Direct, microwave-assisted substitution of anomeric nitrate-esters

Article abstract of DOI:10.1016/j.carres.2017.02.005

A series of carbohydrate 2-azido-1-nitrate-esters, protected at the C-3, C-4, and C-6 positions, were hydrolyzed thermally under reagent free conditions. This preliminary result was extended to direct exchange of the 1-nitrate-ester modality for alcohol,

Full text of DOI:10.1016/j.carres.2017.02.005

Accepted Manuscript
Direct, microwave-assisted substitution of anomeric nitrate-esters
D. Jamin Keith, Steven D. Townsend
PII:
S0008-6215(17)30044-7
10.1016/j.carres.2017.02.005
CAR 7324
DOI:
Reference:
To appear in: Carbohydrate Research
Received Date: 17 January 2017
Revised Date: 21 February 2017
Accepted Date: 21 February 2017
Please cite this article as: D.J. Keith, S.D. Townsend, Direct, microwave-assisted substitution of
anomeric nitrate-esters, Carbohydrate Research (2017), doi: 10.1016/j.carres.2017.02.005.
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Direct, Microwave-Assisted Substitution of Anomeric Nitrate-Esters
D. Jamin Keitha and Steven D. Townsenda,b*
a Department of Chemistry, Vanderbilt University, Nashville, TN 37235
b Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232
* E-mail: steven.d.townsend@vanderbilt.edu
ABSTRACT
A series of carbohydrate 2-azido-1-nitrate-esters, protected at the C-3, C-4, and C-6 positions,
were hydrolyzed thermally, under reagent free conditions. This preliminary result was extended
to direct exchange of the 1-nitrate-ester modality for alcohol, alkoxy, and azide coupling partners
with minimal purification. While direct glycosylation of nitrate esters ultimately proved unsuc-
cessful, we have demonstrated that an anomeric nitrate-ester can be converted directly to a tri-
chloroacetimidate in a short and simple one-pot procedure, bypassing lower-yielding two-step
sequences.
GRAPHICAL ABSTRACT
KEY WORDS
Azido-Nitration
Nitrate-Ester
Hydrolysis
Glycosidation
Glycosylation
Trichloroacetimidate

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Introduction
The Lemieux azidonitration of protected O-glycals is a valuable tool for synthesizing 2-
amino-2-deoxy sugars; where the newly installed amino group is masked as an azide.[1-4] In the
well-studied event (Figure 1A), a glycal (1) is reacted with sodium azide and ceric ammonium
nitrate (CAN) in aqueous acetonitrile to produce a 2-azido-1-nitrate-ester (2). From this scaf-
fold, a variety of synthetic maneuvers are available to exchange the nitrate-ester for a useful re-
active handle (Figure 1B).[3-5] Traditionally, the nitrate-ester is converted to a latent leaving
group directly or via the intermediacy of an anomeric alcohol, while the amine is revealed during
the deprotection sequence and functionalized (i.e. to an acetamide), if desired.[1, 6-11]
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Figure 1. Lemieux’s azido-nitration reaction and common manipulations of the nitrate-ester.
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The present study focuses on manipulation of the nitrate-ester and commenced with the
observation that converting the group to useful functionality, in theory a trivial synthetic maneu-
ver, is usually accomplished using strong nucleophiles under harsh reaction conditions. From a
structural standpoint, we viewed the anomeric nitrate-ester as inherently unstable, a characteristic
that should render the group susceptible to reaction under milder conditions. Thus, we hypothe-
sized direct nucleophilic substitution should be feasible if nitrate-esters are treated with nucleo-
philes at elevated temperatures (Figure 1C).
Results and Discussion
The program commenced by examining the reagent free hydrolysis of a nitrate-ester. We
believed successful completion of this reaction would provide an advance to the concept of ami-
no-hydroxylation of glycals, as the reaction could be demonstrated, for the first time, without the
use of strong nucleophiles. Moreover, as the reaction would produce nitric acid as a sole by-
product, no column chromatography would be required, vide infra. The only additive to the reac-
tion is pyridine, which acts as an acid scavenger. Importantly, acid stable substrates undergo re-
action without addition of pyridine. In an orienting experiment (Table 1, entry 1) the per-
benzylated azido nitrate-ester (6) was dissolved in aq. acetone and pyridine, and heated in a mi-
o
crowave reactor at 120 C, for 10 minutes. In the event, we observed clean conversion of (6) to
its corresponding alcohol (7) in quantitative yield. Conventional heating by oil bath, to the same
temperature, required longer times and was low yielding (not shown). Similarly, the peracetylat-
ed azido nitrate-esters (8) and (10) (entries 2 and 3) were hydrolyzed in reactions that required 15
o
minutes of heating at 110 C to give alcohols (9) and (11) in quantitative yield with no need for
purification. In entry 5, a lactose derivative (14) was reacted in order to ensure glycosidic link-
ages would remain intact after microwave irradiation. Indeed, this substrate was stable to the
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short reaction conditions as the alcohol (15) was obtained in 95% yield. The next phase of the
study focused on exchanging the acetates for acid labile groups (entries 4 - 8) such as acetonides
and silyl ethers. Each protective group pattern proved compatible with the reaction conditions, as
we were able to observe yields ranging from 86% to greater than >95% yield.
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Table 1. Microwave-assisted removal of the nitrate-ester in aqueous solvent.
Conditions
Yield
Entry
Nitrate-ester
Product
120oC
1
10 min.
>95%
110oC
15 min.
>95%
2
110oC
15 min.
>95%
3
4
100oC
10 min. 86%
120oC
5
6a
7a
8
10 min.
>95%
100oC
15 min. 93%
120oC
20 min.
>95%
100oC
15 min. 90%
General Procedure: A 2-azido-1-nitrate ester (1.0 eq, 0.20 mmol) is dissolved in 20% aq. acetone (2.0 mL) and treated with pyridine (5.0 eq, 1.0
mmol). The reaction is heated by microwave irradiation to 120 °C until the starting material is consumed (usually 10 min.). The reaction mixture
is transferred to a separatory funnel, diluted with EtOAc (20 mL) and washed with 1N HCl (1 x 5 mL), water (2 x 5 mL), and brine (1 x 5 mL).
The organics are dried over MgSO4, filtered, and concentrated in vacuo to give the anomeric alcohol as a yellow oil. Of note, other amine and
inorganic bases such as triethylamine and sodium bicarbonate work equally well as an acid scavenger. aAcetonitrile or THF was used because the
substrate was insoluble in acetone.
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Mechanistically, nucleophilic attack at nitrogen or oxygen would trigger collapse of the
nitrate-ester (Figure 2). Given that oxygen-based nucleophiles are hard bases, we speculated the
nucleophile engages at carbon (Pathway B), as it is the harder electrophilic site.[12]
Figure 2. Mechanistic analysis of the azido-nitrate hydrolysis.
Based on this mechanistic analysis, we postulated that if the reaction proceeded through
nucleophilic attack at carbon via an Sn1 or Sn2 pathway, the reaction could be extended to direct
nucleophilic displacement, glycosidation, or glycosylation of nitrate-esters. Thus, the next step
in our study involved evaluating direct reaction of the nitrate-ester with a pool of nucleophiles
(Figure 3). In the first reaction, the peracetylated nitrate-ester (8) underwent effective meth-
anolysis to provide methyl acetal (26) in quantitative yield. Similarly, reaction with isopropanol
gave isopropyl acetal (27), similarly in quantitative yield. In an interesting reaction, a per-
benzylated nitrate-ester successfully underwent substitution with NaN3 to provide anomeric az-
ide (28). This reaction in effect, produces the direct precursor to a 1,2-diamino sugar in a 2-step
process from a glycal.[5, 13] Of note is that the reaction proceeds with complete anomeric ste-
reo-control, providing only the β-isomer. As a final mechanistic control, a perbenzylated azido-
nitrate ester (6) was reacted with NaCN, a soft nucleophile. Based on our analysis that hard nu-
cleophiles attack directly at carbon, we anticipated this soft nucleophile would engage the mole-
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cule at the nitrogen center to generate an anomeric alcohol. As expected, the reaction provided a
quantitative yield of the previously synthesized hemiacetal (7) and no generation of cyanide (29).
OBn
O
OBn
O
BnO
BnO
BnO
BnO
CH3OH
OCH3
100 °C, 15 min
N
N3
3 ONO2
α:β = 1:9, 70%
(6)
(25)
OAc
O
OAc
O
AcO
AcO
AcO
AcO
CH3OH
100 °C, 15 min
α:β = 1:1, >95%
ONO2
OCH3
N3
N3
(26)
(8)
OAc
AcO
AcO
OAc
O
AcO
AcO
(CH3)2CHOH
CH2Cl2
O
OiPr
ONO2
N3
N3
120 °C, 30 min
α:β = 6:1, >95%
(8)
(27)
OBn
O
OBn
O
BnO
BnO
BnO
NaN3
N3
BnO
DMF
100 °C, 30 min
β only, 69%
N3
N3
ONO2
(28)
(6)
OBn
O
OBn
O
BnO
BnO
BnO
BnO
NaCN
CN
DMF
N3
N3
(29)
100 °C, 30 min
ONO2
(6)
Figure 3. Direct substitution of the anomeric nitrate-ester.
The next segment of the program focused on using glycosyl acceptors as nucleophiles to
study the direct glycosylation of a nitrate-ester. From the onset, it was our hope that a successful
reaction between these substrates would produce a new glycosidic linkage, thereby enabling the
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nitrate-ester to serve as a latent leaving group in glycosylation chemistry. Unfortunately, thor-
ough screening of this reaction never provided the glycosidic linkage in a reasonable yield (Table
2).
A subset of the reaction conditions screened is listed below. The starting point was to use
primary alcohol (30) as the acceptor in a reaction with nitrate-ester (6). As is shown in reaction
1, irradiation with equimolar donor and acceptor failed to generate the desired disaccharide. Ex-
tended irradiation for several hours led to polymerization of (6). In light of this observation, we
moved forward and conducted additional reactions where we used excess amounts of both the
donor and the acceptor. Still, only trace amounts of product formation, regardless of reaction
conditions, was observed. Ultimately, the only productive system to give any isolable quantity
of disaccharide (31) was one, which featured a 5:1 ratio of donor (6) to acceptor (30) in THF.
This reaction mixture was heated in the presence of pyridine at 130 oC for 2 hours to yield 5% of
(31) alongside unreacted acceptor (30) and uncharacterized polymerized byproducts.
In order to change the electronics of the system, a donor featuring electron-withdrawing
acetate groups was examined (reaction 2). Additionally, a second donor compound (33), was
examined (reaction 3). Both systems proved to be resistant to glycosylation.
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Figure 4. Attempted direct glycosylation of 1-nitrate esters.
Because the direct glycosylation of a nitrate-ester was unproductive, we felt it would be
advantageous to use the chemistry described above, to improve on the conversion of a nitrate-
ester to a trichloroacetimidate imidate. Typically, this sequence is carried out in a two-step pro-
cess requiring two individual chromatographic purifications. Using microwave mediated reac-
tion conditions; this transformation can be achieved in quantitative yield using a one-pot proce-
dure shown in Figure 5.
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Figure 5. One-pot generation of a trichloroacetimidate glycosyl donor from an anomeric nitrate
ester.
Conclusion
To close, we have demonstrated that anomeric nitrate-esters can be readily hydrolyzed or
converted into useful building blocks under reagent free conditions. This methodology repre-
sents an advance from standard denitration reaction conditions that typically require the use of
strongly basic or strongly nucleophilic reagents. These systems are often plagued by loss of
product, due to unwanted side reactions. Here, thermal decomposition of the nitrate-ester, when
occurring in the presence of water, hard nucleophiles, or alcoholic solvents produces, clean, high
yields of the corresponding substituted saccharide with minor purification in short reaction times.
While this reaction could not be extended to a useful glycosylation procedure, we were able to
use the reaction conditions to quickly achieve a one-pot conversion of the anomeric-nitrate func-
tionality to synthetically useful trichloroacetimidate donors in quantitative yields.
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ASSOCIATED CONTENT
Supporting Information
Experimental procedures and characterization data (including spectra for new compounds). This
material is available free of charge via the internet at http://pubs.acs.org
AUTHOR INFORMATION
Corresponding Author
* E-mail: steven.d.townsend@vanderbilt.edu
ACKNOWLEDGMENTS
The authors would like to acknowledge Vanderbilt University and the Institute of Chemical Bi-
ology for financial support. Mr. Berkley Ellis and Prof. John McLean are acknowledged for
High-Resolution Mass Spectral Analysis.
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•
•
•
•
Short Reaction Times
Minimal Reagents
70-100% yield
One-Pot Conversion of a Nitrate-Ester to a Schmidt Imidate