 4 h, after which MeOH (40 mL) was added and
stirring was continued further for 2 h. Evaporation of the reaction
mixture followed by column chromatography (4% MeOH in CHCl3)
gave 8 (solid, 2.3 g, 69%). For physical data of this compound,
see ref 8.
Reaction of 14 with Allyltrimethylsilane in the Presence of
SnCl4. To a CH2Cl2 (5 mL) solution of 14 (116.1 mg, 0.2 mmol)
were added allyltrimethylsilane (0.16 mL, 1.0 mmol) and SnCl4
(0.6 mL, 0.6 mmol) at 0 °C under Ar atmosphere. After being stirred
for 20 h at room temperature, the reaction mixture was partitioned
between CHCl3/saturated aq NaHCO3. Column chromatography
(hexane/EtOAc ) 3/1-1/1) of the organic layer gave a mixture of
23, 24a, and 24b. These products were separated by preparative
TLC (hexane/EtOAc ) 2/1) to give 23 (13.6 mg, 14%, syrup), 24a
(9.4 mg, 9%, syrup), and 24b (14.1 mg, 14%, syrup).
Physical data of 25: 1H NMR (CDCl3) δ 0.09 and 0.13 (6H,
each as s), 0.90 (9H, s), 1.93 (3H, d, J ) 1.2 Hz), 1.93-2.04 (1H,
m), 2.46 (1H, dd, J ) 9.8 and 3.9 Hz), 2.68-2.75 (1H, m), 3.72
(1H, dd, J ) 12.2 and 9.8 Hz), 3.86 (1H, dd, J ) 12.2 and 3.9
Hz), 4.36 (1H, dd, J2′a,3′ ) J2′b,3′ ) 6.4 Hz, H-3′), 5.13-5.21 (2H,
m), 5.75-5.86 (1H, m), 6.17 (1H, t, J ) 6.6 Hz), 7.88 (1H, d, J )
1.2 Hz), 8.33 (1H, br); 13C NMR (CDCl3) δ -5.2, -4.7, 12.6, 17.8,
25.6, 39.4, 41.8, 66.0, 75.2, 82.5, 87.8, 111.0, 119.6, 132.2, 136.1,
150.4, 163.6. NOE experiment: H-6/H-5′a (0.8%), H-6/H-5′b
(0.5%), H-1′/CH2-CHdCH2 (1%), H-1′/CH2-CHdCH2 (0.9%), and
H-3′/CH2-CHdCH2 (2.4%). High-resolution FAB-MS (m/z) calcd
for C19H33N2O5Si: 397.2159 [M + H]+. Found: 397.2167.
1-[5-O-Benzoyl-3-O-(tert-butyldimethylsilyl)-4-C-cyano-2-deoxy-
â-D-threo-pentofuranosyl]thymine (26a) and 1-[5-O-Benzoyl-3-
O-(tert-butyldimethylsilyl)-4-C-cyano-2-deoxy-r-L-erythro-pento-
furanosyl]thymine (26b). Compounds 26a and 26b were obtained
in 29% and 23% yields, respectively, from 14 (50 mg, 0.086 mmol)
and cyanotrimethylsilane (0.07 mL, 0.69 mmol) by the procedure
employed for the preparation of 24. HPLC (hexane/EtOAc ) 11/
9) separation gave analytically pure samples (26a, foam, tR 12.8
min; 26b, foam, tR 20.6 min).
Physical data for 23: 1H NMR (CDCl3) δ -0.28 and -0.21
(6H, each as s), 0.77 (9H, s), 1.86 (1H, ddd, J ) 14.6, 7.3, and 2.0
Hz), 1.89 (3H, d, J ) 1.2 Hz), 2.72-2.74 (2H, m), 2.99 (1H, ddd,
J ) 14.6, 8.3, and 5.1 Hz), 3.97-4.01(2H, m),4.25 (1H, d, J ) 9.9
Hz), 5.01-5.08 (2H, m), 5.69-5.78 (1H, m), 6.44 (1H, dd, J )
8.3 and 2.0 Hz), 7.29-7.46 (5H, m), 7.47 (1H, d, J ) 1.2 Hz),
8.60 (1H, br); 13C NMR (CDCl3) δ -5.6, -5.1, 12.6, 17.8, 25.5,
29.7, 40.0, 45.4, 69.2, 74.9, 84.0, 110.5, 112.6, 114.7, 118.6, 125.4,
128.2, 128.3, 131.7, 136.4, 141.2, 150.1, 163.4. NOE experiment:
H-6/H-5′b (1.4%). FAB-MS (m/z) 501 (M+ + H). High-resolution
FAB-MS [M + H]+ calcd for C26H37N2O6Si: 501.2421 (M+ + H).
Found: 501.2419.
Physical data for 26a: UV (MeOH) λmax 266 nm (ꢀ 10000), λmin
248 nm (ꢀ 6900); 1H NMR (CDCl3) δ 0.13 and 0.15 (6H, each as
s), 0.91 (9H, s), 1.93 (3H, d, J ) 1.0 Hz), 2.15 (1H, dd, J ) 15.2
and 2.8 Hz), 3.04-3.09 (1H, m), 4.64 (1H, d, J ) 11.5 Hz), 4.77
(1H, d, J2′b,3′ ) 4.1 Hz, H-3′), 4.84 (1H, d, J ) 11.5 Hz), 6.57 (1H,
dd, J ) 8.3 and 2.8 Hz), 7.46-7.50 (3H, m), 7.61-7.63 (1H, m),
8.08-8.10 (2H, m), 9.49 (1H, br); 13C NMR (CDCl3) δ -5.2, -4.9,
12.5, 18.0, 25.5, 40.7, 62.8, 75.2, 82.4, 85.12, 111.6, 116.6, 125.7,
128.6, 129.9, 133.8, 135.2, 150.0, 163.1, 165.5. NOE experiment:
H-6/H-5′a (0.9%), H-6/H-5′b (2.1%); IR (neat) 2240 cm-1 (CN).
FAB-MS (m/z) 486 [M + H]+. Anal. Calcd for C24H31N3O6Si: C,
59.36; H, 6.43; N, 8.65. Found: C, 59.03; H, 6.44; N, 8.34.
Physical data for 26b: UV (MeOH) λmax 266 nm (ꢀ 10000),
Physical data for 24a: 1H NMR (CDCl3) δ 0.05 and 0.07 (6H,
each as s), 0.86 (9H, s), 1.84 (3H, d, J ) 1.0 Hz), 2.23-2.58 (3H,
m), 2.84 (1H, ddd, J ) 14.3, 7.3, and 6.0 Hz), 4.45(1H, d, J )
11.7 Hz), 4.64 (1H, t, J ) 12.6 Hz), 5.09-5.25 (3H, m), 5.81-
5.88 (1H, m), 6.22-6.26 (1H, m), 7.45-7.49 (2H, m), 7.57-7.64
(2H, m), 8.03-8.05 (1H, m), 8.78 (1H, br); 13C NMR (CDCl3) δ
-5.3, -4.8, -0.03, 12.4, 17.8, 25.5, 39.3, 41.5, 65.0, 74.0, 84.0,
88.1, 110.8, 120.0, 128.5, 129.5, 131.8, 133.3, 136.0, 150.3, 163.6,
166.1. NOE experiment: H-6/H-5′a (1.1%), H-6/H-5′b (3.6%), and
H-2′/H-5′b (1.2%). FAB-MS (m/z) 501 (M+ + H). High-resolution
λ
min 248 nm (ꢀ 7000); 1H NMR (CDCl3) δ 0.11 and 0.17 (6H, each
as s), 0.91 (9H, s), 1.98 (3H, d, J ) 1.0 Hz), 2.27 (1H, dt, J ) 14.3
and 4.6 Hz), 2.81 (1H, dd, J ) 14.3 and 6.4 Hz), 4.51-4.55 (3H,
m), 6.40 (1H, dd, J ) 6.4 and 4.6 Hz), 7.47-7.51 (2H, m), 7.57
(1H, d, J ) 1.0 Hz), 7.62-7.64 (1H, m), 8.06-8.08 (2H, m), 8.81
(1H, br); IR (neat) 2252 cm-1 (CN); 13C NMR (CDCl3) δ -5.1,
-5.0, 12.7, 17.9, 25.4, 40.0, 64.0, 73.3, 85.2, 86.1, 111.6, 115.7,
128.5, 128.7, 129.9, 134.0, 135.2, 150.1, 163.2, 165.4. NOE
experiment: CH2-5′/H-2′b (1.3%). FAB-MS (m/z) 486 [M + H]+.
Anal. Calcd for C24H31N3O6Si·1/2 H2O: C, 58.92; H, 6.47; N, 8.59.
Found: C, 58.93; H, 6.43; N, 8.28.
FAB-MS [M + H]+ calcd for C26H37N2O6Si: 501.2421 (M+
H). Found: 501.2416.
+
Physical data for 24b: 1H NMR (CDCl3) δ 0.10 and 0.11 (6H,
each as s), 0.92 (9H, s), 1.91 (3H, d, J ) 1.2 Hz), 2.23 (1H, m),
2.36-2.46 (2H, m), 2.62-2.66 (1H, m), 4.31(1H, d, J ) 12.1
Hz),4.52 (1H, d, J ) 12.1 Hz), 4.55 (1H, dd, J ) 4.0 and 3.5 Hz),
5.18-5.22 (2H, m), 5.90-5.98 (1H, m), 6.23 (1H, t, J ) 6.3 Hz),
7.45-7.50, 7.58-7.63, 8.01-8.03 (6H, each as m), 8.26 (1H, br);
13C NMR (CDCl3) δ -5.1, -4.6, 12.2, 18.0, 25.7, 36.6, 41.1, 66.1,
72.5, 84.0, 87.2, 111.0, 119.3, 128.7, 129.4, 129.5, 132.7, 133.6,
134.9, 150.0, 163.4, 166.0. NOE experiment: H-3′/H-5′a (2.1%)
and tert-Bu/CH2CHdCH2 (0.2%). FAB-MS (m/z) 501 [M + H]+.
High-resolution FAB-MS (m/z) calcd for C26H37N2O6Si: 501.2421
(M+ + H). Found: 501.2443.
Reaction of 14 with MeAlCl2 Followed by Allyltrimethylsilane
in a One-Pot Manner. To a CH2Cl2 (4 mL) solution of 14 (58.1
mg, 0.1 mmol) was added MeAlCl2 (1 M hexane solution, 0.5 mL,
0.5 mmol) at 0 °C under Ar atmosphere, and the mixture was stirred
for 2 h. The resulting mixture containing 17 was further reacted
Acknowledgment. Financial support from the Japan Society
for the Promotion of Science (KAKENHI No.17590093 to K.H.
and No. 17590094 to H.T.), the Research Foundation of
Pharmaceutical Sciences (to K.H.), and the Japan Health
Sciences Foundation (SA 14804 to H.T.) are gratefully ac-
knowledged. The authors are also grateful to Ms. K. Shiobara
and Y. Odanaka (Center for Instrumental Analysis, Showa
University) for technical assistance with NMR, MS, and
elemental analyses.
Supporting Information Available: General experimental
procedures, details of the preparation of 3, 10-13, 15-16, and
19, and spectral data. This material is available free of charge via
the Internet at http://pubs.acs.org.
JO060194M
4438 J. Org. Chem., Vol. 71, No. 12, 2006