New approaches in the synthesis of ulosonic acids and analogues

Article abstract of DOI:10.1055/s-2001-18742

A direct synthesis of bicyclic precursors of ulosonic acids is achieved by reaction of cis-α,β-epoxyaldehydes with ethyl 2-(trimethylsilyloxy)-2-propenoate in the presence of boron trifluoride diethyl etherate.

Full text of DOI:10.1055/s-2001-18742

LETTER
1905
New Approaches in the Synthesis of Ulosonic Acids and Analogues
New
A
pproaches
l
in the
a
Synthesis
o
u
f
Ulosonic
A
d
cids and
A
na
i
logue
s
a H. Sugisaki, Yvan Ruland, Ingrid Le Clezio, Michel Baltas*
Synthèse et Physicochimie de Molécules d’Intérêt Biologique, UMR 5068 CNRS - Université Paul Sabatier, 118 route de Narbonne,
31062 Toulouse cedex 04, France
Fax +33(561)556011; E-mail: baltas@chimie.ups-tlse.fr
Received 11 October 2001
incorporation, starting from an , -epoxyaldehyde. The
target compound was obtained in 7 steps and 19% yield.
Recently, exploring a more direct access to heptulosonic
analogues, we have developed a new methodology based
on [4+3] carbon atom incorporation.11 The Mukaiyama
reaction of trans- , -epoxyaldehydes with ethyl 2-(trime-
thylsilyloxy)-2-propenoate 4, in the presence of the Lewis
acid BF3-etherate, led to the direct synthesis of a separable
mixture of 5- and 6-fluoroheptulosonic analogues in their
pyranosidic or furanosidic form (Scheme 1).
Abstract: A direct synthesis of bicyclic precursors of ulosonic ac-
ids is achieved by reaction of cis- , -epoxyaldehydes with ethyl 2-
(trimethylsilyloxy)-2-propenoate in the presence of boron trifluo-
ride diethyl etherate.
Key words: aldol reaction, epoxides, higher carbohydrates, ring
opening, bicyclic products
Higher 3-deoxy-2-ulosonic acids are natural carbohy-
drates possessing between 7 and 9 carbon atoms along
with a ketone functionality at the -position of a carboxy-
lic acid. Ulosonic acids act in many important biological
processes. An example is 3-deoxy-D-arabino-2-heptu-
losonic acid (DAH; 1) which, in its 7-phosphate form, is
an important intermediate in the shikimic acid pathway.1
3-Deoxy-D-manno-octulosonic acid (KDO; 2), which, in
its 8-phosphate form, is a component of the outer mem-
brane lipopolysaccharide of Gram-negative bacteria2 and
it is an important target for the design of inhibitors for en-
zymatic cell wall assembly. 5-N-Acetyl neuraminic acid
(Neu5Ac; 3) has emerged as a key biomolecule in cellular
recognition, adhesion phenomena and in cell infection by
certain viruses (Figure).3
Scheme 1
These promising results led us to investigate this reaction
further. We would like to report in this work a completely
distinct reaction pathway observed when cis-, instead of
trans- , -epoxyaldehydes, are employed.
Three cis- , -epoxyaldehydes were synthesized, possess-
ing n = 4 carbon atoms 17 and n = 5 with identical or dis-
tinct hydroxyl protecting groups 15, 16. These two last
epoxyaldehydes 15 and 16 were prepared as potential pre-
cursors to octulosonic analogues via [5+3] carbon atom
incorporation. Racemic cis- , -epoxyaldehyde 17 was
synthesized in 3 steps, starting from commercially avail-
able cis-1,4-butene-2-diol, in 48% total yield.12 Cis- , -
epoxyaldehydes 15 and 16 were synthesized from com-
mercially available compound 9. Reduction of the ester
group, acetate protection of the primary hydroxyl group
and deprotection of the acetonide were easily realized in
good yield. The desired differentiation of hydroxyls can
be achieved in the next step: firstly, the primary hydroxyl
group was protected by using 1.2 equivalents of TBDM-
SCl, in the presence of DMAP (1.8 equivalents) in
CH2Cl2. The monoprotected compound was exclusively
Figure
Work towards the elaboration of ulosonic acids and ana-
logues has accelerated and several such endeavors, in-
cluding enzymatic and chemoenzymatic syntheses,
starting from carbohydrates and de novo ones have al-
ready appeared in the literature.4–9
Some years ago, we reported10 a versatile synthesis of a
protected DAH, starting from a non-carbohydrate precur-
sor. The methodology was based on [4+2+1] carbon atom
Synlett 2001, No. 12, 30 11 2001. Article Identifier:
1437-2096,E;2001,0,12,1905,1908,ftx,en;D21501ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1906
C. H. Sugisaki et al.
LETTER
obtained in 86% yield. The secondary hydroxyl group was
then protected as a tert-butyl diphenyl silylether group
(TBDPS) resulting in the compound 12 (Scheme 2).13
Scheme 3
sult, and bicyclic products 19a and 19b were obtained in
78% yield.
This good result was also obtained starting from erythro
cis- , -epoxyaldehyde 16 and employing this optimized
condition. Thus compounds 20a and 20b were obtained in
78% yield. Compounds 21a and 21b, resulting from
deprotection of the TBDMS group, were also obtained, in
10% yield (total yield of 88%). A Mukaiyama reaction
was also realized with the threo cis- , -epoxyaldehyde
diastereoisomers 15 and 16, the corresponding bicyclic di-
astereoisomers of 19 and 20 being obtained in moderate
yields (50% and 55%, respectively).
The structural assignment of the bicyclic compounds was
established on the basis on NMR spectroscopy17 and liter-
ature data. In fact there is only one example in the litera-
ture where bicyclic compounds of this type have been
synthesized as masked octulosonic acids. The group of
Baasov18 has reported a multistep synthesis (13 steps)
starting from a differentially protected arabinose deriva-
tive, where an enolpyruvate moiety is introduced under-
going Lewis acid intramolecular condensation. An X-ray
Scheme 2 Reagents and conditions: a) DIBAL-H/CH2Cl2/0 °C,
95%; b) Et3N/DMAP/Ac2O/CH2Cl2/r.t., 98%; c) 2 M HCl (aq)/
CH3CN/0 °C
r.t., 85%; d) TBDPSCl/imidazole/CH2Cl2/r.t., 70%;
e) TBDMSCl (1.2 equiv)/DMAP/CH2Cl2/r.t., 86%; f) KOH/MeOH/
r.t., 92%; g) m-CPBA/NaHCO3/CH2Cl2/0 °C r.t., 75% for 13, 85% for
14; h) diastereoisomers separation by HPLC; i) Cl2(CO)2/Et3N/
DMSO/–78 °C, 95%
The epoxidation step was realized employing meta-chlo-
roperbenzoic acid (m-CPBA) at 0 °C in CH2Cl2 in the
presence of sodium bicarbonate. After 16 hours the mix-
ture was purified yielding the two diastereoisomers in
good total yield (75% for 13 and 85% for 14). The eryth-
ro:threo diastereoselectivity was (66:34) and (86:14), re-
spectively.14 Finally, Swern oxidation led to the desired
cis- , -epoxyaldehydes 15 and 16.
In some initial experiments , -epoxyaldehyde 17 was
treated with ethyl 2-(trimethylsilyloxy)-2-propenoate 415
in the presence of different promoters for a Mukaiyama
aldol reaction (BiCl3/ZnI2 or NaI, Eu(fod)3, LiClO4,
Sn(OTf)2, TMSOTf, BF3-etherate). Only the use of BF3-
etherate gave satisfactory results. Consequently all aldol
reactions of cis- epoxyaldehydes were realized in the pres-
ence of Lewis acid BF3-etherate.16 In all cases, bicyclic
products were obtained. Starting from cis- , -epoxyalde-
hyde 17, anti and syn aldolisation products were formed
leading to epimers 18a and 18b, in 45% yield (Scheme 3).
Initial aldol reactions employing erythro cis- , -epoxyal-
dehyde 15 afforded compounds 19a and 19b in 41% yield
together with 47% of recovered aldehyde (method A,
Scheme 4). Gratifyingly, modifications of the reaction
conditions (method B, Scheme 4) led to an improved re-
Scheme 4 Reagents and conditions: Method A: 4 (1.5 equiv)/
CH2Cl2/BF3-Et2O (1 equiv)/–78 °C (3 h) –40 °C (1 h), 41% for 19a
and 19b; Method B: 4 (4.6 equiv)/CH2Cl2/BF3-Et2O (6.9 equiv)/
–40 °C (6 h), 78% for 19a and 19b, 78% for 20a and 20b, 10% for
21a and 21b
Synlett 2001, No. 12, 1905–1908 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
New Approaches in the Synthesis of Ulosonic Acids and Analogues
1907
structure of one of the synthesized bicycles, along, with losonic bicyclic precursors through [4+3] and [5+3] car-
NMR data are available. According to these data, similar- bon atom incorporation by using cis- , -epoxyaldehydes
ities of the bicyclic frame 23 are observed with compound and ethyl 2-(trimethylsilyloxy)-2-propenoate. Many ana-
1
19b: a) H3b displays only one coupling constant (JH3a- logues of ulosonic acids, starting from differently protect-
H3b = 13.5 Hz); b) 1H3a resonates as dd with JH3a-H4 = 6.5 ed hydroxy groups of the bicyclic compounds, can thus be
Hz; c) 1H5 ( = 4.64 ppm) does not couple with any vicinal easily accessed. It is noteworthy that the aldolisation reac-
proton (singlet); d) 1H6 resonates at higher field ( = 3.69 tion leads to completely different compounds when using
1
ppm) compared to H6 of the isomer 19a ( = 4.77 ppm) trans- , -epoxyaldehydes as we have reported earlier.11
as in the case of Baasov’s compound.
Bicycle formation could be explained by the following
mechanism: first a Mukaiyama aldolisation reaction oc-
curs leading to intermediates -hydroxy , -epoxy ke-
toesters 22a and 22b, which are diastereoisomers at C-4,
in a 63:37 anti:syn ratio in the case of epoxyaldehyde 15
(Scheme 5). The cyclisation process at the C-5 carbon
atom of these epoxyketoesters can be triggered by Lewis
acid mediated intramolecular attack of the carbonyl oxy-
gen atom of the ketone on the epoxide function. Such a cy-
clisation process would lead to the formation of an oxo-
carbenium ion which may react in situ with the just
formed alkoxide, forming the cyclic ketal and thus the bi-
cyclic compounds. The C-4 epimeric bicycles obtained,
reflect the diastereoisomeric ratio of the aldolisation reac-
tion. Considering the cyclisation reaction, these results
are in agreement with all previously reported by our
group19–21 concerning the Lewis acid mediated intramo-
lecular cyclisation of , -epoxy -hydroxyesters. In fact,
in the case of compounds almost symmetrically substitut-
ed around the cis epoxy function, the regioselectivity of
the reaction always leads to the smaller ring on the basis
of steric requirements and better antiparallel alignment of
the incipient and rupturing bonds.
Acknowledgement
We thank the CNRS and the 'Ministère de l’Education Nationale de
la Recherche et des Technologies' for financial support (UMR
5068). C. H. S. and Y. R. acknowledge the 'Ministère de l’Education
Nationale de la Recherche et des Technologies' for post doctoral
and doctoral grants respectively.
References
(1) (a) Ganem, B. Tetrahedron 1978, 34, 3533. (b) Haslam, E.
In Shikimic Acid Metabolism and Metabolites; Wiley: New
York, 1993.
(2) (a) Levi, D. H.; Racker, E. J. J. Biol. Chem. 1959, 234, 2532.
(b) Unger, F. M. Adv. Carbohydr. Chem. Biochem. 1981, 38,
325. (c) Sugai, T.; Shen, G. J.; Ichikawa, Y.; Wong, C.-H. J.
Am. Chem. Soc. 1993, 115, 413. (d) Lubineau, A.; Augé, J.;
Lubin, N. Tetrahedron 1993, 49, 4639.
(3) (a) Sialic Acids, Chemistry Metabolism and Function;
Shauer, R., Ed.; Springer-Verlag: Wien, 1982, Chapter D.
(b) Bacterial Lipopolysaccharides: Structure, Synthesis and
Biological Activities; Anderson, L.; Unger, F. M., Eds.; ACS
Symposium series 231: ACS Washington, DC, 1983.
(4) Some references of chemical syntheses of Neu5Ac:
(a) Kang, S. H.; Choi, H.-W.; Kim, J. S.; Youn, J.-H. Chem.
Commun. 2000, 227. (b) Chan, T.-H.; Xin, Y.-C. J. Org.
Chem. 1997, 62, 3500. (c) Choi, S. K.; Lee, S.; Whitesides,
G. M. J. Org. Chem. 1996, 61, 8739. (d) Julina, R.; Auge,
C.; Gautheron, C.; David, S.; Malleron, A.; Cavayé, B.;
Bouxom, B. Tetrahedron 1990, 46, 201. (e) Muller, I.;
Vasella, A.; Wyler, R. Carbohydr. Res. 1987, 164, 415.
(f) Danishefsky, S. J.; Deninno, M. P. J. Org. Chem. 1986,
51, 2615.
In conclusion we have found a very direct and efficient
method for a one step synthesis of heptulosonic and octu-
(5) Some references of enzymatic syntheses of Neu5Ac:
(a) Lin, C.-H.; Sugai, T.; Halcomb, R. L.; Ichikawa, Y.;
Wong, C.-H. J. Am. Chem. Soc. 1992, 114, 10138. (b) Kim,
M.-J.; Hennen, W. J.; Sweers, H. M.; Wong, C.-H. J. Am.
Chem. Soc. 1988, 110, 7159.
(6) Some references of chemical syntheses of DAH: (a)Barton,
D. H. R.; Liu, W. Tetrahedron Lett. 1997, 38, 367.
(b) Barton, D. H. R.; Liu, W. Tetrahedron 1997, 53(36),
12067. (c) Lubineau, A.; Arcostanzo, H.; Queneau, Y. J.
Carbohydr. Chem. 1995, 14(9), 1295. (d) Dondoni, A.;
Marra, A.; Merino, P. J. Am. Chem. Soc. 1994, 116, 3324.
(7) Some references of enzymatic syntheses of DAH:
(a) Sugai, N. J.; Shen, G. J.; Ichikawa, Y.; Wong, C.-H. J.
Am. Chem. Soc. 1993, 115, 413. (b) Turner, N. J.;
Whitesides, G. W. J. Am. Chem. Soc. 1989, 111, 624.
(c) Frost, J. W.; Knowles, J. R. Biochemistry 1984, 23, 4465.
(8) Some references of chemical syntheses of KDO starting
from carbohydrate precursors: (a) Jiang, S.; Rycroft, A. D.;
Singh, G.; Wang, X.-Z.; Wu, Y.-L. Tetrahedron Lett. 1998,
39, 3809. (b) Lopez-Herrera, F. J.; Saraiba-Garcia, F.
Tetrahedron 1997, 53, 3325. (c) Tsukamoto, H.; Takahashi,
T. Tetrahedron Lett. 1997, 38, 6415.
Scheme 5
Synlett 2001, No. 12, 1905–1908 ISSN 0936-5214 © Thieme Stuttgart · New York

1908
C. H. Sugisaki et al.
LETTER
(9) Some references of de novo syntheses of KDO:
(a) Schlessinger, R. H.; Pettus, L. H. J. Org. Chem. 1998, 63,
9089. (b) Lubineau, A.; Augé, J.; Lubin, N. Tetrahedron
1993, 49, 4639. (c) Smith, D. B.; Wang, Z.; Schreiber, S. L.
Tetrahedron 1990, 46, 4793. (d) Some references of
enzymatic and chemoenzymatic syntheses of KDO: Kragl,
U.; Godde, A.; Wandrey, C.; Lubin, N.; Augé, C. J. Chem.
Soc., Perkin Trans 1 1994, 119. (e) See also: Sugai, T.;
Shen, G.-J.; Ichikawa, Y.; Wong, C.-H. J. Am. Chem. Soc.
1993, 115, 413.
1 H, J7/8a = J7/8b = 3.7 Hz, J7/6 = 6.1 Hz, H-7); 3.64 (dd, 1 H,
J
J
8a/7 = 3.7 Hz, and J 8a/8b = 10.9 Hz, H-8a); 3.56 (dd, 1 H,
8b/7 = 3.7 Hz and J8a/8b = 10.9 Hz, H-8b); 2.38 (dd, 1 H,
J3a/4 = 9.9 Hz and J3a/3b = 12.6 Hz, H-3a); 1.81 (d, 1 H,
3b/3a = 12.7 Hz and J3b/4 = 3.6 Hz, H-3b); 1.23 (t, 3 H,
J
J = 7.2 Hz, CH3 ethyl); 1.07 (s, 9 H, t-Bu); 1.02 (s, 9 H,
t-Bu).
13C NMR (50 MHz, CDCl3): (ppm)= 165.7 (C-1); 136.1,
135.9, 135.7, 129.7, 127.5 (CH phenyl); 134.1, 133.6 (Cq
phenyl); 105.7 (C-2); 79.8 (C-5); 74.4, 73.8 (C-6 and C-7);
68.5 (C-4); 64.9 (C-8); 61.9 (CH2CO2Et); 43.1 (C-3); 27.0,
26.9 (CH3-t-Bu); 19.5, 19.3 (Cq-t-Bu); 14.0 (CH3-ethyl).
Elemental Analysis: Anal. Calcd for C42H52O7Si2: C, 69.58;
H, 7.23. Found: C, 69.48; H, 7.38. Spectral data of
compound 19b: 1H NMR (250 MHz, CDCl3): (ppm)=
7.69–7.25 (m, 20 H, CH-TBDPS); 4.64 (s, 1 H, H-5); 4.27
(q, 2 H, J = 7.6 Hz, CH2 ethyl); 4.06 (d, 1 H, J4/3a = 6.4 Hz,
H-4); 3.81 (ddd, 1 H, J7/8a = 3.3 Hz, J7/8b = 2.8 Hz, J7/6 = 5.9
Hz, H-7); 3.76 (d, 1 H, J6/7 = 5.9 Hz, H-6); 3.59 (dd, 2 H,
(10) Devianne, G.; Escudier, J.-M.; Baltas, M.; Gorrichon, L. J.
Org. Chem. 1995, 60, 7343.
(11) Ruland, Y.; Zedde, C.; Baltas, M.; Gorrichon, L.
Tetrahedron Lett. 1999, 40, 7323.
(12) Nacro, K.; Zedde, C.; Escudier, J.-M.; Baltas, M.;
Gorrichon, L.; Neier, R. Chirality 1998, 10, 804.
(13) Yeola, S. N.; Saleh, S. A.; Brash, A. R.; Prakash, C.; Taber,
D. F.; Blair, I. A. J. Org. Chem. 1996, 61, 838.
(14) erythro and threo configurations were attributed for relative
configurations of asymmetric carbons comparing with
literatures 1H NMR data: Hu, S.; Jayaraman, S.;
Oehlschlager, A. C. J. Org. Chem. 1998, 63, 8843.
(15) (a) Sugimura, H.; Shigekawa, Y.; Uematsu, M. Synlett 1991,
153. (b) Sugimura, H.; Miura, M.; Yamada, N. Tetrahedron:
Asymmetry 1997, 8, 4089.
(16) Typical Procedure: To a solution of epoxyaldehyde and
ethyl 2-(trimethylsilyloxy)-2-propenoate in anhyd
dichloromethane, at temperature indicated in the schemes,
was slowly added BF3 Et2O. After the time of reaction, the
mixture was quenched with a sat. NaHCO3 solution and
extracted with dichloromethane and ethyl acetate. The
combined organic phases were dried over MgSO4, filtered
and evaporated. The crude product was chromatographed on
silica gel (petroleum ether–ethyl acetate,
J
8a/7 = 3.3 Hz and J8a/8b = 10.7 Hz, H-8a); 3.50 (dd, 1 H,
J8b/7 = 2.8 Hz and J8b/8a = 10.7 Hz, H-8b); 2.50 (dd, 1 H,
3a/4 = 6.5 Hz and J3a/3b = 13.5 Hz, H-3a); 1.65 (d, 1 H,
J
J3b/3a = 13.5 Hz, H-3b); 1.29 (t, 3 H, J = 7.6 Hz, CH3 ethyl);
1.08 (s, 9 H, t-Bu); 1.03 (s, 9 H, t-Bu). 13C NMR (50 MHz,
CDCl3): (ppm)= 165.5 (C-1); 136.0, 135.8, 135.6, 129.6,
127.6 (CH phenyl); 133.9, 133.2 (Cq phenyl); 103.9 (C-2);
83.6 (C-5); 76.1, 73.4 (C-6 and C-7); 72.0 (C-4); 64.6 (C-8);
62.0 (CH2CO2Et); 47.0 (C-3); 27.0, 26.9 (CH3-t-Bu); 19.5,
19.3 (Cq-t-Bu); 14.0 (CH3-ethyl). Elementary Analysis:
Anal. Calcd for for C42H52O7Si2: C, 69.58; H, 7.23. Found:
C, 69.13; H, 6.86.
(18) Shoucheng, D.; Plat, D.; Belakhov, V.; Baasov, T. J. Org.
Chem. 1997, 62, 794.
(19) Nacro, K.; Baltas, M.; Escudier, J.-M.; Gorrichon, L.
Tetrahedron 1997, 53, 659.
(20) Nacro, K.; Baltas, M.; Gorrichon, L. Tetrahedron 1999, 55,
5129.
(21) Nacro ,K.; Gorrichon, L.; Escudier, J.-M.; Baltas, M. Eur. J.
Org. Chem. in press.
90:10 70:30 0:100).
(17) Spectral data of compound 19a: 1H NMR (250 MHz,
CDCl3): (ppm)= 7.73–7.29 (m, 20 H, CH-TBDPS); 4.77
(d, 1 H, J = 6.1 Hz, H-6); 4.71 (d, 1 H, J5/4 = 4.6 Hz, H-5);
4.49–4.43 (m, 1 H, H-4); 4.23 (m, 2 H, CH2 ethyl); 3.94 (td,
Synlett 2001, No. 12, 1905–1908 ISSN 0936-5214 © Thieme Stuttgart · New York