One-Pot Regioselective and Stereoselective Synthesis of C-Glycosyl Amides from Glycals Using Vinyl Azides as Glycosyl Acceptors

Article abstract of DOI:10.1021/acs.orglett.8b01602

The reaction of glycals containing good leaving groups with aromatic vinyl azides to give α-C-glycosyl amides in good yields is described. Various vinyl azides with different groups undergo the reaction smoothly. In these reactions, an iminodiazonium intermediate is generated by the attack of the vinyl azide onto the glycal under Lewis acid conditions. This undergoes Schmidt-type denitrogenative 1,2-migration to form a nitrilium ion, which, upon hydrolysis, gives the desired C-glycosyl amide.

Full text of DOI:10.1021/acs.orglett.8b01602

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
One-Pot Regioselective and Stereoselective Synthesis of C‑Glycosyl
Amides from Glycals Using Vinyl Azides as Glycosyl Acceptors
Faheem Rasool,† Ajaz Ahmed, Nazar Hussain, Syed Khalid Yousuf,*
,‡
†,‡
†,‡
,‡,§
,†,§
and Debaraj Mukherjee*
†
Natural Product Chemistry Division, Indian Institute of Integrative Medicine (IIIM), Jammu, India
Academy of Scientific and Innovative Research (AcSIR-IIIM), Jammu-180001, India
Medicinal Chemistry Division, Indian Institute of Integrative Medicine (IIIM), Srinagar, India
‡
§
*
S Supporting Information
ABSTRACT: The reaction of glycals containing good leaving
groups with aromatic vinyl azides to give α-C-glycosyl amides
in good yields is described. Various vinyl azides with different
groups undergo the reaction smoothly. In these reactions, an
iminodiazonium intermediate is generated by the attack of the
vinyl azide onto the glycal under Lewis acid conditions. This
undergoes Schmidt-type denitrogenative 1,2-migration to
form a nitrilium ion, which, upon hydrolysis, gives the desired
C-glycosyl amide.
C-Glycosides have gained widespread attention in recent years,
because of their potential for use as inhibitors of carbohydrate-
1
−3
processing enzymes, their metabolic stability compared to O-
glycosides, and their applicability as intermediates in the
4
−9
synthesis of biologically important molecules.
This has led
to a surge in the development of synthetic strategies for C-
glycoside formation. Over the past few years, we have also tasted
success in solving many of the problems faced in stereoselective
C-glycosylation exploiting different glycosyl acceptors, such as
boronic acids, unactivated alkynes, arylmethyl ketones, unac-
tivated uracils, and benzenesulfonyl chlorides under palladium
10
and Lewis acid catalysis. Despite these advances, the vast
diversity and distribution of C-glycosides, along with their
unending medical applications, have left the subject of C-
glycosylation open to further developments.
Figure 1. Biologically important C-glycosides having methylene amide
linkage.
Small molecule screening libraries containing methylene
amide linkages have resulted in the discovery of many chemical
several other demerits, such as the use of BuLi in the generation
of silylketene acetals as nucleophiles under cryogenic conditions
and the lack of stereoselectivity (mixtures of α/β diastereomers)
during the crucial glycosylation step, thereby leaving the scope
for further modifications.
11
probes and drug leads in recent times. C-Glycosides that have a
methylene amide linkage as a part of the aglycon are no
exception to this and are used as probes for a wide range of
1
2,13
inheritable diseases and cardiovascular diseases.
For
There is no report to date that involves a direct introduction
of the amide functionality into the aglycon part during a C-
glycosylation. In this respect vinyl azides, which can be easily
example, glycoside I (see Figure 1) activates the MAPKerk
signaling pathways by up-regulating early response genes such as
TRIB1 and LDLR, thereby leading to remarkable changes in
lipoprotein metabolism. This results in a decrease in VLDL
production and the upregulation of LDL uptake in cells of
hepatic origin, thus having major implications in coronary artery
16
derived from terminal alkynes, are versatile substrates mainly
used for nitrogen-containing molecules of importance in
17
medicinal chemistry and materials science. We envisaged
(Scheme 1b) that, under Lewis acid activation, the anomeric
carbon of the glycosyl donor might act as an electrophile in the
formation of a C−C glycosidic bond with an enamine-type
1
2
disease. However, the limited availability of these new
chemical entities has restricted their study in biological targets.
The chemical synthesis of such C-glycosides with methylene
amide functionality requires multiple steps with late-stage amide
linkage introduction, using the aminolysis of acids derived from
Received: May 21, 2018
13−15
esters (see Scheme 1a).
These conventional strategies have
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01602
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Previous Report and Current Work
nucleophile generated from vinyl azide. This would form a
glycosyl imino diazonium ion intermediate, which might
undergo a Schmidt-type 1,2-migration to form nitrilium ion
proton from δ 6.6 ppm to δ 4.6 ppm, together with the formation
of new peaks at δ 2.5 ppm and δ 2.7 ppm in the H NMR (400
1
MHz) of 1a in CDCl , corresponding to two diastereotopic
3
with the elimination of dinitrogen (N ). Upon hydrolysis, we
hydrogens of methylene carbon, clearly indicated the formation
2
1
3
envisaged that this might produce glycosides bearing methylene
amide linkages. As there is no report of using vinyl azides as
glycosyl acceptors in C-glycosylation, and also considering the
importance of the product, we took up the challenge of probing
this as a one-step route to such C-glycosides.
of a C-glycosyl amide. This was further confirmed by C NMR
spectroscopy which showed a new CH peak at δ 40.8 ppm. The
2
stereochemistry at the anomeric center was determined by two-
dimensional nuclear magnetic resonance (2D NMR) (COSY,
NOESY, HSQC, and HMBC). The NOESY spectrum of 1a
shows strong correlations between peaks of H1 and H6ab, as
well as those of H5 and H7ab, but no correlation was found
between signals of H1 and H5 (Figure 2), confirming the linkage
at the anomeric center as α.
In order to probe the potential of vinyl azides as glycosyl
acceptors, tri-O-acetyl-D-glucal (1) and 3-chlorophenyl vinyl
azide (2) were chosen. Initial reaction in the presence of
TMSOTf at 0 °C gave a mixture of two products 1a and 1b in
1
:2 ratio in 30% overall yield (see Table 1, entry 1), although
Table 1. Reaction of Tri-O-acetyl-D-glucal with 3-
Chlorophenyl Vinyl Azide under Various Conditions
a
b
Lewis acid
(equiv)
temperature
time
(h)
yield
entry
solvent
CH Cl
(°C)
(1a:1b)
1
2
3
4
5
6
7
8
9
TMSOTf (1)
TMSOTf (1)
TMSOTf (0.5) CH Cl
0
−20
−20
−20
−20
−20
−20
−20
−20
0
3
4
4
4
4
4
4
4
4
2
1
30 (1:2)
40 (1:2)
35 (1:2)
20 (1:2)
30 (1:2)
30 (1:2)
60 (2:1)
70 (2:1)
70 (2:1)
77 (1:0)
50 (1:0)
2
2
CH Cl
2
2
2
2
2
2
2
2
2
2
2
2
InCl (0.5)
CH Cl
3
2
FeCl (0.5)
CH Cl
3
2
CuOTf (0.5)
CH Cl
2
Figure 2. NOESY correlations of 1a.
BF ·Et O (0.5) CH Cl
3
2
2
BF ·Et O (1)
CH Cl
3
2
2
In order to check the substrate scope of the method, we
performed the reaction of tri-O-acetyl-D-glucal with various vinyl
azides under the optimized reaction conditions. In all cases, the
reaction was found to proceed smoothly, affording the desired
C-glycosyl amide in good to excellent yield with high
stereoselectivity (see Scheme 2, entries 2a−15a). A variety of
vinyl azides carrying aryl substituents possessing either electron-
donating or electron-withdrawing groups were observed to
undergo the reaction smoothly. Aryl rings having EDG groups at
the para or meta positions gave the desired C-glycosyl amide in
somewhat better yields, in comparison to substrates having
EWG groups at any position. A series of other glycals (D-galactal,
D-xylal, and L-rhamnal) were also examined under the standard
reaction conditions. Both L-rhamnal and D-galactal provided the
desired products with excellent stereoselectivity (see Scheme 1,
entries 11a and 12a). However, in the case of D-xylal, a mixture of
diastereomers (αβ, 1:1) was obtained. Other glycals with
benzoyl protection reacted smoothly under the reaction
conditions with 3-chloro vinyl azide to give the desired C-
glycosyl amide (Scheme 2, entry 15a) while no reaction
occurred with benzyl protecting groups, which resulted in
hydrolysis of the vinyl azide itself.
BF ·Et O (1.5) CH Cl
3
2
2
1
1
0
1
BF ·Et O (1)
CH Cl
3
2
2
c
BF ·Et O (2)
CH Cl
rt
3
2
2
a
In all cases, reactions were performed using 1 (1 equiv) and 2 (1.1
equiv). Isolated yield after silica gel column chromatography. Room
temperature.
b
c
most of the starting material was consumed. Decreasing the
temperature to −20 °C or the mole percentage of TMSOTf to
0% prevented the degradation of the starting material but there
was no increase either in the yield or the proportion of 1a in
comparison to 1b (Table 1, entries 2 and 3). In order to obtain
a as the sole product, the reaction was performed under various
conditions, and the results are presented in Table 1. Screening of
different solvents proved dichloromethane to be the best, giving
predominantly 1a in good yield (see the Supporting Information
SI), as well as Table 1). Use of 1 equiv of BF ·Et O at 0 °C in
DCM (Table 1, entry 10) proved to be the best conditions for
this purpose.
The structure of the product 1a was confirmed by
spectroscopic analysis. Upfield chemical shift of the anomeric
5
1
(
3 2
B
DOI: 10.1021/acs.orglett.8b01602
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 2. Substrate Scope of C-Glycosyl Amides under Optimized Reaction Conditions
a
Reaction conditions: To a solution of glycal (1 equiv) in CH Cl (2 mL) was added BF ·Et O (1 equiv) at 0 °C, followed by slow addition of the
2
2
3
2
aryl vinyl azide (1.1 equiv) at the same temperature and maintained for 2 h. Values given in parentheses indicate isolated yields after silica gel
column chromatography.
In order to expand the substrate scope of the reaction, the
reactivity of vinyl azides derived from aliphatic alkynes as
glycosyl acceptors was examined. Interestingly, a vinyl azide
having an α-methylene phenoxy group (3) under a similar set of
reaction conditions reacted differently to produce C-glycosyl
Scheme 4. Plausible Mechanism for the Formation of C-
Glyoside Amides from Glycals and Vinyl Azides
amides (Scheme 3a, entries 16a and 17a) bearing a CH −NH−
2
COPh instead of a CH −CO−NHPh as exclusive products.
2
However, an inseparable mixture of two regioisomers was
obtained from vinyl azides having long carbon chains (Scheme
3
b).
A possible mechanism for the reaction is shown in Scheme 4.
The formation of oxacarbenium ion (I) from glycal in the
Scheme 3. Reaction of Tri-O-acetyl-D-glucal with Various
Aliphatic Vinyl Azides under Optimized Reaction Conditions
C
DOI: 10.1021/acs.orglett.8b01602
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
presence of BF ·Et O is followed by the nucleophilic attack of
Notes
3
2
vinyl azide from the bottom face to form an iminodiazonium
intermediate (II), which undergoes Schmidt-type 1,2-migration
with elimination of dinitrogen to form the nitrilium ion III or IV.
Upon hydrolysis, this gives corresponding amides V or VII,
depending on the migratory aptitude of the substituents. The
regioselectivity of the reaction is decided at this stage. Groups
such as aryl, which have higher migratory aptitude than the
sugar, take pathway (a) to form the nitrilium ion III, while α-
methylene phenoxy groups, having lower migratory aptitude
than the sugar, take the other route (b) to form intermediate IV.
In the case of the groups that have comparable migrating ability,
a mixture of two regioisomers is obtained as observed in the case
of vinyl azides having long carbon chains. Indeed, while working
with ortho-chlorophenyl vinyl azide (Scheme 5), we were able to
isolate and characterize both the regioisomers 18a (major) and
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors are thankful to DST-India for funding uner the
project GAP-2155 and under INSPIRE faculty programme
■
(
IFA-11-CH-18, GAP-1179). F.R and N.H thank CSIR-New
Delhi and UGC-New Delhi for senior research fellowships. A.A
thanks CSIR-New Delhi for junior research fellowship. IIIM
Publication No. IIIM/2221/2018.
REFERENCES
■
(
(
1) Zou, W. Curr. Top. Med. Chem. 2005, 5, 1363−1391.
2) Sutherlin, D. P.; Stark, T. M.; Hughes, R.; Armstrong, R. W. J. Org.
Chem. 1996, 61, 8350−8354.
(3) Weatherman, R. V.; Mortell, K. H.; Chervenak, M.; Kiessling, L.
L.; Toone, E. J. Biochemistry 1996, 35, 3619−3624.
1
9a (minor) in a 7:3 ratio.
(4) Danishefsky, S. J.; DeNinno, S.; Lartey, P. J. Am. Chem. Soc. 1987,
1
(
(
(
09, 2082−2089.
Scheme 5. Reaction of Tri-O-acetyl-D-glucal with
Orthochlorophenyl Vinyl Azide
5) Paterson, I.; Keown, L. E. Tetrahedron Lett. 1997, 38, 5727−5730.
6) Kira, K.; Isobe, M. Tetrahedron Lett. 2000, 41, 5951−5955.
7) Gallagher, B. M., Jr.; Zhao, H.; Pesant, M.; Fang, F. G. Tetrahedron
Lett. 2005, 46, 923−926.
8) Sasaki, M.; Tsubone, K.; Shoji, M.; Oikawa, M.; Shimamoto, K.;
Sakai, R. Bioorg. Med. Chem. Lett. 2006, 16, 5784−5787.
9) (a) Levy, D. E.; Tang, C. The Chemistry of C-Glycosides; Elsevier
Science: Tarrytown, NY, 1995. (b) Postema, M. H. D. Tetrahedron
992, 48, 8545−8599. (c) Bililign, T.; Griffith, B. R.; Thorson, J. S. Nat.
Prod. Rep. 2005, 22, 742−760. (d) Hultin, P. G. Curr. Top. Med. Chem.
005, 5, 1299−1331.
10) (a) Rasool, F.; Mukherjee, D. Org. Lett. 2017, 19, 4936−4939.
b) Kusunuru, A. K.; Tatina, M.; Yousuf, S. K.; Mukherjee, D. Chem.
(
(
1
2
(
Based on our experimental results, the migratory aptitude of
(
the different groups is Ar ≫ CH −sugar = −(CH ) −CH (n >
Commun. 2013, 49, 10154−10156. (c) Tatina, M.; Kusunuru, A. K.;
Yousuf, S. K.; Mukherjee, D. Chem. Commun. 2013, 49, 11409−11411.
(d) Lambu, M. R.; Hussain, A.; Sharma, D. K.; Yousuf, S. K.; Singh, B.;
Tripathi, A. K.; Mukherjee, D. RSC Adv. 2014, 4, 11023−11028.
(e) Mukherjee, D.; Sarkar, S. K.; Chowdhury, U. S.; Taneja, S. C.
Tetrahedron Lett. 2007, 48, 663−667. (f) Kusunuru, A. K.; Yousuf, S.
K.; Tatina, M.; Mukherjee, D. Eur. J. Org. Chem. 2015, 2015, 459−462.
2
2 n
3
2
) > CH OPh. The stereoselectivty at the anomeric center is
2
governed by conformational effects (Scheme 4b), where the α-
attack is favored because it leads to the energetically more
O
favorable half-chair conformation H (II), compared to β-
5
attack, which results in energetically less favorable high-energy
1
,4
18
boat conformation B (VII).
(g) Kusunuru, A. K.; Jaladanki, C. K.; Tatina, M.; Bharatam, P. V.;
In conclusion, we have developed an efficient method for the
synthesis of C-glycosides using vinyl azides as enamine-type
nucleophilic reagents. For the first time, vinyl azides have been
used as glycosyl acceptors in a C-glycosylation. The synthesis of
C-glycosides proceeded stereoselectivily giving only the α-
anomer as a single product. The glycosylation proceeds with the
formation of a single C-glycosyl amide product with most aryl
vinyl azides. We anticipate that the present method can be
readily adapted for the synthesis of biologically and medicinally
important amide-containing C-glycosides.
Mukherjee, D. Org. Lett. 2015, 17, 3742−3745. (h) Tatina, M.;
Kusunuru, A. K.; Mukherjee, D. Org. Lett. 2015, 17, 4624−4627.
(
i) Dash, A. K.; Madhubabu, T.; Yousuf, S. K.; Raina, S.; Mukherjee, D.
Carbohydr. Res. 2017, 438, 1−8.
(11) Gerry, C. J.; Schreiber, S. L. Nat. Rev. Drug Discovery 2018, 17,
333−352.
(12) Nagiec, M. M.; Skepner, A. P.; Negri, J.; Eichhorn, M.;
Kuperwasser, N.; Comer, E.; Muncipinto, G.; Subramanian, A.; Clish,
C.; Musunuru, K.; Duvall, J. R.; Foley, M.; Perez, J. R.; Palmer, M. A. J.
PLoS One 2015, 10, 1−26.
(13) Nagiec, M. M.; Perez, J. R.; Palmer, M. A.; Skepner, A. P.; Comer,
E. Modulators of Hepatic Lipoprotein Metabolism, International
Patent No. WO/2016/100711, 2016.
(14) Gerard, B.; Lee, M. D.; Dandapani, S.; Duvall, J. R.; Fitzgerald, M.
́
E.; Kesavan, S.; Lowe, J. T.; Marie, J.-C.; Pandya, B. A.; Suh, B.-C.;
O’Shea, M. W.; Dombrowski, M.; Hamann, D.; Lemercier, B.; Murillo,
T.; Akella, L. B.; Foley, M. A.; Marcaurelle, L. A. J. Org. Chem. 2013, 78,
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b01602.
1
13
Experimental procedures, H and C NMR spectra, and
characterization of all compounds (PDF)
5
160−5171.
(15) Gerard, B.; Marie,
́
J.-C.; Pandya, B. A.; Lee, M. D., IV; Liu, H.;
Marcaurelle, L. M. J. Org. Chem. 2011, 76, 1898−1901.
(
(
16) Liu, Z.; Liao, P.; Bi, X. Org. Lett. 2014, 16, 3668−3671.
17) (a) Hayashi, H.; Kaga, A.; Chiba, S. J. Org. Chem. 2017, 82,
AUTHOR INFORMATION
Corresponding Authors
■
*
*
1
1981−11989. (b) Zhang, F.-L.; Wang, Y.-F.; Lonca, G. H.; Zhu, X.;
E-mail: khalidiiim@gmail.com (S. K. Yousuf).
E-mail: dmukherjee@iiim.ac.in (D. Mukherjee).
ORCID
Chiba, S. Angew. Chem., Int. Ed. 2014, 53, 4390−4394.
(18) (a) Leng, W.-L.; Yao, H.; He, J.-X.; Liu, X.-W. Acc. Chem. Res.
2
018, 51, 628−639. (b) Nicolaou, K. C.; Hwang, C.-K.; Duggan, M. E.
J. Chem. Soc., Chem. Commun. 1986, 925−926.
Debaraj Mukherjee: 0000-0002-2162-7465
D
DOI: 10.1021/acs.orglett.8b01602
Org. Lett. XXXX, XXX, XXX−XXX