Diastereoselective routes to side-chain truncated analogues of N-acetylneuraminic acid

Article abstract of DOI:10.1039/a708594j

Vitamin C 3 has been converted, in a completely stereo-controlled manner, into the side-chain truncated analogues 4 and 5 of N-acetylneuraminic acid 1.

Full text of DOI:10.1039/a708594j

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Diastereoselective routes to side-chain truncated analogues of
N-acetylneuraminic acid†
Martin Banwell,*a‡ Chris De Savi,a David Hocklessa 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
Vitamin C 3 has been converted, in a completely stereo-
controlled manner, into the side-chain truncated analogues
4 and 5 of N-acetylneuraminic acid 1.
in a completely diastereoselective fashion.11 Oxidation of the
latter compound with the Swern reagent afforded ketone 13
{90%, [a]D 272.9 (c 2.5)} and this was immediately reduced
with NaBH4 in EtOH to alcohol 14 {82%, [a]D 25.9 (c 2.3)}
which proved to be the only isolable product of the reaction.
Attempts to cleave the CNC double bond12 within this last
compound using ozone failed because of competing reaction at
the aromatic rings associated with the N,N-dibenzylamino
moiety. Consequently, a somewhat more circuitous method was
devised for achieving this end. Thus, compound 14 was
N-Acetylneuraminic acid 1 (Neu5Ac) and other members of the
sialic acid class of carbohydrates play fundamental roles in
many important biological processes, including cell adhesion
and differentiation, immune responses, tumour metastasis and
the development of neural cells.1 In addition, they constitute a
ligand commonly recognised by many infectious pathogens
such as viruses, bacteria and parasites.1 Consequently, sialic
acids and various derivatives including the potent anti-influenza
drug GG167 22 are assuming increasing importance as
pharmacological tools and/or therapeutic agents.3 In this regard
there is now considerable interest4 in side-chain truncated
analogues of Neu5Ac which are currently only accessible via
degradation of the natural product 1.3,4 Therefore, we report
herein on the stereocontrolled conversion of abundant vitamin C
3 into compounds 4 and 5, each of which embodies the sialic
O
O
i
iii
3
O
EtO2C
O
EtO2C
N3
OR
8
6 R = H
7 R = Tf
ii
iv
HN
OH
O
O
O
vi
OH
HO2C
O
O
4
1
NH2
HO
HO
OH
N
HO2C
OH
NHAc
O
H
R
OH
O
NR2
H
NBn2
11
H
H
H
9 R = H
10 R = Bn
8
HO
HO
OH
v
OH
O
9
O
OH
2 R = NHAc
OH
vii EtO2C
1
3
Br
OAc
OAc
OMe
R
O
O
N
O
HO
EtO2C
OH
R
R′
1
x
4
MeO2C
OAc
NHAc
O
O
O
O
NBn2
4
EtO2C
S
NBn2
NBn2
OAc
OAc
16 R = TMS
12 R = OH, R′ = H
13 RR′ = O
14 R = H, R′ = OH
15 R = H, R′ = OTMS
4
5
vi
viii
ix
xi
acid core but lacks the C-8/C-9 (side-chain) assemblage
associated with the parent system 1. The reaction sequences
used for these conversions offer possibilities for the synthesis5
of a range of novel sialic acid analogues which can vary in both
the nature and stereochemistry of the substituents attached to
the pyranose ring.
The reaction sequence (Scheme 1) leading to compound 4
starts with a literature procedure6 for the oxidative degradation
of vitamin C 3 to the a-hydroxy ester 6. The triflate derivative
7 of the latter compound was then prepared in quantitative yield
by standard methods7 and underwent a smooth SN2 reaction
with lithium azide8 in DMF at room temperature to give the
azide 8 {80%, [a]D 214.7 (c 2.6)§}. Reduction of this a-azido
ester with LAH afforded the amino alcohol 9 {100%, [a]D
210.5 (c 1.5)} which was immediately protected as its N,N-
dibenzyl derivative 10 {90%, [a]D +1.2 (c 2.1)}. Oxidation of
compound 10 using the Swern reagent gave aldehyde 119 {95%,
[a]D +3.9 (c 3.8)} which upon reaction with ethyl (2-bromo-
methyl)acrylate, zinc dust and saturated aq. NH4Cl10 in THF
afforded the homoallylic alcohol 12 {87%, [a]D 214.8 (c 2.1)}
OAc
R
O
O
O
xiii
xii
MeO2C
OAc
NBn2
4
O
O
EtO2C
NBn2
OAc
17 R = TMS
18
Scheme 1 Reagents and conditions: i, see ref. 6; ii, Tf2O (1.3 equiv.),
2,6-lutidine (1.3 equiv.), CH2Cl2, 250 to 210 °C, 0.75 h; iii, LiN3 (2.5
equiv.), DMF, 18 °C, 3 h; iv, LAH (3.5 equiv.), THF, 18 to 65 °C, 3 h; v,
BnBr (2.2 equiv.), K2CO3 (2 equiv.), MeCN, 60 °C, 14 h; vi, (COCl)2 (1.2
equiv.), DMSO, CH2Cl2, 278 to 0 °C, 1 h, then Et3N (2.6 equiv.); vii, Zn
dust (1.2 equiv.), sat. aq. NH4Cl, THF, 60 °C, 0.75 h; viii, NaBH4 (6 equiv.),
EtOH, 210 °C, 1.5 h; ix, TMSCl (4.0 equiv.), hexamethyldisilazane (4.0
equiv.), pyridine, 0 to 18 °C, 19 h; x, AD-mix-a (2.2 equiv.), ButOH, H2O,
18 °C, 22 h; xi, Pb(OAc)4 (0.9 equiv.), CaCO3 (11 equiv.), CH2Cl2, 18 °C,
0.33 h; xii, 6% w/v HCl in MeOH, 18 °C, 18 h then Ac2O (10 equiv.),
DMAP (trace), pyridine, 18 °C, 20 h; xiii, Pd black, 5% w/v HCO2H in
MeOH, 18 °C, 0.5 h, then Ac2O (10 equiv.), DMAP (trace), pyridine, 18 °C,
20 h
Chem. Commun., 1998
645

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converted into the corresponding Me3Si-ether 15 {83%, [a]D
212.9 (c 3.0)} and the CNC double bond within this latter
compound was dihydroxylated using AD-mix-a.13 The result-
ing 1:1 mixture of diastereoisomeric diols 16 (83%) was then
cleaved with lead tetraacetate to give the a-keto ester 17 {90%,
[a]D 221.7 (c 2.3)}. Treatment of compound 17 with 6% w/v
methanolic HCl at room temperature for 18 h and subsequent
peracetylation of the crude reaction mixture resulted in
formation of the sialic acid analogue 18 {72%, [a]D 281.3 (c
5.7)}. The benzyl protecting groups within this last compound
could be removed using palladium black and formic acid14 in
MeOH and the resulting primary amine was acetylated to give
the target compound 4 {80% at 80% conversion, [a]D 297.1 (c
1.0)}, the structure of which follows from spectroscopic data.
Extension of this chemistry to the preparation of compound 5
is readily achieved. Thus, aldol condensation of the enolate
anion derived from 2-acetylthiazole15 with aldehyde 11 af-
forded the b-hydroxy ketone 19 {72%, [a]D 258 (c 0.7)} in a
completely stereoselective manner. Reaction of this last com-
pound with 20% w/v methanolic HCl at room temperature for
18 h and subsequent peracetylation of the crude reaction
mixture afforded compound 5 {70%. [a]D 2182.1 (c 1.0)}
together with quantities (30%) of the open-chain dehydration
product 20 {[a]D 2154.2 (c 0.6)}.
alcohol 22 {83%, [a]D + 1.0 (c 5.7)} which was converted into
the N,N-dibenzyl derivative 23 {92%, [a]D 280.0 (c 6.8)}.
Oxidation of this latter compound afforded the C-2 epimer of
a-amino aldehyde 11, namely compound 24 {88%, [a]D +58.7
(c 7.9)}, which underwent stereoselective aldol condensation
with the enolate anion derived from 2-acetylthiazole to give
amino alcohol 25 {79%, [a]D 25.5 (c 3.7)}. The stereo-
chemistry at C-4 within compound 25 has not been rigorously
proven but is assigned as illustrated on the basis of the well-
known9,11 directing effect of an a-(N,N-dibenzylamino) sub-
stituent on nucleophilic additions to aldehydes. In an effort to
achieve a cyclisation reaction, compound 25 was treated with
8% w/v methanolic HCl, then the crude reaction mixture was
subjected to exhaustive acetylation. However, no cyclisation
products were observed. The only compound obtained was the
open-chain dehydration product 26 {70%, mp 123–125 °C, [a]D
+106.3 (c 0.7)}, the structure of which was established by
spectroscopic and X-ray crystallographic methods.¶
Notes and References
† The work described herein is the subject of a patent application (AIPO
Patent Office Provisional Application No. PO8998, lodged September 5th,
1997).
‡ E-mail: mgb@rsc.anu.edu.au
§ All optical rotations were determined in CHCl3 at 20 °C.
O
OH
O
OAc
¶ Crystal data for 26: C27H28N2O5S, M = 492.59, T = 193(1) K,
O
monoclinic, space group P21, a = 11.346(4), b = 7.778(2), c = 15.473(6)
Å, b = 109.34(3)°, U = 1288.4(3) Å3, Dc (Z = 2) = 1.270 g cm23, F(000)
= 520, m(Cu-Ka) = 14.42 cm21, semi-empirical absorption correction;
2085 unique data (2qmax = 120.1°), 1583 with I > 3s(I); R = 0.033, wR
= 0.029, GOF = 1.44. CCDC 182/739.
O
N
N
OAc
S
S
NBn2
NBn2
19
20
While the reaction sequence just described delivers a sialic
acid analogue 5 which possesses the unnatural configuration at
C-4, there are some constraints associated with the stereo-
chemical variations that are available. This situation is high-
lighted by the outcome of the reaction sequence outlined in
Scheme 2. Thus, treatment of triflate 7 with sodium azide in
DMF at 75 °C for 6 h afforded azide 21 {85%, [a]D +42.5 (c
2.7)} together with minor amounts (ca. 8%) of its C-2 epimer 8
which could be removed chromatographically. Reduction of
compound 21 with LAH then provided the corresponding amino
1 S.-K. Choi, S. Lee and G. M. Whitesides, J. Org. Chem., 1996, 61, 8739
and references cited therein.
2 G. B. Kok, D. R. Groves and M. von Itzstein, Chem. Commun., 1996,
2017 and references cited therein.
3 M. von Itzstein and R. J. Thomson, Top. Curr. Chem., 1997, 186, 119
and references cited therein.
4 M. J. Bamford, J. C. Pichel, W. Husman, B. Patel, R. Storer and N. G.
Weir, J. Chem. Soc., Perkin Trans. 1, 1995, 1181.
5 For discussions of approaches to the total synthesis of sialic acid
derivatives see ref. 3 and M. P. DeNinno, Synthesis, 1991, 583.
6 K. S. Kim, I. H. Cho, Y. H. Anh and J. I. Park, J. Chem. Soc., Perkin
Trans. 1, 1995, 1783; E. Abushanab, P. Vemishetti, R. W. Leiby, H. K.
Singh, A. B. Mikkilineni, D. C.-J. Wu, R. Saibaba and R. P. Panzica,
J. Org. Chem., 1988, 53, 2598.
7 J. N. Vos, J. H. van Boom, C. A. A. van Boeckel and T. Beetz,
J. Carbohydr. Chem., 1984, 3, 117. For a review on carbohydrate
triflates, see R. W. Binkley and M. G. Ambrose, ibid., 1984, 3, 1.
8 N. Hofman-Bang, Acta. Chem. Scand., 1957, 11, 581.
9 Reetz and co-workers have highlighted the value of using N,N-dibenzyl-
protected a-amino aldehydes in reactions (at the aldehyde carbon) with
nucleophiles because of the configurational stability and high levels of
diastereofacial control exerted by this protecting group (see M. T. Reetz,
Angew. Chem., Int. Ed. Engl., 1991, 30, 1531 and, for example, R. V.
Hoffman and J. Tao, J. Org. Chem., 1997, 62, 2292).
10 R. C. Anand and V. Singh, Heterocycles, 1993, 36, 1333.
11 For related work see: S. Hanessian, H. Park and R.-Y. Yang, Synlett,
1997, 351 and 353.
12 In the reaction sequence culminating in this cleavage step, the
organozinc species derived from ethyl (2-bromomethyl)acrylate is
functioning as an equivalent for the pyruvate anion. For a review on,
inter alia, pyruvate anion equivalents, see L. Kova´cs, Recl. Trav. Chim.
Pays-Bas, 1993, 112, 471.
O
OH
O
i
ii
O
O
EtO2C
7
N3
21
NR2
22 R = H
23 R = Bn
iii
iv
O
O
OH
O
O
v
O
O
N
4
S
NBn2
NBn2
25
24
vi
O
OAc
OAc
N
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.
14 B. ElAmin, G. M. Anantharamaiah, G. P. Royer and G. E. Means,
J. Org. Chem., 1979, 44, 3442; B. D. Gray and P. W. Jeffs, J. Chem.
Soc., Chem. Commun., 1987, 1329; A. M. Diederich and D. M.
Ryckman, Tetrahedron Lett., 1993, 34, 6169.
S
NBn2
26
Scheme 2 Reagents and conditions: i, NaN3 (2 equiv.), DMF, 75 °C, 6 h; ii,
LAH (3.5 equiv.), THF, 18 to 65 °C, 3 h; iii, BnBr (2.2 equiv.), K2CO3 (2
equiv.), MeCN, 60 °C, 14 h; iv, (COCl)2 (1.2 equiv.), DMSO, CH2Cl2, 278
to 0 °C, 1 h then Et3N (2.6 equiv.); v, ButOH (1 equiv.), BunLi (1.2 equiv.),
THF, 18 °C, 0.66 h, then 2-acetylthiazole (1.2 equiv.), 250 °C, 2.5 h; vi, 8%
w/v HCl in MeOH, 18 °C, 18 h, then Ac2O (10 equiv.), DMAP (trace),
pyridine, 18 °C, 20 h
15 A. Dondoni and D. Perrone, Aldrichim. Acta, 1997, 30, 35 and
references cited therein.
Received in Cambridge, UK, 28th November 1997; 7/08594J
646
Chem. Commun., 1998