Stereoselective entry to 1′-C-branched 4′-thionucleosides from 4-thiofuranoid glycal: Synthesis of 4′-thioangustmycin C

Article abstract of DOI:10.1016/S0040-4039(02)01131-0

A stereoselective synthetic method for the synthesis of novel 1′-C-carbon-substituted 4′-thionucleosides has been developed. The present method consists of the following steps: (1) preparation of the 1-C-carbon-substituted 4-thiofuranoid glycals based on lithiation, and (2) NIS- or PhSeCl-initiated stereoselective glycosidation to these 1-substituted glycals. This synthetic sequence enabled us to synthesize the 4′-thio analogue of antitumor antibiotic angustmycin C.

Full text of DOI:10.1016/S0040-4039(02)01131-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 5657–5660
Stereoselective entry to 1%-C-branched 4%-thionucleosides from
4-thiofuranoid glycal: synthesis of 4%-thioangustmycin C
Kazuhiro Haraguchi,* Haruhiko Takahashi and Hiromichi Tanaka
School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan
Received 2 May 2002; revised 5 June 2002; accepted 7 June 2002
Abstract—A stereoselective synthetic method for the synthesis of novel 1%-C-carbon-substituted 4%-thionucleosides has been developed.
The present method consists of the following steps: (1) preparation of the 1-C-carbon-substituted 4-thiofuranoid glycals based on
lithiation, and (2) NIS- or PhSeCl-initiated stereoselective glycosidation to these 1-substituted glycals. This synthetic sequence enabled
us to synthesize the 4%-thio analogue of antitumor antibiotic angustmycin C. © 2002 Elsevier Science Ltd. All rights reserved.
The discovery that the simple replacement of the fura-
nose ring-oxygen with sulfur atom leads to promising
antiviral or antitumor nucleosides, such as 4%-thio-
thymidine (1) and 4%-thio-2%-deoxycytidine (2),1 has
stimulated the synthesis of this class of nucleosides,
Two types of the 4-thiofuranoid glycals 5 and 6, pre-
pared in our previous study,6 were used as substrates
for the introduction of carbon-substituents to the 1-
position based on lithiation.9 Although the 3,5-bis-O-
TBDMS (tert-butyldimethylsilyl) glycal (5) underwent
successful lithiation with BuLi (1.2 equiv.) as evidenced
by deuteration (96%), reaction of the lithiated species
with MeI (5 equiv.) resulted in the sole formation of the
aromatized product 7 (92%). On the other hand, when
the 3,5-O-TIPDS (tetraisopropyldisiloxane-1,3-diyl)-
especially those modified at the sugar moiety.2–4
A
major drawback of commonly adopted synthetic meth-
ods for these 4%-thionucleosides is the lack of b-
stereoselectivity5 that is crucial for their activities. We
have recently reported a highly b-selective synthetic
method for pyrimidine 2%-deoxy-4%-thionucleosides
based on an electrophilic glycosidation to 4-thiofuran-
oid glycal.6
The present study was motivated by the occurrence of
an antitumor nucleoside antibiotic angustmycin C (3)
which is structurally unique in being branched at the
anomeric position. We describe herein (1) preparation
of the 1-C-carbon-substituted 4-thiofuranoid glycals
based on lithiation, (2) stereoselective electrophilic gly-
cosidation to these 1-substituted glycals, and (3) the
synthesis of 4%-thioangustmycin C (4)7 as an application
of the present strategy.8
Keywords: nucleosides; glycals; glycosidation; antibiotics.
* Corresponding author. Tel.: 81-3-3784-8187; fax: 81-3-3784-8252; e-mail: harakazu@showa-u.ac.jp
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01131-0

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glycal (6) was lithiated with LDA (5 equiv.) and then
treated with MeI (10 equiv.), the expected product 8 was
obtained in good yield (isolated yields are given in
parentheses). The 1-silyloxymethyl and 1-methoxycar-
bonylethenyl derivatives (9 and 10) were prepared by
reacting DMF (6 equiv.) as an electrophile followed by
either reduction with NaBH4 and subsequent silylation
or the Wittig reaction. Introduction of an ethynyl group
was carried out by cross-coupling reaction10 between the
1-iodo derivative (11), prepared by reacting the lithiated
species with iodine, and (trimethylsilyl)acetylene in the
presence of (Ph3P)2PdCl2/CuI in DMF to give 12.
the cyclized by-product 20 was also formed. Stereochem-
istry of these glycosylated products (14–16, and 18) was
determined based on NOE experiment, wherein correla-
tions between H-3%/H-6 (2–3%) and H-2%/H-3% (9–10%)
were observed.
We next examined the use of PhSeCl as an electrophile
inthereactionsoftheglycals 8and9, becausethesynthesis
of 4%-thioangustmycin C 4 requires the 2%-down hydroxyl
group to be introduced, which could be done by means
of a seleno-Pummerer reaction.11 When 8 was reacted at
−40°C with PhSeCl (1.5 equiv.) in the presence of 13 (1.5
equiv.) in CH3CN, a mixture of the two anomers
(21/22=15/1) was obtained in 62% yield together with
a by-product 23 (8%). Compound 23 had apparently
resulted from methyl-proton abstraction of the initially
formed 1,2-episeleniranium ion followed by electrophilic
glycosidation to the exo-methylene intermediate. The
reaction of 9, on the other hand, gave solely the b-anomer
24 in 49% yield.
Electrophilic glycosidation between the 1-substituted
TIPDS-glycals (8–10 and 12) as glycosyl donors and
bis-O-(trimethylsilyl)uracil (13) as a nucleobase was
examined first by using NIS (N-iodosuccimide) as an
electrophile (Scheme 1). When 8 was treated with NIS (1.5
equiv.) in the presence of 13 (1.5 equiv.) in CH3CN at
0°C, a high yield of the desired b-anomer 14 was observed
as the exclusive product (isolated yields are given in
parentheses). This was also the case for the 1-silyl-
oxymethyl glycal (9), forming 15 exclusively in high
yield.6a Unlike 8 and 9, it is conceivable that electrophilic-
ity of the glycal double bond of 10 and 12 is reduced due
to the conjugation of a multiple bond. In fact, under the
above reaction conditions, these glycosyl donors were
recovered unchanged and the formation of 5-iodouracil
was confirmed by TLC analysis of the reaction mixtures.
Quite unexpectedly, however, upon conducting these
reactions at a much lower temperature of −40°C, the
b-4%-thionucleosides 16 and 18 were obtained along with
their 5-iodo derivatives (17 and 19). In the reaction of 12,
Finally, as shown in Scheme 2, the synthesis of 4%-thioan-
gustmycin C (4) was investigated. The glycosidation
reaction between 9 and bis(trimethylsilyl)-N6-benzoyl-
adenine (25) was carried out at −40°C to give the
b-anomer 26 (40%) exclusively, although the by-product
2712 was also formed in 34% yield. The depicted regio-
chemistry of 26 was confirmed by UV spectroscopy after
converting to 28.13 The stereochemistry of 26 came from
the following NOE data: H-2%/H-8 (1%), H-2%/H-2 (1%),
and H-2%/H-3% (7%). Desilylation (Bu4NF/THF) of 26
followed by acetylation (Ac2O/iPr2NEt/DMAP/CH2Cl2)
Scheme 1.

K. Haraguchi et al. / Tetrahedron Letters 43 (2002) 5657–5660
5659
Scheme 2.
gave the tri-O-acetyl derivative 29 in 90% yield. For
selective oxidation of 29 at the selenium atom, its
reaction with m-CPBA was performed at −70°C. After
extract workup, the resulting selenoxide was subjected
to the seleno-Pummerer reaction (10 equiv. of Ac2O/
CH2Cl2, at room temperature overnight). This gave the
monoselenoacetal 30 in 96% yield as a mixture of two
epimers. Removal of the 2%-phenylselenenyl group of 30
was achieved by the radical reaction using Bu3SnH (2
equiv.)/Et3B. Stereochemical outcome of this reaction
(ratio of 31/32) was found to be highly dependent on
the reaction temperature. Thus, at room temperature in
benzene, 31 having the right 2%-configuration was
obtained only in 46% yield (32, 22%).14 At −20°C in
toluene, the yield of 31 increased to 67% (32, 21%). At
−70°C in toluene, a highest yield of 74% was attained
for 31, while the yield of 32 decreased to 8%. The target
molecule 4 was obtained in 72% yield simply by depro-
tecting 31 with NH3/MeOH.
cyclonucleoside chemistry. The present synthesis of 4%-
thioangustmycin C (4) also suggests that similar trans-
formations would be feasible even in the cases of purine
counterparts. We are currently evaluating the biological
activity of 4%-thioangustmycin C.
Acknowledgements
Financial support from the Ministry of Education,
Culture, Sports, Science and Technology (Grant-in-Aid
No. 11771391 to K.H.) is gratefully acknowledged.
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