Formal synthesis of 3-deoxy-d-manno-octulosonic acid (KDO) and 3-deoxy-d-arabino-2-heptulosonic acid (DAH)

Article abstract of DOI:10.1055/s-0032-1317932

Practical synthetic routes to 3-deoxy-d-manno-octulosonic acid (KDO) and 3-deoxy-d-arabino-2-heptulosonic acid (DAH) from common sugar substrates are reported. Chain homologation of the sugar substrates was accomplished by Wittig olefination and Corey-Fuchs alkynylation. A new cyclization strategy was investigated to access the desired pyranosyl isomer of the KDO target. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0032-1317932

LETTER
▌219
letter
Formal Synthesis of 3-Deoxy-D-manno-Octulosonic Acid (KDO) and
3-Deoxy-D-arabino-2-heptulosonic Acid (DAH)
Synthesis of Ulosonic Acids
Tapan Kumar Pradhan,a Chun Cheng Lin,b Kwok Kong Tony Mong*a
a
Applied Chemistry Department, National Chiao Tung University (NCTU), Hsinchu, Taiwan, R.O.C.
Fax +886(3)5723764; E-mail: tmong@mail.nctu.edu.tw
b
Chemistry Department, National Tsing Hua University (NTHU), Hsinchu, Taiwan, R.O.C
Received: 05.11.2012; Accepted after revision: 28.11.2012
carbohydrate small molecules.5 Particularly attractive is
the use of the sugar substrates because the chirality of the
substrates is incorporated into the desired KDO target. For
practical reasons, the proposed scheme used D-mannose
Abstract: Practical synthetic routes to 3-deoxy-D-manno-octulo-
sonic acid (KDO) and 3-deoxy-D-arabino-2-heptulosonic acid
(DAH) from common sugar substrates are reported. Chain homolo-
gation of the sugar substrates was accomplished by Wittig olefina-
tion and Corey–Fuchs alkynylation. A new cyclization strategy was as a starting material. The typical procedure for KDO syn-
investigated to access the desired pyranosyl isomer of the KDO tar-
get.
thesis from carbohydrate substrates involves: (i) elonga-
tion of the sugar carbon chain, (ii) installation of an α-keto
Key words: carbohydrates, Wittig, Corey–Fuchs, cyclization
ester function, followed by (iii) cyclization of the α-keto
ester to yield the desired pyranose isomer.
Previously, different approaches have been developed and
the chemistry employed included: (i) ring-closing
metathesis5h or Diels–Alder cycloaddition for formation
of the pyranose scaffold,7 and (ii) Horner–Emmons–
Wittig reaction,8 thiane anion addition,5a allylation,9 or
propargylation for elongation of the sugar chain.10 Despite
this progress, the possibility of adapting these methods for
large-scale preparation remains a concern. A point in case
is the cyclization step in KDO synthesis, in which forma-
tion of undesired furanose isomer occurs frequently;5h,10
this creates difficulties in product purification and de-
creases the reaction yield. We herein report a new synthet-
ic scheme for a fully protected KDO hemiacetal. The
reported scheme is highly selective for the formation of
the desired pyranose isomer. In addition, we applied the
same strategy for the preparation of protected 3-deoxy-D-
arabino-2-heptulosonic acid (DAH).
3-Deoxy-2-ulosonic acids constitute a specific class of
acidic monosaccharides that are present in a wide range of
complex oligosaccharides and glycoconjugates. These
compounds have been found to play important roles in
many biological systems.1 For example, 3-deoxy-D-manno-
octulosonic acid (KDO) is the key component of the core
structure of a number of lipopolysaccharides (LPSs),
which are found in nearly all members of Enterobacteria-
ceae bacteria (Figure 1).2 N-Acetyl-neuraminic acid
(Neu5Ac) is the non-reducing-end saccharide residue of
most mammalian oligosaccharides.3 3-Deoxy-D-arabino-
2-heptulosonic acid (DAH) is an intermediate generated
in the biosynthesis of aromatic amino acids.4 The poten-
tial use of 3-deoxy-2-ulosonic acids and their analogues as
enzyme inhibitors or starting materials for complex oligo-
saccharide synthesis justifies the interest in developing
practical schemes to prepare these carbohydrate targets.5,6
OR
OH
8
RO
7
OH/R OR
O
HO
HO
OH
O
RO
RO
5
cyclization
OH
OH
6
O
OR
1
RO
HO
HO
AcHN
HO
HO
HO
4
COOH
O
O
2
OR
OR
O
3
COOH
COOH
COOH
OH
OH
α-keto ester
protected KDO
pyranose α/β > 9:1
OH
OH
Neu5Ac
DAH
KDO
carbon chain
homologation
Figure 1 Structures of KDO, Neu5Ac, and DAH
O
H
O
In a project relating to the synthesis of complex lipooligo-
saccharides, gram quantities of KDO monosaccharide
building blocks were required. Literature reports revealed
that the KDO building blocks can be prepared from carbo-
hydrate substrates with a shorter carbon chain or non-
O
OH
R/HO
OR
O
RO
OR
O
O
OR
protected aldehyde
protected D-mannose 1
SYNLETT 2013, 24, 0219–0222
Advanced online publication: 21.12.2012
Scheme 1 Retrosynthetic analysis
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1317932; Art ID: ST-2012-W0953-L
© Georg Thieme Verlag Stuttgart · New York

220
T. K. Pradhan et al.
LETTER
Scheme 1 lays out the retrosynthetic analysis of the KDO
target. Disconnection at the C2–Oring bond gives a linear α-
keto ester, which is derived from oxidative cleavage of an
alkyne intermediate. The alkyne intemediate is made
available from an acetonide-protected mannose precursor
through olefination, hydroboration-oxidation, and Corey–
Fuchs alkynylation. It should be noted that the proposed
aldehyde precursor is derived from commercially avail-
able acetonide-protected D-mannose.
O
OR
O
OH
O
(i)
(ii)
O
O
O
O
O
O
2a R = TBS
2b R = Bn
1
H
OR
OH
OR
O
O
(iv)
(iii)
O
O
O
O
Synthesis of the target KDO commenced with diaceton-
ide-protected D-manno-furanose, which was obtained
from D-mannose by standard procedures.11 The D-manno-
furanose was submitted to Wittig olefination and subse-
quent protection of the C5 hydroxyl as the tert-butyldi-
methylsilyl ether function (TBS) furnished the expected
alkene 2a in 69% yield (Scheme 2). Regioselective reduc-
tion of 2a by 9-BBN afforded alcohol derivative 3a in
high yield (75%) as a single regioisomer. Alcohol 3a was
oxidized to yield an aldehyde that underwent Corey–
Fuchs reaction to afford the desired alkyne 4a.12 Conver-
sion of 4a into the desired α-keto ester 6a was achieved by
sequential bromination13 and alkyne oxidative cleavage
by KMnO4.10 At this stage, the desired KDO should be ob-
tained after TBS ether deprotection and cyclization
(Scheme 3). In practice, the silyl ether deprotection was
non-trivial. Treatment of 6a with either HF-pyridine14 or
TBAF/acetic acid15 resulted in a complex reaction mix-
ture, and the desired KDO pyranose isomer 7 was ob-
tained in disappointing yield (20% at best). We reasoned
that migration of the acetal function might occur during
the deprotection, leading to the complex mixture of KDO
diastereomers.10,16
O
O
4a R = TBS
4b R = Bn
3a R = TBS
3b R = Bn
Br
O
O
OMe
OR
OR
O
(v)
O
O
O
O
O
O
O
6a R = TBS
6b R = Bn
5a R = TBS
5b R = Bn
Scheme 2 Reagents and conditions: (i) Ph3P=CH2, THF, t-BuOK, –
78 °C to r.t., 6 h (85%); For 2a, TBSOTf, CH2Cl2, 2,6-lutidine, 0 °C
to r.t., 10 min (87%); For 2b, BnBr, NaH, TBAI, THF, 0 °C to r.t., 6
h (93%); (ii) 9-BBN, THF, 0 °C to r.t., overnight, H2O2, 4% NaOH,
4–5 h; for 3a 75% and for 3b 70%; (iii) a. (COCl)2, DMSO, Et3N,
CH2Cl2, –78 °C, 2 h; b. CBr4, TPP, Et3N, CH2Cl2, 0 °C, 2 h; c. or
EtMgBr, THF, –78 to 0 °C, 1 h; for 4a 65% over three steps and 4b
70% over three steps; (iv) NBS, AgNO3, acetone, 0 °C to r.t.; for 5a,
30 min, 95% and for 6a, 1 h, 85%; (v) KMnO4, NHCO3, MgSO4,
MeOH–H2O (5:1), 0 °C; for 6a, 4 h, 80% and for 6b, 5 h, 75%.
(a)
O
(i) or (ii)
O
Taking lessons from the aforementioned observations, we
then employed neutral conditions in pyranose cyclization.
O
6a
O
CO2Me
O
After olefination of 1, the C5 hydroxyl function of the re-
sulting alkene was protected with a benzyl ether function
to give alkene 2b. The latter was submitted to the same re-
action sequence, affording the expected α-keto ester 6b
via intermediates 3b, 4b, and 5b. The overall yield of 6b
was 29% from 2b. Final deprotection of the benzyl ether
in 6b was conducted under mild hydrogenolysis condi-
tions using Pd-C as the catalyst. To our delight, the result-
ing O-6 unprotected α-keto ester cyclized to furnish the
KDO hemiacetal 7 in 90% yield without issue (Scheme 3).
Unexpectedly, the α/β-anomeric ratio of 7 was found to be
dependent on the solvent conditions. Hydrogenolysis in
polar MeOH solution furnished 7 with ca. 1:1 α/β-ano-
meric ratio, but in less polar hexane–EtOAc (1:1) mixture,
the α-anomer was formed predominantly (α/β, ≥9:1). For
confirmation of the α-configuration, the α-anomer of 7
was converted into a known acetyl-protected α-KDO de-
rivative 7a, the NMR data of which were in good agree-
ment with the literature data.5h,17,18 For example, in the 1H
NMR spectra, the difference in chemical shift between the
C3 axial and equatorial protons is 0.6 ppm; which is con-
sistent with the literature value observed for the α-anomer
of the KDO sugar (0.6–1.19 ppm) and, hence, confirms
the α-configuration of 7a.18
OH
7
(b)
(iii) or (iv)
O
6b
O
O
O
O
O
+
O
O
CO2Me
O
OH
O
OH
CO2Me
α-anomer of 7
β-anomer of 7
(v)
7a
Scheme 3 Reagents and conditions: (i) HF·Py, THF, 10 h, 20% (re-
covered yield); (ii) TBAF, acetic acid, THF, 0 °C, 10 min, product not
isolable; (iii) 5% Pd/C, H2, EtOAc–hexane (1:1 v/v), r.t., 10 h, 96%,
α/β >9:1; (iv) 5% Pd/C, H2, MeOH, r.t., 1–2 h, 90%, α/β ca. 1:1; (v)
Ac2O, pyridine, r.t., quantitative.
After preparation of the protected KDO 7, we were inter-
ested in applying this method for the synthesis of other
ulosonic acids. Thus, protected DAH was selected as the
target, which was prepared from readily available D-arab-
inose. Scheme 4 outlines the synthetic route to our DAH
target. The scheme commenced with per-O-benzyl D-ara-
Synlett 2013, 24, 219–222
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Ulosonic Acids
221
binosyl hemiacetal 8,19 which underwent Wittig olefina- the carbon chain. A new cyclization strategy was de-
tion, hydroxyl protection by TBS silyl ether, and scribed that was used to obtain the desired KDO pyranose
hydroboration to give arabinotitol derivative 10 in 62% isomer in good yield.
yield over three steps. The alditol was oxidized to furnish
the desired aldehyde by Swern oxidation, and followed by
conversion into alkyne 11 through Corey–Fuchs alkynyl-
Acknowledgment
We thank the National Science Council of Taiwan (NSC 101-2627-
M-009-005) and the Center for Interdisciplinary Science of NCTU
for support.
ation. Subsequent bromination and KMnO4-mediated ox-
idative cleavage of the alkyne produced the desired α-keto
ester. Final deprotection of the TBS ether function at the
C5 hydroxyl group furnished the protected α-anomer of
DAH 14 in 67% yield (from 13).5h,20 Unlike the KDO syn-
Supporting Information for this article is available online at
thesis, deprotection of the TBS function and cyclization http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoprimntgirSatnoIuipfog
r
t
iornat
took place under acidic conditions (HCl in MeOH/CH2Cl2
mixture), which favored α-anomer formation. In addition,
because no acetal functions are present in 14, complica-
tions arising from migration of the acetal groups were
eliminated.
References and Notes
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O
(i) ref. 19
BnO
OH
OBn
(ii)
D-arabinose
BnO
8
OH
OTBS
OH
OBn
(
BnO
iii)
Lipopolysaccharides; Vol. 1; Morrison, D. C.; Ryan, J. L.,
Eds.; CRC: Boca Raton, 1992, 135.
BnO
H
OBn
OBn
OBn
(5) For recent syntheses of KDO and their analogues, see:
(a) Reiner, M.; Schmidt, R. R. Tetrahedron: Asymmetry
2000, 11, 319. (b) Sarabia, F.; Chammaa, S.; López Herrera,
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D.; Sugai, T.; Ohira, S. Tetrahedron Lett. 2004, 45, 4545.
(g) Hsu, C.-C.; Hong, Z.; Wada, M.; Franke, D.; Wong, C.-
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Yamasaki, R. J. Carbohydr. Chem. 2009, 28, 53. (k) Kosma,
P.; Hofinger, A.; Mueller, L. S.; Brade, H. Carbohydr. Res.
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Tetrahedron 2011, 67, 5964. (n) Qian, Y.; Feng, J.; Pervez,
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2001, 40, 1475. (q) Tanaka, H.; Takahashi, D.; Takahashi, T.
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9
10
OTBS
(iv)
(v)
BnO
OBn
OBn
11
O
Br
O
OTBS
(vi)
OTBS
OMe
BnO
BnO
OBn
OBn
OBn
13
OBn
12
BnO
OH
OMe
O
(vii)
ref. 5h
DAH
O
BnO
OBn
14
Scheme 4 Reagents and conditions (i) see Collam and Lowry;19 (ii)
Ph3P=CH2, THF, t-BuOK, –78 °C to r.t., 30 min, 80%; (iii) a.
TBSOTf, CH2Cl2, 2,6-lutidine, 0 °C to r.t., 10 min, 85%; b. 9-BBN,
THF, 0 °C to r.t., overnight, H2O2, 4% aq NaOH, 5 h, 92%; (iv) a.
(COCl)2, DMSO, Et3N, CH2Cl2, –78 °C, 2 h; b. CBr4, TPP, Et3N,
CH2Cl2, 0 °C, 1 h; c. EtMgBr, THF, –78 to 0 °C, 1 h, 60% over three
steps; (v) NBS, AgNO3, acetone, 0 °C to r.t., 1 h, 93%; (vi) KMnO4,
NaHCO3, MgSO4, MeOH–H2O (5:1), 0 °C, 2–3 h, 80%; (vii) 6% aq
HCl, CH2Cl2–MeOH (2:3 v/v), 0 °C to r.t., 90%; (viii) see Hekking et
al.5h TPP = triphenylphosphine; TBSOTf = tert-butyldimethylsilyl
triflate.
(6) (a) Claesson, A.; Jansson, A. M.; Pring, B. G.; Hammond, S.
M.; Ekstroem, B. J. Med. Chem. 1987, 30, 2309. (b) Adachi,
H.; Kondo, K.-I.; Kojima, F.; Umezawa, Y.; Ishino, K.;
Hotta, K.; Nishimura, Y. Nat. Prod. Res., Part B 2006, 20,
361.
In conclusion, we have developed a practical scheme for
the preparation of protected 3-deoxy-D-manno-octulo-
sonic acid (KDO) and 3-deoxy-D-arabino-2-heptulosonic
acid (DAH) from small sugar substrates. The Wittig olefi-
nation and Corey–Fuchs alkylation were used to elongate
(7) Danishefsky, S. J.; Pearson, W. H.; Segmuller, B. E. J. Am.
Chem. Soc. 1985, 107, 1280.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 219–222

222
T. K. Pradhan et al.
LETTER
(8) Mlynarski, J.; Banaszek, A. Tetrahedron 1999, 55, 2785.
(9) Gao, J.; Harter, R.; Gordon, D. M.; Whitesides, G. M. J. Org.
Chem. 1994, 59, 3714.
(10) Li, L. S.; Wu, Y. L. Tetrahedron 2002, 58, 9049.
(11) (a) Bell, D. J. J. Chem. Soc. 1947, 1461. (b) The acetonide
D-mannose is also commercially available.
2.9, 6.5 Hz, 1 H), 2.03 (t, J = 2.6 Hz, 1 H), 1.50 (s, 3 H), 1.41
(s, 3 H), 1.36 (s, 3 H), 1.34 (s, 3 H); 13C NMR (100 MHz,
CDCl3): δ = 138.3, 128.2, 127.3, 127.2, 108.8, 108.4, 80.5,
78.9, 77.7, 77.0, 75.4, 73.6, 70.1, 66.3, 26.9, 26.2, 25.6, 24.9,
20.3. HRMS (ESI): m/z [M + Na]+ calcd for C15H24O8Na:
355.1355; found: 355.1363
(12) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 3769.
(13) Hofmeister, H.; Annen, K.; Laurent, H.; Wiechert, R.
Angew. Chem., Int. Ed. Engl. 1984, 23, 727.
(14) Nicolaou, K. C.; Webber, S. E. Synthesis 1986, 453.
(15) Higashibashi, S.; Shinko, K.; Ishizu, T.; Hashimoto, K.;
Shirahama, H.; Nakata, M. Synlett 2000, 1306.
(16) This step produced a mixture of pyranose and furanose
isomers. For the acid-catalyzed cyclization, see: Tsukamoto,
S.; Takahashi, T. Tetrahedron Lett. 1997, 38, 6415.
(17) Analytical data of 7: [α]D33 +22.8 (c 0.326, CHCl3) {Lit. 5h
[α]D22 +21.1 (c 0.25 in CHCl3)}. 1H NMR (400 MHz,
CDCl3): δ = 7.42–7.21 (m, 5 H), 4.91 (d, J = 11.6 Hz, 1 H),
4.75 (d, J = 11.6 Hz, 1 H), 4.36 (dd, J = 12.9, 6.7 Hz, 1 H),
4.23–4.15 (m, 2 H), 4.09 (dd, J = 8.3, 6.4 Hz, 1 H), 3.96 (dd,
J = 8.3, 7.7 Hz, 1 H), 3.91 (t, J = 4.5 Hz, 1 H), 2.60 (td, J =
(18) Fukase, K.; Kamikawa, T.; Iwai, Y.; Shiba, T.; Rietschel, E.
T.; Kusumoto, S. Bull. Chem. Soc. Jpn. 1991, 64, 3267.
(19) Collam, C. S.; Lowry, T. L. J. Chem. Educ. 2001, 78, 73.
(20) Analytical data of 14: [α]D33 +25.94 (c 0.175, CHCl3); 1H
NMR (400 MHz, CDCl3): δ = 7.45–7.12 (m, 15 H), 4.91 (d,
J = 10.6 Hz, 1 H), 4.65 (dd, J = 17.3, 11.6 Hz, 2 H), 4.59 (d,
J = 12.2 Hz, 1 H), 4.57 (d, J = 10.6 Hz, 1 H), 4.51 (d, J =
12.2 Hz, 1 H), 4.04 (m, 1 H), 3.83 (s, 3 H), 3.82–3.57 (m,
4 H), 2.30 (dd, J = 12.6, 5.0 Hz, 1 H), 2.09 (t, J = 12.6 Hz,
1 H); 13C NMR (100 MHz, CDCl3): δ = 170.3, 138.4, 138.3,
138.2, 128.4, 128.3, 127.9, 127.8, 127.6, 127.6, 127.5, 94.9,
78.0, 77.5, 74.9, 73.3, 73.1, 71.8, 68.9, 53.3, 36.1; HRMS
(ESI): m/z [M + Na]+ calcd for C29H32O7Na: 515.2030;
found: 515.2040.
Synlett 2013, 24, 219–222
© Georg Thieme Verlag Stuttgart · New York