Diastereoselective synthesis of (-)-N-acetylneuraminic acid (Neu5Ac) from a non-carbohydrate source

Article abstract of DOI:10.1039/a804524k

cis-1,2-Dihydrocatechol 2, a product of microbial oxidation of chlorobenzene, has been converted into a protected form, 17, of (-)-Neu5Ac (1) via a fifteen step reaction sequence.

Full text of DOI:10.1039/a804524k

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Diastereoselective synthesis of (؊)-N-acetylneuraminic acid
(Neu5Ac) from a non-carbohydrate source†
Martin Banwell,*,a Chris De Savia and Keith Watsonb
a Research School of Chemistry, Institute of Advanced Studies,
The Australian National University, Canberra, ACT 0200, Australia
b Biota Chemistry Laboratory, Chemistry Department, Monash University,Clayton,
Victoria 3168, Australia
cis-1,2-Dihydrocatechol 2, a product of microbial oxid-
ation of chlorobenzene, has been converted into a protected
form, 17, of (؊)-Neu5Ac (1) via a fifteen step reaction
sequence.
compound 6 was achieved using dihydrogen in the presence of
10% palladium on carbon and the resulting aminotriol 7 was
immediately subjected to reaction with benzyl bromide in the
presence of K2CO3. The N,N-dibenzylated material 8 {90% from
6, [α]D Ϫ13 (c 4.7)} so-formed was treated with acetone and a
trace of trifluoromethanesulfonic acid (TfOH) and the ensuing
reaction produced bis-acetonide 9 {62%, [α]D ϩ59 (c 1.3)}
which was identical with an authentic sample prepared from
δ-gluconolactone.¶ Subjection of compound 9 to Swern oxid-
ation conditions afforded the -mannosamine derivative
10 {100%, [α]D ϩ52 (c 3.9)} which was condensed with the
organozinc reagent derived from bromoacrylate 11 to give
the anti-addition product 12 {85% at 90% conversion, [α]Dϩ5 (c
5.9)}.12 Swern oxidation of this last compound then provided
the highly unstable ketone 13 which was immediately reduced,
in a diastereoselective fashion, with NaBH4. The resulting
alcohol was protected as the corresponding TMS ether 14 {60%
from 12 at 67% conversion [α]D ϩ0.4 (c 2.3)}. Ozonolysis of the
C᎐C double bond within alkene 14 could not be effected select-
ively because of competing oxidation of the N,N-dibenzyl
moiety so the compound was reacted with AD-mix-α13 and the
resulting mixture of diastereoisomeric diols cleaved with lead
tetraacetate to give the unstable ketone 15 (89%). Treatment of
product 15 with methanolic HCl at room temperature for 18 h
followed by acetylation of the crude reaction mixture afforded
the nonulosonic acid derivative 16 {60%, [α]D Ϫ51 (c 0.7)}.
Debenzylation of the latter compound was readily achieved
using formic acid–palladium black14 and the intermediate
amine acetylated to give the sialic acid derivative 1715 {75%,
[α]D Ϫ27 (c 1.0)}. This material was identical, in all respects,
with an authentic sample {[α]D Ϫ26 (c 1.4)} prepared from
sialic acid according to the method15 of Sinaÿ. Compound 17 is
a versatile building block that has found considerable use16 in
the preparation of a wide range of sialic acid analogues.
Sialic acids such as N-acetylneuraminic acid [(Ϫ)-Neu5Ac, 1]
have been implicated in a wide range of biologically important
processes including cell-to-cell recognition, cell-adhesion, neural
cell development and tumour metastasis.1 These compounds
also constitute a ligand class commonly recognised by many
infectious pathogens such as viruses, bacteria and parasites.
Consequently, there has been considerable interest in developing
effective methods for the synthesis2 of both sialic acids and
analogues that would help elucidate their roles in vivo. Various
enzymatic procedures including an aldolase-catalysed conden-
sation of N-acetyl--mannosamine with pyruvic acid have been
shown to provide useful quantities of compound 1.3 Elegant
OH
OH
HO2C
H
OH
O
NHAc
H
OH
HO
OH
Cl
OH
2
1
chemical variations on this approach which use, in the pen-
ultimate step, 2-(metallomethyl)acrylates as pyruvate anion
equivalents have been developed by the groups of Vasella,4
Chan5 and Whitesides.6 We now report an enantiospecific and
diastereoselective synthesis of a protected form of (Ϫ)-Neu5Ac
that involves a related end game but which starts with the
enantiopure cis-1,2-dihydrocatechol 2,7 a compound available
in quantity via microbial oxidation of chlorobenzene. The
only previous synthesis of the title compound from a non-
carbohydrate source has been reported by Danishefsky et al.8
who used a hetero-Diels–Alder reaction between a diene and
an aldehyde to establish the pyranoid core. The present work
was modelled on our recently disclosed9 synthesis of KDN and
should allow for the preparation of a wide range of 17O-, 13C-
and/or 2H-labelled (Ϫ)-Neu5Ac derivatives.
The reaction sequence leading from compound 2 to the pro-
tected form, 17, of (Ϫ)-Neu5Ac is shown in Scheme 1. Thus, the
acetonide derivative, 3,10 of 2 was converted into the azido alco-
hol 4 by established procedures.11 The benzyl ether derivative, 5‡
{70%, [α]D Ϫ113 (c 5.3)§}, of compound 4 was subjected
to ozonolytic cleavage and a reductive work-up with NaBH4
and in this way the diol 6 {70%, [α]D ϩ10 (c 1.0)} was obtained.
Hydrogenolysis of the azido and benzyl ether moieties within
Experimental
Compound 6
A solution of compound 5 (1.30 g, 3.86 mmol) in methanol
(20 ml) was cooled to Ϫ78 ЊC (dry-ice–acetone bath) and treated
with a stream of ozone (ca. 40% ozone in oxygen) being pro-
duced by a Fischer Model 502 ozone generator. When the blue
colour of ozone persisted and TLC analysis indicated that no
starting material remained (ca. 0.66 h), the reaction mixture
was purged with nitrogen for 0.5 h then warmed to 0 ЊC over
0.5 h. Sodium borohydride (1.00 g, 26 mmol) was added, in por-
tions over 3 h, to the reaction mixture which was then warmed
to 18 ЊC and treated with additional quantities of sodium boro-
hydride (285 mg, 7.4 mmol). After a further 5.0 h, the reaction
mixture was diluted with water (50 ml) then acidified (using 1 
aqueous HCl) to pH 3.0 and extracted with ethyl acetate
(4 × 200 ml). The combined organic extracts were washed with
brine (2 × 300 ml) then dried (MgSO4), filtered and concen-
† The work described herein is the subject of a patent application (AIPO Patent
Office Provisional Application No. PO8998, lodged September 5th, 1997).
‡ All new and stable compounds had spectroscopic data (IR, UV, NMR, mass
spectrum) consistent with the assigned structure. Satisfactory combustion and/or
high resolution mass spectral data were obtained for new compounds and/or
suitable derivatives.
§ All optical rotations were determined in chloroform solution at 20 ЊC.
¶ Details of this synthesis will be disclosed shortly.
J. Chem. Soc., Perkin Trans. 1, 1998
2251

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trated under reduced pressure to give a light-yellow oil. Subjec-
OR
Cl
tion of this material to flash chromatography (silica gel, 3:2
hexane–ethyl acetate elution) afforded, after concentration of
the appropriate fractions (Rf 0.2), the azido diol 6 (920 mg, 70%)
N3
O
O
O
O
i
ii
2
ϩ
ؒ
as a clear, colourless oil [Found: (M Ϫ CH3 ) , 322.1408.
ϩ
C16H23N3O5 requires (M Ϫ CH3 ) , 322.1403]; νmax(NaCl)/cmϪ1
3854 and 2101; δH(300 MHz, CDCl3) 7.40–7.27 (5 H, m), 4.80
(1 H, d, J 11.2 Hz), 4.74 (1 H, d, J 11.2 Hz), 4.35 (1 H, t, J 6.1
Hz), 4.26 (1 H, q, J 6.1 Hz), 3.96 (1 H, m), 3.90–3.79 (2 H,
complex m), 3.77–3.60 (3 H, complex m), 2.29 (1 H, br s), 2.07
(1 H, br s), 1.52 (3 H, s), 1.40 (3 H, s); δC(75 MHz, CDCl3) 137.5
(C), 128.4 (CH), 128.0 (CH), 127.9 (CH), 108.6 (C), 78.2 (CH),
77.5 (CH), 76.7 (CH), 74.1 (CH2), 64.5 (CH), 61.6 (2 × CH2),
ؒ
Cl
4 R = H
5 R = Bn
3
iii
iv
OH
OH
OBn
R2N
HO
N3
v
O
O
O
O
ϩ
ؒ
27.5 (CH3), 25.4 (CH3); m/z (EI, 70 eV) 322 [<1%, (M Ϫ CH3 ) ],
ϩ
ؒ
278 {21, [M Ϫ (H3C)2CO Ϫ H ] }, 91 (100).
HO
OH
7 R = H
8 R = Bn
Acknowledgements
vi
6
We thank the Institute of Advanced Studies for financial sup-
port and the ARC for the provision of an APA (Industry)
Scholarship to C. D. S. Dr Gregg Whited (Genencor Inter-
national Inc.) is thanked for providing generous quantities of
compound 2.
vii
O
CO2Et
Br
O
O
O
Bn2N
O
O
O
Bn2N
HO
viii
+
References
1 M. von Itzstein and R. J. Thompson, Top. Curr. Chem., 1997, 186,
119 and references cited therein.
O
O
2 For the most recently reported chemical synthesis of (Ϫ)-Neu5Ac,
see T. Takahashi, H. Tsukamoto, M. Kurosaki and H. Yamada,
Synlett, 1997, 1065. For a useful review of earlier synthetic studies,
see M. P. DeNinno, Synthesis, 1991, 583.
10
11
9
3 (a) C.-H. Wong and G. M. Whitesides, Enzymes in Synthetic Organic
Chemistry, Tetrahedron Organic Chemistry Series Volume 12,
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A. Kuboki, S. Hiramatsu, H. Okazaki and H. Ohta, Bull. Chem.
Soc. Jpn., 1995, 68, 3581 and references cited therein.
ix
O
CO2Et
OAc
X
4 F. Baumberger and A. Vasella, Helv. Chim. Acta, 1986, 69, 1205.
5 T.-H. Chan and M.-C. Lee, J. Org. Chem., 1995, 60, 4228.
6 D. M. Gordon and G. M. Whitesides, J. Org. Chem., 1993, 58, 7937.
7 For reviews on the applications of cis-1,2-dihydrocatechols
in synthesis, see (a) T. Hudlicky, D. A. Entwistle, K. K. Pitzer and
A. J. Thorpe, Chem. Rev., 1996, 96, 1195; (b) T. Hudlicky and
A. J. Thorpe, Chem. Commun., 1996, 1993; (c) T. Hudlicky and
J. W. Reed, in Advances in Asymmetric Synthesis, ed. A. Hassner,
JAI, Greenwich, CT 1995, vol. 1, p. 271; (d) S. M. Brown and
T. Hudlicky, in Organic Synthesis: Theory and Applications, ed.
T. Hudlicky, JAI, Greenwich, CT 1993, vol. 2, 113; (e) H. A. J.
Carless, Tetrahedron: Asymmetry, 1992, 3, 795; ( f ) D. A. Widdow-
son, D. W. Ribbons and S. D. Thomas, Janssen Chim. Acta, 1990, 3.
8 S. J. Danishefsky, M. P. DeNinno and S. Chen, J. Am. Chem. Soc.,
1988, 110, 3929.
9 M. Banwell, C. De Savi and K. Watson, Chem. Commun., 1998, 1189.
10 T. Hudlicky, T. Nugent and W. Griffith, J. Org. Chem., 1994, 59, 7944.
11 T. C. Nugent and T. Hudlicky, J. Org. Chem., 1998, 63, 510.
12 For examples of related reactions, see (a) S. Hanessian, H. Park and
R.-Y. Yang, Synlett, 1997, 351 and 353; (b) M. Banwell, C. De Savi,
D. Hockless and K. Watson, Chem. Commun., 1998, 645.
MeO2C
H
OAc
NBn2
R
O
O
xii
O
R'
H
Bn2N
AcO
OAc
O
OAc
12 X = CH2, R = OH, R' = H
13 X = CH2, R,R' = O
14 X = CH2, R = H, R' = OTMS
15 X = O, R = H, R' = OTMS
16
viii
xi
x
xiii
OAc
MeO2C
OAc
NHAc
O
H
H
AcO
OAc
OAc
13 K. B. Sharpless, W. Amberg, Y. L. Bennani, G. A. Crispino,
J. Hartung, K.-S. Jeong, H.-L. Kwong, K. Morikawa, Z.-M. Wang,
D. Xu and X.-L. Zhang, J. Org. Chem., 1992, 57, 2768.
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17
Scheme 1 Reagents and conditions: (i) see reference 10; (ii) see refer-
ence 11; (iii) NaH (1.1 mol equiv.), THF, 0 ЊC, 0.75 h then BnBr (1.3
mol equiv.), 0–18 ЊC, 4 h; (iv) O3, MeOH, Ϫ78 to 0 ЊC, 0.05 h then
NaBH4 (9.0 mol equiv.), 18 ЊC, 7 h; (v) dihydrogen (50 psi), 10%
Pd on C (20 wt%), MeOH, 18 ЊC, 16 h; (vi) BnBr (2.3 mol equiv.),
K2CO3 (2.2 mol equiv.), 2:1 MeCN–H2O, 60 ЊC, 16 h; (vii) Me2CO,
TfOH (cat.), 0 ЊC, 3 h; (viii) (COCl)2 (1.2 mol equiv.), DMSO, CH2Cl2,
Ϫ78 to 0 ЊC, 1 h then Et3N (2.6 mol equiv.); (ix) Zn dust (1.2 mol
equiv.), sat. aq. NH4Cl, THF, 0 to 18 ЊC, 0.75 h; (x) NaBH4 (6 mol
equiv.), EtOH, Ϫ10 ЊC, 4 h then TMSCl (4.0 mol equiv.), HMDS
(4.0 mol equiv.), pyridine, 0 to 18 ЊC, 19 h; (xi) AD-mix-α (2.2 mol
equiv.), ButOH, H2O, 18 ЊC, 22 h then Pb(OAc)4 (0.9 mol equiv.),
CaCO3 (11 mol equiv.), CH2Cl2, 18 ЊC, 0.33 h; (xii) 6% w/v HCl in
MeOH, 18 ЊC, 18 h then Ac2O (10 mol equiv.), DMAP (trace), pyridine,
18 ЊC, 20 h; (xiii) Pd black, 5% w/v HCO2H in MeOH, 18 ЊC, 0.5 h
then Ac2O (10 mol equiv.), DMAP (trace), pyridine, 18 ЊC, 20 h. Bn =
C6H5CH2; DMAP = 4-(N,N-dimethylamino)pyridine; HMDS = hexa-
methyldisilazane.
Paper 8/04524K
Received 15th June 1998
Accepted 24th June 1998
2252
J. Chem. Soc., Perkin Trans. 1, 1998