Organo-zinc Promoted Diastereoselective C-Arylation of 1,2-Anhydrosugars from Arylboronic Acids

Article abstract of DOI:10.1021/acs.orglett.5b02364

α-C-arylglycosides can be obtained through the addition of aryl zinc reagents to sugar epoxides. The required aryl zinc nucleophiles can be easily obtained from the corresponding boronic acids by B-Zn exchange and attack sugar 1,2 epoxides in a highly diastereoselective fashion to generate 1,2-cis-α-hexapyranosyl aryl glycosides under ligand- and base-free conditions.

Full text of DOI:10.1021/acs.orglett.5b02364

Letter
pubs.acs.org/OrgLett
Organo-zinc Promoted Diastereoselective C‑Arylation of 1,2-
Anhydrosugars from Arylboronic Acids
Madhu Babu Tatina,† Anil Kumar Kusunuru,† and Debaraj Mukherjee*,†
†Academy of Scientific and Innovative Research (AcSIR), Indian Institute of Integrative Medicine (IIIM-CSIR), NPC-Division,
Jammu-180001, India
S
* Supporting Information
ABSTRACT: α-C-arylglycosides can be obtained through the
addition of aryl zinc reagents to sugar epoxides. The required
aryl zinc nucleophiles can be easily obtained from the
corresponding boronic acids by B−Zn exchange and attack
sugar 1,2 epoxides in a highly diastereoselective fashion to
generate 1,2-cis-α-hexapyranosyl aryl glycosides under ligand-
and base-free conditions.
report is available in the literature which deals with the
intramolecular delivery of the aryl group from a 2-O-
aryldialkylsilyl substituent.8b However, the above-mentioned
method requires multistep generation of a monosaccharide unit
with a silicon-tethered electron-rich aryl group at the 2-position
and an O-pentenyl group at the anomeric center, thus limiting
the substrate scope.8b
C-Aryl glycosides are an important class of compounds often
possessing significant biological properties.1 Several of them,
Figure 1. Medicinally important C-aryl glycosides.
such as Vitexin, Orientin,2 Bergenin,3 and Papulacandin D4
(Figure 1), are naturally occurring with promising medicinal
activity. They can also serve as inhibitors of carbohydrate
processing enzymes.5 The importance of aryl C-glycosides can
be realized from the fact that some of them (Figure 1) are now
FDA approved drugs for diabetics,6 e.g. Dapagliflozin,
Canagliflozin, etc.
Although there are several methods for the synthesis of the
β-aryl glycosides,7 only a few methods are available for the α-
epimers.8 One way of achieving this is to perform metal-
catalyzed cross-coupling reactions between 1-bromo glycosides
and organometallics where stereoselectivity depends strongly
on the nature of the sugar unit; e.g., bromo mannoside and
galactoside afforded desired α-glycosides whereas bromogluco-
sides gave a mixture of anomers, all in moderate yield. From a
synthetic point of view, the stereoselective generation of 1,2-cis-
α-hexapyranosyl aryl glycosides is challenging and only one
It is therefore desirable to have a direct practical strategy for
the synthesis of medicinally important 1,2-cis-α-hexapyranosyl
aryl glycosides with a broad substrate scope and predictable
stereoselectivity. In continuation of our efforts in the field of C-
Received: August 16, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02364
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Optimization of Diethylzinc (2) Promoted One-Pot
Arylglycosylation Using Phenylboronic Acid (1) and Glucal
Epoxide (3)
Scheme 1. Substrate Scope of Arylboronic Acids for α-
Arylation with Glucal Epoxide
reaction conditions
b
time
(h)
yield
(%)
a
c
entry solvent t (°C)
additive
α/β
1
2
3
4
5
6
7
8
toluene
toluene
THF
rt
60
rt
rt
rt
rt
rt
rt
−
−
−
−
6
36
α only
α only
20/1
d
3
68
6
25
20
35
42
40
45
DCM
6
20/1
toluene
toluene
toluene
toluene
BF3·OEt2
ZnCl2 in THF
AlCl3 in THF
0.33
0.33
0.33
0.33
20/1
α only
20/1
e
ZnBr2 in
toluene
α only
9
toluene
rt
Cu(OTf)2
0.33
20
3/1
a
b
c
20 mol % of Lewis acid was used. Isolated yields. Diastereomeric
d
ratio determined from 1H NMR of crude product. Other minor
byproducts were ethyl glycoside (15−20%) and diol from hydrolysis of
e
the epoxide. Under the same reaction conditions, 20% of β-
arylglycoside was obtained when phenylboronic acid was replaced by
4-tert-butylphenylboronic acid.
glycosylation,9 now we would like to disclose a ligand- and
base-free general strategy for the diastereoselective synthesis of
α-C-aryl glycosides through regioselective ring opening of 1,2-
anhydro sugars with aryl zinc reagents derived by facile B−Zn
exchange. There are a few reports available in the literature
which describe the opening of 1,2-sugar epoxides by different
organometallic nucleophiles such as phenyl-derived aluminu-
m,11a titanium,11b boron,11c zinc,11d,e magnesium,11f,g cop-
per,11h and lithium11i reagents. However, it is difficult to
predict the stereochemical outcome of such processes, which
appears to be substrate and/or nucleophile specific, and
sometimes mixtures of α- and β-C-glycosides are obtained.8a
Further, site nonspecific metal−halogen exchange for dihalo-
substituted aryl compounds can generate undesired side
products making them synthetically less practical. Other
limitations include the lack of commercial availability of many
aryl nucleophiles and requirement for conducting reactions at
cryogenic temperatures.11
diethylzinc.12 The organozinc species could be easily
generated13 from the corresponding readily available14
arylboronic acids via a facile B−Zn exchange process thereby
greatly expanding the scope of C-aryl glycoside formation.
With the above-mentioned background, we initiated our
study with phenylboronic acid (1), which was converted to
requisite phenyl zinc reagent by the reaction with diethyl zinc
reagent in toluene. The exchange reaction occurred within 1 h
at 60 °C. Subsequent addition of glucal 1,2-epoxide (3)
resulted in a new product which was characterized as the aryl
glycoside from spectroscopic analysis. The stereochemistry of
the α-C-glycosides was assigned from the coupling constant, the
J1,2 value ranging from 4.2 to 5.9 Hz. This small J1,2 value was
indicative of their cis arrangement (α-C-aryl glycosides) which
In order to overcome all these above limitations we thought
of an alternative strategy for the opening of glycal epoxides by
arylzinc reagents generated from aryl boronic acids and
B
DOI: 10.1021/acs.orglett.5b02364
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
butylphenylboronic acid (Table 1, footnote e) was used as the
aryl nucleophile.
Scheme 2. Substrate Scope for α-Arylation with D-Galactal
and D-Xylal Epoxide
The substrate scope of this methodology was tested using
various phenylboronic acids (3b−3p) derived from electron-
rich and electron-deficient aryl boronic acids, and the results are
summarized in Scheme 1. The reaction worked well in the case
of aryl nucleophiles derived from electron-rich aryl boronic
acids, and the desired products (3f, 3k) were obtained in
reasonably good yield.
In the case of dihalo substituted phenylboronic acid,
chemoselective activation of boron in the presence of a halogen
occurred to afford the corresponding products (3m, 3n).
Finally in the case of o/m/p-alkyl substituted aryl boronic acids,
the expected products (3b, 3g−3j, 3l) were isolated in good
yields. Unfortunately 4-nitro phenyl (3q) and 4-pyridyl boronic
acids (3r) failed to react under the optimized reaction
conditions.
This methodology was further elaborated to other glycal
epoxides such as D-galactal epoxide and D-xylal epoxide, and in
those cases the expected products (Scheme 2, 4a−4e) were
isolated in good yields. Even though it is not possible to
synthesize arylmannosides via this method, it is easy to convert
α-C-arylglucoside to α-C-arylmannosides (Scheme 3) by
oxidation−reduction due to the availability of the free C-2
hydroxyl group.
Scheme 3. Conversion of α-Arylglucoside to α-
The high diastereoselectivity observed for the α-arylation of
the sugar epoxides may be explained in the following way
(Scheme 4). The Lewis acidic character of in situ generated
PhZnEt activates the epoxide ring (I, Scheme 4) and thereby
assists oxocarbonium ion (II) formation. The intramolecular
delivery of the aryl substituent to the anomeric carbon may take
place thereafter. In this working model, the syn attack of the
arylzinc reagent to the anomeric carbon results in diaster-
eomerically pure α-aryl glycoside.
Arylmannoside
In summary, we have developed an organo-zinc promoted
diastereoselective C-arylation of 1,2-anhydrosugars from aryl
boronic acids. High diastereoselectivity was achieved using
these in situ generated, ortho/meta/para-substitued arylzinc
reagents and sugar epoxides. Our methodology allows transfer
of a broad range of aryl groups, since a large number of arylzinc
reagents can be efficiently prepared from the corresponding
boronic acids. The presence of a free C-2 hydroxyl group in the
products makes them a suitable acceptor for 2-branched
oligosaccharide or natural product synthesis.
Scheme 4. Plausible Mechanism for the Formation of α-Aryl
Glycoside
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02364.
Experimental procedures; 1H, 13C spectra of all
compounds (PDF)
was further confirmed by comparing the literature data.11a
Other aprotic solvents such as CH2Cl2 and THF failed to give
satisfactory yields, thus identifying toluene as the solvent of
choice. It is pertinent to mention that addition of external
Lewis acids such as BF3·OEt2, AlCl3, Cu(OTf)2, ZnCl2, and
ZnBr2 (Table 1, entries 5−9) only accelerated the product
formation with decreased yield and selectivity Surprisingly,
addition of the external Lewis acid ZnBr2 in toluene led to the
formation of the β-aryl glycoside in lower yield when 4-tert-
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: dmukherjee@iiim.ac.in.
Notes
The authors declare no competing financial interest.
IIIM Publication Number: IIIM/1827/2015.
C
DOI: 10.1021/acs.orglett.5b02364
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(9) (a) Lambu, M.; Hussain, A.; Sharma, D. K.; Yousuf, S. K.; Singh,
B.; Tripathi, A. K.; Mukherjee, M. RSC Adv. 2014, 4, 11023.
(b) Tatina, M.; Kusunuru, A. K.; Yousuf, S. K.; Mukherjee, D. Org.
Biomol. Chem. 2014, 12, 7900−7903. (c) Kusunuru, A. K.; Yousuf, S.
K.; Tatina, M.; Mukherjee, D. Eur. J. Org. Chem. 2015, 2015, 459−462.
(d) Tatina, M.; Kusunuru, A. K.; Yousuf, S. K.; Mukherjee, D. Chem.
Commun. 2013, 49, 11409. (e) Kusunuru, A. K.; Tatina, M.; Yousuf, S.
K.; Mukherjee, D. Chem. Commun. 2013, 49, 10154. (f) Kusunuru, A.
K.; Jaladanki, C. K.; Tatina, M. B.; Bharatam, P. V.; Mukherjee, D. Org.
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ACKNOWLEDGMENTS
■
Authors are thankful to CSIR-IIIM (MLP4015, BSC0108) for
generous funding. T.M.B. and A.K. thank CSIR-New Delhi for
senior research fellowships.
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