Synthesis of the sialic acid (-)-KDN and certain epimers from (-)-3-dehydroshikimic acid or (-)-quinic acid

Article abstract of DOI:10.1021/ol049048y

(-)-3-Dehydroshikimic acid (3-DHS, 4), a C₇-building block now available in large quantity from corn syrup, has been converted into the sialic acid (-)-KDN (3) as well as its C-7- and C-8-epimers. (-)-Quinic acid can be used for the same purpos

Full text of DOI:10.1021/ol049048y

ORGANIC
LETTERS
2004
Vol. 6, No. 16
2737-2740
Synthesis of the Sialic Acid (−)-KDN
and Certain Epimers from
(−)-3-Dehydroshikimic Acid or (−)-Quinic
Acid
Martin G. Banwell,* Natasha L. Hungerford, and Katrina A. Jolliffe
Research School of Chemistry, Institute of AdVanced Studies,
The Australian National UniVersity, Canberra, ACT 0200, Australia
mgb@rsc.anu.edu.au
Received May 23, 2004
ABSTRACT
(−)-3-Dehydroshikimic acid (3-DHS, 4), a C -building block now available in large quantity from corn syrup, has been converted into the sialic
7
acid (−)-KDN (3) as well as its C-7- and C-8-epimers. (−)-Quinic acid can be used for the same purpose.
Sialic acids, representative examples of which include
Neu5Ac (1) and (+)-KDN (2), are abundant in nature and
play pivotal roles in many significant biological events,
including cell-to-cell recognition.1,2 As such, these com-
pounds have been the subject of intense scrutiny, and there
has been an accompanying effort to develop effective
syntheses of them3,4 as well as certain analogues.5
most invariably a pivotal step used in constructing the full
carbon framework of the target sialic acid involves formation
of the C-1/C-2, C-2/C-3, or C-3/C-4 bond, with the last of
these processes being biomimetic in nature and the most
common variation. For example, Wong has shown4d,f that
condensation of D- or L-mannose with sodium pyruvate in
(3) (a) Danishefsky, S. J.; DeNinno, M. P.; Chen, S.-h. J. Am. Chem.
Soc. 1988, 110, 3929. (b) Banwell, M.; De Savi, C.; Watson, K. Chem.
Commun. 1998, 1189. (c) Banwell, M.; De Savi, C.; Watson, K. J. Chem.
Soc., Perkin Trans. 1 1998, 2251. (d) Kang, S. H.; Choi, H.-w.; Kim, J. S.;
Youn, J.-H. Chem. Commun. 2000, 227. (e) Voight, E. A.; Rein, C.; Burke,
S. D. J. Org. Chem. 2002, 67, 8489.
(4) (a) Baumberger F.; Vasella, A. HelV. Chim. Acta 1986, 69, 1205.
(b) Shirai, R.; Nakamura, M.; Hara, S.; Takayanagi, H.; Ogura, H.
Tetrahedron Lett. 1988, 29, 4449. (c) Nakamura, M.; Furuhata, K.; Ogura,
H. Chem. Pharm. Bull. 1988, 36, 4807. (d) Lin, C.-H.; Sugai, T.; Halcomb,
R. L.; Ichikawa, Y.; Wong, C.-H. J. Am. Chem. Soc. 1992, 114, 10138. (e)
Yamamoto, T.; Teshima, T.; Inami, K.; Shiba, T. Tetrahedron Lett. 1992,
33, 325. (f) Sugai, T.; Shen, G.-J.; Ichikawa, Y.; Wong, C.-H. J. Am. Chem.
Soc. 1993, 115, 413. (g) Gordon, D. M.; Whitesides, G. M. J. Org. Chem.
1993, 58, 7937. (h) Sato, K.; Miyata, T.; Tanai, I.; Yonezawa, Y. Chem.
Lett. 1994, 129. (i) Dondoni, A.; Marra, A.; Merino, P. J. Am. Chem. Soc.
1994, 116, 3324. (j) Chan, T.-H.; Lee, M.-C. J. Org. Chem. 1995, 60, 4228.
(k) Takahashi, T.; Tsukamoto, H.; Kurosaki, M.; Yamada, H. Synlett 1997,
1065. (l) Tsukamoto, H.; Takahashi, T. Tetrahedron Lett. 1997, 38, 6415.
(m) Li, L.-S.; Wu, Y.-L. Tetrahedron 2002, 58, 9049. For references to
earlier syntheses, see: DeNinno, M. P. Synthesis 1991, 583.
Various approaches have been described, including those
employing non-carbohydrate-based starting materials.3 Al-
(1) Angata, T.; Varki, A. Chem. ReV. 2002, 102, 439 and references
therein.
(2) Kiefel, M. J.; von Itzstein, M. Chem. ReV. 2002, 102, 471 and
references therein.
10.1021/ol049048y CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/14/2004

the presence of sialic acid aldolase (NeuAc aldolase) results
in an aldol condensation with accompanying formation of
KDN (2) or its enantiomer (3), respectively. Effective
chemical variations on this approach,3b,4g,j which involve
construction of the C-3/C-4 bond and the conjoining of a
three- and a six-carbon building block (the so-called “3 +
6” approach), often employ a synthetic equivalent for the
rather intractable pyruvate anion.
Scheme 1
While being enormously useful, these approaches preclude
ready construction of sialic acids that vary in the nature and
stereochemistry of substituents at the C-7 and C-8 positions.
Since these sites are now recognized as having significant
potential in the development of sialic acid analogues with
therapeutic6 and/or diagnostic7 utility, we detail herein new
and relevant methodology. In particular, we report the first
example of a “7 + 2” approach to sialic acids wherein the
C-1 to C-7 fragment is obtained from the abundant chiron
(-)-3-dehydroshikimic acid [(-)-3-DHS or 4]8 and the
remaining two carbons are derived from the commercially
available ylide (triphenylphosphoranylidene)acetaldehyde
[Ph3PdC(H)CHO]. This approach results in the installation
of a ∆7-double bond within the sialic acid framework, which
can be manipulated in various ways to construct, for example,
stereochemically novel analogues of (-)-KDN (3) as detailed
below. Furthermore, since we have recently demonstrated
that (-)-3-DHS can be converted into appropriate derivatives
of (+)-3-DHS,9 the work detailed here allows for access to
both the natural and non-natural enantiomeric forms of a
wide-range of sialic acids.
DHS. Thus, the trans-diol moiety associated with the readily
derived methyl ester, 5,9 of (-)-3-DHS, was protected as
the so-called “dispoke” acetal 69 (79%) using the procedures
developed by Ley and co-workers.10 Alternately (Scheme
2), the readily derived methyl ester, 8,11 of commercially
Scheme 2
The opening stages of our approach are shown in Scheme
1, which outlines the first of two distinct and simple methods
for the synthesis of a suitably protected form, 6, of (-)-3-
(5) (a) Kok, G. B.; Mackey, B. L.; von Itzstein, M. Carbohydr. Res.
1996, 289, 67. (b) Hasegawa, A.; Suzuki, N.; Kozawa, F.; Ishida, H.; Kiso,
M. J. Carbohydr. Chem. 1996, 15, 639. (c) Kok, G. B.; Norton, A. K.; von
Itzstein, M. Synthesis 1997, 1185. (d) Kok, G. B.; von Itzstein, M. Synthesis
1997, 769. (e) Sun, X.-L.; Kai, T.; Takayanagi, H.; Furuhata, K. J.
Carbohydr. Chem. 1997, 16, 541. (f) Kai, T.; Sun, X.-L.; Takayanagi, H.;
Furuhata, K. J. Carbohydr. Chem. 1997, 16, 521. (g) Chan, T.-H.; Xin,
Y.-C.; von Itzstein, M. J. Org. Chem. 1997, 62, 3500. (h) Banwell, M.; De
Savi, C.; Hockless, D.; Watson, K. Chem. Commun. 1998, 645. (i) Chappell,
M. D.; Halcomb, R. L. Org. Lett. 2000, 2, 2003. (j) Kumaran, G.; Mootoo,
D. R. Tetrahedron Lett. 2001, 42, 3783. (k) Warwel, M.; Fessner, W.-D.
Synlett 2002, 2104. For a useful review on the synthesis of sialic acid
derivatives and sialylmimetics, see ref 2.
(6) Andrews, D. M.; Cherry, P. C.; Humber, D. C.; Jones, P. S.; Keeling,
S. P.; Martin, P. F.; Shaw, C. D.; Swanson, S. Eur. J. Med. Chem. 1999,
34, 563.
(7) McKimm-Breschkin, J. L.; Colman, P. M.; Jin, B.; Krippner, G. Y.;
McDonald, M.; Reece, P. A.; Tucker, S. P.; Waddington, L.; Watson, K.
G.; Wu, W.-Y. Angew. Chem., Int. Ed. 2003, 42, 3118.
available (-)-quinic acid (7) was similarly protected as the
“dispoke” acetal 9 (57%), which upon treatment with
pyridinium chlorochromate (PCC) in the presence of 4 Å
molecular sieves and pyridine afforded a mixture of the target
enone 6 and the â-hydroxyketone precursor 10. Reaction of
this mixture with acetic anhydride in the presence of DMAP
and Hu¨nig’s base then afforded enone 6 in 67% yield (from
9).
Stereoselective 1,2-reduction of enone 6 was accomplished
with K-selectride, and the resulting methyl shikimate deriva-
tive 11 (86%) (Scheme 3) was then subjected to the first
pivotal step of the synthesis, namely, ozonolysis followed
(8) Kambourakis, S.; Frost, J. W. J. Org. Chem. 2000, 65, 6904 and
references therein.
(9) Banwell, M. G.; Edwards, A. J.; Essers, M.; Jolliffe, K. A. J. Org.
Chem. 2003, 68, 6839.
(10) Ley, S. V.; Osbourne, H. M. I. Org. Synth. 1999, 77, 212 and
references therein.
(11) Frank, M.; Miethchen, R. Carbohydr. Res. 1998, 313, 49.
2738
Org. Lett., Vol. 6, No. 16, 2004

Scheme 3
by reductive workup with dimethyl sulfide. Presumably,
tion by sequential treatment with 95:5 v/v trifluoroacetic acid
(TFA)/water (to cleave the bis-acetal unit) and then aqueous
sodium hydroxide (to saponify the C-1 ester) thus affording,
after treatment with an acidic resin, 7-epi-(-)-KDN (7-epi-
the corresponding keto-aldehyde is the first-formed pro-
duct of this process but the highly electrophilic ketone
carbonyl is trapped by the tethered C-6 hydroxyl to give the
observed cyclic hemi-acetal 12 (63%), which was obtained
as a single anomer. In the next and second pivotal step
of the synthesis, the associated aldehyde was reacted, over
16 h at 18 °C, with (triphenylphosphoranylidene)ace-
taldehyde in a Wittig reaction to give the R,â-unsaturated
aldehyde 13 (78%), incorporating the nine-carbon framework
associated with most sialic acids, including those being
targeted here.
1,2-Reduction of compound 13 was best effected using
the Luche reagent,12 viz. NaBH4/CeCl3‚7H2O, with 2,6-
lutidine present as a buffering agent. Buffering was necessary
to ensure that the reaction medium did not become too acidic
since, under such conditions, the substrate and/or product
decompose rapidly. The resulting allylic alcohol 14 (50%)
was subjected to cis dihydroxylation using the UpJohn
procedure,13 and a ca. 1:1 mixture of triols 15 and 16 (68%
combined yield) was obtained. These products could be
separated by careful flash chromatographic techniques, and
the more mobile one (15) was subjected to global deprotec-
1
3) (76%), the H and 13C NMR spectral data for which
matched those reported4d for the enantiomer. Application of
the same deprotection regime to isomer 16 afforded 8-epi-
(-)-KDN (8-epi-3) (69%). These free sialic acids were
independently subjected to sequential reaction with AG 50W-
X8 cation ion-exchange resin in methanol and then acetic
anhydride in the presence of DMAP and pyridine. In this
manner the lipophilic derivatives 17 (56% from 15) and 18
(50% from 16) were obtained, each of which was subjected
to full spectroscopic characterization.
(-)-KDN itself could be obtained (Scheme 4) by photo-
isomerization of enal 13 to its chromatographically separable
(Z)-isomer 19 (100% at 42% conversion) followed by Luche
reduction12 to give the corresponding allylic alcohol (39%).
In contrast to the observations of Kishi14 and Danishefsky15
concerning the stereoselectivity of osmium tetroxide-medi-
ated oxidation of allylic alcohols and alkenylpyranosides,
(14) (a) Cha, J. K.; Christ, W. J.; Kishi, Y. Tetrahedron Lett. 1983,
24, 3943. (b) Cha, J. K.; Christ, W. J.; Kishi, Y. Tetrahedron 1984, 40,
2247.
(15) DeNinno, M. P.; Danishefsky, S. J.; Schulte, G. J. Am. Chem. Soc.
1988, 110, 3925.
(12) Luche, J.-L. J. Am. Chem. Soc. 1978, 100, 2226.
(13) VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976,
1973.
Org. Lett., Vol. 6, No. 16, 2004
2739

cis dihydroxylation of the latter compound using the previ-
ously employed UpJohn conditions13 selectively afforded the
illustrated triol 20 (42%), representing a protected form of
(-)-KDN, as the major product of reaction. Stepwise
deprotection of compound 20 then afforded (-)-KDN (3),
which was fully characterized as the readily derived per-
acetylated methyl ester 21 {42% over three steps, mp 100-
102 °C, [R]D + 26.2 (c 0.18, CHCl3), lit.3b mp 100-104 °C
(for ent-21), lit.4f [R]D + 26.3 (c 1.14, CHCl3)}, the 1H and
13C NMR data for which matched those recorded3b for the
(+)-enantiomer.
Scheme 4
Acknowledgment. This work was generously supported
by an Australian Research Council Discovery Grant, which
provided a postdoctoral stipend to N.L.H. We also thank the
Institute of Advanced Studies (IAS) for financial support,
including the provision of an IAS postdoctoral Fellowship
to K.A.J. Dr. Gregg Whited (Genencor International, Inc.,
Palo Alto, CA), is warmly acknowledged for providing us
with generous quantities of (-)-3-DHS (4).
Supporting Information Available: Preparation and
characterization of compounds 7-epi-3, 8-epi-3, 5, 6, 8, and
9-21 as well as the 1H and 13C NMR spectra of compounds
6, 8, 9, and 11-21. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL049048Y
2740
Org. Lett., Vol. 6, No. 16, 2004