Concise and stereocontrolled syntheses of phosphonate C-glycoside analogues of β-D-ManNAc and β-D-GlcNAc 1-O-phosphates

Article abstract of DOI:10.1016/j.tetlet.2003.12.081

Diethyl C-(2-deoxy-2-acetamido-β-D-mannopyranosyl)methylphosphonate and dimethyl C-(2-deoxy-2-acetamido-β-D-glucopyranosyl)methylphosphonate were stereoselectively prepared from N-acetyl D-glucosamine. Routes to such compounds starting from D-GlcNAc have

Full text of DOI:10.1016/j.tetlet.2003.12.081

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1773–1775
Concise and stereocontrolled syntheses of phosphonate C-glycoside
analogues of b- -ManNAc and b-
-GlcNAc 1-O-phosphatesq
D
D
Xianghui Wen and Philip G. Hultin*
Department of Chemistry, The University of Manitoba, Winnipeg, MB, Canada R3T 2N2
Received 3 November 2003; revised 10 December 2003; accepted 12 December 2003
Abstract—Diethyl C-(2-deoxy-2-acetamido-b-
glucopyranosyl)methylphosphonate were stereoselectively prepared from N-acetyl
starting from -GlcNAc have been problematic, but we have found short and efficient implementations of this highly desirable
transformation.
D
-mannopyranosyl)methylphosphonate and dimethyl C-(2-deoxy-2-acetamido-b-
D-
D
-glucosamine. Routes to such compounds
D
Ó 2003 Elsevier Ltd. All rights reserved.
C-Glycosyl analogues of sugar 1-O-phosphates have
recently attracted attention due to their potential as
glycosyltransferase inhibitors.1 Convenient routes to
syntheses of analogues 1 and 2, of N-acetyl b-
D
-man-
D-glucosamine 1-O-phos-
nosamine- and N-acetyl b-
phates.9 We have found particularly concise and
attractive routes, beginning from well-known, simple,
and readily-made derivatives of D-GlcNAc.
C-glycosyl analogues of N-acetyl
D-mannosamine 1-O-
phosphate and N-acetyl -glucosamine 1-O-phosphate
D
are particularly desirable2 because carbohydrate
phosphates are key intermediates in the assembly of
oligo- and polysaccharides in bacteria and higher
organisms.
Although many routes to C-glycosides exist, few are
applicable to the preparation of 2-deoxy-2-acetamido
b-C-glycosides.3–8 Even less has been reported on the
preparation of 2-deoxy-2-acetamido C-glycosylphospho-
nates. In fact, the difficulties associated with the
2-acetamido group have induced most researchers to
employ other hexose or pentose starting materials, and
to install the acetamido group after the key C–C bond
forming reaction. Such approaches have typically
entailed many steps and low overall yields.2a–c
The synthesis of D-mannosyl analogue 1 started from N-
acetyl glucosamine derivative 310 (Scheme 1). Treatment
of compound 3 with (EtO)2P(O)CHLiP(O)(OEt)2 in the
presence of ZnBr2 gave a,b-unsaturated phosphonate 4
in good yield. In the absence of ZnBr2, a compound
identified by NMR as 811 was obtained instead, pre-
sumably from retro-aldol reaction of 3 followed by a
Wittig reaction. This was caused by the stronger basicity
of the lithium diphosphonate compared to the zinc
diphosphonate. Similar retro-aldol/Wittig products have
been observed when reducing sugars were treated with
nonstabilized ylides.12
Given the availability and low cost of N-acetyl-D-glu-
cosamine, we were convinced that expeditious routes
directly from this inexpensive material could be devised,
and this has proven to be the case. Here we report the
Compound 4 underwent Michael cyclization upon
treatment with K2CO3/EtOH, to give the b-C-manno-
pyranosyl product 7. We noted that 5 was formed first,
and could in fact be recovered in impure form from
incomplete reactions. Intermediate 5 disappeared over
time with concurrent formation of 7, presumably via the
Keywords: GlcNAc phosphate; ManNAc phosphate; Amino C-glyco-
sides; Amino C-glycosylphosphonates.
q Supplementary data associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2003.12.081
* Corresponding author. Tel.: +1-204-474-9814; fax: +204-474-7608;
e-mail: hultin@cc.umanitoba.ca
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.12.081

1774
X. Wen, P. G. Hultin / Tetrahedron Letters 45 (2004) 1773–1775
Scheme 1. Reagents and conditions: (i) BuLi, ZnBr2 (3 equiv), (EtO)2P(O)CH2P(O)(OEt)2 (6 equiv), THF, )78 °C to rt, 2 h, 85%; (ii) K2CO3, EtOH,
overnight; (iii) 80% HOAc, 80 °C, 1 h, 60% over the last two steps.
intermediate 6. We were unable to detect 6. More
strongly basic conditions (KOt-Bu/THF, EtONa/EtOH,
or NaOH/EtOH) gave low yields of the desired product.
Acid hydrolysis of the benzylidene protecting group in 7
afford 10a. We have not optimized the oxidation of 9,
but we note the possibility that either 10a or 10b might
be obtained by optimal choice of reaction conditions.
furnished the
D
-manno analogue 113 in 60% yield from 4.
Deoxygenation of compound 10 also turned out to be
problematic. Attempted reduction using Zn/HOAc,
NaBH4/TFA, or SmI2/Ac2O/THF failed to produce any
significant amount of 11. Attempts to convert 10a to an
olefin by treatment of its mesylate derivative with DBN
were also unsuccessful. Finally, 10a was converted to the
xanthate, which was reduced by Bu3SnH to give the
desired product 11 in 46% yield from 10a.
The origin of the manno-stereoselectivity in the trans-
formation of 4 to 7 is unclear. There is literature prec-
edent for the formation of both cyclic and acyclic
ManNAc products from the olefination of GlcNAc
derivatives.14 However, calculations and equilibration
studies by Davis and co-workers14b confirm that b-Glc-
NAc-C-pyranosides are the thermodynamically favored
ring forms. We attempted to rationalize the apparent
preference for 6 over 4 using molecular mechanics, but
the results of these preliminary calculations were not
illuminating.
The strategy shown in Scheme 2 suffered from the low
yield of the deoxygenation step, as well as the fact that
starting compound 9 required several steps to prepare
from N-acetyl glucosamine.2e Therefore, we decided to
pursue a more efficient synthetic route.
Our initial approach to the synthesis of
D-gluco ana-
logue 2 began with the known alcohol 92e (Scheme 2).
Swern oxidation of 9 afforded two aldehydes in a 5:1
ratio (as judged by TLC and NMR). The addition of
(EtO)2POLi to the crude aldehydes gave hydroxy
phosphonate 10a in 66% yield, along with 13% of an
isomeric product that appeared by NMR to be 10b
(both were single diastereomers at C-1, but the stereo-
chemistry at this center was not identified). C-Glycosidic
aldehydes may be epimerized under the basic conditions
of the Swern oxidation, favoring an equatorial orienta-
tion.15 Arbuzov-type addition to this isomer would
Our preferred route to 2 is shown in Scheme 3. The
synthesis started from lactone 12,16 available from
D-
GlcNAc in three simple steps. Addition of
(MeO)2POCH2Li to 12 generated b-hydroxy phospho-
nate 13 in excellent yield. Direct reductive deoxygenation
of compound 13 also proved to be difficult. Attempted
reductions with Et3SiH/BF3ÆEt2O, Et3SiH/TFA, Et3SiH/
TMSOTf, Ph3SiH/Et2AlCl, and NaBH4/TFA did not
afford 2. However, when compound 13 was treated with
Ac2O/NaOAc at 100 °C, olefin 1417 could be obtained in
good yield. Other elimination conditions (oxalyl chlo-
Scheme 2. Reagents and conditions: (i) Oxalyl chloride, DMSO, Et3N,
CH2Cl2, )78 °C to rt, 30 min; (ii) HOP(OEt)2, BuLi, THF, )78 °C to
rt, 2.5 h, 66% of 10a+13% of 10b; (iii) CS2, NaH, MeI, THF, rt,
overnight; (iv) Bu3SnH, AIBN, toluene, 80 °C, 20 min, 46% over the
last two steps.
Scheme 3. Reagents and conditions: (i) (MeO)2POCH2Li, THF,
)78 °C, 96%; (ii) Ac2O, AcONa, 100 °C, 70%; (iii) H2 (g), Pd/C, HOAc,
quant.

X. Wen, P. G. Hultin / Tetrahedron Letters 45 (2004) 1773–1775
1775
8. Xie, J.; Molina, A.; Czernecki, S. J. Carbohydr. Chem.
1999, 18, 481–498.
ride/pyridine, SOCl2/pyridine, POCl3/pyridine) only
afforded complex mixtures. Hydrogenation of olefin 14
quantitatively furnished the product 2. Efficient methods
for the conversion of C-glycosylphosphonate diesters
similar to 1 and 2 to the corresponding phosphonate
monoesters or phosphonic acids have been reported.18
9. For the a C-glycosyl analogues of N-acetyl mannosamine
and N-acetyl glucosamine 1-O-phosphates, see Ref. 2b.
10. Holmquist, L. Acta Chem. Scand. 1970, 24, 173–178.
11. Compound 8 was obtained under a variety of reaction
conditions. It was identified as diethyl (3S,4R)-3,5-O-
benzylidene-4-hydroxy-(E)-1-pentene-1-phosphonate from
the following data, supported by DEPT, COSY, HSQC,
We have established completely stereoselective and
highly efficient routes to the b C-glycosyl analogues of
N-acetyl mannosamine 1-O-phosphate and N-acetyl
glucosamine 1-O-phosphate, starting from well-known
and readily prepared derivatives of the inexpensive
and NOE experiments: ½aꢀ )54.5° (c 1.05, CH2Cl2); 1H
D
NMR (300 MHz, CDCl3): d 1.33 (dt, 6H, J ¼ 0:8 and 7.1),
3.62 (dddd, 1H, J ¼ 10:1, 4.1, 5.0, and 8.8, H-4), 3.68 (dd,
1H, J ¼ 10:1 and 10.1, H-5), 4.00–4.14 (m, 4H), 4.23 (dd,
1H, J ¼ 8:8, 3.2, and 2.0, H-3), 4.32 (dd, 1H, J ¼ 10:1 and
4.1, H-5), 5.44 (d, 1H, J ¼ 5:0, OH), 5.58 (s, 1H), 6.11
(ddd, 1H, J ¼ 21:6, 17.2, and 2.0, H-1), 7.26 (ddd, 1H,
J ¼ 3:2, 17.2, and 23.3, H-2), 7.34–7.57 (m, 5H); 13C
NMR (75.5 MHz, CDCl3) d 16.64 (d, J ¼ 6:5), 62.44 (d,
J ¼ 5:6), 62.46 (d, J ¼ 5:5), 65.36 (d, J ¼ 1:9), 72.00 (s),
81.36 (d, J ¼ 20:5), 101.10 (s), 116.36 (d, J ¼ 188:9),
149.99 (d, J ¼ 6:7); 31P NMR (121.5 MHz, CDCl3): d
20.41; ESI-MS (m/z): 343.34.
D
-GlcNAc. These are not only useful as structural
components of potential glycosyltransferase inhibitors,
but they may also serve as precursors to more elaborate
2-amino b-C-glycosides via Horner–Emmons reaction
of the phosphonate groups.
Supplementary data. Experimental procedures and
spectroscopic data for compounds 1, 2, 4, 10a, 11, 13,
and 14. The supplementary data are available online
with the paper in ScienceDirect.
12. Giannis, A.; Munster, P.; Sandhoff, K.; Steglich, W.
Tetrahedron 1988, 44, 7177–7180.
13. Compound 1 was obtained as a glassy solid. Its config-
uration was confirmed by NOE correlations between
0 0
0 0 0 0
NH–H4 , H1–H4 , H1 –H2 , and H1 –H3 .
H
Acknowledgements
This work was supported by a Discovery Grant from the
Natural Sciences and Engineering Research Council of
Canada (NSERC). We also thank Dr. Kirk Marat for
his assistance in obtaining NMR spectra.
References and notes
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