A novel approach towards the stereoselective synthesis of 2-azido-2-deoxy-β-D-mannosides

Article abstract of DOI:10.1016/S0040-4039(01)01880-9

Low temperature mannosylation of glycosyl acceptors under the agency of S-(4-methoxyphenyl) benzenethiosulfinate (MPBT) and trifluoromethanesulfonic anhydride (Tf₂O) with p-methoxyphenyl 2-azido-3-O-benzyl-4,6-O-benzylidene-2-deoxy-1-thio-α-D-

Full text of DOI:10.1016/S0040-4039(01)01880-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8693–8696
A novel approach towards the stereoselective synthesis of
2-azido-2-deoxy-b- -mannosides
D
Remy E. J. N. Litjens, Michiel A. Leeuwenburgh, Gijsbert A. van der Marel and
Jacques H. van Boom*
Leiden Institute of Chemistry, PO Box 9502, 2300 RA Leiden, The Netherlands
Received 24 August 2001; accepted 5 October 2001
Abstract—Low temperature mannosylation of glycosyl acceptors under the agency of S-(4-methoxyphenyl) benzenethiosulfinate
(MPBT) and trifluoromethanesulfonic anhydride (Tf2O) with p-methoxyphenyl 2-azido-3-O-benzyl-4,6-O-benzylidene-2-deoxy-1-
thio-a-
D-mannopyranoside, readily available from D-mannosamine hydrochloride, affords 2-azido-2-deoxy-D-mannosides with
high b-selectivity in good yields. © 2001 Elsevier Science Ltd. All rights reserved.
In 1989, Kulaev et al.1 reported that the bacteriolytic
complex lysoamidase, isolated from a bacterium of the
genus Xanthomonas, is highly efficient in combating
external infectious diseases caused by Gram-positive
bacteria. Structure analysis revealed2 that the high
molecular mass (1300 kDa) acidic polysaccharide 1
with the following trisaccharide repeating unit consti-
tutes the main component of the bacteriolytic enzy-
matic preparation. It was also established3 that the
activity of lysoamidase is significantly stabilized by the
interaction of the bacteriolytic enzymes,4 which only
amount to 2% of the total mass, with the acidic
polysaccharide 1. With the ultimate goal to study in
depth the interaction of the lysoamidase enzymes with
well-defined fragments of the linear polysaccharide 1,
we report here our preliminary results in preparing
dimers containing an orthogonally protected 2-azido-2-
Of the methods thus far developed for the introduction
of the b-ManNAc motif, the use of the 2-(benzoyloxy-
imino)-2-deoxy-a- -arabino-hexapyranosyl bromide 2
D
(see Fig. 1) as a glycosyl donor5,6 proved to be superior,
in terms of easy accessibility and b-selectivity, to the
originally proposed 2-azido-2-deoxy-a-D-mannopyran-
osyl bromides 3a,b.7 On the other hand, the methodol-
ogy involving the a posteriori introduction of the azido
function via SN2-substitution at C-2 in b-linked
glucosides8 was very rewarding in the elaboration of the
b-ManNAc element in the repeating unit of Streptococ-
cus pneumoniae 19F capsular polysaccharide.9,10
Recently, Crich and Sun11 attained a high b:a ratio and
good yield of
D-mannosides by activation of 2,3-di-O-
alkyl-4,6-O-benzylidene-1-thio-a- -mannosides 4a,b at
low temperature with in situ generated phenylsulfenyl
D
deoxy-b-
a progenitor for the b-linked 2-acetamido-2-deoxy-
mannuronic acid (b- -ManpNAcA) unit in 1.
D-mannopyranosyl moiety, which will serve as
D
-
D
Keywords: b-mannosidation; p-methoxyphenyl 2-azido-3-O-benzyl-
4,6-O-benzylidene-2-deoxy-1-thio-a-
polysaccharide.
D
-mannopyranoside;
acidic
* Corresponding author. Tel.: +31 71 5274274; fax: +31 71 5274307;
e-mail: j.boom@chem.leidenuniv.nl
Figure 1.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01880-9

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R. E. J. N. Litjens et al. / Tetrahedron Letters 42 (2001) 8693–8696
triflate (PhSOTf) and subsequent addition of glycosyl
acceptors. The mannosidation protocol could be
improved substantially12 from a practical point of view
using the combination of crystalline and stable S-(4-
methoxyphenyl) benzenethiosulfinate (MPBT) and tri-
fluoromethanesulfonic anhydride (Tf2O), instead of
PhSOTf, in the transformation of donors 4a,b into the
a-mannosyl triflates, which are proposed11–13 to play a
decisive role14 in b-product formation. It was envisaged
that condensation of the similarly protected ethyl-
(phenyl) 2-azido-2-deoxy-1-thio-mannosides 5a,b with
glycosyl acceptors by the latter glycosidation approach
nosamine hydrochloride 6 is presented in Scheme 1. For
example, subjection of 6 to diazo transfer reaction15 and
subsequent acetylation led to fully acetylated derivative
7 as a mixture of anomers. Treatment of 7 with
ethanethiol in the presence of BF3·OEt2 followed by
deacetylation gave ethyl 1-thio-a-D-mannopyranoside
9b. Acetalisation of 9b with benzaldehyde dimethylacetal
under the agency of HBF4·OMe2 afforded, after benzy-
lation, ethylthio donor 5b in an overall yield of 50% based
on 6.
In the first instance, phenylthio donor 5a in dry CH2Cl2
was activated for 5 min at −60°C with MBPT/Tf2O in
the presence of 2,6-di-tert-butylpyridine (DTBMP).
would give access to 2-azido-2-deoxy-b-D-mannosides.
The synthesis of the requisite thiomannosides 5a,b via a
Addition of diacetone-
mixture, after additional stirring for 10 min at −60°C,
D
-galactose 11 and analysis of the
six-step sequence from commercially available
D-man-
NH2.HCl
O
N3
O
iii or iv
or v
N3
O
HO
HO
HO
i, ii
AcO
AcO
AcO
AcO
AcO
AcO
OH
OAc
SR
6
7
8a,b,e
a: R=Ph
b: R=Et
e: R=p-OMePh
vi
N3
O
N3
O
HO
HO
HO
O
Ph
viii
vii
O
5a,b,e
HO
SR
SR
10a,b,e
9a,b,e
Scheme 1. Reagents and conditions: (i) TfN3, K2CO3, CuSO4 (cat.), H2O, MeOH, CH2Cl2; (ii) Ac2O, DMAP (cat.), pyridine, 7:
88% (two steps); (iii) EtSH, BF3·OEt2, CH2Cl2, 35°C, 8a: 55%; (iv) PhSH, BF3·OEt2, CH2Cl2, 35°C, 8b: 70%; (v) p-OMePhSH,
BF3·OEt2, CH2Cl2, 35°C, 8e: 59%; (vi) KOtBu, MeOH, 9a/b/e: quant.; (vii) PhCH(OMe)2, HBF4·OMe2, DMF, 10a: 88%, 10b:
91%, 10e: 88%; (viii) BnBr, NaH, DMF, 5a: 96%, 5b: 90%, 5e: 97%.
Table 1. Mannopyranoside formation of 4,6-O-benzylidene protected donor 5e with acceptors 11 to 14

R. E. J. N. Litjens et al. / Tetrahedron Letters 42 (2001) 8693–8696
8695
Acknowledgements
revealed the presence of starting materials and no
trace of the expected coupling products. Moreover,
executing the activation step at higher temperatures
(−60“−20°C) or prolonged reaction times was also not
successful. In addition, glycosidation at temperatures
above −20°C led to intractable mixtures of products.
Similar results were also obtained in subjecting the
ethylthio donor 5b to the same glycosidation
conditions.
The authors thank Fons Lefeber and Cees Erkelens for
recording the NMR spectra and Hans van den Elst for
performing the mass spectrometric analyses.
References
1. Kulaev, I. S.; Severin, A. I.; Stepnaya, O. A.; Kruglaya,
O. V. Biokhimiya 1989, 54, 201.
2. Likhosherstov, L. M.; Senchenkova, S. N.; Knirel, Y. A.;
Shashkov, A. S.; Shibaev, V. N.; Stepnaya, O. A.;
Kulaev, I. S. FEBS Lett. 1995, 368, 113.
The failure of activating donors 5a,b at low tempera-
ture can be explained16 by taking into consideration
that the nucleophilicity of the sulfur atom at the
anomeric center will be decreased due to the electron
withdrawing effect of the 2-azido group.17 It was there-
fore, envisaged that replacement of the anomeric func-
tions in 5a,b by the more electron donating
p-methoxyphenylthio group would have a beneficial
effect on the activation step. Indeed, it turned out that
activation of donor 5e,18 prepared in a similar fashion
as 5a,b (Scheme 1), for 15 min at −35°C followed by the
3. Stepnaya, O. A.; Severin, A. I.; Kulaev, I. S. Biokhimiya
1986, 51, 1117.
4. Stepnaya, O. A.; Ledova, L. A.; Kulaev, I. S. Bio-chem-
istry (Moscow) 1993, 58, 1523.
5. Kaji, E.; Lichtenthaler, F. W.; Nishino, T.; Yamane, A.;
Zen, S. Bull. Chem. Soc. Jpn. 1988, 61, 1291.
6. Kaji, E.; Lichtenthaler, F. W.; Osa, Y.; Takahashi, K.;
Zen, S. Bull. Chem. Soc. Jpn. 1995, 68, 2401.
7. Paulsen, H.; Lorentzen, J. P. Carbohydr. Res. 1984, 133,
C1.
8. Sato, K.-I.; Yoshimoto, A. Chem. Lett. 1995, 39.
9. Nilsson, M.; Norberg, T. J. Chem. Soc., Perkin Trans. 1
1998, 1699.
addition at −60°C of diacetone- -galactose 11, led to
D
the expected disaccharide 15 (entry 1 in Table 1)19 as a
mixture of anomers in good yield within 10 min. The
stereochemistry of the mannosidic bond in the resulting
individual anomers was firmly ascertained20 on the
basis of the C1ꢀH1 heteronuclear one-bond coupling
constants (1JC1,H1). An increase of b-selectivity was
observed (entry 2) in the glycosylation of methyl 2,3,4-
O-benzoyl-glucopyranoside 12 with 5e. On the other
hand, condensation of 5e (entry 3) with the relatively
more inert primary alcoholic function in the sphin-
gosine derivative 13 led to the exclusive formation,
although in moderate yield, of the 2-azido-2-deoxy-b-
mannoside 17. A similar result was observed (entry 4)
in the glycosidation of 5e with the secondary hydroxyl
group in acceptor 14. At this stage, it is also of interest
to note that the stereochemistry and yield of the man-
nosidations summarized in Table 1 do not deviate
substantially from those observed earlier by Crich and
10. Bousquet, E.; Khitri, M.; Lay, L.; Nicotra, F.; Panza, L.;
Russo, G. Carbohydr. Res. 1998, 311, 171.
11. Crich, D.; Sun, S. Tetrahedron 1998, 54, 8321.
12. Crich, D.; Smith, M. Org. Lett. 2000, 25, 4067.
13. Crich, D.; Sun, S. J. Am. Chem. Soc. 1997, 119, 11217.
14. In a recent comparative study (see Ref. 21) towards the
b-selective low temperature glycosidation of 4,6-O-ben-
zylidene protected mannopyranosyl trichloroacet-imidate
4d and the similarly protected a-D-mannopyranosyl S-
ethyl sulfoxide, a twist-boat type intermediate was pro-
posed as the glycosylating species. This intermediate was
believed, for stereo-electronic and steric reasons, to favor
b-product formation.
15. Alper, P. B.; Hung, S.-C.; Wong, C.-H. Tetrahedron Lett.
1996, 37, 6029.
Smith using the corresponding a- -thiomannoside 4b
D
as donor. However, the b-selectivity of the condensa-
tion of 5e with acceptor 12 (entry 2) is less pronounced
in comparison with the nearly exclusive formation of
the b-mannoside resulting from the coupling of the
corresponding partially acetylated glucose acceptor
16. Zuurmond, H. M.; Van der Laan, S. C.; Van der Marel,
G. A.; Van Boom, J. H. Carbohydr. Res. 1991, 215, C1.
17. Biffin, M. E. C.; Miller, J.; Paul, D. B. In The Chemistry
of the Azido Group; Patai, S., Ed.; John Wiley & Sons,
1971; p. 205.
with phenyl a- -thio-mannoside 4b.
D
1
18. All new compounds were fully characterized by H, 13C
1
NMR and MS. Relevant data of donor 5e: H NMR lH
In conclusion, the results thus far obtained indicate that
the readily accessible and orthogonally protected p-
(200 MHz, CDCl3): 7.58–7.30 (m, 12H), 6.86 (d, 2H, J
6.5 Hz), 5.63 (s, 1H), 5.26 (bs, 1H), 4.82 (AB, 2H), 4.35
(m, 1H), 4.20 (m, 4H), 3.82 (t, 1H, J 10.2 Hz), 3.77 (s,
3H). 13C NMR lC (50.1 MHz, CDCl3): 160.19, 137.93,
137.51, 135.14, 129.01, 128.53, 128.26, 127.89, 127.65,
126.19, 122.77, 114.94, 101.60, 87.89, 79.25, 75.88, 73.34,
68.30, 65.03, 63.88, 55.23. MS (ESI): m/z=528.4 (M+
Na)+.
methoxy-phenyl 2-azido-2-deoxy-a- -mannoside 5e
D
shows promise in the construction of the (1“3) cis-
linked ManpNAcA structural element of the target
molecule 1. Moreover, in analogy with the earlier
observed high b-mannoselectivity of the ethyl(phenyl)
sulfoxide11 4c and trichloroacetimidate21 4d donors, it
would also be of interest to examine the disarming
effect of the 2-azido group on the low temperature
activation of the corresponding 2-azido-2-deoxy donors
5c and 5d. Both aspects are currently under investiga-
tion and will be reported in due course.
19. General experimental procedure for the preparation of
2-azido-2-deoxy-D-mannosides 15–18: To a stirred solu-
tion of thiomannoside 5e (0.20 mmol), MPBT (66 mg,
0.25 mmol), DTBMP (102 mg, 0.5 mmol) and activated 3
,
A powdered molecular sieves in anhydrous dichloro-

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R. E. J. N. Litjens et al. / Tetrahedron Letters 42 (2001) 8693–8696
methane (2.5 mL) at −35°C under argon was added Tf2O
lowed by brine, dried (Na2SO4) and concentrated under
reduced pressure. The anomers where then separated, if
appropriate, by silica gel chromatography (ethyl acetate/
toluene).
(70 mL; 0.4 mmol). After 15 min, the reaction mixture
was cooled down to −60°C and subsequently a solution
of the glycosyl acceptor (0.40 mmol) in anhydrous
dichloromethane (2 mL) was added dropwise. The reac-
tion mixture was stirred for 10 min at −60°C and then
quenched with methanol, warmed to room temperature,
filtered, washed with saturated aqueous NaHCO3, fol-
20. Bock, K.; Pedersen, C. J. Chem. Soc., Perkin Trans. 2
1974, 293.
21. Weingart, R.; Schmidt, R. R. Tetrahedron Lett. 2000, 41,
8753.