Synthesis of Structurally Diverse Substituted Aziridinyl Glycoconjugates via Base-Mediated One-Pot Post-Ugi Cyclization

Article abstract of DOI:10.1021/acs.orglett.9b00862

The base-promoted intramolecular cyclization of Ugi-azide adduct has been demonstrated for the synthesis of highly substituted aziridinyl glycoconjugates in one pot. The reactions are scalable and efficient and have an operationally simple broad substrate

Full text of DOI:10.1021/acs.orglett.9b00862

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Synthesis of Structurally Diverse Substituted Aziridinyl
Glycoconjugates via Base-Mediated One-Pot Post-Ugi Cyclization
Rekha Sangwan,† Atul Dubey, Gurudayal Prajapati, Ravi Sankar Ampapathi,*
,‡
†
§
,§,‡
,
†,‡
and Pintu Kumar Mandal*
†
§
Medicinal & Process Chemistry Division and NMR Centre, SAIF, CSIR-Central Drug Research Institute, BS-10/1, Sector 10,
Jankipuram extn, Sitapur Road, P.O. Box 173, Lucknow 226031, India
‡
Academy of Scientific and Innovative Research, New Delhi 110001, India
S Supporting Information
*
ABSTRACT: The base-promoted intramolecular cyclization
of Ugi-azide adduct has been demonstrated for the synthesis of
highly substituted aziridinyl glycoconjugates in one pot. The
reactions are scalable and efficient and have an operationally
simple broad substrate scope. To gain insight into the
mechanism of aziridine formation, DFT and control experi-
ments show that the cyclization of the aziridine glycoconjugate
pathway was preferred, as it proceeds with a low activation
−
1
energy barrier (0.57 kcal mol ), which supports our experimental observation.
n organic chemistry the smallest nitrogen-containing
heterocycle motif, aziridines, constitutes a highly interesting
source to olefins, (b) transfer of a suitable carbon source to
I
imines, and (c) intramolecular cyclization of chiral 1,2-vicinal
haloamines or amino alcohol derivatives. The literature on
aziridine synthesis via intramolecular cyclization is dominated
synthetic building block as well as an important synthetic
1
target. Ring strain of these spring-loaded heterocycles
11a
11b
provides a distinctive advantage as it can be used as a
by the Wei
and Jacobsen group,
who reported the
2
precursor for the synthesis of more complex molecules.
preparation of stereoselective aziridines. Furthermore, Hayashi
12
Together, the biological activity displayed by the aziridine ring
containing natural compounds (Figure 1) makes them a
and co-workers developed a one-pot synthesis of enantioen-
riched aziridines having a β-hydroxyethyl moiety using diaryl
13
prolinolsilyl ether. Similarly, Bartoli et al. developed a one-
pot procedure for enantioenriched N-Boc-protected aziridine
synthesis using the Co(III)−Salen catalyst.
On the other hand, the development of synthetic methods
for rapid access to N-functionalization with complexity and
diversity, through multicomponent reactions (MCRs), is an
eye-catching area to access biologically and pharmaceutically
important complex molecules. Apart from the synthesis of
several established strategies, the preparation of highly
substituted aziridinyl glycoconjugates is attracting immense
interest.
Figure 1. Bioactive compounds containing an aziridine core.
prudent choice in synthesizing novel molecules. Introducing
aziridine rings as sugar derivatives is also quite significant and
3
Despite all these facts, the efficient synthesis of highly
substituted aziridines from glycosyl amino alcohols has not yet
been attempted. In view of these, in the current work, we have
successfully demonstrated the novel usefulness of isocyanide-
indispensable in the area of glycobiology.
For expanding the field of glycoscience, it is essential to
synthesize biologically relevant oligosaccharides, glycoconju-
4
−6
gates, glycomimetics, and other analogues.
For example,
1
4
based multicomponent Ugi reaction followed by post-
Hou et al. reported that the intramolecular aziridination
followed by reductive ring opening provided the synthesis of
intramolecular S 2 cyclization for the construction of highly
N
7
substituted aziridinyl glycoconjugates. We identified a class of a
three-membered strained ring, highly substituted aziridinyl
glycoconjugate product, signifying the unique reactivity
associated with glycosyl amine (Scheme 1). To the best of
our knowledge, herein we report for the first time the synthesis
immunostimulant, the 4′-epimer of α-CGalCer.
With considerable interest and extensive research, chemical
N-functionalization of carbohydrate derivatives with amine
8
substitution will be a suitable option due to their potential
9
bioactivity as well as the synthetic challenges. Therefore, new
synthetic approaches for the construction of aziridine moieties
are an important research area. Currently available synthetic
methodologies involve (a) transfer of a suitable nitrogen
Received: March 10, 2019
1
0
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00862
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Strategies for the Synthesis of Substituted
Aziridinyl Glycoconjugates from Glycosyl Amino Alcohols
Table 1. Optimization of Cyclization of the Ugi-Azide
a
Adduct to the Aziridinyl Glycoconjugate
a
entry
base
equiv temp (°C), time
solvent
yield (%)
1
2
3
4
5
6
7
8
9
NaH
NaH
NaH
NaH
2
2
2
2
2
2
2
2
2
2
2
2
0−rt, 1 h
0−rt, 1 h
0−rt, 45 min
0−rt, 5 h
rt, 24 h
rt, 24 h
rt, 24 h
rt, 24 h
rt, 24 h
DMF
THF
52
53
82
72
-
-
-
-
49
42
44
66
CH CN
3
CH CN
of structurally diverse strained aziridinyl glycoconjugates via a
one-pot Ugi-cyclization procedure from functionalized glycosyl
amino alcohols.
In this study we employed the Ugi reaction by reacting with
suitable glycosyl amino alcohol (1a, 1.0 equiv) and
chloroacetone (2, 1.0 equiv) in the presence of cyclohexyl
3
Et N
CH CN
3
3
DIPEA
DBU
DABCO
CH CN
3
CH CN
3
CH CN
3
K CO3
CH CN
3
2
1
1
1
0
1
2
KOH NaOMe
t-BuOK
rt, 24 h
rt, 24 h
rt, 24 h
CH CN
3
isocyanide (3a, 1.0 equiv) and TMS-N (4, 1.0 equiv) in
3
CH CN
3
methanol at room temperature to access the corresponding
Ugi-azide adduct 5a as a diastereomeric mixture (product ratio
CH CN
3
a
7
3:27) in good 86% yield (Scheme 2, also see the Supporting
General conditions: 1a (1.0 mmol), base (2.0 equiv), solvent (2.0
b
mL). Isolated yield after silica gel column chromatography.
Scheme 2. MCR for the Ugi-Azide Adduct 5a and Synthesis
of Strained Aziridinyl Glycoconjugates 6a
cyclization, we have carried out extensive NMR analysis
employing both homo- and heteronuclear 2D experiments.
HMBC correlations of C H (δ 3.02 and δ 2.45 ppm) with C
6
7
(
δ 40.45 ppm), C H (δ 2.18 and 1.87 ppm), with C (δ 55.28
7
6
ppm), CIII (δ 32.3 ppm), and CIV (δ 155.54 ppm) supported
the formation of the aziridine ring unequivocally (for details,
please see SI, Figures S2, S3, and S4). Due to its highly
strained nature, aziridine ring formation was not favorable;
instead, one would expect the formation of a less strained 6-
membered morpholine glycoconjugate 6′. However, we have
not observed even a trace amount of the O-alkylated product
(
6′). The Ugi-azide adduct generated in situ underwent a more
favored 3-exotet cyclization, leading to the aziridinyl
glycoconjugate formation, due to the excess nucleophilic
nature of the secondary amine than the hydroxyl group.
Further, we attempted to improve the yield of 6a (which was
only 52% in NaH, DMF), and for the optimization studies we
have treated 5a with a variety of solvents, bases, and
temperature and at different reaction time periods as well
(Table 1). As a result from the optimization of reaction
conditions, it was identified that acetonitrile was the most
suitable solvent for cyclization in comparison with other
solvents such as THF and DMF (Table 1, entries 1−3). In
addition, we have also explored the impact of various organic
bases using triethyl amine, DIPEA, DBU, DABCO, as well as
inorganic bases like K CO , KOH, NaOMe, t-BuOK, and NaH
1
5
Information (SI)). However, diastereomers were separated
on the column by slow elution, with (R,R)-5a eluting first and
S,R)-5a later. The exact structure of 5a and stereochemistry at
the new stereogenic center were unequivocally established by
carrying out extensive NMR studies, especially by analyzing the
NOEs and J scalar coupling constant values (for details, please
see SI, Figure-S1). The top 20 minimum energy conforma-
tions, from the 1nS restrained molecular dynamic simulations,
were superimposed and represented in Figures S6 and S7.
Then we proceeded further to the intramolecular cyclization
with Ugi-azide adduct 5a, in the presence of NaH and dry
DMF. However, we only observed 52% product formation
Table 1, entry 1). The H NMR spectrum of the resulted
product 6a was showing a singlet at δ 2.18 and δ 1.87 ppm
corresponding to one proton each, which was present on the
carbon at δ 32.3 ppm (please see SI). However, it was rather
surprising to see the geminal protons having a J coupling
constant value as zero. The small value or zero geminal
coupling constants are rare and reported for strained ring
(
3
2
3
on the overall yield of the reaction. No product formation was
observed in the case of organic bases (Table 1, entries 5−8),
but in the presence of K CO , KOH, NaOMe, and t-BuOK,
2
3
1
(
there was no improvement in the yield of the desired product
6a (Table 1, entries 9, 10, 11, and 12), even after longer
reaction time periods. Therefore, we deduced that the reaction
carried out in sodium hydride (82% yield) and acetonitrile for
45 min at 0 °C to rt was proven to be an excellent choice for
the cyclization (Table 1, entry 3).
Once the synthesis of aziridinyl glycoconjugate 6a was
achieved in good yields, we further explored the scope and
generality of the reaction for the synthesis of different Ugi-
2
16
systems such as 3-membered rings. In order to elucidate the
structure of the product formed from intramolecular
B
DOI: 10.1021/acs.orglett.9b00862
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
azide adducts (see SI Scheme S4). In this regard, the effect of
the furanose form of mannose and glucose amino alcohols with
various protecting groups was also investigated, where both of
these functionalities were unaffected and found in general
moderate to good yields of Ugi-azide adducts.
To further simplify the synthesis, we turned our attention to
propose a one-pot Ugi-cyclization procedure for the synthesis
of highly substituted aziridinyl glycoconjugates. We planned to
remove the Ugi solvent methanol after formation of 5a without
purification, followed by the addition of NaH in acetonitrile at
0
°C to rt for 45 min (under optimized reaction conditions,
Table 1, entry 3). We have obtained the exclusively aziridinyl
glycoconjugates (6a) in 80% yield with no trace amount of the
O-alkylated product. Encouraged by this remarkable one-pot
protocol, we tested various isocyanides and glycosyl amino
alcohols and found in general moderate to good yields of
highly substituted aziridinyl glycoconjugates (Scheme 3).
1
Figure 2. Section of H NMR spectra of the cyclization step.
Scheme 3. One-Pot Ugi-Cyclization for the Synthesis of
Aziridinyl Glycoconjugates
of NaH was added and after 15 min, both the protons of OH
and NH disappeared (stage-3), without any formation of the
product. However, after 25 min of incubation at room
temperature, we observed that the signal intensity of the
peaks corresponding to the starting material started diminish-
ing for, e.g., peaks of C7HA and C7HB at δ 4.32 and δ4.21 ppm,
respectively, and simultaneously we noticed the appearance of
a new set of singlets at δ 2.16 and δ 1.81 ppm (stage-4).
Incubation was continued, and after 45 min, we noticed
complete disappearance of C7HA and C7HB (δ 4.32 and δ 4.21
ppm) of the starting material, which then resonated at δ 2.16
and δ 1.81 ppm, clearly indicating the formation of an N-
alkylated aziridine ring. We also noticed the appearance of the
OH proton in stage-5. From these experiments, it clearly
demonstrates that the deprotonation of the OH takes place
first followed by the deprotonation of the NH proton. The
intramolecular cyclization takes place through amine forming
the strained 3-membered aziridine ring rather than the 6-
membered morpholine ring (Figure 3). To validate the
experimental results toward the formation of cyclized aziridine
glycoconjugates, DFT calculations were performed using G09,
Gauss view program. The cyclization of aziridinyl glycoconju-
,
a b
a
General conditions: To a solution of chloroacetone 2 (1.0 equiv) in
methanol (1M) at room temperature were added glycosyl amino
alcohols 1a−d (1.0 equiv), isocyanide 3 (1.0 equiv), and
b
trimethylsilylazide (2.0 equiv). One-pot overall isolated yield.
Diastereoisomeric ratio was determined by H NMR analysis. Not
1
*
separated isomers.
However, there were some questions to address: First, the
deprotonation takes place either from the hydroxyl group or
from the NH group or both. Second, how does the substitution
of chlorine occur? Third, does the aziridine ring form
exclusively or will there be any formation of the O- alkylated
product? In order to investigate the reaction mechanism, the
1
cyclization step was monitored by acquiring a series of H
NMR spectra (Figure 2).
In the NMR sample tube, initially we have dissolved the Ugi-
azide adduct 5a in deuterated CD CN and acquired a proton
3
spectrum which is represented as stage-1 in Figure 2.
Then, after we have added 1 equiv of NaH to the mixture
incubated at 0 °C. After 5 min of incubation, the proton
spectrum was acquired, and it was observed that the peak of
OH disappeared. We also have noticed that the NH peak was
intact (stage-2). However, there is no formation of O-alkylated
product even after longer time. Further, when one more equiv
Figure 3. Possible mechanism depicted by NMR study.
C
DOI: 10.1021/acs.orglett.9b00862
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
gate proceeds with low activation energy compared to the
morpholine cyclization pathway (please see the SI, Figure S5).
In conclusion, we have shown a general one-pot post-Ugi
cyclization reaction as an innovative synthetic method for the
synthesis of carbohydrate-derived highly strained substituted
aziridine. This robust and operationally simple two-step, air-
and moisture-tolerant procedure furnished fast-track strategy
with various advantageous features including synthesis of
highly strained complex molecules from simple starting
materials. This small nitrogen-containing building block is
imposed by complexity involved in the synthesis due to the
ring strain that makes them useful precursors in the fields of
synthetic and medicinal chemistry.
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00862.
Detailed experimental procedures, complete character-
ization data, DFT calculation and copies of NMR
spectra. The authors declare no competing financial
interest (PDF)
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AUTHOR INFORMATION
Corresponding Authors
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(
10) (a) Singh, G. S. Mini-Rev. Med. Chem. 2016, 16, 892−904.
*
E-mail: pintuchem06@gmail.com.
E-mail: ravi_sa@cdri.res.in.
(b) Fingerhut, A.; Serdyuk, O. V.; Tsogoeva, S. V. Green Chem. 2015,
*
17, 2042−2058. (c) Degennaro, L.; Trinchera, P.; Luisi, R. Chem. Rev.
2014, 114, 7881−7929. (d) Jat, J. L.; Paudyal, M. P.; Gao, H.; Xu, Q.-
ORCID
L.; Yousufuddin, M.; Devarajan, D.; Ess, D. H.; Kurti, L.; Falck, J. R.
Science 2014, 343, 61−65. (e) Chawla, R.; Singh, A. K.; Yadav, L. D.
S. RSC Adv. 2013, 3, 11385−11403. (f) Cockrell, J.; Wilhelmsen, C.;
Rubin, H.; Martin, A.; Morgan, J. B. Angew. Chem., Int. Ed. 2012, 51,
Ravi Sankar Ampapathi: 0000-0003-1637-7630
Pintu Kumar Mandal: 0000-0002-5813-9756
Notes
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842−9845. (g) Chai, Z.; Bouillon, J.-P.; Cahard, D. Chem. Commun.
2012, 48, 9471−9473.
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The authors declare no competing financial interest.
(
ACKNOWLEDGMENTS
Wang, Y.; Shi, X. Chin. J. Chem. 2012, 30, 391−399. (b) Kim, S. K. K.;
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Jacobsen, E. N. Angew. Chem., Int. Ed. 2004, 43, 3952−3954.
Financial support by the Science and Engineering Research
Board, DST, Govt. of India (Grant No.EMR/2017/001791), is
gratefully acknowledged. R.S., A.D., and G.D. are grateful to
CSIR-New Delhi for the Research Fellowship. We thank SAIF
division, CDRI, for the analytical facility. CDRI communica-
tion no. 9827.
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