Additive pummerer reaction of 3,5-O-(Di-tert-butyl)silylene-4-thiofuranoid glycal: A high-yield and β-selective entry to 4-thioribonucleosides

Article abstract of DOI:10.1021/jo802615h

Upon reacting 3,5-O-(di-tert-butyl)silylene-4-thiofuranoid glycal S-oxide (6) with Ac₂O/TMSOAc/BF₃·OEt₂ in CH ₂Cl₂, the additive Pummerer reaction proceeded to furnish the corresponding 1,2-di-O-acetyl-4-thioribofuranose 7. Compound 7 serves as a highly β-selective glycosyl donor in the Vorbrueggen condensation carried out in the presence of TMSOTf. Thus, the 4-thio-β-D-ribofuranosyl derivatives of uracil, thymine, N⁴-acetylcytosine, 6-chloropurine, and 2-amino-6-chloropurine were synthesized. The use of 7 can be extended to the β-selectivesynthesis of 4-thio-C-ribonucleosides.

Full text of DOI:10.1021/jo802615h

Additive Pummerer Reaction of
3,5-O-(Di-tert-butyl)silylene-4-thiofuranoid Glycal:
A High-Yield and ꢀ-Selective Entry to
4′-Thioribonucleosides
Kazuhiro Haraguchi,* Hiromitsu Matsui, Shin Takami, and
Hiromichi Tanaka
FIGURE 1. 2′-Deoxy-4′-thionucleosides and 4′-thioribonucleosides.
School of Pharmaceutical Sciences, Showa UniVersity, 1-5-8
SCHEME 1. Synthesis of the ꢀ-Anomer of
2′-Deoxy-4′-thionucleosides on the Basis of Electrophilic
Glycosidation with DTBS-4-thiofuranoid Glycal 5
Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan
harakazu@pharm.showa-u.ac.jp
ReceiVed December 04, 2008
furanosyl chloride was reacted with silylated uracil or 5-sub-
stituted uracils in the presence of Hg(OAc)2 to give the
corresponding 4′-thiouridine derivatives with an anomeric ratio
of ꢀ/R ) ca. 6/1,6 which contrasts to the usual ribofuranosyl
cases that result in the exclusive formation of the ꢀ-anomer.
Such lower ꢀ-selectivity observed in the synthesis of 4-thiori-
bofuranosyl nucleosides has been explained by computational
studies of model compounds7 that, due to inferior cationic
character of the R-thiocarbocation intermediate, neighboring
group participation of the 2-acyloxy group does not function
Upon reacting 3,5-O-(di-tert-butyl)silylene-4-thiofuranoid
glycal S-oxide (6) with Ac2O/TMSOAc/BF3 ·OEt2 in CH2Cl2,
the additive Pummerer reaction proceeded to furnish the
corresponding 1,2-di-O-acetyl-4-thioribofuranose 7. Com-
pound 7 serves as a highly ꢀ-selective glycosyl donor in the
Vorbru¨ggen condensation carried out in the presence of
TMSOTf. Thus, the 4-thio-ꢀ-D-ribofuranosyl derivatives of
uracil, thymine, N4-acetylcytosine, 6-chloropurine, and
2-amino-6-chloropurine were synthesized. The use of 7 can
beextendedtotheꢀ-selectivesynthesisof4′-thio-C-ribonucleosides.
effectively. In the Pummerer glycosidation reaction,8-10
a
significant improvement in the ꢀ-selectivity has been made, as
reported by Matsuda et al.,8 by employing 2-O-(2,4-dimethoxy-
benzoyl)-3,5-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)-4-
thio-D-ribitol as a glycosyl donor.
We have previously reported the ꢀ-selective electrophilic
glycosidation between the 3,5-O-(di-tert-butyl)silylene (DTBS)-
protected 4-thiofuranoid glycal (5) and silylated nucleobases
in the presence of phenylselenenyl chloride (Scheme 1). The
glycosidation product I can readily be converted into the 2′-
deoxy-4′-thionucleosides II by homolytic removal of the phe-
nylseleno group.11,12 In this paper, we describe a high yield
and the ꢀ-selective synthesis of 4′-thionucleosides having the
ribo-configuration, the outline of which is shown in Scheme 2.
Nucleoside analogues are recognized as an important class
of biologically active compounds, especially as antiviral and
antitumor agents.1 The recent discovery that a simple replace-
ment of the furanose ring-oxygen with a sulfur atom leads to
promising antiviral or antitumor nucleosides, such as 4′-
thiothymidine (1) and 2′-deoxy-4′-thiocytidine (2), has stimu-
lated the synthesis of this class of nucleosides (Figure 1).2-4 It
has also been reported that 4′-thio-Cl-IB-MECA (4), a 4′-
thioribonucleoside, exhibits a higher binding affinity to the
human adenosine A3 receptor than the parent compound 3.5
Synthesis of these 4′-thionucleosides has been carried out
based on either the Vorbru¨ggen condensation or Pummerer
reaction. In one former example, 2,3,5-tri-O-acetyl-4-thioribo-
(6) Bobek, M.; Bloch, A.; Parthasarathy, R. J. Med. Chem. 1975, 18, 784–
787.
(7) Naka, T.; Nishizono, N.; Minakawa, N.; Matsuda, A Tetrahedron Lett.
1999, 40, 6297–6300.
(8) Naka, T.; Minakawa, N.; Abe, H.; Kaga, D.; Matsuda, A. J. Am. Chem.
Soc. 2000, 122, 7233–7243.
(9) In glycosidation with 1,2,3,5-tetra-O-acetyl-2-ꢀ-methyl-4-thio ribofura-
nose, the respective 4′-thio-ꢀ-ribonucleosides have been obtained stereoselectively
Dukhan, D.; Bosc, E.; Peyronnet, J.; Storer, R.; Gosselin, G. Nucleosides
Nucleotides Nucleic Acids 2005, 24, 577–580.
(10) A practical synthesis of 4′-thioribonucleosides by Pummerer-type
glycosidation has been recently reported: Yoshimura, Y.; Kuze, T.; Ueno, M.;
Komiya, F.; Haraguchi, K.; Tanaka, H.; Kato, F.; Yamada, K.; Asami, K.;
Kaneko, N.; Takahata, H. Tetrahedron Lett. 2006, 47, 591–594.
(11) Haraguchi, K.; Nishikawa, A.; Sasakura, E.; Tanaka, H.; Nakamura,
K. T.; Miyasaka, T. Tetrahedron Lett. 1998, 39, 3713–3716.
(12) Haraguchi, K.; Takahashi, H.; Shiina, N.; Horii, C.; Yoshimura, Y.;
Nishimura, A.; Sasakura, E.; Nakamura, K. T.; Tanaka, H. J. Org. Chem. 2002,
67, 5919–5927.
(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) Dyson, M. R.; Coe, P. L.; Walker, R. T. J. Med. Chem. 1991, 34, 2782–
2786.
(3) Secrist, J. A., III; Tiwari, K. N.; Riordan, J. M.; Montgomery, J. A. J. Med.
Chem. 1991, 34, 2361–2366.
(4) For a review, see: Yokoyama, M. Synthesis, 2000, 1637-1655.
(5) Jeong, L. S.; Jin, D. Z.; Kim, H. O.; Shin, D. H.; Moon, H. R.; Gunaga,
P.; Chun, M. W.; Kim, Y.-C.; Meiman, N.; Gao, Z. C.; Jacobson, K. A. J. Med.
Chem. 2003, 46, 3775–3777.
2616 J. Org. Chem. 2009, 74, 2616–2619
10.1021/jo802615h CCC: $40.75 2009 American Chemical Society
Published on Web 02/25/2009

TABLE 1. Additive Pummerer Reaction of 6
isolated yields (%)
entry
1
reaction conditions (equiv)
Ac2O (5.0)/reflux
7
8
9
10
no reaction
-
11
6
2
3
4
5
6
Ac2O (1.5)/TMSOTf (0.5)/rt
Ac2O (3.0)/SnCl4 (2.0)/rt
Ac2O (5.0)/BF3 ·OEt2 (5.0)/rt
Ac2O (5.0)/BF3 ·OEt2 (5.0)/TMSOAc (5.0)/rt
Ac2O (7.0)/BF3 ·OEt2 (7.0)/TMSOAc (7.0)/rt
20
-
23
35
61
22
-
-
-
-
-
40
-
-
-
-
-
trace
-
34
48
trace
-
27
trace
3
11
trace
7
SCHEME 2. Synthetic Scheme for 4′-Thioribonucleosides
from 4-Thiofuranoid Glycal
SCHEME 3. Additive Pummerer Reaction of
4-Thiofuranoid Glycal S-Oxide 6
FIGURE 2. 4′-Thiopyrimidine- and purine-ribonucleosides.
TABLE 2. Vorbru¨ggen-Type Glycosidation between 7 and
Nucleobase
temp
isolated
ratio
entry
nucleobse
uracil
(°C)
products
yield (%) of ꢀ/R
1
2
3
4
60
80
60
80
12ꢀ + 12r
13ꢀ + 13r
14ꢀ + 14r
15ꢀ + 15r
16ꢀ + 16r
17ꢀ + 17r
18ꢀ + 18r
93
93
91
58
21
49
22
22:1
22:1
23:1
24:1
23:1
23:1
13:1
thymine
N4-Ac-cytosine
6-Cl-purine
5
2-NH2-6-Cl-purine
100
a The anomeric ratio was determined by comparison of integration of
the proton at the base moiety.
The first step of this approach is an additive Pummerer
reaction13-15 of the 4-thioglycal sulfoxide III, leading to the
4-thioribofuranose derivative IV.16 The 4′-thioribonucleoside
V can be obtained from IV by way of the Vorbru¨ggen method.
When the 4-thioglycal 5 was oxidized with m-CPBA at 0
°C, the corresponding sulfoxide 6 was obtained as a mixture of
two diastereomers in 84% yield: 6a (major isomer)/6b (minor
isomer) ) 2.8/1 (Scheme 3). No reaction took place upon
reacting 6 with Ac2O (5 equiv) in refluxing CH2Cl2 (entry 1 in
Table 1). As shown in entry 2, the presence of TMSOTf as a
Lewis acid accelerated the additive Pummerer reaction to give
the desired 1,2-di-O-acetyl-3,5-O-DTBS-4-thioribofuranose 7
in 20% yield as an anomeric mixture (ꢀ/R ) 12/1). Additional
products obtained in entry 2 were the 2′-O-triflates 8, which
undoubtedly derived from TMSOTf. This observation led us to
employ other Lewis acids. As shown in entry 3, the use of SnCl4
resulted in cleavage of the cyclic silyl protecting group to give
9 as the sole product. In entry 4, when SnCl4 was replaced with
BF3 ·OEt2 (5 equiv), there were formed three products, the
desired 7 (23%) along with the partially desilylated products
10 (27%) and 11 (11%). When this BF3 ·OEt2-assisted reaction
was carried out in the presence of TMSOAc (entry 5), the
formation of 10 and 11 was suppressed to a trace amount,
although a considerable amount of 6 was recovered. The highest
yield of 7 (61%) was obtained by increasing the amounts of
the reagents (entry 6). To see if the stereochemistry of the
sulfoxide has any influence on the yield of 7, 6a and 6b were
separately reacted under the conditions of entry 6, but no
significant difference was seen: 59% yield from 6a and 61%
yield from 6b.
With the glycosyl donor 7 in hand, its Vorbru¨ggen condensa-
tion with nucleobases was examined (Figure 2 and Table 2).
When 7 was reacted with bis-O-TMS-uracil in the presence of
TMSOTf in CH3CN/CH2Cl2 at 50 °C for 24 h, the 4′-thiouridine
derivative 12 was obtained in 93% yield in a highly ꢀ-selective
manner (entry 1). The depicted structure of 12ꢀ was determined
on the basis of NOE experiment [H-1′/H-4′ (2.5%), H-6/H-2′
(2.5%), H-6/H-5′a (6.2%), 2′-O-COCH3/H-4′ (0.6%)].17 The
ꢀ-stereochemistry of other 4′-thioribonucleosides (13ꢀ-18ꢀ)
was confirmed also by NOE experiments. The reaction of
thymine and N4-acetylcytosine also proceeded successfully both
in terms of the yield and ꢀ-selectivity (entries 2 and 3). The
use of 6-chloropurine (entry 4) maintained the high ꢀ-selectivity,
although yield of the desired N9-ꢀ-4-thioriboside 15ꢀ decreased
due to the formation of the N7-isomer (16). The high ꢀ-selectiv-
ity was also the case for the formation of the N9-isomer 17 of
2-amino-6-chloropurine (entry 5), but comparatively lower
ꢀ-selectivity was observed in the formation of the N7-isomer
(18). At the moment, we do not have a clear explanation for
this result.
(13) Craig, D.; Daniels, K.; MacKenzie, A. R. Tetrahedron 1993, 49, 11263–
11304.
(14) Yamagiwa, S.; Sato, H.; Hoshi, N.; Kosugi, H.; Uda, H. J. Chem. Soc.,
Perkin Trans. 1 1979, 570-583.
(15) Paquette, L. A.; Fabris, F.; Gallou, F.; Dong, S. J. Org. Chem. 2003,
68, 8625–8634.
(17) 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.
(16) Sung, Z.-H.; Wang, B. J. Org. Chem. 2008, 73, 2462–2465.
J. Org. Chem. Vol. 74, No. 6, 2009 2617

FIGURE 5. Compounds 22-25.
FIGURE 3. Intermediate VI and compound 19.
SCHEME 4. Synthesis of 4′-Thiotiazofurin
FIGURE 4. 4′-Thio-C-nucleosides 20ꢀ and 21ꢀ
The above observed high ꢀ-selectivity, with the exception
of the formation of 18, suggested that the 3,5-O-DTBS-
protection may provide the incipient sulfonium ion VI with a
favorable conformation for effective participation by the
neighboring 2-acetoxy group. Inspection of a molecular model
revealed that the 4-thiofuranose ring of VI is fixed as the 3-endo
conformation as depicted in Figure 3, which accommodates the
2-acetoxy group in quasi-axial orientation. We assume that this
3-endo-fixed conformation would contribute to the observed
uniformly high ꢀ-selectivity. It should be mentioned that the
authors of ref 8 examined the reaction between the 3,5-O-cyclic
silyl-protected 4-thioribofuranose 19 and silylated uracil in
CH3CN in the presence of TMSOTf (Figure 3). Although this
reaction gave the ꢀ-anomer of the respective glycosidated
product stereoselectively, the yield was not satisfactory being
only 35% even after 35 h with the recovery of 19 in 13% yield.
At this stage, we turned our attention to the synthesis of
4′-thio-C-nucleosides18-20 by employing 7. When 2-(tributyl-
stannyl)thiophene was reacted with 7 in CH2Cl2 in the presence
of TMSOTf at 0 °C, the (thiophen-2-yl)nucleoside 20 was
obtained in 79% yield with a ratio of ꢀ/R ) 23/1 (Figure 4).
This C-glycosidation constitutes the first example for the
ꢀ-selective synthesis of a 4′-thio-C-nucleoside. The reaction of
2-(tributylstannyl)furan under similar reaction conditions gave
21 in 61% yield again with a high ꢀ-selectivity (ꢀ/R ) 24/1).
The observed highly stereoselective C-glycosidation encour-
aged us to synthesize the 4′-thio-counterpart of tiazofurin, which
is known as a synthetic C-nucleoside having antitumor activity.21
However, when 4-bromo-2-(tributylstannyl)thiazole22 was re-
acted with 7, a mixture of unknown products was formed. The
reported synthetic route for tiazofurin has utilized a 1-C-
cyanoribofuranose derivative as a key precursor.23 The reaction
of 7 with TMSCN/TMSOTf carried out in this context resulted
in intramolecular cyclization of the 2-O-acetyl group to give
the cyclic acetal 22a (27%) and 22b (10%) (Figure 5). An
apparent solution of this problem is to prepare a 2-O-silyl
derivative corresponding to 7. Compound 7 was converted to
the 1-phenylthio derivative 23 (87%) by reacting with (phe-
nylthio)trimethylsilane in the presence of SnCl4 (Figure 5).
Deacetylation of 23 with NH3/MeOH and subsequent silylation
gave 24 in 89% yield. The 2-O-TBDMS glycosyl donor 25 was
obtained in 96% yield by acetolysis of 24 with Hg(OAc)2/AcOH.
Unexpectedly, the reactions of 25 with TMSCN by using
several different Lewis acids (SnCl4, BF3 ·OEt2, TMSOTf, and
EtAlCl2) all gave complex mixtures of products. In contrast to
this, when the bromosugar 26, prepared by reacting 25 with
TMSBr, was reacted with Hg(CN)2, the desired 1-C-cyano
derivative 27 was obtained in 63% overall yield as the sole
product, the anomeric configuration of which was determined
on the basis of NOE experiment: H-1/H-4 (0.9%) (Scheme 4).
According to the published procedure,23 27 was reacted with
cysteine ethyl ester to give the tiazolin derivative 28, which
subsequently was converted to the thiazole 4-carboxylic ethyl
ester 29 by reacting with BrCCl3. Ammonolysis of 29 furnished
the protected 4′-thiotiazofurin 30 in 87% overall yield from 27.
Deprotection of 30 with Bu4NF gave 31.
In conclusion, we have prepared 1,2-di-O-acetyl-3,5-O-
DTBS-4-thioribofuranose 7 by means of the additive Pummerer
reaction of the glycal S-oxide 6. The utility of 7 as a glycosyl
donor for the ꢀ-selective synthesis of 4′-thioribonucleosides has
been demonstrated by the preparation of 4′-thio analogues of
pyrimidine- (12ꢀ-14ꢀ) and purine-ribonucleosides (15ꢀ and
17ꢀ) based on the Vorbru¨ggen method. By reacting 7 with the
2-tributylstannyl derivatives of thiophene and furan in place of
a nucleobase, the corresponding 4′-thio-C-ribonucleosides (20ꢀ
and 21ꢀ) were also synthesized, which constitutes the first
example of a stereoselective synthesis of 4′-thio-C-nucleosides.
(18) Uenishi, J.; Sohma, A.; Yonemitsu, O. Chem. Lett. 1996, 595-596.
(19) Franchetti, P.; Marchetti, S.; Cappellacci, L.; Jayaram, H. N.; Yalowitz,
J. A.; Goldstein, B. M.; Barascut, J.-L.; Dukhan, D.; Imbach, J.-M.; Grifantini,
M. J. Med. Chem. 2000, 43, 1264–1270.
(20) Ulgar, V.; Lopez, O.; Maya, I.; Fernandez-Bolanos, J. G.; Bols, M.
Tetrahedron 2003, 59, 2801–2809.
(21) Watanabe, K. A. In Chemistry of Nucleosides and Nucleotides;
Townsend, L. B., Ed.; Plenum Press: New York, 1994: Vol. 3, pp 421-535.
(22) Kelly, T. R.; Lang, F. Tetrahedron Lett. 1995, 36, 9293–9296.
(23) Brown, R. S.; Dowden, J.; Moreau, C.; Potter, B. V. L. Tetrahedron
Lett. 2002, 43, 6561–6562.
2618 J. Org. Chem. Vol. 74, No. 6, 2009

and 1.11 (18H, each as s), 2.06, 2.08, 2.10, and 2.14 (12H, each as
Synthesis of the 4′-thio-counterpart of tiazofurin (31) has also
been carried out.
s), 3.79 (1H, dt, J ) 2.0 Hz, J ) 4.8 Hz, and J ) 6.8 Hz), 410
(1H, dd, J4,5a ) 4.8 Hz and J5a,5b ) 10.8 Hz), 4.15 (1H, dd, J4,5b
)
6.8 Hz and J5a,5b ) 10.8 Hz), 4.90 (1H, dd, J2,3 ) 4.4 Hz and J3,4
) 2.0 Hz), 5.28 (1H, dd, J1,2 ) 5.6 Hz and J2,3 ) 4.4 Hz), 6.24
(1H, d, J1,2 ) 5.6 Hz). 13C NMR (CDCl3) δ (ꢀ-anomer) 20.3, 20.5,
20.5, 20.7, 22.1, 26.8, 26.9, 48.6, 64.9, 72.4, 74.7, 77.3, 78.7, 169.3,
169.4, 169.5, 167.0; δ (R-anomer) 20.6, 20.6, 20.9, 21.3, 22.5, 27.0,
27.1, 27.2, 50.0, 64.9, 74.5, 76.2, 76.3, 169.6, 169.7, 170.1, 170.3.
FAB-MS (m/z) 433 (M+ - OAc). Anal. Calcd for C21H36O9SSi:
C, 51.20; H, 7.37. Found: C, 51.41; H, 7.56.
1-[2-O-Acetyl-3,5-O-(di-tert-butylsilylene)-4-thio-ꢀ,r-D-ribo-
furanosyl]uracil (12). To an CH3CN (3.5 mL) solution of bis-O-
trimethylsilyluracil, prepared from uracil (90.8 mg, 0.81 mmol) and
BSA (0.4 mL, 1.62 mmol), was added an CH2Cl2 (3.5 mL) solution
of 7 (104.1 mg, 0.27 mmol) and TMSOTf (0.21 mL, 1.08 mmol)
at 0 °C under Ar atmosphere and the mixture was stirred at 60 °C
for 24 h. The reaction mixture was partitioned between CHCl3/
saturated aq NaHCO3 and column chromatography (hexane/AcOEt
) 3/1) of the organic layer gave 12 (111.7 mg, 93%, 12ꢀ/12r )
Experimental Section
Additive Pummerer Reaction of 6 with Ac2O/TMSOAc/
BF3 ·OEt2: Formation of 7, 10, and 11. To a CH2Cl2 (25 mL)
solution of 6 (1.15 g, 3.99 mmol) was added Ac2O (2.6 mL, 27.93
mmol), TMSOAc (4.2 mL, 27.93 mmol), and BF3 ·OEt2 (3.5 mL,
27.93 mmol) at 0 °C under Ar atmosphere then the mixture was
stirred overnight. The reaction mixture was partitioned between
CHCl3/saturated aq NaHCO3 and column chromatography (hexane/
AcOEt ) 40/1-20/1) of the organic layer gave 7 (967.2 mg, 62%,
solid, ꢀ-isomer/R-isomer ) 13:1), 10 (54.3 mg, 3%, syrup,
ꢀ-isomer/R-isomer ) 13:1), and 11 (334.9 mg, 17%, syrup,
ꢀ-isomer/R-isomer ) 4.9:1).
1
Physical data for 7 (ꢀ-anomer): m.p. 105-107 °C. H NMR
(CDCl3) δ 1.00 and 1.07 (18H, each as s, Si-t-Bu), 2.10 and 2.13
(6H, each as s, Ac), 3.66-3.73 (2H, m), 4.02 (1H, t, J ) J ) 11.2
Hz), 4.28-4.35 (2H, m), 5.47 (1H, d, J ) 3.2 Hz), 5.70 (1H, s);
NOE experiment: H-1/H-4 (1.7%) and H-2/H-3 (7.3%); 13C NMR
(CDCl3) δ 20.79, 20.86, 22.67, 26.91, 27.18, 44.61, 68.43, 78.55,
79.06, 169.30, 169.48. FAB-MS (m/z) 391 (M+ + H) and 331 (M+
- OAc). Anal. Calcd for C17H30O6SSi: C, 52.28; H, 7.74. Found:
C, 52.42; H, 7.89. Physical data for 7 (R-anomer): 1H NMR (CDCl3)
δ 1.01 and 1.04 (18H, each as s, Si-t-Bu), 2.07 and 2.19 (6H, each
as s, Ac), 3.91-3.99 (2H, m), 4.17 (1H, dd, J ) 4.6 and J ) 7.4
Hz), 4.27 (1H, dd, J ) 3.2 and J ) 10.8 Hz), 6.70 (1H, t, J ) J )
4.6 Hz), 6.21 (1H, d, J ) 4.6 Hz); NOE experiment: H-1/H-2 (12%)
and H-1/H-3 (4.8%); 13C NMR (CDCl3) δ 20.12, 20.67, 22.74,
26.88, 27.16, 45.94, 72.73, 75.28, 78.69, 169.76, 169.88. FAB-
MS (m/z) 391 (M+ + H) and 331 (M+ - OAc). Anal. Calcd for
C17H30O6SSi: C, 52.28; H, 7.74. Found: C, 52.56; H, 7.87.
22:1) as a foam: UV (MeOH) λ
264 nm (ꢀ 10500), λ
232
min
max
nm (ꢀ 2400). 1H NMR (CDCl3) (12ꢀ) δ 1.00 and 1.05 (18H, each
as s), 2.15 (3H, s), 3.70-3.76 (1H, m), 4.12 (1H, dd, J4′,5′a ) 10.4
Hz and J5′a,5′b ) 11.2 Hz), 4.27 (1H, dd, J2′,3′ ) 4.4 Hz and J3′,4′
)
10.0 Hz), 4.41 (1H, dd, J4′,5′b ) 4.4 Hz and J5′a,5′b ) 11.2 Hz), 5.50
(1H, dd, J1′,2′ ) 0.8 Hz and J2′,3′ ) 4.4 Hz), 5.83 (1H, d, J5,6 ) 8.2
Hz), 5.96 (1H, d, J1′,2′ ) 0.8 Hz), 7.61 (1H, d, J5,6 ) 8.2 Hz), 9.18
(1H, br); (12r, selected data) δ 1.01 and 1.07 (18H, each as s),
2.12 (3H, s), 5.21 (1H, dd, J1′,2′ ) 7.2 Hz and J2′,3′ ) 9.5 Hz), 5.89
(1H, d, J5,6 ) 8.2 Hz), 6.11 (1H, d, J1′,2′ ) 7.2 Hz), 7.86 (1H, d,
J5,6 ) 8.2 Hz). NOE experiment (ꢀ-isomer): H-1′/H-4′ (1.2%), H-6/
H-2′ (2.5%), H-6/H-5′a (6.2%), COCH3/H-4′ (0.6%). 13C NMR
(CDCl3) δ (12ꢀ) 20.1, 20.8, 22.8, 26.8, 27.2, 27.3, 46.3, 63.6, 67.8,
79.4, 103.4, 140.3, 149.7, 162.0, 168.9. FAB-MS (m/z) 443 (M+
+ H). Anal. Calcd for C19H30N2O6SSi ·1/4AcOEt: C, 51.70; H, 6.94;
N, 6.02. Found: C, 51.98; H, 7.07; N, 5.83.
1
Physical data for 10: H NMR (CDCl3) (ꢀ-isomer) δ 1.05 and
1.06 (18H, each as s, Si-t-Bu), 2.07, 2.09, and 2.13 (9H, each as
s), 3.64-3.69 (1H, m), 4.18 (1H, dd, J4,5a ) 7.2 Hz and J5a,5b
)
11.6 Hz), 4.43 (1H, dd, J4,5b ) 5.6 Hz and J5a,5b ) 11.4 Hz), 4.59
(1H, dd, J2,3 ) 5.6 Hz and J3,4 ) 8.8 Hz), 5.41 (1H, dd, J1,2 ) 3.2
Hz and J2,3 ) 3.6 Hz), 5.81 (1H, d, J1,2 ) 3.2 Hz); (R-isomer,
selected data) δ 3.40-3.45 (1H, m), 4.52 (1H, dd, J4,5b ) 4.6 Hz
and J5a,5b ) 11.4 Hz), 5.21 (1H, dd, J1,2 ) 4.4 Hz and J2,3 ) 9.2
Hz), 5.94 (1H, d, J1,2 ) 4.4 Hz). 13C NMR (CDCl3) δ (ꢀ-anomer)
20.1, 20.7, 20.9, 26.7, 26,8, 27,2, 29.7, 49.1, 64.9, 74.5, 77.9, 79.2,
169.7, 169.9, 170.4; δ (R-isomer, selected data) 26.8, 45.8, 65.5,
74.2, 76.1, 78.1, 170.4. FAB-MS (m/z) 393 (M+ - OAc). Anal.
Calcd for C19H33FO7SSi·1/3AcOEt: C, 50.67; H, 7.46. Found: C,
51.02; H, 7.37.
Acknowledgment. Financial support from the Japan Society
for the Promotion of Science (KAKENHI No. 19590106 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.) is gratefully acknowl-
edged. The authors are also grateful to Ms. K. Shiohara and Y.
Odanaka (Center for Instrumental Analysis, Showa University)
for technical assistance with NMR, MS, and elemental analyses.
1
Physical data for 11: H NMR (CDCl3) (ꢀ-isomer) δ 1.07 and
Supporting Information Available: Experimental proce-
dures, full characterization, and copies of spectra for compounds
6-18 and 20-31. This material is available free of charge via
the Internet at http://pubs.acs.org.
1.08 (18H, s, Si-t-Bu), 2.10, 2.13 and 2.15 (12H, each as s),
3.68-3.73 (1H, m), 4.12 (1H, dd, J4,5a ) 7.6 Hz and J5a,5b ) 11.6
Hz), 4.51 (1H, dd, J4,5b ) 4.4 Hz and J5a,5b ) 11.6 Hz), 4.79 (1H,
dd, J2,3 ) 3.6 Hz and J3,4 ) 7.2 Hz), 5.50 (1H, dd, J1,2 ) 2.8 Hz
and J2,3 ) 3.6 Hz), 5.77 (1H, d, J1,2 ) 2.8 Hz); (R-isomer) δ 1.09
JO802615H
J. Org. Chem. Vol. 74, No. 6, 2009 2619