One-Step TEMPO-Catalyzed and Water-Mediated Stereoselective Conversion of Glycals into 2-Azido-2-deoxysugars with a PIFA-Trimethylsilyl Azide Reagent System

Article abstract of DOI:10.1021/acs.orglett.8b00814

An unprecedented water-mediated and TEMPO-catalyzed, one-step, highly regiospecific and stereoselective functionalization of glycals to 2-azido-2-deoxysugars has been developed using a PIFA-Me₃SiN₃ reagent system in the presence of B

Full text of DOI:10.1021/acs.orglett.8b00814

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
One-Step TEMPO-Catalyzed and Water-Mediated Stereoselective
Conversion of Glycals into 2‑Azido-2-deoxysugars with a PIFA−
Trimethylsilyl Azide Reagent System
Ande Chennaiah and Yashwant D. Vankar*
Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur 208016, India
S
* Supporting Information
ABSTRACT: An unprecedented water-mediated and TEMPO-catalyzed,
one-step, highly regiospecific and stereoselective functionalization of glycals
to 2-azido-2-deoxysugars has been developed using a PIFA−Me3SiN3 reagent
system in the presence of Bu4NHSO4 as a phase-transfer catalyst. The method
is metal-free, proceeds under mild reaction conditions, and tolerates a variety
of protecting groups. Using this method, the synthesis of an important
trisaccharide unit bound by the monoclonal anti-I Ma antibody has also been
demonstrated.
Scheme 1. Literature Methods and Present Work for the
Synthesis of 2-Azido-2-deoxysugars
he biological importance of complex carbohydrates
1
Tpresent in living cells is now very well-known.
To
understand their precise biological roles, they must be procured
in pure forms and in large amounts by synthetic means.2
Glycoconjugates such as glycoproteins,3 glycosaminoglycans,4
TN-antigen, and T-antigen5 contain a 2-amino-2-deoxysugar
moiety. Although commercially available glucosamine and
galactosamine are used in the synthesis of these glycoconju-
gates, methods to procure differently protected 2-amino-2-
deoxysugar moieties have been introduced in the literature to
ensure alternatives in such synthetic pursuits. However, the
neighboring group participating nature of 2-acetamido-2-
deoxysugars limits their utility in obtaining 1,2-trans-glycosides
only,6 and the corresponding 1,2-cis-glycosides need to be
procured in different ways. In this regard, glycal-based
methodologies involving sulfonamidoglycosylation developed
by Danishefsky7a,b and cycloaddition of an azodicarboxylate
reported by Leblanc7c,d are useful.
More importantly, installation of an azide moiety at the C-2
position as a source of an amino group has proven to be an
excellent method to circumvent the problem of procuring1,2-
cis-glycosides. One of the most powerful approaches to
introduce an azide group at the C-2 of a glycal is the
azidonitration protocol developed by Lemieux8a,b (Scheme 1).
This involves reacting glycals with ceric ammonium nitrate
(CAN) and sodium azide in acetonitrile leading to 2-azido-2-
deoxyglycosyl nitrates as the major products with an azide
radical initiating the attack at C-2 and the nitrate group
attaching at the anomeric center. The anomeric nitrate, thus
formed, is then converted into a leaving group such as an
−OAc, halogen, or −OH group to allow glycosylations to give
oligosaccharides. This reaction protocol to arrive at 2-azido-2-
deoxyglycosyl nitrates from glycals, although very popular,
demands vigorously anhydrous conditions. Subsequent to this,
other procedures of glycal functionalization have also been
developed that include azidophenylselenation9a,b and azido-
chlorination.9c,d Another method involving diazo transfer to
glycosamine, developed by Vasella et al.,10 to afford 2-azido-2-
deoxysugars has also been useful (Scheme 1).
Among these, 2-azido-2-deoxysugars are ideal precursors for
oligosaccharide synthesis since the hydroxy group at the
anomeric center can readily be converted into a leaving group
such as a trichloroacetimidate or a thioglycoside, among others.
However, this transformation from glycals (or glycosamines) is
generally accomplished in two or three steps11 (Scheme 1).
Received: March 13, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00814
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
We have had a long-standing interest in the functionalization
of glycals and their application in the synthesis of a variety of
carbohydrate derivatives.12 As a continued activity, we recently
reported13 a one-step method for the conversion of glycals into
a mixture of 1-azido-2-acetoxy sugars and 2-azido-1-acetoxy
sugars upon treatment with phenyliodine diacetate (PIDA) and
TMSN3 in the presence of 30 mol % of TMSOTf, with the
latter being the major products. However, since the formation
of 2-azido sugars was accompanied by the formation of 1-azido-
2-acetoxy sugars, we sought to develop a new protocol that
selectively gives 2-azido-2-deoxysugars in one step. In this
context, a systematic study by Magnus14a,b for direct α- and β-
azido functionalization of triisopropylsilyl enol ethers using
TEMPO in combination with PhIO and TMSN3, involving an
azide radical, is noteworthy. More recently, the formation of an
azide radical is also proposed in the reaction of PIFA and
TMSN3 in other organic transformations.14c In view of these
literature reports and our own experience (vide supra)13 of
using such reagent combinations in glycal functionalizations, we
decided to revisit the reaction of glycals and find an alternate
route to introduce an azido moiety exclusively at C-2. We had
anticipated that the azide radical, if formed, would add on to
glycals at C-2, generating a radical at the anomeric center which
could either (i) react with another azide radical to give a 1,2-
diazide or (ii) undergo oxidation with PIFA, leading to an
oxonium ion, which can be trapped by a nucleophile to give the
corresponding 2-azido-2-deoxyglycosides. In this paper, we
report the results of our study wherein we have found that
glycals react with a combination of PIFA, TMSN3, and
TEMPO, along with water, as a nucleophile, in the presence
of Bu4NHSO4 as a phase-transfer catalyst, leading to 2-azido-2-
deoxysugars in one step.
conditions, we examined the scope of this reaction with
differently protected glycal derivatives. Accordingly, glucals and
galactals having different protecting groups such as acetyl,
benzyl, silyl, benzoyl, methyl, and MOM were smoothly
converted to the corresponding 2-azido-2-deoxysugars in
moderate to good yields, as summarized in Table 1.
Furthermore, we found that the acid-sensitive benzylidene
protecting group in 25 and 27 survived the reaction conditions.
Table 1. Substrate Scope for the Conversion of Glycals into
2-Azido-2-deoxysugars
In our initial studies, tri-O-acetyl-D-galactal 1 was reacted
with 1 equiv of PIFA, 1 equiv of TMSN3 and 0.1 equiv of
TEMPO at −30 °C in CH2Cl2, but no product formation was
noticed by TLC analysis. However, the reaction mixture, on
aqueous work-up, led to the formation of a small amount of 2-
azido-2-deoxygalactose 2. We surmised that it is quite likely
that the trace amount of moisture may have acted as a
nucleophile on the carbocation formed at the anomeric center,
as per the expected second alternative mentioned above. If
indeed water does act as a nucleophile, it is possible that if we
deliberately used water as a reactant it might result in a better
yield of 2. Therefore, we used 1 equiv of water under the same
reaction conditions as above at 0 °C and observed an increased
(∼18%) formation of the azido alcohol 2, along with recovered
starting material. This strongly suggested the involvement of a
carbocation at the anomeric center. In order to further increase
the yield of the product, an extensive screening was done (see
the Supporting Information) with respect to the amount of
TMSN3, PIFA, and TEMPO, along with use of Bu4NHSO4 as a
phase-transfer catalyst for increasing the solubility and thus
reactivity of water. Accordingly, it led us to realize that the ideal
reaction conditions used 2 equiv of PIFA, 3 equiv of TMSN3,
0.2 equiv of TEMPO, 0.2 equiv of Bu4NHSO4, and 50 equiv of
water, which gave 80% yield of 2 in about 35 min. To the best
of our knowledge, this is the first report of a one-step
conversion of glycals into 2-azido-2-deoxysugars. It is note-
worthy that other hypervalent iodine reagents such as PIDA
and PhIO were found to be ineffective in this reaction.
a
Approximately 5% of the corresponding enone formation was
b
observed. Isolated yields.
It is important to note that glucal derivatives did not lead to
any manno-configured product which is generally a problem
associated with the azidonitration method of Lemieux.
Seeberger et al.8b have provided a very useful and practical
solution to this problem by protecting C-4 and C-6 hydroxyl
groups of glucals as cyclic acetals viz. isopropylidines or
benzylidenes whereby the formation of a manno-configured
product is considerably reduced. On the other hand, the
present method is simple in that it does not give any amount of
the manno-configured product and directly leads to 2-azido-2-
deoxysugars. Further, acetyl- as well as benzyl-protected D-
arabinals 29 and 31 and D-xylals 33 and 35 also underwent
smooth conversion to the corresponding 2-azido-1-hydrox-
ysugars (Table 1), thus enhancing the scope of the present
methodology. It is noteworthy that the arabinal-derived
Apart from CH2Cl2, when the reaction was carried out in
solvents such as DMF, THF, and toluene, no product
formation was observed. Having established the reaction
1
products 30 and 32 were found to have C4 conformations
with the azide moiety at C-2 being equatorially oriented. The
B
DOI: 10.1021/acs.orglett.8b00814
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
present reaction conditions were also successfully applied to the
lactose-derived disaccharide glycals 37 and 39, and the
corresponding 2-azido-2-deoxy lactose derivatives 38 and 40
were obtained without affecting the glycosidic linkages.
reacts with the oxonium ion to form the observed 2-azido-2-
deoxysugars.
We have made use of the current methodology in the
synthesis (Scheme 3) of the trisaccharide unit 54 bound by the
To define the scope of this transformation, we performed the
reaction on up to 5 g scale with tri-O-acetyl-D-galactal 1, tri-O-
benzyl-D-glucal 13, and peracetylated lactal 37 ,and the
corresponding products 2, 14, and 38 were obtained without
much difference in the isolated yields. A small amount (∼5%)
of the unreacted starting material, however, was recovered even
when additional amounts of reagents were employed. Never-
theless, the reactions were very clean and high-yielding on large
scale also and led to easy isolation of the products.15
Scheme 3. Synthesis of the Trisaccharide 54 from Lactal-
Derived 2-Azido-2-deoxysugar 38
The absolute stereochemistry of compounds 16, 24, 30, and
34 was proven by single-crystal X-ray analysis. Additionally, the
azido alcohols 2 and 12 were converted to the corresponding
known tert-butyldiphenylsilyl (TBDPS) derivatives 4116b and
42,16c and the azido alcohol 14 was oxidized to the lactone
4316a,d whose spectral data matched well with the literature
values. It is therefore clear that with excellent stereoselectivity
with respect to the azide group at C-2, and regiospecificity with
respect to −N3 and −OH groups, the current protocol appears
to be the best choice to procure 2-azido-2-deoxysugars from the
corresponding glycals in one step. Besides water, the only other
nucleophile added at the anomeric center was methanol, and
the anomeric products 4416a and 4516a were formed. Further,
when acetonitrile was used as a solvent, the corresponding N-
acetamido-3,4,6-tri-O-acetyl-2-azido-2-deoxy-α-D-galactopyra-
nosylamine 4616a,17 was formed upon reaction of the
carbocation at the anomeric center with acetonitrile.
monoclonal anti-I Ma antibody18 for which, surprisingly, there
is only one report in the literature.19 Thus, the 2-azido-2-
deoxysugar 38 derived from peracetylated lactal 37 (entry 19,
Table 1) was subjected to −OTBDPS protection to afford the
β-anomer 47. Compound 47 was then reduced20 with Zn/
AcOH/Ac2O to form compound 48 in 82% yield which, upon
deprotection of the −OTBDPS group with TBAF/AcOH16a
led to product 49. The corresponding trichloroacetimidate 50,
readily prepared by following a literature procedure,21 was first
converted into the oxazoline 51upon treatment with TMSOTf.
This oxazoline intermediate 51 smoothly reacted as a glycosyl
donor with 52 under Yb(OTf)3 catalysis23 to form the
trisaccharide 5324 which was deprotected25 to form 54.18
Formation of the oxazoline intermediate 5122 additionally
confirms the stereochemistry of the α-azide group addition at
C-2 of the peracetylated lactal.
On the basis of this data, a plausible mechanism for the
formation of 2-azido-2-deoxysugars is shown in Scheme 2.
Scheme 2. Proposed Mechanism for the Formation of 2-
Azido-2-deoxysugars
In conclusion, we have developed a new metal-free protocol
for one-step highly regisospecific (with respect to −N3 and
−OH groups) and stereoselective (in terms of azide moiety at
C-2) conversion of glycals into 2-azido-2-deoxysugars by using
a new reagent system composed of PIFA−Me3SiN3−H2O,
catalyzed by TEMPO, and in the presence of n-Bu4NHSO4 as a
phase-transfer catalyst. The reaction conditions are mild (0 °C)
and the yields of the products are generally high, requiring only
short reaction time (20−60 min), and the substrate scope is
also large with differently protected glycals. Further, since the
formation of manno-configured products with glucals is not an
issue in the present methodology, there is no need to protect
the C-4 and C-6 hydroxyl groups as cyclic acetals specifically for
this purpose. In addition, the present methodology does not
require stringent conditions to exclude moisture. These
reactions can also be done on gram scale in high yield and
thus can be useful for providing starting materials for
oligosaccharide synthesis. We have also shown its application
Thus, we suggest the formation of PhI(N3)2 (A) from the
reaction between PIFA and TMSN3, as has also been proposed
by others.14 Further, as suggested by Magnus,14a,b we anticipate
that the intermediate B is formed from A and TEMPO. The
glycal then reacts with B leading to an oxonium ion D via π-
complex C. Since a large excess (50 equiv) of water is used, it
C
DOI: 10.1021/acs.orglett.8b00814
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ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00814.
1
Experimental procedures, optimization details, H and
13C NMR spectra, crystallographic data, and other
supplementary data (PDF)
Accession Codes
(12) (a) Dharuman, S.; Vankar, Y. D. Org. Lett. 2014, 16, 1172−
1175. (b) Rawal, G. K.; Kumar, A.; Tawar, U.; Vankar, Y. D. Org. Lett.
2007, 9, 5171−5174. (c) Reddy, B. G.; Madhusudanan, K. P.; Vankar,
Y. D. J. Org. Chem. 2004, 69, 2630−2633. (d) Reddy, B. G.; Vankar, Y.
D. Angew. Chem., Int. Ed. 2005, 44, 2001−2004. (e) Pachamuthu, K.;
Gupta, A.; Das, J.; Schmidt, R. R.; Vankar, Y. D. Eur. J. Org. Chem.
2002, 2002, 1479−1483.
CCDC 1812127, 1818675, 1818677, and 1826411 contain the
supplementary crystallographic data for this paper. These data
can be obtained free of charge via www.ccdc.cam.ac.uk/
data_request/cif, or by emailing data_request@ccdc.cam.ac.
uk, or by contacting The Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44
1223 336033.
(13) Chennaiah, A.; Bhowmick, S.; Vankar, Y. D. RSC Adv. 2017, 7,
41755−41762.
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3994. (b) Magnus, P.; Lacour, J.; Evans, P. A.; Roe, M. B.; Hulme, C. J.
Am. Chem. Soc. 1996, 118, 3406−3418. (c) Matcha, K.; Antonchick, A.
P. Angew. Chem., Int. Ed. 2013, 52, 2082−2086.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: vankar@iitk.ac.in.
ORCID
(15) Interestingly, substrates such as 3-O-benzyl-(or silyl-)protected
glycals led to the formation of a small amount (∼ 5%) of the
corresponding enones. It is important to add all the reagents, including
water, in quick succession, or else the amount of the corresponding
enone increases. We are working on exploring the full potential of this
observation, and details will be reported in due course
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(c) Johnson, C. L.; Guo, Z. J. Carbohydr. Chem. 2013, 32, 301−323.
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E.; Toyokuni, T. J. Org. Chem. 2001, 66, 3220−3223.
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Yashwant D. Vankar: 0000-0003-1987-8473
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the DST, New Delhi, for the J. C. Bose Fellowship to
Y.D.V. (Grant No. JCB/SR/S2/JCB-26/2010) and the CSIR,
New Delhi, for a senior research fellowship to A.C.
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