Asymmetric synthesis of N-acetylneuraminic acid

Article abstract of DOI:10.1039/a909400h

A highly diastereoselective synthesis of N-acetylneuraminic acid 1 has been completed by stereoselective functionalization of cis-olefin 6 and trans-olefin 10 via intramolecular phenylselenoamidation and osmylation, respectively.

Full text of DOI:10.1039/a909400h

Asymmetric synthesis of N-acetylneuraminic acid
Sung Ho Kang,*a Hyeong-wook Choi,a Joon Seop Kima and Joo-Hack Younb
a National Creative Research Institute Center for Asymmetric Reactions, Department of Chemistry, Korea Advanced
Institute of Science and Technology, Taejon 305-701, Korea. E-mail: shkang@kaist.ac.kr
b Department of Chemical Engineering, Sun Moon University, Asan Si, Chung-Nam 336-840, Korea
Received (in Cambridge, UK) 29th November 1999, Accepted 6th January 2000
A highly diastereoselective synthesis of N-acetylneuraminic
acid 1 has been completed by stereoselective functionaliza-
tion of cis-olefin 6 and trans-olefin 10 via intramolecular
phenylselenoamidation and osmylation, respectively.
bromide in the presence of methyl trichloroacetimidate in a 4+1
mixture of MeCN and propylene oxide to provide trans-
oxazoline 7, [a]2D1 218.4 (c 1.1, CHCl3), in 67% yield. While
the stereoisomeric cis-oxazoline could not be identified in the
phenylselenocyclization, 9% of the enantiomerically pure
tetrahydrofuran 8 was isolated as the major side product after
hydrolysis. It is noted that methyl trichloroacetimidate and
propylene oxide were expected to function as dehydrating agent
and acid scavenger. The oxazoline ring of 7 was partially
hydrolyzed in the presence of PPTS in aqueous acetone and the
residual phenylselenyl group was oxidatively eliminated to
afford trans-olefin 9, [a]2D4 + 19.0 (c 1.2, CHCl3), in 75%
overall yield along with 5–6% of the corresponding cis-
isomer.
Sialic or neuraminic acids are a family of amino sugars
comprising nine or more skeletal carbon atoms, and usually
occur at the nonreducing terminal positions of oligosaccharides,
glycoproteins and glycolipids.1 They are involved in the
modulation of a variety of important biological phenomena2
such as cellular aggregation,3 recognition,4 lifetime5 and
viscosity of biofluids.6 The family provides a potential
therapeutic lead in developing inhibitors of sialidase7 and
sialyltransferase.8 The most common member is the nine-
carbon derivative 5-(acetylamino)-3,5-dideoxy-
D-glycero-
D-
The pendent amino and hydroxy groups of 9 were variously
functionalized in order to induce the best stereoselectivity in the
subsequent dihydroxylation of the olefinic double bond. In
consequence, 9 was converted into dihydroxy oxazolidinone 10,
mp 110.3–111.0 °C, [a]2D5 + 23.9 (c 1.05, CHCl3), in 91%
galacto-2-nonulosonic acid (N-acetylneuraminic acid,
1
Neu5Ac),9 which is an essential constituent of sialoglycos-
phingolipids (ganglioside) and other glycoconjugates which
mediate cellular interactions, differentiations and growth.10
While most of the known syntheses of Neu5Ac have been
attained from carbohydrate sources,11 only two syntheses have
been established from noncarbohydrate precursors via hetero-
Diels–Alder cycloaddition12 and azido hydroxylation of cis-
1,2-dihydrocatechol,13 respectively. Its intriguing molecular
structure and biological significance also led us to the
enantioselective synthesis of N-acetylneuraminic acid 1 from
diol 4, which had been readily prepared from (S)-butane-
1,2,4-triol.14 The key steps of our synthetic route to 1 include
the intramolecular phenylselenoamidation of cis-olefinic allylic
trichloroacetimidate 3 and the stereoselective dihydroxylation
of trans-olefin 2, followed by introduction of the indispensable
a-keto carboxylic acid functional group (Scheme 1).
Diol 4 was regioselectively protected by reacting with
dibutyltin oxide in toluene using a Dean–Stark trap and
subsequently with 2,4,6-trimethylbenzyl chloride in the pres-
ence of TBAB15 to give a 7+1 mixture of the desired ether 5,
[a]2D0 + 19.9 (c 1.2, CHCl3), and the isomeric secondary alkyl
benzyl ether in 96% combined yield (Scheme 2). For the
disposition of the required amino group and (E)-olefinic double
bond, the allylic alcohol 5 was sequentially subjected to
Cl3CCN in the presence of DBU in MeCN and benzeneselenyl
Scheme 2 Reagents and conditions: i, Bu2SnO, PhMe, Dean–Stark trap,
then 2,4,6-trimethylbenzyl chloride, Bu4NBr, 80 °C; ii, Cl3CCN, DBU,
MeCN, 230 to 220 °C; iii, PhSeBr (3 equiv.), MeOC(NNH)CCl3 (3
equiv.), propylene oxide–MeCN (1+4), 230 to 0 °C; iv, PPTS, H2O–
acetone (1+4), 20 °C; v, 30% H2O2, THF, 20 °C; vi, DBU, CH2Cl2, 20 °C,
then BzCl, DMAP, Et3N, 0 °C; vii, H2O–AcOH (1+4), 20 °C; viii, OsO4,
NMO, H2O–acetone (1+7), 0 °C; ix, Ba(OH)2, H2O–EtOH (1+2), 70 °C,
then Ac2O, 0 to 20 °C.
Scheme 1
Chem. Commun., 2000, 227–228
This journal is © The Royal Society of Chemistry 2000
227

was exposed to O3 in MeOH to provide a-keto ester 19, [a]D16
211.9 (c 1.46, CHCl3), in 71% overall yield from 16.
Triacetonide 19 was consecutively deprotected and cyclized
with methanolic HCl, and then the generated methyl ester
2017,18 was hydrolyzed to N-acetylneuraminic acid 1, [a]1D7
232.0 (c 1.19, H2O),11b in 84% overall yield. For further
identification, 20 was peracetylated with Ac2O to produce a 6+1
mixture of pentaacetate 21, [a]1D8 232.0 (c 0.54,
CHCl3),11f,17c,18 and the corresponding anomeric acetate.19
This work was supported by Creative Research Initiatives of
the Korean Ministry of Science and Technology.
Notes and references
1 Sialic Acids: Chemistry, Metabolism and Function in Cell Biology
Monographs, ed. R. Schauer, Springer Verlag, Wien, New York, 1982,
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2 M. von Itzstein and R. J. Thompson, Top. Curr. Chem., 1997, 186,
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3 R. B. Kemp, J. Cell Sci., 1970, 6, 751.
4 R. Schauer, Pure Appl. Chem., 1984, 56, 797; R. Schauer, Trends
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5 J. M. Jancik, R. Schauer and H. J. Z. Streicher, Physiol. Chem., 1975,
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6 F. Ahmad and P. McPhie, Int. J. Biochem., 1980, 11, 91.
7 E. Zbiral, E. Schreiner, R. Chiristian, R. G. Kleineidam and R. Schauer,
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8 M. Hartann, R. Chiristian and E. Zbiral, Liebigs Ann. Chem., 1990, 83;
E. Schreiner, R. Chiristian and E. Zbiral, Liebigs Ann. Chem., 1990,
93.
Scheme 3 Reagents and conditions: i, C(OMe)2Me2, PPTS, CHCl3, 70 to
80 °C; ii, H2, 20% Pd(OH)2/C, NaHCO3, EtOH, 20 °C; iii, RuCl3 hydrate,
NaIO4, MeCN–CCl4–H2O (2+2+3), 20 °C; iv, CH(NPPh3)CN, EDCl,
DMAP, CH2Cl2, 20 °C; v, O3, MeOH, 278 °C; vi, AcCl, MeOH, 20 °C; vii,
K2CO3, H2O, MeOH, 20 °C, then Dowex 50WX8-100 ion-exchange resin;
viii, Ac2O, DMAP, pyridine, 20 °C.
overall yield by a sequence of cyclization with DBU, in situ
benzoylation with BzCl and deprotection in aqueous AcOH.
The following dihydroxylation of 10 produced a mixture of
several compounds, which seemed to be generated from
migration of N-benzoyl group in the dihydroxylated products.
The mixture was completely hydrolyzed with Ba(OH)2 and the
demasked amino group was acetylated in one pot to furnish an
18+1 mixture of the desired pentaol 13, mp 190.4–191.0 °C,
[a]2D2 223.0 (c 0.3, MeOH) and the diastereomeric pentaol in
81% combined overall yield. Interestingly, dihydroxylation of
acetyl carbamate 11 and pivaloyl carbamate 12 resulted in much
lower stereoselectivities of 9+1 and 7+1, respectively.
Since 13 comprises all the requisite chiral functional groups
of N-acetylneuraminic acid 1, the remaining synthetic operation
is to transform the benzyloxy group into an a-keto carboxylic
acid functionality. Accordingly, 13 was protected as a triacet-
onide using 2,2-dimethoxypropane in the presence of PPTS in
CHCl3 to give the desired triacetonide 14 [a]2D2 214.3 (c 1.2,
CHCl3), in 74% yield along with 12% of diacetonide oxazoline
15, which was more significantly formed under a variety of
other attempted reaction conditions (Scheme 3). After
debenzylation of 14 in 94% yield by hydrogenolysis, Wasser-
man’s protocol16 was employed for the installation of a-keto
carboxylate moiety to primary alcohol 16, [a]2D4 216.0 (c 0.9,
CHCl3). Alcohol 16 was oxidized with NaIO4 in the presence of
RuCl3, followed by coupling with CH(NPPh3)CN in the
presence of EDCI and DMAP. The resulting phosphorane 18
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1991, 583; (b) T. Yamamoto, T. Teshima, K. Inami and T. Shiba,
Tetrahedron Lett., 1992, 32, 325; (c) L.-H. Lin, T. Sugai, R. L.
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(f) T. Takahashi, H. Tsukamoto, M. Kurosaki and H. Yamada, Synlett,
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18 The spectroscopic data of the synthetic 20 and 21 are identical to those
of 20 and 21 prepared from the commercially available Neu5Ac 1
(Aldrich).
19 All new compounds showed satisfactory spectral data.
Communication a909400h
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Chem. Commun., 2000, 227–228