Alkylidenecarbene insertion at anomeric C-H bonds. Synthesis of 3-deoxy-D-arabino-2-heptulosonic acid (DAH) and 3-deoxy-D-manno-2-octulosonic acid (KDO)

Article abstract of DOI:10.1016/S0040-4039(02)01078-X

A novel method for the homologation of glycals to the corresponding 3-deoxy-2-ulosonic acids, based on the [1,5]-C-H bond insertion of alkylidenecarbenes, is presented. The application of this approach is illustrated through the synthesis of 3-deoxy-D-arabino-2-heptulosonic acid (DAH) and 3-deoxy-D-manno-2-octulosonic acid (KDO).

Full text of DOI:10.1016/S0040-4039(02)01078-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 5389–5391
Alkylidenecarbene insertion at anomeric CꢀH bonds. Synthesis
of 3-deoxy- -arabino-2-heptulosonic acid (DAH) and
3-deoxy- -manno-2-octulosonic acid (KDO)
D
D
Duncan J. Wardrop* and Wenming Zhang
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, IL 60607-7061, USA
Received 23 May 2002; accepted 7 June 2002
Abstract—A novel method for the homologation of glycals to the corresponding 3-deoxy-2-ulosonic acids, based on the [1,5]-CꢀH
bond insertion of alkylidenecarbenes, is presented. The application of this approach is illustrated through the synthesis of
3-deoxy-
D
-arabino-2-heptulosonic acid (DAH) and 3-deoxy-
D
-manno-2-octulosonic acid (KDO). © 2002 Published by Elsevier
Science Ltd.
The ulosonic acids are a family of complex monosac-
charides that participate in a wide range of biological
CꢀH insertion reaction of alkylidenecarbenes generated
from 2-oxopropyl glycosides 5.9 As part of a study to
examine the use of these insertion products as synthetic
building blocks, we now report the preparation of
DAH (1) and KDO (2) using the strategy outlined in
Scheme 1. We envisioned that a range of ulosonic acids
7 could be readily accessed via homologation of glycals
4 through a sequence of glycosylation, alkylidenecar-
bene CꢀH insertion, to form 6,10 and oxidative cleavage
of the dihydrofuran ring to unmask the C-2 carboxylate
group. In addition to being applicable to a variety of
glycal precursors, we anticipated that this approach
would also offer an entry point to 3-substituted ulo-
sonic acids, including KO (3) as well as provide confor-
mationally restricted scaffolds, i.e. 6, with which to
construct analogs of 1 and 2.
processes.
3-Deoxy-
D
-arabino-2-heptulosonic
acid
(DAH, 1), for example, is a key intermediate in the
biosynthesis of aromatic amino acids in plants and
bacteria via the shikimic acid pathway,1 while 3-deoxy-
D
-manno-2-octulosonic acid (KDO, 2)2 and
D
-glycero-
D
-talo-octulosonic acid (KO, 3)3 are key components of
the lipopolysaccharides (LPS) present on the surface of
Gram-negative bacteria. The increasing occurrence of
bacterial pathogens resistant to antibiotics, has stimu-
lated much interest in the biosynthesis of shikimic acid
and LPS, which are essential for normal bacterial cell
growth yet absent in humans.4 It is not surprising then,
given the pivotal role which ulosonic acids play in these
pathways, that there is much interest in the develop-
ment of synthetic routes to DAH (1),5 KDO (2),6 KO
(3),7 and analogs of these natural products.8
We recently reported a novel method for the prepara-
tion of [4.5]spiroketal glycosides 6 based on the [1,5]-
Scheme 1. A general approach to the synthesis of ulosonic
acids from glycals based on the [1,5]-CꢀH insertion reaction
of alkylidenecarbenes.
* Corresponding author. Tel.: 1-312-355-1035; fax: 1-312-996-0431;
e-mail: wardropd@uic.edu
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)01078-X

5390
D. J. Wardrop, W. Zhang / Tetrahedron Letters 43 (2002) 5389–5391
Our route to 1 commenced from tri-O-benzyl-
D
-glucal
Removal of the 2-oxopropyl group was then accom-
plished by treatment of 12 with 2 equiv. of samarium
diiodide in methanol,17 which selectively cleaved the
CꢀO bond of the a-alkoxy ketone to furnish hemiacetal
13 as a single a-anomer. No further reduction was
observed; a-alkoxy esters are known to be inert under
these conditions.17 Finally, hydrogenolytic removal of
the O-benzyl groups, saponification of the ester moiety
and ion exchange with DOWEX 50W resin afforded
DAH (1), which was then converted to the ammonium
salt 14 by treatment with ammonia in methanol. The
spectral and physical properties of this material were in
accordance with those previously reported.18
(8)11 which underwent efficient glycosylation with
methallyl alcohol, in the presence of triphenylphosphine
hydrobromide (TPHB),12 to provide a chromatographi-
cally inseparable mixture of 2-deoxy glycosides (Scheme
2). This mixture was then subjected to Lemieux–John-
son oxidation, which provided the corresponding 2-
oxopropyl glycosides 9 (a:b, 6:1) in high yield. Upon
addition of this mixture of ketones to a solution of
[(trimethylsilyl)diazomethane]lithium in THF at
−78°C,13 insertion proceeded with retention of configu-
ration to provide spiroketal glycosides 10a and 10b in
76% yield, again in a 6:1 ratio. While these compounds
proved to be chromatographically inseparable, brief
exposure to aqueous ammonium chloride triggered the
selective rearrangement of the minor spiroketal
diastereomer 10b to furan 11.14 This alcohol could then
be easily separated by flash chromatography to provide
pure 10a in 65% overall yield from 9.
Our synthesis of KDO (2) began from 2,3,5,6-di-O-iso-
propylidene-
-manno-furanose (15),19 which underwent
D
olefination with the Wittig reagent derived from
(methoxymethyl)triphenylphosphonium chloride to
provide a chromatographically inseparable mixture of
enol ethers (E:Z, 7:3) in excellent yield (Scheme 3).20
Pyrolysis of this material, under reduced pressure in the
presence of catalytic Hg(OAc)2, now gave 16 through
intramolecular vinyl transetherification.21
Ozonolysis of dihydrofuran 10a now gave the expected
keto aldehyde which, because of its instability, was
immediately subjected to a sequence of Pinnick oxida-
tion (NaClO2)15 and methylation (CH2N2) to provide
DAH glycoside 12 in an overall yield of 55% from 10a.
The relative stereochemistry of the anomeric center of
12 was determined using a gated proton decoupled 13C
NMR experiment which revealed a JC-1,H-3ax value of
1.0 Hz that is consistent with the expected a-anomer.16
Scheme 3. Synthesis of KDO (2). Reagents and conditions: (a)
Ph3PCH2(OMe)Cl, t-BuOK, THF, reflux, 4 h, 96%; (b)
Hg(OAc)2 (30 mol%), 110°C, 20 mmHg, 3 h, 60%; (c) methal-
lyl alcohol, TPHB (3 mol%), CH2Cl2, rt, 15 min, 81%; (d)
OsO4 (2 mol%), NaIO4, THF, H2O, rt, 2.5 h, 95%; (e)
Me3SiCLiN2, THF, −78“0°C, 90 min, 65%; (f) (i) O3/O2,
CH2Cl2, −78°C, 5 min, then Zn, AcOH, −78°C“rt, 3 h, (ii)
NaClO2, NaH2PO4·H2O, t-BuOH, 2-methyl-2-butene, rt, 6 h,
(iii) CH2N2, Et2O, 0°C, 2 min, 61% from 18; (g) SmI2, THF,
MeOH, −78°C, 5 min, 81%; (h) (i) AcOH, H2O, 90°C, 50 min,
(ii) NaOH, H2O, rt, 2 h, then Dowex 50W, (iii) NH3, MeOH,
99%.
Scheme 2. Synthesis of DAH (1). Reagents and conditions: (a)
methallyl alcohol, TPHB (3 mol%), CH2Cl2, rt, 15 min, 80%;
(b) OsO4 (2 mol%), NaIO4, THF, H2O, rt, 2.5 h, 95%; (c)
Me3SiCLiN2, THF, −78“0°C, 90 min, then NaHCO3, H2O,
76%; (d) NH4Cl, H2O, rt, 10 min; (e) (i) O3/O2, CH2Cl2,
−78°C,
5 min, then Zn, AcOH, 3 h, (ii) NaClO2,
NaH2PO4·H2O, t-BuOH, 2-methyl-2-butene, 6 h, (iii) CH2N2,
Et2O, 0°C, 2 min, 55% from 10a; (f) SmI2, THF, MeOH,
−78°C, 5 min, 83%; (g) (i) H2 (1 atm), Pd(OH)2/C, MeOH, rt,
3 h, (ii) NaOH, MeOH, H2O, rt, 2 h, then Dowex 50W, 99%.

D. J. Wardrop, W. Zhang / Tetrahedron Letters 43 (2002) 5389–5391
5391
Acid-catalyzed (TPHB) addition of methallyl alcohol to
this glycal proceeded with complete diastereoselectivity
to yield the a-glycoside which, upon oxidative cleavage,
was converted to 2-oxopropyl glycoside 17 in good
overall yield. Exposure of this ketone to [(trimethylsi-
lyl)diazomethane]lithium, as before, now furnished
spiroketal glycoside 18 as a single diastereomer in 65%
yield. Ozonolysis of 18 gave the keto aldehyde, which
was converted to KDO a-glycoside 19 through oxida-
tion (NaClO2) and methylation (CH2N2). Treatment of
this glycoside with SmI2 then furnished hemiacetal 20
as a 5:1 mixture of a and b anomers respectively.22
Chem. 2002, 1, 57–60; (b) Dondoni, A.; Marra, A.;
Merino, P. J. Am. Chem. Soc. 1994, 116, 3324–3336; (c)
Crich, D.; Ritchie, J. J. J. Chem. Soc., Chem. Commun.
1988, 985–986 and references cited therein.
6. For recent syntheses of KDO and listings of earlier
approaches, see: (a) Kumaran, G.; Mootoo, D. R. Tetra-
hedron Lett. 2001, 42, 3783–3785; (b) Reiner, M.;
Schmidt, R. R. Tetrahedron: Asymmetry 2000, 11, 319–
335; (c) Mlynarski, J.; Banaszek, A. Org. Lett. 1999, 1,
1709–1711; (d) Burke, S. D.; Sametz, G. M. Org. Lett.
1999, 1, 71–74; (e) Bra¨uer, N.; Kirschning, A.; Schau-
mann, E. Eur. J. Org. Chem. 1998, 68, 1168–1169 and
references cited therein.
7. For syntheses of KO and its derivatives, see: (a) Sarabia,
F.; Lo´pez-Herrera, F. J. Tetrahedron Lett. 2001, 42,
8801–8804; (b) Wimmer, N.; Brade, H.; Kosma, P. Car-
bohydr. Res. 2000, 329, 549–560.
Removal of the isopropylidene groups and saponifica-
tion of the methyl ester now furnished KDO (1), which
was isolated and characterized as the crystalline ammo-
nium salt 21. A comparison of the spectral and physical
properties of this material with those previously
reported indicated a close match.23
8. For selected approaches to ulosonic acid analogs, see: (a)
Sugisaki, C. H.; Ruland, Y.; Le Clezio, I., Baltas, M.
Synlett 2001, 12, 1905–1908 (DAH); (b) Craig, D.; Pen-
nington, M. W.; Warner, P. Tetrahedron 1999, 55, 13495–
13512 (KDO) and references cited therein.
In summary, we report a novel method for the prepara-
tion of ulosonic acids involving the homologation of
glycals through a sequence of glycosylation, alkylidene-
carbene CꢀH insertion and oxidative cleavage. This
strategy was successfully applied to the synthesis of the
natural products DAH (1) and KDO (2). Furthermore,
compounds 12 and 19 are potential masked DAH and
KDO glycosyl donors; 2-oxopropyl glycosides are read-
ily converted, via Baeyer–Villiger oxidation, to the cor-
9. Wardrop, D. J.; Zhang, W.; Fritz, J. Org. Lett. 2002, 4,
489–492.
10. For reviews covering the [1,5]-CꢀH insertion reaction of
alkylidenecarbenes, see: (a) Kirmse, W. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 1164–1170; (b) Taber, D. F. In
Methods of Organic Chemistry, 4th ed.; Helmchen, G.,
Ed.; Georg Thieme: Stuttgart, 1995; Vol. E21, pp. 1127–
1148; (c) Stang, P. J. Angew. Chem., Int. Ed. Engl. 1992,
31, 274–285.
responding
O-acetoxymethyl
glycosides,
which
Mereyala has recently developed as a novel class of
glycosyl donors.24 Further studies aimed at establishing
this possibility and expanding our synthetic approach
to other ulosonic acids are currently underway.
11. Blackburne, I. D.; Fredericks, P. M.; Guthrie, R. D. Aust
J. Chem. 1976, 29, 381.
12. Bolitt, V.; Mioskowski, C.; Lee, S.-G.; Falck, J. R. J.
Org. Chem. 1990, 55, 5812–5813.
13. Ohira, S.; Okai, K.; Moritani, T. J. Chem. Soc. Chem.
Commun. 1992, 721–722.
Acknowledgements
14. For a recent report that documents the facility with
which 2-alkoxy-2,5-dihydrofurans undergo aromatiza-
tion, see: Walker, L. F.; Bourghida, A.; Connolly, S.;
Wills, M. J. Chem. Soc., Perkin Trans. 1 2002, 965–981.
15. Bal, B. S.; Childers, W. E.; Pinnick, H. W. Tetrahedron
1981, 37, 2091–2096.
We thank the National Institutes of Health (GM59157-
01) and the University of Illinois at Chicago for finan-
cial support. W.Z. thanks the University of Illinois for
a University Graduate Fellowship.
16. Hori, H.; Nakajima, T.; Nishida, Y.; Ohrui, H.; Meguro,
H. Tetrahedron Lett. 1988, 29, 6317–6320.
References
17. Molander, G. A.; Hahn, G. J. Org. Chem. 1986, 51,
1135–1138.
18. Auge´, C; Delest, V. Tetrahedron: Asymmetry 1995, 6,
863–866.
19. Kim, C.; Hoang, R.; Theodorakis, E. A. Org. Lett. 1999,
1, 1295–1297.
20. Duan, J. J.-W.; Kishi, Y. Tetrahedron Lett. 1993, 34,
7541–7544.
21. Newton, R. F.; Wadsworth, A. H. J. Chem. Soc., Perkin
Trans. 1 1982, 823–830.
22. Imoto, M.; Kusumoto, S.; Shiba, T. Tetrahedron Lett.
1987, 28, 6235–6238.
23. Sugai, T.; Shen, G.-J.; Ichikawa, Y.; Wong, C.-H. J. Am.
Chem. Soc. 1993, 115, 413–421.
24. Mereyala, H. B.; Gurrala, S. R. Chem. Lett. 1998, 863–
864.
1. Haslam, E. Shikimic Acid Metabolism and Metabolites;
Wiley: New York, 1993.
2. (a) Unger, F. M. Adv. Carbohydr. Chem. Biochem. 1981,
38, 323–388; (b) Anderson, L.; Unger, F. M., Eds. Bacte-
rial Lipopolysaccharides: Structure, Synthesis, and Biolog-
ical Activities; ACS Symposium Series 231; American
Chemical Society: Washington, DC, 1983.
3. (a) Isshiki, Y.; Kawahara, K.; Zahringer, U. Carbohydr.
Res. 1998, 313, 21–27; (b) Vinogradov, E. V.; Mu¨ller-
Loennies, S.; Petersen, B. O.; Meshkov, S.; Thomas-
Oates, J. E.; Holst, O.; Brade, H. Eur. J. Biochem. 1997,
247, 82–90.
4. Baasov, T.; Tkacz, R.; Sheffer-Dee-Noor, S.; Belakhov,
V. Curr. Org. Chem. 2001, 5, 127–138.
5. For syntheses of DAH and listings of earlier approaches,
see: (a) Reiner, M.; Stolz, F.; Schmidt, R. R. Eur. J. Org.