Synthesis of Tunicaminyluracil Derivatives

Article abstract of DOI:10.1081/NCN-120027831

A tunicaminyluracil derivative, which is a key component of the tunicamycin nucleoside antibiotics, was synthesized using a samarium diiodide (Sml₂) mediated aldol reaction and intramolecular Pummerer reaction as the key steps. The α-phenylthio

Full text of DOI:10.1081/NCN-120027831

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Synthesis of Tunicaminyluracil Derivatives
Satoshi Ichikawa a & Akira Matsuda a
a Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita‐12, Nishi‐6,
Kita‐ku, Sapporo, 060‐0812, Japan
Version of record first published: 01 Jun 2007.
To cite this article: Satoshi Ichikawa & Akira Matsuda (2004): Synthesis of Tunicaminyluracil Derivatives , Nucleosides,
Nucleotides and Nucleic Acids, 23:1-2, 239-253
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS
Vol. 23, Nos. 1 & 2, pp. 239–253, 2004
Synthesis of Tunicaminyluracil Derivativesy,#
*
Satoshi Ichikawa and Akira Matsuda
Graduate School of Pharmaceutical Sciences, Hokkaido University,
Kita-ku, Sapporo, Japan
ABSTRACT
A tunicaminyluracil derivative, which is a key component of the tunicamycin
nucleoside antibiotics, was synthesized using a samarium diiodide (SmI2) mediated
aldol reaction and intramolecular Pummerer reaction as the key steps. The a-
phenylthio ketone 11, the precursor of the samarium enolate, was prepared from D-
galactose. Treatment of 11 with SmI2 at ꢀ40°C resulted in complete conversion to
the corresponding samarium enolate, and subsequent addition of uridine 5’-aldehyde
12 afforded the desired aldol products 13a,b. Compound 13a was converted to the
sulfoxide 15 by a sequential diastereoselective reduction of the ketone and an
oxidation with mCPBA. Activation of 15 with Tf2O provided the desired cyclized
compound 17. In this reaction, the aldol product 13a was also obtained as a
consequence of a competitive intramolecular version of DMSO-oxidation via a 7-
membered ring intermediate. Compound 18 or 19 are ready for use as a glycosyl donor
yIn honor and celebration of the 70th birthday of Professor Leroy B. Townsend.
#This paper constitutes Part 225 of Nucleosides and Nucleotides: Shuto, S.; Fukuoka, M.; Kudoh,
T.; Garnham, C.; Galione, A.; Potter, B. V. L.; Matsuda, A. J. Med. Chem. 2003, 46, 4741.
*Correspondence: Akira Matsuda, Graduate School of Pharmaceutical Sciences, Hokkaido
University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan; Fax: + 81-11-706-4980; E-mail:
matuda@pharm.hokudai.ac.jp.
239
DOI: 10.1081/NCN-120027831
1525-7770 (Print); 1532-2335 (Online)
www.dekker.com
Copyright D 2004 by Marcel Dekker, Inc.

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Ichikawa and Matsuda
in glycosylations to provide a range of analogues as potential glycosyltransferase
inhibitors as well as related natural products.
Key Words: Tumicamycins; Tunicaminyluracil; Antibiotics; Samarium diiodide;
Aldol reaction; Pummerer reaction.
INTRODUCTION
Tunicamycins[1–6] (1, Figure 1), isolated from the fermentation broths of
Streptomces lysosuperficus in 1971, are nucleoside antibiotics composed of uridine,
N-acetylglucosamine (GlcNAc), an aminoundecose which is a unique higher carbon
sugar called tunicamine, and an amide-linked fatty acyl side chain.[3–5] They exhibit a
variety of biological properties including antibacterial, antiviral, antifungal, and
antitumor activities.[7–10] Treatment of eukaryotic cells with tunicamycins results in
the complete truncation of the oligosaccharides from N-linked glycopeptides. Therefore,
tunicamycins are also utilized as a biological tool to reveal functions of the oligo-
saccharides in the N-linked glycopeptides. Tunicamycins strongly and reversibly in-
hibits UDP-GlcNAc:polyprenol phosphate GlcNAc-1-P translocase, the enzyme which
is responsible for the first N-acetylglucosamination of the N-linked glycopeptide in
endothelial reticulum (ER). It is suggested that the structure of tunicamycins closely
resemble the transition state of the transfer reaction of UDP-GlcNAc onto a dolicol
monophosphate in the ER membrane catalyzed by the translocase (Figure 1). In
particular, the C7’–C11’ moiety of the tunicamycin structure forming a galactopyrano-
side can be considered as a mimic of the structure of a divalent metal chelated di-
phosphate. This structural mimicry has been utilized to design inhibitors of
glycosyltransferases, which are responsible for oligosaccharide biosynthesis.[11,12]
Thus, tunicaminyluracil (2), which lacks the GlcNAc moiety and the fatty acyl chain
of the tunicamycins, would be expected to be a versatile synthetic intermediate for the
synthesis of various glycosyltransferase inhibitors (for a recent review associated with
glycosyltransferase inhibitors: Ref. [13]).
Their structural complexity also renders them worthy targets in organic synthesis.
The total synthesis of tunicamycins has been accomplished by the groups of Suami’s[14,15]
Figure 1. Structure of tunicamycins (1) and UDP-NacG1c.

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Scheme 1. Samarium diiodide (Sml2)-mediated aldol reaction.
and Myers,[16,17] and other synthetic studies of related compounds have also been
reported.[18–23]
Previously, we applied the samarium diiodide (SmI2) mediated C–C bond
formation reaction to nucleoside chemistry[24,25] and developed a novel aldol reaction
via the samarium enolate (B) generated by two electron reductions of the a-phenylthio
ketone (A) (Scheme 1).[26] The neutral and mild reaction conditions and the reactivity
of the regioselectively generated samarium enolate (B) are suitable for the carbon-chain
elongation to a base-labile nucleoside 5’-aldehyde derivative. This reaction was
successfully applied to the total synthesis of the nucleoside antibiotic, herbicidin B.[27]
This SmI2-mediated aldol reaction could also be applied to the synthesis of tu-
nicaminyluracil (2), the structure of which is a 5’-carbon-branched uridine derivative
(Scheme 2). Here we describe the synthesis of tunicaminyluracil (2) as an extension of
our SmI2-mediated aldol reaction.
Our strategy includes the regioselective generation of a samarium enolate from the
a-phenylthio ketone (G), aldol reaction with the uridine 5’-aldehyde (F) to assemble the
undecose system (E). After stereoselective reduction of the 7’-keto group in E,
cyclization of the resulting 7’-hydroxyl group in D to the carbon atom at the 11’-
position by an intramolecular Pummerer reaction can be expected to give 2. If such
a cyclization occurs effectively, further introduction of certain carbohydrates using
the resulting phenylthio pyranoside 2 as a versatile intermediate could be realized.
Scheme 2. Retro-synthetic analysis of tunicaminyluracil.

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Therefore, this approach would provide a ready access to a range of sugar analogues
for the development of glycosyltransferase inhibitors.
RESULTS AND DISCUSSION
The synthesis of the key a-phenylthio ketone 11 is summarized in Scheme 3.
Protection of 2-azido-2-deoxy-3,4,6-tri-O-acetylgalactose 3[28] with a TBDPS group
gave only the b-galactoside 4, and successive removal of the acetyl groups followed by
protection of the resulting secondary alcohols with an isopropylidene group under
thermodynamic conditions provided 5. Introduction of a phenylthio group at the 6-
position, which would become a leaving group when the samarium enolate is
generated, was conducted by activation of the hydroxyl group as its triflate, followed
by displacement with thiophenol to afford 6 in 93% yield in 2 steps. After deprotection
of the TBDPS group of 6 with tetrabutylammonium fluoride (TBAF), followed by
reductive ring opening of the resulting pyranose by NaBH4, the desired diol 7 was
obtained in 86% yield. Subsequent protecting group manipulations afforded the mono-
benzoate 8 (83% yield for 3 steps) at the 5 position, and the remaining primary alcohol
at position 1 was further converted to a phenylthio group in 90% yield as in the
procedure for the preparation of 6. It should be noted that selective activation of the
primary alcohol of 7 with Tf2O followed by substitution with thiophenol was un-
successful and gave a tetrahydropyran derivative as a result of ring closure of the
triflate intermediate. Deprotection of the benzoyl group followed by Dess–Martin
periodinane oxidation afforded the a-phenylthio ketone 11 without oxidizing either of
the phenylthio groups in quantitative yield.
The key SmI2-mediated aldol reaction was conducted (Scheme 4) and the results
are summarized in Table 1. Our previous study revealed that the two-electron reduction
Scheme 3. Preparation of a-phenylthio ketone.

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Scheme 4. Sml2-mediated aldol reaction.
by SmI2 to generate a samarium enolate from a 1-phenylthio-2-ulose derivative
occurred at ꢀ78°C. However, the treatment of a-phenylthio ketone 11 with 2.2 equiv
of SmI2 followed by addition of 1.0 equiv of the aldehyde 12a at ꢀ78°C gave the
desired aldol products 13a,b in 13% yield (Table 1, entry 1, 5’R/5’S = 64/36). The low
yield of the products and the large amount of the unreacted 11 observed in the reaction
mixture indicated that the a-phenylthio ketone 11 without a hetero atom adjacent to the
phenylthio group is less reactive to the two-electron reduction than that with an oxygen
atom.[26,27] After several attempts to optimize the reaction temperature, the reaction at
ꢀ40°C gave complete consumption of 11. Addition of the aldehyde 12 at ꢀ78°C after
generation of the samarium enolate provided 13a,b in 71% (entry 3, 5’R/5’S = 66/34),
although the addition at 0°C resulted in inverted selectivity (entry 2, 5’R/5’S = 28/72).
It is known that SmI2 can reduce an azido group to the corresponding amino group.
However, no such reduction of the azido group in 13 was detected, and therefore the
two-electron reduction was chemoselectively accomplished.
Stereoselective reduction of the ketone 13a was required in the next step.
Intramolecular hydride delivery from NaBH(OAc)3 via a 6-membered transition state
selectively afforded the desired 1,3-anti-diol 14 in quantitative yield. If the resulting
hydroxyl group at the 7’ position cyclized with the carbon atom at the 11 position to
form a hexopyranose via an intramolecular Pummerer reaction, the desired
tunicaminyluracil derivative 17 could be obtained. There are several methods available
to promote the Pummerer reaction including the direct activation of a sulfide or of the
corresponding sulfoxide. Direct activation of the sulfide 14 by treatment with NIS in
the presence of a catalytic amount of TfOH resulted in the iodo-etherification product
16 between the 5’-hydroxyl group and the 5,6-double bond within the uracil base, and
the desired cyclization failed to occur. Next, the activation of the corresponding
sulfoxide 15 was examined (Ref. [29] a review for intramolecular Pummerer reaction:
Ref. [30]). Oxidation of 14 with mCPBA provided the corresponding sulfoxide 15 as a
mixture of diastereomers. An initial effort to activate 15 with (CF3CO)2O resulted in
extensive trifluoroacetylation of the alcohols and only a trace amount of the desired
product 17 was obtained. However, treatment of the sulfoxide 15 with Tf2O in the
presence of pyridine at ꢀ20°C provided the desired product 17 along with 13a as an
inseparable mixture in a ratio of 62:38. After the mixture was treated with
NaBH(OAc)3, compound 17 could be separated from the corresponding reduced
aThe uridine 5’-aldehyde derivative 12 was prepared by Dess–Martin periodinane oxidation of
2’,3’-di-O-TBS uridine.

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Table 1.
Temp. (°C)*
Entry
A
B
Yield (%)
Ratio (13a/13b)
1
2
3
ꢀ78
ꢀ40
ꢀ40
ꢀ78
0
13
62
71
64/36
28/72
66/34
ꢀ78
*A: temperature at the addition of 11. B: temperature at the addition of 12.
product 14 by the usual silica gel column chromatography. The phenylthio glycoside 17
was a single b-anomer. The stereochemistry of 17 was determined by an NOE (3.6%)
between H7’ and H11’ (Scheme 5).
Sulfonylation of the sulfoxide with Tf2O promotes b-elimination to give a
thiocarbenium intermediate. Intramolecular nucleophilic attack of the 7’-hydroxyl group
on the 11’-carbon atom affords the cyclized product 17 (Scheme 6, path a). We suppose
Scheme 5. Synthesis of tunicaminyluracil derivative.

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245
Scheme 6. Reaction pathways to give 16 and 13a.
that the aldol product 13a is produced through the nucleophilic attack of the 7’-
hydroxyl group on the activated thionium cation with the formation of a 7-membered
ring followed by hydrogen abstraction and elimination resulting in the oxidation of the
alcohol, an intramolecular version of the DMSO-oxidation (Scheme 6, path b). The fact
that the 5’-keto derivative or the sulfoxide of 13a, which is also possible a product if
this reaction proceeds in an intermolecular fashion, was not detected in the reaction
mixture indicates that the mechanism of the oxidation involves the intramolecular
pathway b. Following acetylation of the 5’-hydroxyl group of 17, the 10’-azido group
of the corresponding acetate 18 was reduced with PhSeH in the presence of Et3N. The
liberated amine was then protected with a phthaloyl group to afford 19, a fully
protected tunicaminyluracil.
In conclusion, the tumicaminyluracil derivative 19 has been synthesized by an
aldol reaction via the samarium enolate generated from the a-phenylthio ketone 11 and
the intramolecular Pummerer reaction as the key steps. The SmI2-mediated aldol
reaction was successfully applied to the carbon-chain elongation of the uridine
5’-aldehyde derivative 12. Compound 18 or 19 would then be ready for use as glycosyl
donor in glycosylations to provide a range of sugar analogues as well as related nat-
ural products.
EXPERIMENTAL
1
General methods. Physical data were measured as follows: H and 13C NMR
spectra were recorded at 500 MHz and 125 MHz instruments in CDCl3 as the solvent
with tetramethylsilane as an internal standard. Chemical shifts are reported in parts per
million (d), and signals are expressed as s (singlet), d (doublet), t (triplet), q (quartet),
m (multiplet), or br (broad). All exchangeable protons were detected by addition of
D2O. Assignment of 1H signals was based on two-dimentional NMR and NOE
experiments. Mass spectra were measured on JEOL JMS-D300 spectrometer. TLC was
done on Merck Kieselgel F254 precoated plates. Silica gel used for column
chromatography was Merck silica gel 5715.

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tert-Butyldiphenylsilyl 2-Azido-3,4,6-tri-O-acetyl-2-deoxy- -D-galactopyrano-
side (4). A mixture of 3 (2.50 g, 7.50 mmol), TBDPSCl (2.34 mL, 9.00 mmol), and
imidazole (1.23 g, 18.0 mmol) in DMF (40 mL) was stirred for 3 h at 50°C. After MeOH
(5 mL) was added, the mixture was partitioned between AcOEt (200 mL) and H2O
(200 mL), and the organic layer was washed with H2O (200 mL), brine (100 mL), dried
(Na2SO4), and evaporated under reduced pressure. The residue was purified by column
chromatography (SiO2, 25% AcOEt/hexane) to give 4 (3.10 g, 73% as a colorless syrup):
[a]D ꢀ 9.29° (c 0.96, CHCl3); 1H NMR (CDCl3, 500 MHz) d 7.73–7.36 (m, 10H), 5.23
(d, 1H, J = 3.0 Hz), 3.68 (dd, 1H, J = 3.3, 10.8 Hz), 4.46 (d, 1H, J = 7.7 Hz), 3.96 (dd,
1H, J = 6.6, 11.2 Hz), 3.89 (dd, 1H, J = 6.6, 11.2 Hz), 3.72 (dd, 1H, J = 7.6, 10.7 Hz),
3.53 (t, 1H, J = 6.6 Hz), 2.17 (s, 3H), 2.03 (s, 3H), 1.91 (s, 3H); 13C NMR (CDCl3, 125
MHz) d 170.5, 170.3, 170.0, 136.1, 136.0, 133.1, 132.6, 130.3, 130.1, 127.9, 127.7, 97.2,
71.5, 70.8, 66.7, 63.7, 61.4, 27.0, 20.9, 20.8, 20.7, 19.4; MS (FAB) m/z 568 (MH+);
Exact MS (FAB) Calcd for C28H29N3O8Si: 570.2271, found: 570.2291.
tert-Butyldiphenylsilyl 2-Azido-2-deoxy-3,4-O-isopropylidene- -D-galactopyra-
noside (5). A mixture of 4 (2.84 g, 5.00 mmol) in MeOH (50 mL) containing
NaOMe in MeOH (28%, 100 mL) was stirred for 2 h at room temperature. After
neutralized by adding Dowex 50 (H+), the resin was removed by filtration, and the
filtrate was evaporated under reduced pressure. The residue was coevaporated with
toluene (3 ꢁ 10 mL). The residue and anhydrous p-TsOH (85 mg, 0.5 mmol) in
acetone (50 mL) was stirred for 5 h at room temperature. The mixture was neutralized
with saturated aqueous NaHCO3, and the mixture was concentrated under reduced
pressure. The residue was partitioned between AcOEt (200 mL) and H2O (200 mL),
and the organic layer was washed with H2O (200 mL), brine (100 mL), dried
(Na2SO4), and evaporated under reduced pressure. The residue was purified by flush
column chromatography (SiO2, 25% AcOEt/hexane) to give 5 (3.10 g, 73% as a
1
colorless syrup): [a]D 52.8° (c 1.01, CHCl3); H NMR (CDCl3, 500 MHz) d 7.75–7.38
(m, 10H), 4.43 (d, 1H, J = 8.3 Hz), 3.91 (dd, 1H, J = 1.7, 5.2 Hz), 3.85 (dd, 1H,
J = 5.4, 8.1 Hz), 3.66 (dd, 1H, J = 8.1, 11.9 Hz), 3.48 (dd, 1H, J = 5.6, 11.9 Hz), 3.43
(t, 1H, J = 8.1 Hz), 3.38 (ddd, 1H, J = 1.7, 5.6, 8.1 Hz), 1.56 (s, 3H), 1.30 (s, 3H); 13C
NMR (CDCl3, 125 MHz) d 137.4, 137.3, 135.2, 134.1, 131.7, 131.6, 129.4, 129.1,
112.3, 98.1, 79.2, 75.4, 74.5, 69.6, 63.7, 29.9, 28.4, 27.8, 20.6; MS (FAB) m/z
484 (MH+); Exact MS (FAB) Calcd for C25H34N3O5Si: 484.2267, found: 484.2251.
Anal. Calcd for C25H33N3O5Si: C, 62.09; H, 6.88; N, 8.69. Found: C, 62.05; H, 6.89;
N, 8.73.
tert-Butyldiphenylsilyl 2-Azido-2-deoxy-3,4-O-isopropylidene-6-S-phenyl-6-
thio- -D-galactopyranoside (6). A mixture of 5 (370 mg, 0.76 mmol) and Tf2O
(258 mL, 1.56 mmol) in CH2Cl2 (8 mL) containing pyridine (129 mL, 1.72 mmol) was
stirred for 5 min at ꢀ20°C. The mixture was diluted with CH2Cl2 (20 mL), washed with
H2O (50 mL), saturated aqueous NaHCO3 (30 mL), and brine (100 mL), dried (Na2SO4),
and evaporated under reduced pressure. A solution of PhSH (117 mL, 1.17 mmol) and
Et3N (214 mL, 1.56 mmol) in CH2Cl2 (8 mL) was added to the above residue in CH2Cl2
(5 mL). The mixture was stirred for 1 h at room temperature, diluted with CH2Cl2
(20 mL), and washed with H2O (50 mL). The organic layer was evaporated under
reduced pressure. The residue was purified by column chromatography (SiO2, 4%

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AcOEt/hexane) to give 6 (406 mg, 93% as a colorless syrup): [a]D 21.0° (c 1.11,
1
CHCl3); H NMR (CDCl3, 500 MHz) d 7.73–7.16 (m, 15H), 4.27 (d, 1H, J = 8.2 Hz),
4.10 (dd, 1H, J = 2.1, 5.2 Hz), 3.78 (dd, 1H, J = 5.3, 8.1 Hz), 3.42 (t, 1H, J = 8.2
Hz), 3.34 (ddd, 1H, J = 2.1, 5.3, 8.8 Hz), 1.54 (s, 3H), 1.26 (s, 3H); 13C NMR
(CDCl3, 125 MHz) d 136.0, 135.9, 135.6, 133.1, 132.6, 130.8, 129.9, 129.8, 129.1,
129.0, 127.6, 127.4, 127.1, 126.2, 110.2, 96.4, 72.7, 71.8, 67.9, 33.2, 28.3, 26.8, 26.1,
19.1; MS (FAB) m/z 576 (MH+); Exact MS (FAB) Calcd for C31H38N3O4SSi:
576.2352, found: 576.2330.
(2S,3R,4S,5R)-2-Azido-3,4-(dimethylmethylenedioxy)-6-phenylthio-1,5-hexane-
diol (7). A mixture of 6 (3.60 g, 6.26 mmol) and TBAF (1 M, 6.89 mL, 6.89 mmol)
in THF (60 mL) was stirred for 30 min at ꢀ20°C and evaporated under reduced
pressure. Sodium borohydride (950 mg, 25.0 mmol) was added to the above residue in
MeOH (60 mL) at ꢀ20°C, and the mixture was stirred for 30 min. The mixture was
evaporated under reduced pressure, and then the residue was coevaporated with MeOH
(3 ꢁ 10 mL). The residue was partitioned between AcOEt (200 mL) and H2O
(200 mL), and the organic layer was washed with H2O (200 mL) and brine (100 mL),
dried (Na2SO4), and evaporated under reduced pressure. The residue was purified by
column chromatography (SiO2, 33% AcOEt/hexane) to give 7 (1.83 g, 86% as a
1
colorless syrup): [a]D ꢀ 29.8° (c 0.99, CHCl3); H NMR (CDCl3, 500 MHz) d 7.38
(d, 2H, J = 7.7 Hz), 7.29 (t, 2H, J = 7.5 Hz), 7.21 (t, 1H, J = 7.4 Hz), 4.31 (dd, 1H,
J = 1.8, 6.8 Hz), 4.27 (t, 1H, J = 6.5 Hz), 3.80 (m, 2H), 3.65 (m, 2H), 3.17 (dd, 1H,
J = 6.5, 13.7 Hz), 3.06 (dd, 1H, J = 6.8, 13.7 Hz), 2.83 (d, 1H, J = 6.7 Hz, exchanged
with D2O), 2.27 (t, 1H, J = 5.7 Hz, exchanged with D2O), 1.56 (s, 3H), 1.36 (s, 3H);
13C NMR (CDCl3, 125 MHz) d 135.2, 129.8, 129.3, 129.2, 128.6, 126.7, 126.5, 126.1,
108.9, 68.0, 63.0, 61.7, 38.2, 26.5; MS (FAB) m/z 340 (MH+); Exact MS (FAB) Calcd
for C15H22N3O4S: 340.1331, found: 340.1339.
(2S,3R,4S,5R)-2-Azido-5-benzoyloxy-3,4-(dimethylmethylenedioxy)-6-phenyl-
thio-1-hexanol (8). A mixture of 7 (500 mg, 1.47 mmol), TBSCl (243 mg, 1.67
mmol), and imidazole (220 mg, 3.23 mmol) in DMF (20 mL) was stirred for 1 h at
0°C. After MeOH (5 mL) was added, the mixture was partitioned between AcOEt (100
mL) and H2O (100 mL), and the organic layer was washed with H2O (100 mL) and
brine (50 mL), dried (Na2SO4), and evaporated under reduced pressure. BzCl (256 mL,
2.21 mmol) was added to the residue in pyridine (20 mL), and the mixture was stirred
for 12 h at room temperature. After MeOH (1 mL) was added, the mixture was
evaporated under reduced pressure. The residue was partitioned between AcOEt (100
mL) and H2O (100 mL), and the organic layer was washed with H2O (100 mL) and
brine (50 mL), dried (Na2SO4), and evaporated under reduced pressure. A mixture of
the residue and TBAF (1 M, 1.67 mL, 1.67 mmol) in THF (20 mL) was stirred for 2
h at 0°C. The mixture was evaporated under reduced pressure, and the residue was
purified by column chromatography (SiO2, 10% AcOEt/hexane) to give 8 (534 mg,
1
83% as a colorless syrup): [a]D ꢀ 52.7° (c 1.04, CHCl3); H NMR (CDCl3, 500 MHz)
d 8.12–7.18 (m, 10H), 5.22 (ddd, 1H, J = 1.6, 5.2, 8.8 Hz), 4.70 (dd, 1H, J = 1.6, 6.4
Hz), 4.39 (m, 1H), 3.53 (m, 2H), 3.47 (dd, 1H, J = 5.2, 13.7 Hz), 3.26 (dd, 1H, J = 8.8,
13.7 Hz), 1.96 (t, 1H, J = 5.2 Hz, exchanged with D2O), 1.67 (s, 3H), 1.44 (s, 3H); 13C
NMR (CDCl3, 125 MHz) d 166.7, 135.2, 133.7, 130.1, 130.0, 129.6, 129.3, 128.8,

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126.7, 109.5, 75.1, 72.1, 62.9, 61.6, 33.8, 26.8, 25.6; MS (FAB) m/z 444 (MH+); Exact
MS (FAB) Calcd for C22H26N3O5S: 444.1593, found: 444.1580.
(2S,3R,4S,5R)-2-Azido-5-benzoyloxy-3,4-(dimethylmethylenedioxy)-1,6-
di(phenylthio)hexane (9). A mixture of 8 (570 mg, 1.28 mmol) and Tf2O (261 mL,
1.53 mmol) in CH2Cl2 (15 mL) containing pyridine (129 mL, 1.72 mmol) was stirred
for 5 min at ꢀ20°C, and diluted with CH2Cl2 (20 mL). The mixture was washed with
H2O (50 mL), saturated aqueous NaHCO3 (30 mL), and brine (100 mL), dried
(Na2SO4), and evaporated under reduced pressure. A mixture of the residue in CH2Cl2
(15 mL), PhSH (394 mL, 3.84 mmol), and Et3N (720 mL, 5.12 mmol) was stirred for 1 h
at room temperature, diluted with CH2Cl2 (20 mL), and washed with H2O (50 mL).
The organic layer was evaporated under reduced pressure. The residue was purified by
column chromatography (SiO2, 4% AcOEt/hexane) to give 9 (614 mg, 90% as a
1
colorless syrup): [a]D 23.9° (c 1.02, CHCl3); H NMR (CDCl3, 500 MHz) d 8.03–7.12
(m, 15H), 5.07 (ddd, 1H, J = 3.0, 4.8, 8.3 Hz), 4.62 (dd, 1H, J = 3.0, 6.5 Hz), 4.41 (t,
1H, J = 6.8 Hz), 3.45 (dd, 1H, J = 6.8, 12.3 Hz), 3.41 (dd, 1H, J = 4.9, 13.8 Hz), 3.17
(dd, 1H, J = 8.4, 13.8 Hz), 2.97 (dd, 1H, J = 5.3, 13.8 Hz), 2.92 (dd, 1H, J = 7.0, 13.7
Hz), 1.61 (s, 3H), 1.39 (s, 3H); 13C NMR (CDCl3, 125 MHz) d 166.2, 135.0, 134.5,
133.5, 131.2, 130.1, 129.9, 129.8, 129.5, 129.4, 128.7, 127.6, 126.9, 109.7, 78.3, 75.1,
71.7, 59.5, 36.9, 33.8, 25.7, 25.4; MS (FAB) m/z 536 (MH+); Exact MS (FAB) Calcd
for C28H30N3O4S2: 536.1677, found: 536.1670.
(2S,3R,4S,5R)-2-Azido-3,4-(dimethylmethylenedioxy)-1,6-di(phenylthio)hexane
(10). A mixture of 9 (4.70 g, 8.74 mmol) in MeOH (90 mL) containing NaOMe in
MeOH (28%, 0.8 mL) was stirred for 1 h at room temperature. After neutralized by
adding Dowex 50 (H+), the resin was removed by filtration, and the filtrate was
evaporated under reduced pressure. The residue was purified by column chromatog-
raphy (SiO2, 4% AcOEt/hexane) to give 10 (3.40 g, 90% as a colorless syrup):
1
[a]D ꢀ 14.5° (c 1.11, CHCl3); H NMR (CDCl3, 500 MHz) d 7.37–7.20 (m, 15H), 4.32
(dd, 1H, J = 4.8, 6.9 Hz), 4.26 (dd, 1H, J = 2.8, 6.9 Hz), 3.68 (ddd, 1H, J = 2.9, 6.4,
9.1 Hz), 3.57 (dd, 1H, J = 6.4, 11.5 Hz), 3.06 (m, 3H), 2.98 (dd, 1H, J = 6.5, 13.7 Hz),
1.51 (d, 1H, J = 5.8 Hz, exchanged with D2O), 1.54 (s, 3H), 1.33 (s, 3H); 13C NMR
(CDCl3, 125 MHz) d 135.3, 134.7, 131.2, 130.1, 129.5, 129.4, 127.6, 127.0, 126.3,
109.3, 68.1, 60.6, 59.6, 38.5, 36.9, 26.6, 25.0, 21.3; MS (FAB) m/z 432 (MH+); Exact
MS (FAB) Calcd for C21H26N3O3S2: 432.1415, found: 432.1422.
(3R,4R,5S)-5-Azido-3,4-(dimethylmethylenedioxy)-1,6-di(phenylthio)-2-hexa-
none (11). A mixture of 10 (1.20 g, 2.79 mmol) and Dess–Martin periodinane (1.79 g,
4.19 mmol) in CH2Cl2 (30 mL) was stirred for 30 min at room temperature. After a
mixture of saturated aqueous NaHCO3 and saturated aqueous Na2S2O3 (5:1, 50 mL)
was added, the mixture was vigorously stirred until the organic layer turned to be clear.
The organic layer was washed with H2O (50 mL) and brine (50 mL), dried (Na2SO4),
and evaporated under reduced pressure. The residue was purified by column
chromatography (SiO2, 8% hexane/AcOEt) to give 11 (1.20 g, 99%. as a colorless
syrup): [a]D 23.9° (c 1.17, CHCl3); 1H NMR (CDCl3, 500 MHz) d 7.40–7.19 (m,
15H), 4.69 (dd, 1H, J = 1.1, 8.7 Hz), 4.62 (d, 1H, J = 8.7 Hz), 4.19 (d, 1H, J = 15.7
Hz), 3.93 (d, 1H, J = 15.7 Hz), 3.34 (t, 1H, J = 6.6 Hz),3.27 (s, 2H), 1.60 (s, 3H), 1.32

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249
(s, 3H); 13C NMR (CDCl3, 125 MHz) d 204.4, 135.0, 134.4, 130.5, 130.2, 129.3, 129.0,
127.2, 126.9, 110.5, 79.7, 78.7, 57.7, 42.1, 34.8, 25.9, 23.8; MS (FAB) m/z 430 (MH+);
Exact MS (FAB) Calcd for C21H24N3O3S2: 430.1259, found: 430.1254.
1-[10-Azido-2,3-di-O-(tert-butyldimethylsilyl)-6,10,11-trideoxy-8,9-O-isopropyli-
dene-11-S-phenyl-11-thio-L-lyxo-D-allo-undeculofuranosyl-(1,4)]uracil (13a) and 1-
[10-Azido-2,3-di-O-(tert-butyldimethylsilyl)-6,10,11-trideoxy-8,9-O-isopropylidene-
11-S-phenyl-11-thio-L-lyxo-L-talo-undeculofuranosyl-(1,4)]uracil (13b). Compound
11 (85 mg, 0.2 mmol) in THF (2 mL) was added dropwise to a THF solution of
SmI2 (0.1 M, 4.4 mL, 0.44 mmol) at ꢀ40°C. After the TLC analysis indicated the
disappearance of 11, oxygen gas was passed through the mixture. Then, 12 (94 mg,
0.2 mmol) in THF (2 mL) was added dropwise, and the mixture was stirred for 15 min
at ꢀ78°C. After the mixture was allowed to warm to room temperature, saturated
aqueous NH4Cl was added. The mixture was filtrated through a Celite pad, and the
filtrate was partitioned between AcOEt (50 mL) and H2O (50 mL), and the organic
layer was washed with saturated aqueous NaHCO3 (20 mL) and brine (20 mL), dried
(Na2SO4), and evaporated under reduced pressure. The residue was purified by flush
column chromatography (SiO2, 33% AcOEt/hexane) to give 13a (74 mg, 47% as a
white foam, fast moving) and 13b (38 mg, 24% as a white foam, slow moving).
1
For 13a: H NMR (CDCl3, 500 MHz) d 8.95 (br s, 1H, exchanged with D2O), 8.04
(d, 1H, J = 8.2 Hz), 7.43 (d, 2H, J = 7.7 Hz), 7.53 (t, 2H, J = 7.8 Hz), 7.26 (d, 1H,
J = 7.7 Hz), 5.83 (d, 1H, J = 4.6 Hz), 5.69 (dd, 1H, J = 1.8, 8.1 Hz), 4.72 (d, 1H, J = 8.8
Hz), 4.48 (d, 1H, J = 8.8 Hz), 4.31 (t, 1H, J = 4.5 Hz), 4.26 (d, 1H, J = 10.2 Hz), 3.93
(d, 1H, J = 4.2 Hz), 3.43 (d, 1H, J = 2.1 Hz), 3.33 (m, 3H), 3.29 (dd, 1H, J = 10.1, 19.3
Hz), 2.88 (dd, 1H, J = 1.9, 19.3 Hz), 1.62 (s, 3H), 1.31 (s, 3H), 0.92 (s, 9H), 0.90 (s, 9H),
0.11 (s, 6H), 0.07 (s, 6H); 13C NMR (CDCl3, 125 MHz) d 212.4, 163.6, 150.7, 141.4,
134.6, 130.7, 129.5, 127.5, 110.8, 102.3, 90.0, 87.1, 80.6, 79.2, 75.4, 72.4, 65.5, 57.9,
44.4, 35.2, 26.2, 26.1, 26.0, 24.0, 18.3, 18.2, ꢀ4.2, ꢀ4.4, ꢀ4.5, ꢀ4.6; MS (FAB) m/z 792
(MH+); Exact MS (FAB) Calcd for C36H58N5O9SSi2: 792.3493, found: 792.3521.
For 13b:1H NMR (CDCl3, 500 MHz) d 8.87 (br s, 1H, exchanged with D2O), 7.75
(d, 1H, J = 8.1 Hz), 7.41 (d, 2H, J = 7.6 Hz), 7.32 (t, 2H, J = 7.4 Hz), 7.26 (d, 1H,
J = 7.4 Hz), 5.85 (d, 1H, J = 6.6 Hz), 5.73 (dd, 1H, J = 1.7, 8.1 Hz), 4.71 (d, 1H,
J = 8.8 Hz), 4.47 (d, 1H, J = 8.8 Hz), 4.36 (dd, 1H, J = 4.5, 6.5 Hz), 4.29 (d, 1H,
J = 11.1 Hz), 4.19 (dd, 1H, J = 1.4, 4.2 Hz), 3.86 (br s, 1H), 3.65 (d, 1H, J = 2.0 Hz),
3.29 (br s, 3H), 3.07 (d, 1H, J = 7.7 Hz), 2.76 (dd, 1H, J = 10.6, 18.7 Hz), 1.59 (s, 3H),
1.31 (s, 3H), 0.93 (s, 9H), 0.86 (s, 9H), 0.12 (s, 3H), 0.11 (s, 3H), 0.03 (s, 3H), ꢀ0.02
(s, 3H); 13C NMR (CDCl3, 125 MHz) d 212.1, 163.4, 150.6, 141.8, 134.6, 130.8, 130.7,
129.5, 127.5, 110.8, 102.7, 89.6, 88.4, 80.5, 79.2, 74.8, 71.8, 67.8, 57.7, 43.7, 35.1,
26.1, 26.0, 24.0, 23.9, 18.3, 18.2, ꢀ4.1, ꢀ4.2, ꢀ4.4, ꢀ4.6; MS (FAB) m/z 792 (MH+);
Exact MS (FAB) Calcd for C36H58N5O9SSi2: 792.3493, found: 792.3486.
1-[10-Azido-2,3-di-O-(tert-butyldimethylsilyl)-6,10,11-trideoxy-8,9-O-isopropyli-
dene-11-S-phenyl-11-thio-L-galacto-D-allo-undecofuranosyl-(1,4)]uracil (14). Sodi-
um borohydride (7.1mg, 189 mmol) was added to a mixture of AcOH and CH2Cl2
(1:2, 1 mL) at ꢀ20°C, and then a solution of 13a (50 mg, 63 mmol) in CH2Cl2 (0.5 mL)
was added dropwise to the mixture. After being stirred for 30 min at ꢀ20°C, the
mixture was evaporated under reduced pressure, and the residue was coevaporated with

ORDER
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Ichikawa and Matsuda
MeOH (3 ꢁ 1 mL). The residue was partitioned between AcOEt (30 mL) and H2O
(20 mL), and the organic layer was washed with saturated aqueous NaHCO3 (20 mL)
and brine (100 mL), dried (Na2SO4), and evaporated under reduced pressure. The
residue was purified by column chromatography (SiO2, 33% AcOEt/hexane) to give 14
(55 mg, quant. as a white foam): 1H NMR (CDCl3, 500 MHz) d 9.49 (br s, 1H,
exchanged with D2O), 7.61 (d, 1H, J = 8.0 Hz), 7.42 (d, 2H, J = 7.8 Hz), 7.29 (t, 2H,
J = 7.8 Hz), 7.21 (d, 1H, J = 7.7 Hz), 5.69 (d, 1H, J = 8.0 Hz), 5.69 (d, 1H, J = 5.7
Hz), 4.60 (t, 1H, J = 5.1 Hz), 4.46 (dd, 1H, J = 2.2, 6.4 Hz), 4.24 (ddd, 1H, J = 6.3,
9.6, 12.6 Hz), 4.13 (d, 2H), 4.08 (dd, 1H, J = 6.7, 9.4 Hz), 3.91 (d, 1H, J = 2.4 Hz),
3.68 (dd, 1H, J = 2.0, 7.1 Hz), 3.43 (d, 1H, J = 6.2 Hz), 3.33 (dd, 1H, J = 7.1, 13.6Hz),
3.27 (dd, 1H, J = 4.3, 13.6 Hz), 2.09 (ddd, 1H, J = 3.3, 3.8, 13.8 Hz), 1.70 (ddd, 1H,
J = 1.8, 6.5, 13.8 Hz), 1.49 (s, 3H), 1.31 (s, 3H), 0.90 (s, 9H), 0.87 (s, 9H), 0.09 (s,
3H), 0.08 (s, 3H) , 0.07 (s, 3H), 0.01 (s, 3H); 13C NMR (CDCl3, 125 MHz) d 163.7,
150.8, 143.9, 135.2, 130.7, 129.3, 127.1, 109.3, 102.4, 94.8, 89.1, 78.7, 77.9, 73.2, 73.0,
67.7, 67.6, 58.6, 38.1, 36.5, 27.0, 26.1, 26.0, 25.1, 18.3, 18.2, ꢀ4.2, ꢀ4.4, ꢀ4.5, ꢀ4.7;
MS (FAB) m/z 794 (MH+); Exact MS (FAB) Calcd for C36H60N5O9SSi2: 794.3650,
found: 794.3666.
1-[10-Azido-2,3-di-O-(tert-butyldimethylsilyl)-6,10,11-trideoxy-8,9-O-isopropyli-
dene-11-phenylsulfinyl-L-galacto-D-allo-undecofuranosyl]uracil (15). A mixture of
14 (30 mg, 26 mmol) and mCPBA (4.6 mg, 26 mmol) in CH2Cl2 (5 mL) was stirred for
30 min at 0°C. After a mixture of saturated aqueous NaHCO3 and saturated aqous
Na2S2O3 (4:1, 5 mL) was added, the organic layer was washed with brine (5 mL), dried
(Na2SO4), and evaporated under reduced pressure. The residue was purified by column
chromatography (SiO2, 66% AcOEt/hexane) to give a diastereomeric mixture of 15 (32
mg, quant. as a white foam): MS (FAB) m/z 810 (MH+); Exact MS (FAB) Calcd for
C36H60N5O10SSi2: 810.3599, found: 810.3598.
Thioglycoside 17. A mixture of 15 (7.0 mg, 8.7 mmol) and Tf2O (10.7 mL, 52
mmol) in CH2Cl2 (100 mL) containing pyridine (6.6 mL, 104 mmol) was stirred for 5 min
at ꢀ20°C, and diluted with CH2Cl2 (5 mL). The mixture was washed with H2O (3 mL),
saturated aqueous NaHCO3 (3 mL), and brine (3 mL), dried (Na2SO4), and evaporated
under reduced pressure. The residue was purified by column chromatography (SiO2,
33% AcOEt/hexane) to give an inseparable mixture of 17 and 13a (5.7 mg, 89% as a
1
glass, the ratio of 17 and 13a was 62:38 by H NMR). To isolate pure 17, the next
experiment was performed. NaBH4 (9.4 mg, 189 mmol) was added to a mixture of
AcOH and CH2Cl2 (1:2, 2 mL) at ꢀ20°C, and then the mixture of 17 and 13a (50 mg,
63 mmol, the ratio of 17 and 13a was 57:43) in CH2Cl2 (1 mL) was added dropwise to
the above mixture. After being stirred for 30 min, the mixture was evaporated under
reduced pressure, and the residue was coevaporated with MeOH (3 ꢁ 2 mL). The
residue was partitioned between AcOEt (30 mL) and H2O (20 mL), and the organic
layer was washed with saturated aqueous NaHCO3 (20 mL) and brine (10 mL), dried
(Na2SO4), and evaporated under reduced pressure. The residue was purified by flash
column chromatography (SiO2, 33% AcOEt/hexane) to give 17 (26 mg, 51.6% as a
white foam, fast moving) and 14 (23 mg, 46% as a white foam, slow moving).
1
For 17: H NMR (CDCl3, 500 MHz) d 8.68 (br s, 1H, exchanged with D2O), 7.79
(d, 1H, J = 8.1 Hz), 7.51–7.30 (m, 5H), 5.70 (d, 1H, J = 8.1 Hz), 5.57 (d, 1H, J = 5.1

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Tunicaminyluracil Derivatives
251
Hz), 5.16 (d, 1H, J = 7.5 Hz), 4.43 (t, 1H, J = 4.7 Hz), 4.17 (m, 3H), 4.07 (t, 1H,
J = 4.2 Hz), 3.90 (m, 1H), 3.85 (m, 1H), 3.69 (t, 1H, J = 7.1 Hz), 3.22 (d, 1H, J = 6.5
Hz, exchanged with D2O), 2.13 (m, 1H), 1.68 (m, 1H), 1.60 (s, 3H), 1.39 (s, 3H), 0.92
(s, 9H), 0.91 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H), 0.05 (s, 3H),0.04 (s, 3H); 13C NMR
(CDCl3, 125 MHz) d 163.2, 150.4, 142.6, 134.4, 131.4, 129.4, 127.9, 111.5, 102.3,
92.4, 88.2, 86.7, 76.2, 74.3, 72.6, 69.2, 66.6, 64.0, 38.4, 27.8, 26.1, 26.0, 25.7, 18.3,
18.2, ꢀ4.2, ꢀ4.4, ꢀ4.5, ꢀ4.6; MS (FAB) m/z 792 (MH+); Exact MS (FAB) Calcd for
C36H58N5O9SSi2: 792.3493, found: 792.3496.
The physical data for 14 was in accordance with the compound obtained by
reduction of 13a.
Acetate 18. A mixture of 17 (20 mg, 25 mmol), Ac2O (2.8 mL, 30 mmol), Et3N
(4.2 mL, 30 mmol), and DMAP (1 mg, 7.5 mmol) in CH3CN (1 mL) was stirred for 12 h
at room temperature. After MeOH (1 mL) was added to the mixture, the mixture was
evaporated under reduced pressure. The residue was partitioned between AcOEt (30
mL) and H2O (20 mL), and the organic layer was washed with saturated aqueous
NaHCO3 (20 mL) and brine (10 mL), dried (Na2SO4), and evaporated under reduced
pressure. The residue was purified by flash column chromatography (SiO2, 33%
1
AcOEt/hexane) to give 18 (21 mg, quant. as a white foam): H NMR (CDCl3, 500
MHz) d 8.49 (br s, 1H, exchanged with D2O), 7.78 (d, 1H, J = 8.1 Hz), 7.54–7.27 (m,
5H), 5.88 (d, 1H, J = 4.2 Hz), 5.74 (dd, 1H, J = 1.1, 8.1 Hz), 5.27 (ddd, 1H, J = 3.0,
5.8, 8.2 Hz), 5.07 (d, 1H, J = 7.4 Hz), 4.18 (dd, 1H, J = 3.2, 4.7 Hz), 4.15 (t, 1H,
J = 5.1 Hz), 4.13 (t, 1H, J = 4.4 Hz), 4.04 (m, 1H), 4.03 (t, 1H, J = 4.3 Hz), 3.90 (t,
1H, J = 4.5 Hz), 3.67 (t, 1H, J = 6.9 Hz), 2.17 (ddd, 1H, J = 5.1, 8.3, 14.3 Hz), 2.10 (s
3H), 2.04 (ddd, 1H, J = 3.3, 8.2, 14.3 Hz), 1.55 (s, 3H), 1.37 (s, 3H), 0.88 (s, 9H), 0.87
(s, 9H), 0.09 (s, 3H), 0.06 (s, 3H), 0.05 (s, 3H),0.02 (s, 3H); 13C NMR (CDCl3, 125
MHz) d 181.3, 169.6, 169.3, 163.0, 139.7, 134.6, 132.0, 129.3, 128.1, 111.4, 102.4,
101.7, 100.1, 88.6, 87.2, 84.9, 76.4, 76.2, 75.9, 71.9, 69.5, 68.4, 63.8, 36.0, 30.3, 27.9,
26.0, 21.4, 20.9, ꢀ4.0, ꢀ4.2, ꢀ4.5, ꢀ4.8; MS (FAB) m/z 883 (MH+); Exact MS (FAB)
Calcd for C38H60N5O10SSi2: 834.3599, found: 834.3578.
Protected tunicaminyluracil 19. A mixture of 18 (29 mg, 34 mmol) and PhSeH
(10 mL, 101 mmol) in Et3N (200 mL) was heated for 1 h at 60°C. Additional PhSeH (21
mL, 202 mmol) was added to the mixture, and the mixture was further stirred for 1 h to
complete the reaction. The mixture was evaporated under reduced pressure. A mixture
of the residue, phthalic chloride (15 mL, 101 mmol), and DBU (32 mL, 217 mmol) in
toluene (1 mL) was heated for 3 h at 100°C. The mixture was allowed to cool to room
temperature and evaporated under reduced pressure. The residue was partitioned
between AcOEt (20 mL) and H2O (10 mL), and the organic layer was washed with
brine (10 mL), dried (Na2SO4), and evaporated under reduced pressure. The residue
was purified by column chromatography (SiO2, 33% AcOEt/hexane) to give 19 (31 mg,
1
98% as a pale yellow foam): H NMR (CDCl3, 500 MHz) d 8.04 (br s, 1H, exchanged
with D2O), 7.87–7.17 (m, 10H), 5.92 (d, 1H, J = 4.8 Hz), 5.87 (d, 1H, J = 10.3 Hz),
5.76 (d, 1H, J = 8.2 Hz), 5.27 (ddd, 1H, J = 3.2, 5.4, 8.2 Hz), 4.95 (dd, 1H, J = 6.9,
10.3 Hz), 4.41 (t, 1H, J = 10.4 Hz), 4.33 (t, 1H, J = 7.3 Hz), 4.17 (t, 1H, J = 3.8 Hz),
4.14 (dd, 1H, J = 4.5, 8.1 Hz), 3.98 (t, 1H, J = 4.6 Hz), 3.93 (t, 1H, J = 4.1 Hz), 2.22
(ddd, 1H, J = 4.4, 8.0, 14.1 Hz), 2.15 (s, 3H), 2.11 (ddd, 1H, J = 5.5, 8.9, 14.1 Hz),

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Ichikawa and Matsuda
1.50 (s, 3H), 1.32 (s, 3H), 0.89 (s, 9H), 0.88 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H), 0.05 (s,
3H),0.03 (s, 3H); 13C NMR (CDCl3, 125 MHz) d 169.5, 167.8, 162.6, 150.0, 139.5,
134.3, 131.7, 131.1, 128.9, 127.3, 132.6, 111.6, 102.4, 88.0, 85.2, 83.8, 75.7, 72.8,
72.0, 69.4, 68.8, 53.3, 36.0, 27.5, 25.8, 25.7, 21.2, 18.0, 17.9, ꢀ4.3, ꢀ4.5, ꢀ4.7, ꢀ4.9;
MS (FAB) m/z 938 (MH+); Exact MS (FAB) Calcd for C46H64N3O12SSi2: 938.3749,
found: 938.3724.
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Received August 26, 2003
Accepted October 6, 2003

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