A New reaction for the direct conversion of 4-azido-4-deoxy-D-galactoside into a 4-deoxy-D-erythro-hexos-3-ulose

Article abstract of DOI:10.1021/ol0499046

A new one-step reaction has been developed for converting 4-azido-4-deoxy-D-galactoside into 4-deoxy-D-erythro-hexos-3-ulose by phosphoramidites and tetrazole. It is proposed that the new reaction proceeds via an intramolecular Staudinger reaction of the

Full text of DOI:10.1021/ol0499046

ORGANIC
LETTERS
2004
Vol. 6, No. 9
1365-1368
A New Reaction for the Direct
Conversion of
4-Azido-4-deoxy-D-galactoside into a
4-Deoxy-D-erythro-hexos-3-ulose
Jie Xue, Jian Wu, and Zhongwu Guo*
Department of Chemistry, Case Western ReserVe UniVersity, 10900 Euclid AVenue,
CleVeland, Ohio 44106-7078
zxg5@case.edu
Received January 15, 2004
ABSTRACT
A new one-step reaction has been developed for converting 4-azido-4-deoxy-D-galactoside into 4-deoxy-D-erythro-hexos-3-ulose by
phosphoramidites and tetrazole. It is proposed that the new reaction proceeds via an intramolecular Staudinger reaction of the phosphite
intermediate and a tetrazole-catalyzed elimination reaction of the resultant phosphorimidate. Tetrazole appears to be playing a unique role by
acting as a bifunctional catalyst to facilitate the elimination reaction.
Various derivatives of 4-deoxy-D-erythro-hexos-3-ulose (1)
are useful intermediates for the chemical synthesis of natural
and unnatural carbohydrate mimetics1-3 and natural products
such as amipurimycin4-6 and miharamycin.7,8 Compound 1
and related species have traditionally been prepared by the
oxidation and deoxygenation of sugars3,4 or by the Diels-
Alder reaction of aldehydes and dienes.6,9 This paper reports
a novel method for preparing a protected form of 1, namely,
methyl 2,6-di-O-benzyl-4-deoxy-R-D-erythro-hexopyranosid-
3-ulose (2), from methyl R-D-glucopyranoside (3). A new
reaction has been invented for removing the azido group and
oxidizing the hydroxyl group of methyl 4-azido-2,6-di-O-
benzyl-4-deoxy-R-D-galactopyranoside (4) in one step to
afford the synthetic target 2. The mild conditions of this new
reaction can circumvent one of the potential problems of
ketosugar synthesis, i.e., enolization (under both acidic and
basic conditions) and the resulting side reactions.
(1) Gijsen, H. J. M.; Qiao, L.; Fitz, W.; Wong, C.-H. Chem. ReV. 1996,
96, 443-473.
Intermediate 4 was prepared from 3 by a series of well-
established transformations as shown in Scheme 1.10 Upon
treatment of 4 with phosphoramidite 10A and tetrazole, 2
was formed in an excellent yield (90%). In an effort to
identify more readily available reagents for this new reaction,
other phosphoramidites were also studied. A moderate to
good yield of 2 (60-70%) was obtained using 10B and 10C,
but 10D gave phosphite 11D (80%) nearly exclusively. The
reaction of 10E was complex, affording a mixture of 2 and
two other products, 12 and 13. It was also observed that 4
initially transformed into the phosphites 11A-E quickly (in
(2) Wang, Y.; Babirad, S. A.; Kishi, Y. J. Org. Chem. 1992, 57, 468-
481.
(3) Yunker, M. B.; Fraser-Reid, B. Can. J. Chem. 1978, 56, 2221-2225.
(4) Rauter, A. P.; Fernandes, A. C.; Czernecki, S.; Valery, J. M. J. Org.
Chem. 1996, 61, 3594-3598.
(5) Czernecki, S.; Franco, S.; Valery, J.-M. J. Org. Chem. 1997, 62,
4845-4847.
(6) Garner, P.; Yoo, J.; Ramakanth, S.; Kennedy, V. O.; Youngs, W. J.
Tetrahedron 1998, 54, 9303-9316.
(7) Rauter, A.; Ferreira, M.; Borges, C.; Duarte, T.; Piedade, F.; Silva,
M.; Santos, H. Carbohydr Res. 2000, 325, 1-15.
(8) Hara, K.; Fujimoto, H.; Sato, K. I.; Hashimoto, H.; Yoshimura, J.
Carbohydr. Res. 1987, 159, 65-79.
(9) Garner, P.; Ramakanth, S. J. Org. Chem. 1986, 51, 2609-2612.
10.1021/ol0499046 CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/26/2004

Scheme 1
Scheme 2a
a A small amount was observed by TLC.
It is a reaction that is accompanied by C-N bond fission
probably through a phosphorimidate or phosphoramidate
intermediate, a reaction that has never been observed
previously. In fact, phosphazo compounds usually undergo
Arbusov-type dealkylation by breaking of one of the C-O
bonds.24
These results differ from those of the literature,16,17 which
report that the reactions between 2-azido alcohols and
phosphites give aziridines as the major products. The
literature also suggests that fission of a C-O bond and
formation of a C-N bond occur concurrently. A major
difference between our reaction and those of the literature
is that we utilized phosphorimidates, rather than phosphites,
with tetrazole as the catalyst.
less than 5 min). While 11A-C converted into ketone 2
smoothly within 5-12 h, the conversion of 11E into ketone
2 was much less efficient; 11D, on the other hand, remained
almost unchanged for more than 2 days. For this transforma-
tion, only reagents 10A-C were of practical value, with 10C
being the most readily available reagent.
To probe the role of the tetrazole (pKa 4.70),25 we
substituted it with a simple acid, i.e., acetic acid (pKa 4.75).
It transpired that under these conditions there was almost
no reaction between 4 and 10C (3 days), which indicated
that tetrazole was not simply serving as an acid.
We also studied the reaction between 4 and trimethyl
phosphite, which we expected would first react with the azide
rather than the hydroxyl group. As expected, the neutral
reaction gave phosphoramidate 15 as the major product (entry
1, Scheme 4) as well as a significant amount of a cyclo-
phosphoramidate 14. Similar results were observed (entries
2 and 3) under basic conditions; however, a hydrolysis
product of 15, namely 16, was obtained when DBU was
employed. When acetic acid was included (entry 4), the
reaction was complex and afforded 14, 15, 17, and 18 and
only a small amount of 2. It was only when the tetrazole
was employed that 2 was obtained as the major product (entry
5).
The initial formation of 11 implied that an intramolecular
Staudinger reaction was occurring at a later step. Though
many Staudinger-type reactions have been devised and
widely used in organic synthesis,11-22 to the best of our
knowledge there have been very few examples of the
intramolecular Staudinger reaction.23
(10) Hanessian, S. PreparatiVe Carbohydrate Chemistry; Marcel Dek-
ker: N. Y., 1997.
(11) Gololobov, Y. G.; Zhmurova, I. N.; Kasukhin, L. F. Tetrahedron
1981, 37, 437-472.
(12) Singh, G.; Zimmer, H. Organomet. Chem. ReV. 1967, 2, 279-298.
(13) Nielsen, J.; Caruthers, M. C. J. Am. Chem. Soc. 1988, 110, 6275-
6276.
(14) Alajarin, M.; Vidal, A.; Lopez-Leonardo, C.; Berna, J.; Ramirez
De Arellano, M. C. Tetrahedron Lett. 1998, 39, 7807-7810.
(15) Saxon, E.; Bertozzi, C. R. Science 2000, 287, 2007-2010.
(16) Saxon, E.; Armstrong, J. I.; Bertozzi, C. R. Org. Lett. 2000, 2, 2141-
2143.
(17) Ittah, Y.; Shahak, I.; Tsaroom, S.; Blum, J. J. Org. Chem. 1978,
43, 4271-4273.
(18) Weitzberg, M.; Aizenshtat, Z.; Jerushalmy, P.; Blum, J. J. Org.
Chem. 1980, 45, 4252-4254.
(19) Taher, A.; Eichenseher, S.; Slawin, A. M. Z.; Tennant, G.; Weaver,
G. W. J. Chem. Soc., Perkin Trans. 1 2002, 1968-1972.
(20) Desamparados, V.; Molina, P.; Fresneda, P. M.; Sanz, M. A.
Tetrahedron 2000, 56, 4079-4084.
Our studies have proven that tetrazole has a special
influence on the reaction course. Moreover, because the
acidity of tetrazole is almost the same as that of acetic acid,
this showed that tetrazole must not merely be acting as a
simple acidic catalyst. Tetrazole is a unique acid, as it
(21) Cadogan, J. I. G.; Stewart, N. J.; Tweddle, N. J. Chem. Commun.
1978, 182-183.
(22) Hassner, A.; Galle, J. E. J. Am. Chem. Soc. 1970, 92, 3733-3739.
1366
Org. Lett., Vol. 6, No. 9, 2004

possesses three quite basic nitrogen atoms. Because of this,
we propose that tetrazole is acting as a bifunctional catalyst
with one of its nitrogen atoms behaving as a nucleophile; it
facilitates the concerted process of elimination. Bifunctional
catalysis is frequently observed in biological systems.26,27
Interestingly, neither the acyclic phosphoramidate 15 nor
the cyclophosphoramidate 14 transformed to 2 upon treat-
ment with tetrazole, acetic acid, or triethylamine. Instead,
they gave rise to the dealkylation product 16. No conversion
of 15 into 14 was observed either. These results suggest that
the engaged reactive intermediates are not phosphoramidates,
a conclusion that is consistent with the literature.17,18
Therefore, this reaction might have involved reactive phos-
phazo intermediates such as phosphazides or phosphor-
imidates before dealkylation.
as a stable intermediate. In the case of 10E, since a methyl
group is small, the reactivity of 10E is increased, and the
intermolecular reaction to form 23 becomes competitive. As
a result, besides the pathway to produce 2, a protonation
and dealkylation process (path a) can give rise to a significant
amount of 13. Meanwhile, elimination reaction followed by
electrophilic addition of tetrazole to the resultant vinyl ether
25 can lead to 12 (path b).
For Scheme 2, as trimethyl phosphite does not react with
alcohols, the Staudinger reaction must be happening first
(Scheme 4). In entries 1-3, 26 is probably reacting through
Scheme 4
Accordingly, we propose that 2 is formed from 11 via an
intramolecular Staudinger reaction followed by elimination
(shown in Scheme 3) and that the Staudinger reaction to form
Scheme 3
phosphorimidate 20 is rate-limiting. Phosphorimidates nor-
mally experience Arbusov-type dealkylation to produce
phosphoramidates,28 but under the influence of tetrazole, a
bifunctional catalyst, a concerted elimination reaction occurs
through 21 to give an enol 22 and its tautomer 2. For 10D,
probably because of steric hindrance, the intramolecular
Staudinger reaction is extremely slow, and 11D is isolated
elimination of a nitrogen molecule to give an imidate 27
(path a). However, in the presence of acid (entry 4)
protonation of 26 might be taking place to form a phos-
phonium intermediate 29 (path b). Product 15 is probably
formed by the Arbusov-type dealkylation on 27 (path c). On
the other hand, intramolecular proton transfer, cyclization,
and dealkylation (path d) most probably give rise to 14.
Similarly, cyclization and deprotonation of 29 followed by
dealkylation of 30 more than likely produces the cyclo-
(23) Tikhonina, N. A.; Gilyarov, V. A.; Kabachnik, M. I. Zh. Obshch.
Khim. 1978, 48, 44-50.
(24) Bhattacharka, A. K.; Thyagarajan, G. Chem. ReV. 1981, 81, 415-
430.
(25) Boraei, A. A. A. J. Chem. Eng. Data 2001, 939-943.
(26) Blow, D. M. Acc. Chem. Res. 1976, 9, 145-152.
(27) Rony, P. R. J. Am. Chem. Soc. 1969, 91, 6090-6096.
Org. Lett., Vol. 6, No. 9, 2004
1367

phosphazide 17. Under the influence of tetrazole, however,
a concerted process (shown in 31) is probably favored and
an elimination reaction affords 2. Alternatively, 2 can be
formed via the phosphorimidate 27, mediated by tetrazole
as shown for 32.
The proposed reaction mechanism for 2 requires an
antiperiplanar orientation of the azido group relative to the
departing proton. In agreement with this, the flexible 1-azido-
3-octadecanoxy-propan-2-ol and an analogue of 4 with an
equatorial azido group did not form the corresponding ketone
products.
zole. Judging by our results, this reaction looks rather like a
pinacol-type rearrangement,29 even though their mechanisms
are different. To the best of our knowledge, there has been
no report of the direct conversion of a 2-azido alcohol to a
ketone, despite the fact that many variations of pinacol
rearrangement, e.g., Demjanov30 and Tiffeneau-Demjanov31
rearrangements of amino alcohols, have been established.
We have also highlighted the unique impact that tetrazole
can have on the Staudinger reaction of 11 and subsequent
transformations. To explain why other simple acids or bases
cannot be used to replace tetrazole, we have proposed that
it might be acting as a bifunctional catalyst, promoting a
concerted reaction process. This is somewhat supported by
the findings that, in addition to being an acidic catalyst,
tetrazole is also a good nucleophile, enabling the formation
of reactive phosphorus tetrazolide intermediates during
nucleotide synthesis.32-34 However, in the literature it is not
clear how tetrazolides are formed. Our results now provide
some hints in regard to this issue.
As a further testament to the unique properties of tetrazole
in the proposed mechanism, we also examined the reaction
between trimethyl phosphite and the fully protected analogue
33 of D-galactose under various conditions (Scheme 5). The
Scheme 5
Because the Staudinger reaction involves several steps and
intermediates,11 its reaction pathways and outcomes can be
easily affected by many factors,35 as shown by our results
as well as those in the literature.17,18,21 The reactions between
phosphoramidites and other 2-azido alcohols are currently
under further investigations, and the results will be reported
in due course.
Acknowledgment. This work was financed in part by
the Research Corporation (Research Innovation Award RI
0663) and a PRF grant (37743-G) from the American
Chemical Society. The authors are also grateful to Dr. S.
Chen and Mr. J. Faulk for MS measurements.
Supporting Information Available: Experimental and
selected NMR spectra of the intermediates and products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
neutral and acetic acid-mediated reactions gave phosphor-
amidate 34 (entries 6 and 7), while the reaction that was
conducted in the presence of tetrazole (entry 8) afforded a
complex mixture consisting of 34 (20%), the elimination
product 35 (11%), and two diastereoisomers of each elimina-
tion-addition product 36 (23%) and 37 (17%). Compounds
36 and 37 were not very stable and gradually decomposed
in NMR tubes. The mechanisms proposed for 12 and 25 in
Scheme 3 can be utilized to explain the elimination and
elimination-addition products of these reactions.
In brief, this paper describes an efficient new procedure
for preparing 2 and a new one-pot reaction for converting
an azido galactoside into a 4-deoxy ketosugar by the reaction
with readily available phosphoramidites 10A-C and tetra-
OL0499046
(28) Bhattacharka, A. K.; Thyagarajan, G. Chem. ReV. 1981, 81, 415-
430.
(29) Berson, J. A. Angew. Chem., Int. Ed. 2002, 41, 4655-4660.
(30) Demjanov, N. J.; Lushnikov, M. J. Russ. Phys. Chem. Soc. 1903,
35, 26-30.
(31) Tiffeneau, M.; Weill, P.; Tchoubar, B. Compt. Rend. 1937, 205,
54-56.
(32) Beaucage, S. L.; Caruthers, M. H. Tetrahedron Lett. 1981, 22, 1859-
1862.
(33) Dahl, B. H.; Nielsen, J.; Dahl, O. Nucleic Acids Res. 1987, 15,
1729-1743.
(34) Hayakawa, Y.; Kataoka, M. J. Am. Chem. Soc. 1997, 119, 11758-
11762.
(35) Shalev, D. E.; Chiacchiera, S. M.; Radkowsky, A. E.; Kosower, E.
M. J. Org. Chem. 1996, 61, 1689-1701.
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