An alternative synthetic method for 4′-C-ethynylstavudine by means of nucleophilic substitution of 4′-benzoyloxythymine nucleoside

Article abstract of DOI:10.1080/15257770701503969

For the synthesis of 2′,3′-didehydro-3′-deoxy-4′-C- 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- glycero-pent-4-enofuranosyl)thymine with Pb(OBz)4 allowed

Full text of DOI:10.1080/15257770701503969

Nucleosides, Nucleotides, and Nucleic Acids, 26:835–839, 2007
Copyright ꢀ Taylor & Francis Group, LLC
C
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770701503969
AN ALTERNATIVE SYNTHETIC METHOD FOR
4ꢀ-C-ETHYNYLSTAVUDINE BY MEANS OF NUCLEOPHILIC
SUBSTITUTION OF 4ꢀ-BENZOYLOXYTHYMINE NUCLEOSIDE
Kazuhiro Haraguchi, Masanori Sumino, and Hiromichi Tanaka
School of
2
Pharmaceutical Sciences, Showa University, Shinagawa-ku, Tokyo, Japan
For the synthesis of 2ꢁ,3ꢁ-didehydro-3ꢁ-deoxy-4ꢁ-C-ethynylthymidine (8: 4ꢁ-Ed4T), a recently
2
reported promising anti-HIV agent, a new approach was developed. Since treatment of 1-(2,5-
dideoxy-β-L-glycero-pent-4-enofuranosyl)thymine with Pb(OBz)4 allowed the introduction of a 4’-
benzoyloxy leaving group, nucleophilic substitution at the 4ꢁ-position became feasible for the first
time. Thus, reaction between the 4’-benzoyloxy derivative (11) and Me3SiC≡CAl(Et)Cl as a nucle-
ophile led to the isolation of the desired 4’-“down”-ethynyl derivative (15) stereoselectively in 62%
yield.
Keywords Anti-HIV; diacyloxylation; 4ꢁ,5ꢁ-unsaturated nucleoside; nucleophilic substi-
tution; ethynylation; 4ꢁ-substituted nucleosides; didehydro-3ꢁ-deoxythymidine; organoa-
luminum reagents; organosilicon reagents
INTRODUCTION
Recently, 4ꢁ-substituted nucleosides have attracted much attention be-
cause of the discovery of the potent anti-HIV agents 4ꢁ-C-cyano (1) and
4ꢁ-C-ethynyl (2) analogs of thymidine (Figure 1). Synthesis of these 4ꢁ-
carbon-substituted nucleosides has mostly relied on manipulation of the
4ꢁ-hydroxymethyl derivatives of nucleosides or sugars that can be pre-
pared by the well known aldol-Cannizzaro reaction of the corresponding
aldehyde.[1]
We have already carried out ring-opening of 4ꢁ,5ꢁ-epoxynucleosides with
organosilicon[2] or an organoaluminum[3] reagent. Thus, oxidation of the
4ꢁ,5ꢁ-unsaturated derivative 3 with an acetone solution of dimethyldioxirane
(DMDO) gave 4, which was then reacted with organoaluminum reagents
(R3Al) to furnish the 4ꢁ-carbon-substituted products (5–7) (Scheme 1).
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 (SA14804 to H. T.) are gratefully acknowledged.
Address correspondene to Dr. Kazuhiro Haraguchi, School of Pharmaceutical Sciences, Showa Uni-
versity, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan. E-mail: harakazu@pharm.showa-u.ac.jp
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K. Haraguchi et al.
FIGURE 1 4ꢁ-C-Cyano-(1) and 4ꢁ-C-ethynylthymidine (2).
SCHEME 1 Epoxidation of 3 with DMDO and subsequent ring opening of 4ꢁ-5ꢁ-epoxythymidine deriva-
tive 4 with organoaluminum reagents.
During this study, 2ꢁ,3ꢁ-didehydro-3ꢁ-deoxy-4ꢁ-C-ethynylthymidine (8: 4ꢁ-
Ed4T) prepared from 7 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 (Figure 2).[4] To further evaluate 8 in
animal studies, we were in need of an alternative synthetic method that is
suitable for its large scale preparation, since the route shown in Scheme 1
has a drawback in that a highly concentrated acetone solution of DMDO
is inaccessible. In this study, we demonstrate that the reaction between 3
and Pb(OCOR)4 allows introduction of an acyloxy leaving group to the
4ꢁ-position, and that nucleophilic ethynylation of the resulting 4ꢁ-acyloxy
FIGURE 2 2ꢁ,3ꢁ-didehydro-3ꢁ-deoxy-4ꢁ-C-ethynylthymidine (4ꢁ-Ed4T).

Alternative Synthetic Method for 4 ꢁ-C-Ethynylstavudine
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SCHEME 2 Diacyoxylation of 3 with Pb (OCOR)4.
derivative with an organoaluminum reagent enable us to prepare the title
compound (8) in a fairy large scale.[5]
RESUTS AND DISCUSSION
Diacyloxylation of 4ꢁ,5ꢁ-Unsaturated Thymine Nucleoside
When the reaction of 3 with Pb(OAc)4 was carried out in toluene
at room temperature, the 4ꢁ-acetoxy derivative 9a was obtained (Scheme
2), but the yield was only 28%. The main product in this reaction was
the depicted aldehyde 10a (60%). After several attempts, the presence of
i-Pr2NEt was found to prevent the formation of 10a, but the yield of 9 (32%,
9a/9b = 1/0.4) remained unchanged. This result led us to examine the
use of another lead tetracarboxylate. When Pb(OBz)4 was reacted with 3 in
the presence of i-Pr2NEt in toluene at room temperature, the 4ꢁ-benzoyloxy
derivative 11 was obtained in 71% yield (11a/11b = 1/0.8) without forming
the aldehyde 10b.
Reaction of the 4ꢁ-Benzoyloxy Derivative (11) with
Organoaluminum Reagents
Reaction of the 4ꢁ-benzoyloxy derivative (11) with 4 equiv of Me3Al in
CH2Cl2 at 0◦C gave a mixture of two diastereomers of the spiro nucleosides
(76%, 12a/12b = 1/1) as major products (Scheme 3). On the other hand,
when 11 was reacted with MeAlCl2 under the similar conditions, two iso-
meric 4ꢁ-chlorinated products (13a, 53%; 13b, 14%) were formed. It was
found that further treatment of the above reaction mixture containing 13
with Me3Al (6.0 equiv, at room temperature for 23 h) gave the 4ꢁ-C-methyl
derivatives (14a, 14%; 14b, 19%) in a one-pot manner. Although the yield
of 14 was not high, formation of the spiro derivative 12 was suppressed to a
trace amount.
With these experimental results in hand, introduction of an ethynyl
group to the 4ꢁ-position of 11 was investigated (Scheme 4). One-pot
treatment of 11 with MeAlCl2 followed by ethyl[trimethylsilyl(ethynyl)]

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K. Haraguchi et al.
SCHEME 3 Methylation of 11 with Me3Al.
SCHEME 4 Ethynylation of 11 with Me3SiC≡CAl(Et)Cl.
aluminum chloride Me3SiC≡CAl(Et)Cl furnished the 4ꢁ-C-ethynyl derivative
15 as a single isomer in 51% yield. During this ethynylation reaction of 11,
we noticed that the ethynylaluminum reagent itself was capable of chlori-
nating 11 and that the 4ꢁ-ethynylation of 13 gradually took place afterward.
Thus, when 11 was reacted with 8.0 equiv of Me3SiC≡CAl(Et)Cl in CH2Cl2
at room temperature overnight, 15 was formed stereoselectively and isolated
in 62% yield by silica gel column chromatography. This ethynylation can be
performed in a several-10 g scale.
Preparation of 4ꢁ-Ed4T (8)
The above-prepared 15 was coverted to 8 by a conventional reaction
sequence (Scheme 5). Thus, desilylation of 15 with Bu4NF in THF gave
16(97%), which was sulfonylated with (CF3SO2)O in the presence of pyri-
dine in THF. The resulting 3ꢁ-triflate 17 was not isolated and subjected to
β-elimination with DBN/CH3CN. Removal of the 5ꢁ-O-benzoyl group was

Alternative Synthetic Method for 4 ꢁ-C-Ethynylstavudine
839
SCHEME 5 Preparation of 4ꢁ-Ed4T (8).
carried out in a one-pot manner by adding MeOH to the elimination mix-
ture. This procedure allowed preparation of the title compound 4ꢁ-Ed4T (8)
in 69% overall yield from 15.
CONCLUSION
As an alternative method for the synthesis of 4ꢁ-Ed4T (8), a nucleophilic
substitution approach was investigated. The first step, introduction of a leav-
ing group to the 4ꢁ-position, was accomplished by vicinal diacyloxylation of
the 4ꢁ,5ꢁ-unsaturated thymine nucleoside 3 with Pb(OBz)4 in the presence
of i-Pr2NEt. Nucleophilic ethynylation of the 4ꢁ-benzoyloxy group of 11 was
successfully carried out by using Me3SiC≡CAl(Et)Cl as a nucleophile to give
the desired 4ꢁ-“down”-C-ethynyl derivative 15 exclusively.
REFERENCES AND NOTES
1. For an excellent review dealing with the synthesis and anti-HIV activity of 4ꢁ-C-substituted nucle-
osides, see: Hayakawa, H.; Kohgo, S.; Kitano, K.; Ashida, N.; Kodama, E.; Mitsuya, H.; Ohrui, H.
Antiviral. Chem. Chemother. 2004, 15, 169.
2. Haraguchi, K.; Takeda, S.; Tanaka, H. Ring opening of 4ꢁ,5ꢁ-epoxynucleosides: A novel stereoselective
entry to 4ꢁ-C-branched nucleosides. Org. Lett. 2003, 5, 1399.
3. Haraguchi, K.; Takeda, S.; Tanaka, H.; Nitanda, T.; Baba, M.; Dutschman, G.E.; Cheng, Y.-C. Synthesis
of a highly active new anti-HIV agent 2ꢁ,3ꢁ-didehydro-3ꢁ-deoxy-4ꢁ-ethynylthymidine. Bioorg. Med. Chem.
Lett. 2003, 13, 3775.
4. Nitanda, T.; Wang, X.; Kumamoto, H.; Haraguchi, K.; Tanaka, H.; Cheng, Y.-C.; Baba, M. Anti-
human immunodeficiency virus type 1 activity and resistance profile of 2ꢁ,3ꢁ-didehydro-3ꢁ-deoxy-4ꢁ-
ethynylthymidine in vitro. Antimicrob. Agents Chemother. 2005, 49, 3355.
5. Haraguchi, K.; Sumino, M.; Tanaka, H. Nucleophilic substitution at the 4ꢁ-position of nucleosides:
New access to a promising anti-HIV agent 2ꢁ,3ꢁ-didehydro-3’-deoxy-4’-ethynylthymidine. J. Org. Chem.
2006, 71, 4433.