Total synthesis of fully acetylated N-acetylneuraminic acid (Neu5Ac), 2-deoxy-β-Neu5Ac, and 4-epi-2-deoxy-β-Neu5Ac from D-glucose

Article abstract of DOI:10.1021/ol0055418

(equation presented) Sialic acid and its analogues have been synthesized using a salenCo(ll) complex catalyzed hetero Diels-Alder reaction and oxidative azidation (CAN/NaN₃) of silyl enol ether as the key steps.

Full text of DOI:10.1021/ol0055418

ORGANIC
LETTERS
2
000
Vol. 2, No. 7
91-894
Total Synthesis of Fully Acetylated
N-Acetylneuraminic Acid (Neu5Ac),
8
2
-Deoxy-â-Neu5Ac, and
4-epi-2-Deoxy-â-Neu5Ac from D-glucose
Lian-Sheng Li, Yu-Lin Wu,* and Yikang Wu
State Key Laboratory of Bio-organic and Natural Products Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, China
ylwu@pub.sioc.ac.cn
Received January 12, 2000
ABSTRACT
Sialic acid and its analogues have been synthesized using a salenCo(II) complex catalyzed hetero Diels−Alder reaction and oxidative azidation
CAN/NaN ) of silyl enol ether as the key steps.
(
3
Sialic acids (especially N-acetylneuraminic acid, Neu5Ac 1)
frequently occur at the terminal end of glycoconjugates, such
as glycoproteins, glycolipids, and oligosaccharides, in cell
(Neu5Ac), 2-deoxy-â-Neu5Ac, and 4-epi-2-deoxy-â-Neu5Ac
from D-glucose based on salenCo(II) (3) complex catalyzed
hetero Diels-Alder reactions.
8
1
membranes and nerve tissues of various living organisms.
2
They play a vital role in numerous biological processes
including cell-to-cell recognition, cell-adhesion, and tumor
metastasis. Among the analogues of 1, N-acetyl-2-deoxy-
neuraminic acid (2) and its 4-epimer are of particular interest,
because they are inhibitors of Neu5Ac-associated enzymes
3
such as Vibio cholerae sialidase and influenza viral neuramini-
4
dase. Considerable attention has therefore been paid to
developing effective methods for synthesis of both Neu5Ac
The desired silyloxy diene 8 was prepared from the readily
available D-glucose as shown in Scheme 1. Thus, 2,4-O-
5,6
3,6d,7
(1) and its 2-deoxy-2-H derivative (2).
Herein we wish
to report an efficient approach to N-acetylneuraminic acid
ethylidene-D-erythrose (5) was obtained using the established
9
(
1) Gottschalk, A. Nature 1951, 167, 845.
procedures. Wittig reaction of 5 with Ph
PdCHCOCH
3
3
(2) von Itzstein, M.; Thompson, R. J. Top. Curr. Chem. 1997, 186, 119-
afforded unsaturated ketone 6, which was then protected as
1
70 and references therein.
(
3) Wallimann, K.; Vasella, A. HelV. Chim. Acta 1991, 74, 1520-1532.
(4) Flashner, M.; Kessler, J.; Tanenbaum, St. W. Arch. Biochem. Biophys.
1997, 1065-1066. (e) Chan, T.-H.; Lee, M.-C. J. Org. Chem. 1995, 60,
4228-4232. (f) Gordon, D. M.; Whitesides, G. M. J. Org. Chem. 1993,
58, 7937-7938. (g) Yamamoto, T.; Teshima, T.; Inami, K.; Shiba, T.
Tetrahedron Lett. 1992, 33, 325-328. (h) Csuk, R.; Hugener, M.; Vasella,
A. HelV. Chim. Acta 1988, 71, 609. (i) Danishefsky, S. J.; DeNinno, M. P.;
Chen, S.-H. J. Am. Chem. Soc. 1988, 110, 3929-3940. (j) Julina, R.; M u¨ ller,
I.; Vasella, A.; Wyler, R. Carbohydr. Res. 1987, 164, 415. (k) Baumberger,
F.; Vasella, A. HelV. Chim. Acta. 1986, 69, 1205-1215. (l) Danishefsky,
S. J.; DeNinno, M. P. J. Org. Chem. 1986, 2615-2617.
1
983, 221, 188.
5) For reviews, see: (a) Tuppy, H.; Gottschalk, A. The Structure of
(
sialic acids and their quantitation. In Glycoproteins. Their composition,
structure and function; Gottschalk, A., Ed.; Elsevier: Amsterdam, 1972; p
03. (b) DeNinno, M. P. Synthesis 1991, 583-593. For recently reported
chemical synthesis of Neu5Ac and related compounds, see: (c) Banwell,
M.; Savi, C. D.; Watson, K. J. Chem. Soc., Perkin Trans. 1 1998, 2251-
252. (d) Takahashi, T.; Tsukamoto, H.; Kurosaki, M.; Yamada, H. Synlett
4
2
1
0.1021/ol0055418 CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/09/2000

reaction between compound 8 and ethyl glyoxylate (freshly
distilled) catalyzed by (S,S)-salenCo(II) complex (3) (10%
mol) at room temperature afforded cycloaddition product 9
in 62% isolated yield, along with a small amount of an
Scheme 1a
1
0
isomer (<5% yield) and the byproducts from the Mukai-
yama reaction.
The next key step of our synthesis was to introduce an
amine group at the C-5. We first tried to prepare R-hydroxy
1
1
ketone 10 by an AD reaction of 9 under conditions similar
8
d
to those used previously (Scheme 2). 10 was then trans-
formed in parallel into mesylate 11, tosylate 12, or triflate
1
3 and treated separately with NaN3. To our surprise, the
anticipated S 2 reaction leading to 17 did not occur. Instead,
all runs gave predominantly the elimination product, presum-
N
1
2
ably due to the steric crowding caused by the larger
substituent at C-6. We then tested the Mitsunobu reaction13
a
2 4
Reagents and conditions: (a) Paraldehyde, cat. H SO , 43%;
(
using DEAD, DPPA, Ph
3
P); the reaction was very compli-
(
6
b) NaIO
4
, NaHCO
3
, H
2
O; (c) Ph
3
PdCHCOCH
, CHCl
N, 0 °C, 99%; (f) ethyl
3
, toluene, 90 °C,
6% over two steps; (d) methylal, cat. P
2
O
5
3
, 0 °C f room
cated. The Sharpless asymmetric aminohydroxylation reac-
tion [LiOH/AcNHBr/K
did not afford any 15 either. The Evans’ copper-mediated
aziridination reaction gave the expected R-amino ketone
adduct 14 in 39% isolated yield, when 9 was treated with
10 mol % of CuClO
respect to 9) of PhIdNTs in anhydrous MeCN at -30 °C.
temperature, 88%; (e) TBSOT
glyoxylate, 3 (10% mol), CH Cl , room temperature, 62%.
f
, Et
3
14
2 4 2 2
Os(OH) O in t-BuOH/H O] of 9
2
2
1
5
MOM ether 7 (88% yield). Treatment of compound 7 with
triflate and triethylamine at 0 °C for 30 min provided the
corresponding diene 8 in 99% yield. The hetero Diels-Alder
1
6
4
2
or Cu(OTf) and 1.5 equiv (with
1
7
Scheme 2a
a
Reagents and conditions: (a) K
3 equiv), t-BuOH/H O (1:1), 0 °C, 78%; (b) NaN
Cu(CH CN) ClO (10% mol), CH CN, -20 f -10 °C, 39%; (d) Na/NH
temperature, 90%; (f) NaBH , EtOH, -30 °C, 85%; (g) p-TsOH (2 equiv), EtOH, reflux, then Ac
LiAl[O(CH H, THF, -10 °C, 80%; (i) MOMCl, i-Pr NEt, CH Cl , 91%; (j) H , Pd/C (10%), room temperature, then Ac
DMAP, CH , 95%; (k) same as (g), 92%.
2
OsO
2
(OH)
4
(5% mol), (DHQD)
(3 equiv), CAN (2.5 equiv), CH
, or Na/naphthalene, THF, -78 °C, e 10%; (e) CH
O, Et N, DMAP, CH
2
-PHAL (5% mol), NaHCO
CN, -25 °C, 61%; (c) PhIdNTs (1 equiv),
COSH, room
Cl , 96%; (h)
O, Et N,
3 2 3 3 6
(3 equiv), K CO (3 equiv), K Fe(CN)
(
2
3
3
3
4
4
3
3
3
4
2
3
2
2
3
)
3
]
3
2
2
2
2
2
3
2 2
Cl
892
Org. Lett., Vol. 2, No. 7, 2000

Scheme 3a
a
Reagents and conditions: (a) NaBH
MoOPH, THF, -78 °C, 50%; (d) Ac
DMAP, CH Cl
4
, EtOH, -30 °C, 83%; (b) MOMCl, i-Pr
2
NEt, CH
, room temperature, 84%; (e) H
2
Cl
, Pd/C (10%), EtOH, 30 °C, then Ac
O, Py, DMAP, CH Cl , room temperature, 73%.
2
, 0 °C f room temperature, 90% (c) LDA,
2
O, Py, DMAP, CH
2
Cl
2
2
2
O, Et
3
N,
2
2
, room temperature, 68%; (f) p-TsOH, EtOH, reflux, then Ac
2
2
2
However, the following removal of the tosyl group in 14
using either Na/NH or Na/naphthalene suffered from very
low yield (<10%), although the expected product 15 did
form. This difficulty made us reconsider introducing an azide
group at C-5 first.
in 90% yield. Reduction of the ketone of 15 with NaBH
4
at
3
-30 °C afforded the desired anti product 19 in 85% yield.
All the protecting groups in compound 19 were then removed
by treatment with p-TsOH in refluxing EtOH. Acetylation
of the unmasked hydroxyl groups to afford the corresponding
2
1
Oxidative azidation (CAN/NaN
3
) of silyl enol ether is also
acetate 20 was fulfilled (96%) using acetic anhydride in
the presence of Et N and a catalytic amount of DMAP.
an established means to prepare R-azido ketone. Although
there are reports1 on the ineffectiveness of this reaction,
we found that the yield could be significantly improved by
3
8,19
The 4-epi analogue 24 was also prepared according to
Scheme 2. Reduction of the ketone carbonyl in 17 with the
2
2
modifying the procedure. Thus, treatment of 9 with NaN
3.0 equiv) in anhydrous CH CN at -25 °C followed by
slow addition of CAN (2.5 equiv in CH CN) led to the
3
3 3 3
bulky reducing reagent LiAl[O(CH ) ] H at -10 °C gave
(
3
syn product 21 in 80% isolated yield. After protection of
the C-4 hydroxyl as the MOM ether (22, 91% yield), the
azido functionality was hydrogenated to give an amine, which
was converted to 23 in high yield (95%). Then, under the
same conditions, compound 23 was transformed into 24, the
fully acetylated 4-epi-2-deoxy-â-Neu5Ac, in 92% yield.23
The total synthesis of sialic acid from intermediate 17
require oxidation at C-2. Thus, reduction of the ketone,
3
desired product 17 in a 61% isolated yield, together with a
small amount of 18 (10%). It is noteworthy that unlike all
the previously reported procedures, the present one can be
run easily on larger scales (1.5-2.5 g) without lowering the
yield.
Conversion of 17 to the corresponding acetamide 15 using
20
a modification of Rosen’s method (Scheme 2) was realized
(
14) (a) Phukan, P.; Sudalai, A. Tetrahedron: Asymmetry 1998, 9, 1001-
1
005. (b) Bruncko, M.; Schlingloff, G.; Sharpless, K. B. Angew. Chem.,
(
6) Enzyme synthesis of Neu5Ac and related compounds: (a) Bednarski,
Int. Ed. Engl. 1997, 36, 1483-1486.
M. D.; Chenault, H. K.; Simon, E. S.; Whitesides, G. M. J. Am. Chem.
Soc. 1987, 109, 1283-1285. (b) Auge, C.; David, S.; Gautheron, C.
Tetrahedron Lett. 1984, 25, 4663-4664. (c) Auge, C.; David, S.; Gautheron,
C.; Veyri e` res, A. Tetrahedron Lett. 1985, 26, 2439-2440. (d) Kim, M.-J.;
Hennen, W. J.; Sweers, H. M.; Wong, C.-H. J. Am. Chem. Soc. 1988, 110,
(15) Evans, D. A.; Faul, M. M.; Bilodeau, M. T. J. Am. Chem. Soc.
1994, 116, 2742-2753.
(16) The catalyst was prepared from Cu2O according to the reported
procedure: Kubas, G. J. Inorg. Synth. 1979, 19, 90-92.
(17) The I-N ylide was prepared by following the reported procedure:
Yamada, Y.; Yamamoto, T.; Okawara, M. Chem. Lett. 1975, 361-362.
(18) Auberson, Y.; Vogel, P. Tetrahedron 1990, 46, 7019-7032.
(19) Magnus, P.; Barth, L. Tetrahedron Lett. 1992, 33, 2777-2780.
(20) Rosen, T.; Lico, I. M.; Chu, D. T. W. J. Org. Chem. 1988, 53,
1580-1582.
6
481-6486. (e) Wong, C.-H.; Whitesides, G. M. Enzymes in Synthetic
Organic Chemistry, Tetrahedron Organic Chemistry Series Volume 12;
Pergamon: Oxford, 1994. (f) Sugai, T.; Kuboki, A.; Hiramatsu, S.; Okazaki,
H.; Ohta, H. Bull. Chem. Soc. Jpn. 1995, 68, 3581.
(7) Chemical synthesis of 2-deoxy-2H derivatives of Neu5Ac: (a)
Gervay, J.; Gregar, T. Tetrahedron Lett. 1997, 38, 5921-5924. (b) Bandgar,
B. P.; Zbiral, E. Carbohydr. Res. 1995, 270, 201-210. (c) Wallimann, K.;
Vasella, A. HelV. Chim. Acta 1990, 73, 1359-1372. (d) Bandgar, B. P.;
Hartmann, M.; Schmid, W.; Zbiral, E. Liebigs Ann. Chem. 1990, 1185-
(21) NMR data for compound 20: 1H NMR (300 MHz, CDCl3) δ 5.59
(1H, d, J ) 8.5 Hz, NH), 5.42 (1H, ddd, J ) 7.1, 5.1, 1.2 Hz), 5.25 (1H,
dd, J ) 4.7, 1.6 Hz), 5.11 (1H, ddd, J ) 5.1, dt, J ) 11.5, 4.9 Hz), 4.60
(1H, dd, J ) 12.1, 2.2 Hz), 4.29 (1H, dd, J ) 12.3, 6.9 Hz), 4.22 (2H, dq,
J ) 7.1, 1.3 Hz), 4.05 (1H, dd, J ) 12.1, 2.2 Hz), 3.95 (1H, q, J ) 10.2
Hz), 3.67 (1H, J ) 10.6, 1.4 Hz), 2.39 (1H, ddd, J ) 12.6, 4.9, 2.2 Hz),
2.11, 2.10, 2.06, 2.05, 1.98 (15H, 5s), 1.76 (1H, q, J ) 12.1 Hz), 1.28 (3H,
1
3
195. (e) Schmid, W.; Christian, R.; Zbiral, E. Tetrahedron Lett. 1988, 29,
643-3646.
(8) (a) Hu, Y.-J.; Huang, X.-D.; Yao, Z.-J.; Wu, Y.-L. J. Org. Chem.
13
1
998, 63, 2456-2461. (b) Li, L.-Sh.; Wu, Y.-K.; Hu, Y.-J.; Wu, Y.-L.
t, J ) 7.1 Hz); C NMR (75 MHz, CDCl3) δ 170.81, 170.64, 170.31,
170.25, 170.08, 168.71, 78.70, 74.12, 71.40, 70.82, 69.85, 62.73, 61.50,
51.84, 33.78, 23.24, 21.01, 20.94, 20.91, 20.72, 14.00; EIMS (m/z) 490
Tetrahedron: Asymmetry 1998, 9, 2271-2277. (c) Hu, Y.-J.; Huang, X.-
D.; Wu, Y.-L. J. Carbohydr. Chem. 1998, 17, 1095. (d) Li, L.-Sh.; Wu,
Y.-K.; Wu, Y.-L. J. Carbohydr. Chem. 1999, 18, 1067-1077.
+
(M + 1); [R]D ) 34.2 (c 0.25, CHCl3).
(
9) Barker, R.; MacDonnald, D. L. J. Am. Chem. Soc. 1960, 82, 2301-
(22) Boireau, G.; Deberly, A.; Toneva, R. Synlett 1993, 585-587.
(23) NMR data for compound 24: 1H NMR (600 MHz, CDCl3) δ 5.82
(1H, d, J ) 9.0 Hz, NH), 5.43 (1H, dt, J ) 9.0, 2.4 Hz), 5.26 (1H, dd, J
) 6.6, 3.0 Hz), 5.10 (1H, m), 4.47 (1H, dd, J ) 12.6, 2.4 Hz), 4.43 (1H,
dd, J ) 6.6, 2.4 Hz), 4.28-4.22 (3H, m), 4.12 (1H, t, J ) 7.2 Hz), 4.14-
4.11 (1H, m), 2.52 (1H, ddd, J ) 15.0, 4.2, 2.4 Hz), 2.17, 2.12, 2.05, 2.04,
2.01 (15H, 5s), 2.09 (1H, ddd, J ) 15.0, 7.2, 3.0 Hz), 1.26 (3H, t, J ) 7.1
Hz); 13C NMR (150 MHz, CDCl3) δ 171.08, 171.05, 170.62, 170.38, 170.23,
169.42, 70.83, 70.65, 69.37, 68.78, 62.38, 61.19, 60.35, 47.24, 30.08, 23.19,
2
303.
10) For discussion about the mechanism of related reactions catalyzed
(
by other salen metal complex catalysts, see: Schaus, S. E.; Brnalt, J.;
Jacobsen, E. N. J. Org. Chem. 1998, 63, 403.
(
11) (a) Hashiyama, T.; Morikawa, K.; Sharpless, K. B. J. Org. Chem.
992, 57, 5067-5068. (b) Morikawa, K.; Park, J.; Andersson, P. G.;
Hashiyama, T.; Sharpless, K. B. J. Am. Chem. Soc. 1993, 115, 8463-8064.
12) Neufellner, E.; Kapeller, H.; Griengl, H. Tetrahedron 1998, 54,
1043-11062.
13) Mitsunobu, O. Synthesis 1981, 1-28.
1
(
+
1
20.96, 20.91, 20.75, 20.69, 13.69; EIMS (m/z) 490 (M + 1); [R]D ) 98.6
(c 1.09, CHCl3).
(
Org. Lett., Vol. 2, No. 7, 2000
893

2
5
following protection of the resulting hydroxy, furnished the
30. The physical data of our synthetic sample are identical
5
f
desired anti-azido MOM ether 26 (Scheme 3). Oxidation of
to those reported by Whitesides.
In summary, we have established an effective synthesis
of both sialic acid and its analogues. Further studies on the
total synthesis of Neu2en5Ac and Zanamivir (GG167) are
currently ongoing in this laboratory, and the results will be
reported in due time.
24
5
the lithium enolate of 26 with MoO ‚Py‚HMPA (MoOPH)
gave the 2-R-OH product (along with traces of the 2-â-OH
isomer) in 50% isolated yield (70%, based on recovered 26).
Acetylation of the hydroxyl at C-2 afforded compound 28
2
6
(84%). Then following a procedure similar to that described
above, 28 was transformed into pentaacetylated ethyl ester
Acknowledgment. We thank the Chinese Academy of
Sciences (KJ-952-S1-503, KJ-95-A1-504), the Chinese Natu-
ral Science Foundation (29790126, 29872049), and the State
Ministry of Science and Technology of China (970211006-
(
24) Recently, Burke reported that the total synthesis of KDO from
2
-deoxy-KDO used MoOPH as the oxidant: Burke, S. D.; Sametz, G. M.
Org. Lett. 1999, 1, 71-74. The MoOPH was prepared according to the
reported procedure: Vedejs, E.; Larsen, S. Org. Synth. 1986, 64, 127-
1
37.
(
6
) for financial support.
25) NMR data of compound 30: 1H NMR (300 MHz, CDCl3) δ 5.61
1H, d, J ) 9.3 Hz, NH), 5.49 (1H, ddd, J ) 10.4, 5.8, 3.6 Hz), 5.26 (1H,
(
OL0055418
dd, J ) 5.0, 1.6 Hz), 5.22-5.18 (1H, m), 4.63 (1H, dd, J ) 12.4, 2.5 Hz),
4
1
1
6
1
6
.29 (1H, dd, J ) 9.0, 7.9 Hz), 4.23 (2H, q, J ) 7.1 Hz), 4.12 (1H, q, J )
0.2 Hz), 3.75 (1H, dd, J ) 10.9, 1.9 Hz), 2.36 (1H, dd, J ) 13.5, 4.9 Hz),
.85 (1H, dd, J ) 13.5, 11.2 Hz), 2.09, 2.08, 2.05, 2.04, 2.03, 1.98 (18H,
(26) (a) von Itzstein, M.; Wu, W.-Y.; Kok, G. B.; Pegg, M. S.; Dyason,
J. C.; Jin, B.; Phan, T. V.; Smythe, M. L.; White, H. F.; Oliver, S. W.;
Colman, P. M.; Varghese, J. N.; Ryan, D. M.; Woods, J. M.; Bethell, R.
C.; Hotham, V. J.; Cameron, J. M.; Penn, C. R. Nature 1993, 363, 418-
423. (b) Hayden, F. G.; Treanor, J. J.; Betts, R. F.; Lobo, M.; Esinhart, J.;
Hussey, E. J. Am. Med. Assoc. 1996, 275, 295.
13
s), 1.29 (3H, t, J ) 7.1 Hz); C NMR (75 MHz, CDCl3) δ171.08, 170.75,
70.29 × 2, 170.03, 169.76, 167.29, 98.31, 73.19, 71.25, 69.65, 68.79, 62.83,
1.96, 51.34, 37.53, 23.20, 20.98, 20.91, 20.79, 20.74, 14.00; [R]D ) 40.4
(c 0.52, CHCl3).
894
Org. Lett., Vol. 2, No. 7, 2000