Synthesis of Anomeric Sulfur Analogues of CMP-Neu5Ac Containing Tethered Alkane or Arene

Article abstract of DOI:10.1055/s-2003-43349

A new approach to the synthesis of anomeric sulfur analogues of CMP-Neu5Ac containing alkane or arene linkage 1a-d is described. The procedure involves the high β-stereoselectivity in sialylation of the peracetylated sialic acid methyl ester 4 with mercap

Full text of DOI:10.1055/s-2003-43349

LETTER
37
Synthesis of Anomeric Sulfur Analogues of CMP-Neu5Ac Containing
Tethered Alkane or Arene
Synthesis of
A
nom
a
eric
S
ulfur
i
Analo
-
C
H
M
P-Neu5A
c
suan Chang, Ying Shin Tao, Wen-Shan Li*
Institute of Chemistry, Academia Sinica, Taipei 115, Taiwan
Fax +886(2)27831237; E-mail: wenshan@chem.sinica.edu.tw
Received 19 September 2003
Dedicated to the memory of Professor Ray Lemieux.
provides a way to generate a variety of alcohol linkers.
Next, the phosphitylation reaction5 between the linker
hydroxyl group and cytidinyl phosphitamide 3 forms the
P-O bond. Finally, oxidation of the phosphorous and
Abstract: A new approach to the synthesis of anomeric sulfur ana-
logues of CMP-Neu5Ac containing alkane or arene linkage 1a–d is
described. The procedure involves the high b-stereoselectivity in
sialylation of the peracetylated sialic acid methyl ester 4 with mer-
captoalkyl (aryl) trichloroacetate 5a–d, followed by selective deprotection of CMP-Neu5Ac completes the formation of
deprotection of the trichloroacetyl group to the corresponding hy-
droxyalkyl and hydroxyaryl thioglycosides 2a–d. Subsequent O-
1a–d.
phosphitylation of 2a–d with respective 3a or 3c, followed by oxi-
dation and deprotection led to the isolation of the target compounds
1a–d in good yields.
NH2
N
O
P
N
O
Key words: sialylation, hydroxyalkyl (aryl) thioglycosides, selec-
tive deprotection, sialyltransferase
O
O
O
O
n
S
HO
OH
HO
OH OH
HO
O
CO2
AcHN
Hypersialylation due to enhanced sialyltransferase activi-
ty is of vital importance in various biological events such
as cell-cell adhesion, tumor cell metastasis and inflamma-
tion.1 Sialic acids containing glycoconjugates are in-
volved in different disease states, particularly in the
control of tumor cell growth.2 Sialyltransferase mediates
the biosynthesis of sialylated glycoconjugates and its ac-
tivity has been demonstrated as a potential marker of tu-
morogenesis.3 Therefore, the design of potent and specific
inhibitors of sialyltransferase has become a promising
strategy for cancer treatment. Despite lacking the struc-
ture of the target enzyme or the enzyme-inhibitor com-
plex, recent studies of sialyltransferase inhibitors4
primarily focus on the design of carbohydrate mimetics
including structural analogues of the donor or acceptor
and the transition-state mimetics of the sialyl donor. In or-
der to understand the substructural requirements for the
catalytic and/or binding site of the sialyltransferase, it is
highly desirable to design a specific probe. Our interest is
in development of inhibitors that could explore interac-
tions between inhibition activity and flexibility in the ac-
tive site using a tethered moiety. Here, we would like to
report the synthesis of anomeric sulfur analogues of CMP-
Neu5Ac containing tethered alkane or arene 1a–d
(Figure 1).
1a n = 1
1b n = 2
NH2
N
O
N
O
O
O
P
O
OH OH
O
S
S
HO
OH
HO
HO
HO
NH2
N
O
O
CO2
AcHN
1c
O
N
O
O
O
P
O
O
HO
OH
HO
OH OH
CO2
AcHN
1d
Figure 1 Structure of anomeric sulfur analogues of CMP-Neu5Ac
containing tethered alkane or arene
Classically, synthesis of hydroxyalkyl and hydroxyaryl
thioglycosides could utilize either thioglycosylation or
anomeric S-alkylation strategies.6 Although various pro-
tecting groups (acetyl, benzoyl, trimethylsilyl, tert-butyl-
diphenylsilyl) for the terminal hydroxyl of 5 were made,
thioglycosylation reactions used to prepare 2a–d either
did not react, or formed disulfide, elimination products, or
non-selective deprotection of the terminal alcohol.7 In ad-
dition, S-alkylation pathway would necessitate multiple
steps. Scheme 2 outlines an efficient approach for the syn-
thesis of the requisite anomeric sulfur analogues of sialic
acid 2a–d. Treating the peracetylated sialic acid methyl
ester 48 with boron trifluoride in the presence of a corre-
The retrosynthetic analysis is depicted in Scheme 1. The
sialylation/deprotection process (4 + 5 → 2) is the key-
stone of our strategy since it secures the correct stereo-
chemistry at the anomeric carbon and at the same time
SYNLETT 2004, No. 1, pp 0037–0040
0
5.
0
1.
2
0
0
4
Advanced online publication: 26.11.2003
DOI: 10.1055/s-2003-43349; Art ID: U19003ST
© Georg Thieme Verlag Stuttgart · New York

38
K.-H. Chang et al.
LETTER
Cl
Cl
NH2
N
OAc
CO2Me
AcO
Cl
Cl
OAc
AcO
+
HS linkerO
AcO
O
AcHN
O
O
O
N
O
4
5a-d
O
O
P
O
O
BF3 Et2O
CH2Cl2
Cl
Cl
linker
OH OH
linker
S
S
linkerO
CO2Me
AcO
OAc
AcO
S
HO
AcO
AcO
OH
HO
O
O
HO
CO2
O
AcHN
1a ethyl
1b propyl
70~72%
AcHN
1c p-benzyl
1d o-benzyl
6a-d
pyridine
CH3OH
NHR1
N
linkerOH
CO2Me
AcO
OAc
68~82%
AcHN
R2
AcO
N
O
linker
S
linkerOH
AcO
O
O
P
N
2a ethyl
OAc
O
+
AcO
2b propyl
2c p-benzyl
2d o-benzyl
CO2Me
O
AcHN
OR2 OR1
AcO
2a-d
3
R1 = Ac, Bz
R
Scheme 2
2 = allyl, cyanoethyl
Cl
Cl
OAc
CO2Me
AcO
OAc
+
HS linkerO
gave low yields of desired product, possibly because the
benzoyl protecting group afforded poor solubility of prod-
uct and reactant in the reaction solvent (acetonitrile-N,N-
dimethylformamide).
AcO
O
Cl
O
AcHN
AcO
4
5a-d
Scheme 1 Retrosynthetic analysis of target molecules 1a–d
By changing the protecting group to the smaller acetyl
group5b,11 allowed reaction with 2c,d13 in the presence of
tetrazole furnished the intermediate phosphite triesters in
good yield. Subsequent oxidation under mild conditions
(5.5 M tert-butylhydroperoxide in decane) gave the corre-
sponding O-cyanoethylphosphate triesters 7c,d, which
were used in next step without further purification. Re-
moval of the cyanoethyl group by treatment of 7c,d with
triethylamine afforded the acetyl protected phosphate di-
esters 8c and 8d as triethylammonium salt (Scheme 3,
path B). Alkaline deprotection and subsequent saponifica-
tion, as described for 1a,b, produced the corresponding
sodium salt 1c and 1d in 80–82% yield.
sponding mercaptoalkyl (aryl) trichloroacetate 5a–d9
gave predominantly the b-anomers 6a–d (b:a > 20:1)10 in
70–72% yield without formation of alkyl or aryl disulfides
and elimination products.
The trichloroacetyl group could be removed selectively
by treatment with pyridine–methanol to afford the per-
acetylated hydroxyalkyl and hydroxyaryl thioglycosides
2a–d. The NMR spectra of 2a–d, displaying five sharp
singlets at around d = 2 ppm, confirm the formation of a
single isomer without deacetylation.
In conclusion, a new strategy for the b-stereoselective
sialylation of the peracetylated sialic acid methyl ester 4
with mercaptoalkyl (aryl) trichloroacetate 5a–d has been
described. This one-step reaction avoids the problems of
disulfide formation, elimination and additional steps. The
hydroxyl moiety of the products 6a–d can be selectively
deprotected after sialylation providing the option for fur-
ther regioselective modifications in the sialic acid group.
On the basis of this approach, we have synthesized four
sulfur analogues of CMP-Neu5Ac 1a–d with various link-
ers between the sialic acid and CMP, shortening the
number of synthetic steps to seven with overall yields of
17–25%. These new compounds can then be used to probe
the structure of the active site of sialyltransferase. Appli-
cation of this strategy to the synthesis of cyclic
analogues12 of CMP-Neu5Ac with linkers of variable
length is currently underway.
O-Allylphosphate triesters 7a and 7b were generated from
2a,b via a two-step procedure (Scheme 3). A benzoyl pro-
tected O-allyl tetraisopropylphosphordiamidite deriva-
tive, 3a,5a was attached via phosphoramidite chemistry
and subsequent oxidation with tert-butylhydroperoxide
afforded the respective O-allylphosphate triesters 7a and
7b in 65–68% yield after purification. The allyl groups
were removed under mild conditions by Pd(PPh3)4 with
diethylamine as the nucleophile (Scheme 3, path A). Fi-
nally, deprotection of the acetyl, benzoyl and methylester
groups by sequential treatment of compound 8a and 8b
with sodium methoxide and sodium hydroxide afforded
their corresponding target molecules 1a and 1b.
Mechanistically, the incorporation of CMP into the per-
acetylated hydroxyaryl thioglycosides 2c,d with activated
O-cyanoethyl tetraisopropylphosphordiamidite 3b is also
feasible. However, attempts to prepare the benzoyl pro-
tected O-cyanoethyl tetraisopropylphosphordiamidite 3b
Synlett 2004, No. 1, 37–40 © Thieme Stuttgart · New York

LETTER
Synthesis of Anomeric Sulfur Analogues of CMP-Neu5Ac
39
NHR1
N
S
linkerOH
CO2Me
AcO
OAc
AcO
AcO
O
AcHN
R2
1. Tetrazole, toluene,
O
P
N
O
CH3CN
O
O
2a-d
NHR1
2. t-BuOOH
O
S
linkerO
CO2Me
AcO
OAc
AcO
OR1 OR1
N
AcO
O
R2
O
AcHN
N
O
O
P
7a linker = ethyl, R1 = Bz, R2 = allyl (65%)
O
N
7b linker = propyl, R1 = Bz, R2 = allyl (68%)
7c linker = p-benzyl, R1 = Ac, R2 = cyanoethyl
7d linker = o-benzyl, R1 = Ac, R2 = cyanoethyl
OR1 OR1
3a R1 = Bz, R2 = allyl
3b
3c
R
1 = Bz, R2 = cyanoethyl
1 = Ac, R2 = cyanoethyl
NHR1
N
R
path A
O
N
O
O
O
P
(Ph3P)4Pd, Et2NH,
CH3CN
O
1. NaOCH3
2. NaOH
S
linkerO
CO2Me
AcO
OAc
OR1 OR1
1a-d
AcO
O
80~82%
AcHN
AcO
linker
1a ethyl
1b propyl
1c p-benzyl
1d o-benzyl
8a linker = ethyl, R1 = Bz (74%)
8b linker = propyl, R1 = Bz (79%)
8c linker = p-benzyl, R1 = Ac (60%)
8d linker = o-benzyl, R1 = Ac (65%)
path B
Et3N
Scheme 3
2001, 284, 466. (f) Sun, H.; Yang, J.; Amaral, K. E.;
Horenstein, B. A. Tetrahedron Lett. 2001, 42, 2451.
(g) Schaub, C.; Muller, B.; Schmidt, R. R. Eur. J. Org.
Chem. 2000, 9, 1745. (h) Schröder, P. N.; Giannis, A.
Angew. Chem. Int. Ed. 1999, 38, 1379. (i) Muller, B.;
Schaub, C.; Schmidt, R. R. Angew. Chem. Int. Ed. 1998, 37,
2893. (j) Amann, F.; Schaub, C.; Muller, B.; Schmidt, R. R.
Chem.–Eur. J. 1998, 4, 1106. (k) Schaub, C.; Muller, B.;
Schmidt, R. R. Glycoconjugate J. 1998, 15, 345.
Acknowledgment
We thank the National Science Council (NSC90-2113-M-001-083),
Department of Health (DOH92-TD-1112) and Academia Sinica for
financial support. We thank Dr. Shu-Chuan Jao for her useful dis-
cussion and technical support. We are grateful to Dr. Douglas A.
Klewer for helpful comments on the manuscript.
References
(l) Kleineidam, R. G.; Schmelter, T.; Schwarz, R. T.;
Schauer, R. Glycoconjugate J. 1997, 14, 57. (m) Hinou, H.;
Sun, X.-L.; Ito, Y. J. Org. Chem. 2003, 68, 5602.
(1) (a) Philips, M.; Nudelman, E.; Gaeta, F. C. A.; Perez, M.;
Singhal, A. K.; Hakomori, S.; Paulson, J. C. Science 1990,
250, 1130. (b) Walz, G.; Aruffo, A.; Kolanus, W.;
Bevilacqua, M.; Seed, B. Science 1990, 250, 1132.
(c) Varki, A. Glycobiology 1993, 3, 97. (d) Rosenberg, A.
In Biological of Sialic Acids; Plenum Press: New York,
1995. (e) Schauer, R.; Kamerling, J. P. In Glycoproteins II;
Montreuil, J.; Vliegenthart, J. F. G.; Schachter, H., Eds.;
Elsevier: Amsterdam, 1997, 243–402. (f) Dennis, J. W.;
Granovsky, M.; Warren, C. E. BioEssays 1999, 21, 412.
(g) Bertozzi, C. R.; Kiessling, L. L. Science 2001, 291, 2357.
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GerardySchahn, R.; Rahmann, H. Cancer Res. 1998, 58,
779.
(5) (a) Barone, A. D.; Tang, J. Y.; Caruthers, M. H. Nuclei Acids
Res. 1984, 12, 4051. (b) Kajihara, Y.; Ebata, T.; Koseki, K.;
Kodama, H.; Matsushita, H.; Hashimoto, H. J. Org. Chem.
1995, 60, 5732.
(6) (a) Eisele, T.; Toepfer, A.; Kretzschmar, G.; Schmidt, R. R.
Tetrahedron Lett. 1996, 37, 1389. (b) Kanie, O.; Nakamura,
J.; Itoh, Y.; Kiso, M.; Hasegawa, A. J. Carbohydr. Chem.
1987, 6, 117. (c) Turnbull, W. B.; Field, R. A. J. Chem. Soc.,
Perkin Trans. 1 2000, 1859.
(7) For example, treatment of 4 and 2-mercaptoethyl
trimethylsilyl ether (or 2-mercaptoethyl tert-
butyldiphenylsilyl ether) with boron trifluoride in
dichloromethane gave the desired thioglycoside in low yield,
along with the formation of large amounts of bis-(2-
trimethylsilyloxyethyl) disulfide or bis-(2-tert-
(3) Gessner, P.; Riedl, S.; Quentmaier, A.; Kemmer, W. Cancer
Lett. 1993, 75, 143.
(4) (a) Whalen, L. J.; McEvoy, K. A.; Halcomb, R. L. Bioorg.
Med. Chem. Lett. 2003, 13, 301. (b) Hinou, H.; Sun, X.-L.;
Ito, Y. Tetrahedron Lett. 2002, 43, 9147. (c) Tanaka, T.;
Ozawa, M.; Miura, T.; Inazu, T.; Tsuji, S.; Kajimoto, T.
Synlett 2002, 9, 1487. (d) Schworer, R.; Schmidt, R. R. J.
Am. Chem. Soc. 2002, 124, 1632. (e) Wu, C.-Y.;Hsu, C.-C.;
Chen, S.-T.; Tsai, Y.-C. Biochem. Biophys. Res. Commun.
butyldiphenylsilyloxyethyl) disulfide. Condensation of the
2-chlorosialic acid with the 2-mercaptoethyl benzoate gave
the thioglycoside in low yield. The products were
contaminated with the sialic acid 2,3-elimination product,
see: (a) Moreau, V.; Norrild, J. C.; Driguez, H. Carbohydr.
Res. 1997, 300, 271. (b) Sabesan, S.; Neira, S.; Davidson,
F.; Duus, J.; Bock, K. J. Am. Chem. Soc. 1994, 116, 1616.
(8) Cohen, S. B.; Halcomb, R. L. J. Org. Chem. 2000, 65, 6145.
Synlett 2004, No. 1, 37–40 © Thieme Stuttgart · New York

40
K.-H. Chang et al.
LETTER
(9) The required compounds 5a–d were prepared from
corresponding mercaptoalkyl(aryl) alcohols, respectively,
by treating them with trichloroacetyl chloride in
J = 2.5, 10.5 Hz, 1 H), 4.58 (dd, J = 2.2, 12.3 Hz, 1 H), 4.09
(m, 2 H), 3.56 (s, 3 H), 2.73 (dd, J = 4.7, 13.8 Hz, 1 H), 2.63
(br s, 1 H), 2.15 (dd, J = 11.6, 13.8 Hz, 1 H), 2.11 (s, 3 H),
dichloromethane at 0 °C for 4 h.
2.05 (s, 3 H), 2.04 (s, 3 H), 2.02 (s, 3 H), 1.86 (s, 3 H). 13
NMR (100 MHz, CDCl3): d = 171.36, 171.00, 170.36,
170.25, 170.17, 168.49, 144.64, 136.84, 129.79, 129.25,
127.88, 89.29, 73.24, 73.13, 69.11, 68.76, 62.79, 62.54,
52.74, 48.92, 38.13, 22.93, 20.97, 20.80, 20.72, 20.62.
C
(10) The configuration of 6a–d was determined by measuring the
chemical shifts of H3eq and H4. The formation of b-anomer
6a caused an upfield shift of H3eq to d = 2.52 ppm while the
chemical shift of H3eq of a-anomer 6a remained d = 2.72
ppm. In addition, H4 is shifted in the other direction. Thus H4
in the b-anomer 6a occurs at d = 5.41 ppm in contrast to the
chemical shift of a-anomer at d = 4.84 ppm. Several reports
demonstrated that H3eq of a b-linked alkyl thioglycoside of
sialic acid diplayed a signal upfield relative to that of the
corresponding a-anomer, see: (a) Ponpipom, M. M.;
Bugianesi, R. L.; Shen, T. Y. Can. J. Chem. 1980, 58, 214.
(b) Warner, T. G.; Lee, L. A. Carbohydr. Res. 1988, 176,
211.
HRMS-FAB: calcd for C27H36NO13S (M + H)+: 614.1907.
Found: 614.1913. Compound 1a: 1H NMR (400 MHz, D2O):
d = 8.21 (d, J = 7.6 Hz, 1 H), 6.34 (d, J = 7.6 Hz, 1 H), 5.98
(d, J = 7.6 Hz, 1 H), 4.40–4.35 (m, 3 H), 4.28 (m, 1 H), 4.22
(d, J = 7.6 Hz, 1 H), 4.15 (m, 2 H), 4.04 (m, 2 H), 3.91–3.84
(m, 3 H), 3.70 (dd, J = 7.6 Hz, 1 H), 3.62 (d, J = 7.6 Hz, 1
H), 2.88 (m, 2 H), 2.54 (dd, J = 7.6 Hz, 1 H), 2.09 (s, 3 H),
2.06 (m, 1 H). 13C NMR (100 MHz, D2O): d = 175.01,
173.43, 159.28, 148.55, 144.24, 95.34, 89.94, 85.17, 83.37
(d, J = 8.7 Hz), 74.40, 71.19, 69.99, 69.28, 68.12, 67.42,
64.87 (d, J = 4.0 Hz), 64.16 (d, J = 4.7 Hz), 63.50, 52.27,
39.59, 28.82 (d, J = 7.4 Hz), 22.25. 31P NMR (D2O, H3PO4
reference): d = 0.12. HRMS-MALDI: calcd for
(11) Miyazaki, T.; Sato, H.; Sakakibara, T.; Kajihara, Y. J. Am.
Chem. Soc. 2000, 122, 5678.
(12) CMP-Neu5Ac mimetics that contain a spiro-ring.
(13) Selected physical data. Compound 2a: TLC (100% EtOAc):
Rf = 0.40. 1H NMR (500 MHz, CDCl3): d = 5.89 (d, J = 9.3
Hz, 1 H), 5.44 (s, 1 H), 5.26 (td, J = 4.5, 11.0 Hz, 1 H),
5.21(m, 1 H), 4.96 (dd, J = 2.1, 12.2 Hz, 1 H), 4.42 (d,
J = 10.4 Hz, 1 H), 4.05 (m, 2 H), 3.77 (s, 3 H), 3.75 (m, 1 H),
3.62 (m, 1 H), 2.84 (m, 1 H), 2.76 (m, 1 H), 2.58 (br s, 1 H),
2.50 (dd, J = 4.7, 13.8 Hz, 1 H), 2.12 (m, 1 H), 2.10 (s, 3 H),
C22H35N4O16PSNa (M + 2 H + Na)+: 697.1403. Found:
697.1387. Compound 1b: 1H NMR (400 MHz, D2O): d =
8.00 (d, J = 7.6 Hz, 1 H), 6.17 (d, J = 7.6 Hz, 1 H), 6.03 (d,
J = 4.0 Hz, 1 H), 4.37 (m, 2 H), 4.31 (m, 1 H), 4.22 (m, 1 H),
4.16 (d, J = 10.5 Hz, 1 H), 4.12 (m, 1 H), 4.03 (m, 1 H),
4.00–3.84 (m, 5 H), 3.70 (m, 1 H), 3.57 (d, J = 9.0 Hz, 1 H),
2.62 (m, 2 H), 2.50 (dd, J = 4.8, 13.6 Hz, 1 H), 2.10 (s, 3 H),
1.90 (m, 3 H). 13C NMR (100 MHz, D2O): d = 176.46,
174.89, 165.72, 157.06, 141.69, 96.55, 89.49, 87.54, 82.86
(d, J = 8.7 Hz), 74.37, 71.08, 70.18, 69.42, 68.46, 67.96,
65.08 (d, J = 5.5 Hz), 64.25 (d, J = 4.8 Hz), 63.52, 52.45,
40.98, 29.47 (d, J = 7.2 Hz), 24.63, 22.26. 31P NMR (D2O,
H3PO4 reference): d = 0.36. HRMS-MALDI: calcd for
C23H37N4O16PSNa (M + 2 H + Na)+: 711.1559. Found:
711.1566. Compound 1c: 1H NMR (400 MHz, D2O): d =
8.02 (d, J = 7.9 Hz, 1 H), 7.56 (d, J = 8.1 Hz, 2 H), 7.43 (d,
J = 8.1 Hz, 2 H), 6.10 (d, J = 7.9 Hz, 1 H), 5.88 (d, J = 3.7
Hz, 1 H), 4.96 (d, J = 8.1 Hz, 2 H), 4.50 (d, J = 10.4 Hz, 1
H), 4.30–4.17 (m, 5 H), 4.03 (m, 1 H), 3.95 (t, J = 10.2 Hz,
1 H), 3.84–3.77 (m, 2 H), 3.69–3.63 (m, 2 H), 2.72 (dd,
J = 4.7, 13.7 Hz, 1 H), 2.12 (m, 1 H), 2.11 (s, 3 H). 13C NMR
(100 MHz, D2O): d = 174.97, 171.92, 158.97, 148.26,
144.00, 139.14 (d, J = 6.3 Hz), 135.39, 12911, 128.26,
95.04, 89.95, 89.91, 83.17 (d, J = 8.2 Hz), 74.24, 71.75,
70.20, 68.09, 68.53, 67.22 (d, J = 4.5 Hz), 66.95, 64.17 (d,
J = 4.1 Hz), 63.18, 52.34, 39.95, 22.27. 31P NMR (D2O,
H3PO4 reference): d = 0.15. HRMS-MALDI: calcd for
C27H37N4O16PSNa (M + 2 H + Na)+: 759.1559. Found:
759.1567. Compound 1d: 1H NMR (400 MHz, D2O): d =
7.94 (d, J = 7.7 Hz, 1 H), 7.63 (m, 1 H), 7.50 (m, 1 H), 7.34
(m, 2 H), 6.00 (d, J = 7.7 Hz, 1 H), 5.92 (d, J = 3.7 Hz, 1 H),
5.19 (m, 1 H), 5.05 (m, 1 H), 4.28–4.19 (m, 6 H), 4.07 (m,
1 H), 3.94 (t, J = 10.2 Hz, 1 H), 3.77 (dd, J = 1.7, 11.4 Hz, 1
H), 3.66–3.60 (m, 2 H), 3.53 (d, J = 8.9 Hz, 1 H), 2.68 (dd,
J = 4.6, 13.7 Hz, 1 H), 2.10 (s, 3 H), 1.97 (m, 1 H). 13C NMR
(100 MHz, D2O): d = 175.39, 174.91, 163.51, 154.25,
142.26, 138.00 (d, J = 6.9 Hz), 132.58, 132.06, 129.41,
128.89, 127.92, 95.98, 91.09, 89.80, 82.99 (d, J = 8.6 Hz),
74.47, 72.08, 70.31, 69.20, 68.64, 67.69, 66.50 (d, J = 4.7
2.05 (s, 3 H), 2.00 (s, 3 H), 1.98 (s, 3 H), 1.84 (s, 3 H). 13
C
NMR (125 MHz, CDCl3): d = 171.44, 170.89, 170.85,
170.36, 170.16, 168.47, 84.43, 72.73, 72.19, 69.33, 68.81,
62.52, 60.92, 52.90, 48.96, 36.97, 31.13, 22.99, 20.93,
20.85, 20.75, 20.65. HRMS-FAB: calcd for C22H34NO13S
(M + H)+: 552.1951. Found: 552.1961. Compound 2b: TLC
(100% EtOAc): Rf = 0.40. 1H NMR (400 MHz, CDCl3): d =
5.85 (d, J = 10.2 Hz, 1 H), 5.44 (t, J = 2.3 Hz, 1 H), 2.59 (m,
1 H), 5.23 (m, 1 H), 4.96 (dd, J = 2.5, 12.3 Hz, 1 H), 4.36
(dd, J = 2.3, 10.4 Hz, 1 H), 4.08 (m, 2 H), 3.80 (s, 3 H), 3.67
(m, 2 H), 2.72 (m,2 H), 2.51 (dd, J = 4.9, 13.8 Hz, 1 H), 2.46
(br s, 1 H), 2.17 (m, 1 H), 2.13 (s, 3 H), 2.06 (s, 3 H), 2.02 (s,
3 H), 2.01 (s, 3 H), 1.86 (s, 3 H), 1.77 (m, 2 H). 13C NMR
(100 MHz, CDCl3): d = 171.24, 170.98, 170.86, 170.36,
170.12, 168.35, 84.70, 72.67, 62.22, 69.31, 68.74, 62.52,
60.77, 52.84, 49.10, 37.04, 31.75, 24.83, 22.92, 20.91,
20.79, 20.72, 20.64. HRMS-FAB: calcd for C23H36NO13S
(M + H)+: 556.1907. Found: 556.1911. Anal. Calcd for
C23H35NO13S: C, 48.84; H, 6.24; N, 2.48; S, 5.67. Found: C,
48.59; H, 7.02; N, 2.37; S, 5.61. Compound 2c: TLC (100%
EtOAc): Rf = 0.40. 1H NMR (400 MHz, CDCl3): d = 7.40 (d,
J = 8.2 Hz, 2 H), 7.32 (d, J = 8.2 Hz, 2 H), 5.79 (d, J = 10.2
Hz, 1 H), 5.42 (t, J = 2.5 Hz, 1 H), 5.39 (m, 1 H), 4.79 (td,
J = 2.2, 8.5 Hz, 1 H), 4.66 (s, 2 H), 4.53 (dd, J = 2.5, 5.5 Hz,
1 H), 4.49 (dd, J = 2.4, 7.2 Hz, 1 H), 4.09 (m, 1 H), 4.01 (m,
1 H), 3.63 (s, 3 H), 2.63 (dd, J = 4.8, 13.9 Hz, 1 H), 2.52 (br
s, 1 H), 2.10 (dd, J = 11.7, 13.9 Hz, 1 H), 2.08 (s, 3 H), 2.04
(s, 3 H), 2.03 (s, 3 H), 1.98 (s, 3 H), 1.87 (s, 3 H). 13C NMR
(100 MHz, CDCl3): d = 171.10, 170.92, 170.34, 170.10,
168.31, 143.06, 135.86, 127.60, 127.51, 88.28, 73.09, 72.80,
69.04, 68.81, 64.40, 62.56, 52.67, 49.27, 37.34, 23.05,
20.99, 20.82, 20.66. HRMS-FAB: calcd for C27H36NO13S
(M + H)+: 614.1907. Found: 614.1910. Compound 2d: TLC
(100% EtOAc): Rf = 0.50. 1H NMR (400 MHz, CDCl3): d =
7.53 (m, 1 H), 7.36 (m, 2 H), 7.20 (m, 1 H), 5.93 (d, J = 10.2
Hz, 1 H), 5.41 (m, 2 H), 4.90 (d, J = 12.9 Hz, 1 H), 4.78 (d,
J = 12.9 Hz, 1 H), 4.71 (td, J = 2.2, 8.3 Hz, 1 H), 4.67 (dd,
Hz), 64.02 (d, J = 4.5 Hz), 63.27, 52.38, 41.67, 22.29. 31
P
NMR (D2O, H3PO4 reference): d = 0.17. HRMS-MALDI:
calcd for C27H37N4O16PSNa (M + 2 H + Na)+: 759.1559.
Found: 759.1545.
Synlett 2004, No. 1, 37–40 © Thieme Stuttgart · New York