Construction of Fused Oxabicyclic Scaffolds from Glycals and Styrenes via One-Pot Domino Transformations

Article abstract of DOI:10.1021/acs.orglett.9b00234

Triflic acid catalyzed cascade stereoselective reaction of glycals with styrenes delivers complex oxabicyclic scaffolds such as cis-oxadecalins or cis-cyclopentanofurans simply by tweaking the solvent. In the presence of participating solvents like benzene/toluene, cascade Ferrier C-glycosylation and double Friedel-Crafts reaction leads to densely chiral benzo-fused oxadecalins, whereas in DCM, an unprecedented ring-opening, ring-closing sequence generated cis-cyclopentanofurans. An attempt has been made to explain the above cascade sequences via intermediate trapping, kinetic experiments, and Baldwin's rules.

Full text of DOI:10.1021/acs.orglett.9b00234

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Construction of Fused Oxabicyclic Scaffolds from Glycals and
Styrenes via One-Pot Domino Transformations
Monika Bhardwaj,†,§ Faheem Rasool,†,‡,§ Madhu Babu Tatina,† and Debaraj Mukherjee*,†,‡
†Natural Product Chemistry Division, Indian Institute of Integrative Medicine (IIIM), Jammu 180001, India
‡Academy of Scientific and Innovative Research (AcSIR-IIIM), Jammu 180001, India
S
* Supporting Information
ABSTRACT: Triflic acid catalyzed cascade stereoselective
reaction of glycals with styrenes delivers complex oxabicyclic
scaffolds such as cis-oxadecalins or cis-cyclopentanofurans
simply by tweaking the solvent. In the presence of
participating solvents like benzene/toluene, cascade Ferrier
C-glycosylation and double Friedel−Crafts reaction leads to
densely chiral benzo-fused oxadecalins, whereas in DCM, an
unprecedented ring-opening, ring-closing sequence generated
cis-cyclopentanofurans. An attempt has been made to explain
the above cascade sequences via intermediate trapping, kinetic
experiments, and Baldwin’s rules.
under Lewis acid conditions.5f This prompted us to investigate
reation of molecular complexity from common starting
Cmaterials with high efficiency maintaining stereochemical whether weak nucleophiles like styrene can attack the
anomeric carbon of glycal in the presence of Lewis acids and
to find out the fate of the benzylic carbocation (A) thus
generated (Scheme 1a). Toward this goal, we commenced our
study with tri-O-acetyl-D-glucal (1) and 4-methylstyrene as
model substrates in the presence of various Lewis acids and
solvents at different temperatures. This showed that the nature
of the Lewis acid played a significant role on the fate of the
reaction. For example, in the presence of halogenated Lewis
acids such as FeCl3 or FeBr3, the benzylic carbocation formed
after initial attack on anomeric carbon by styrene was trapped
by the halide nucleophile to produce 3 and 4 (Table 1, entries
1 and 2), respectively, as the only products but as
diastereomeric mixtures. To avoid the use of halogenated
Lewis acids, TfOH was used. With 0.2 equiv of TfOH at −30
°C (Table 1, entry 3), we observed the formation of a UV-
inactive anomeric hydroxyl carbohydrate product 6 without
attachment of styrene. Increasing the proportion of TfOH as
well as temperature (Table 1, entry 4) led to the formation of
products 5 and 6. Further increase of the reaction temperature
to 0 °C (Table 1, entry 5), surprisingly, revealed the formation
of a new product 2 with a decrease in the yield of 5. Detailed
2D NMR analysis revealed the structure 2, an unexpected
cyclopenta[b]furan derivative. It suggested the linkage of
styrene to the anomeric carbon of glucal. Strong correlation
between H1−H6 and H2−H8 signals in 1H−1H COSY of 2
(see Figure 1 in the SI) confirmed their adjacent nature. The
stereochemistry of compound 2 was determined by 2D-
integrity and in minimum synthetic steps while adhering to
economic and environmental considerations constitutes a great
challenge in modern organic synthesis which can be addressed
by domino reactions.1−3 However, doing these types of
consecutive stereoselective reactions in densely functionalized
substrates like carbohydrates poses a challenge. For example,
glycals are cheap and stable carbohydrate-based enol ethers
used extensively in the synthesis of biologically important
complex molecules,4 but these have been employed in only few
cascade reactions.5 During the past several years we have been
involved in the development of new domino reactions of
glycals leading to the synthesis of substituted furfuryl
derivatives,5a vinyl-C-glycosides5c and α,β,γ,δ-conjugated chi-
rons5d using different Lewis acid catalysts. In the present paper,
we would like to disclose unprecedented domino reactions of
glycals (I) with styrenes to generate fused chiral oxabicyclic
scaffolds, namely, chiral cyclopenta[b]furans (II) and
oxadecalins (III) by altering the solvents (Scheme 1a). It is
pertinent to mention here that oxabicycles serve as the
structural core for a diverse variety of natural products and
bioactive molecules. For example, cis-fused 1-oxadecalins and
cyclopenta[b]furans are ubiquitously present in bioactive
natural products6 like Phomactine A, Koninginin, Communiol
E, and Communiol F having different biological activities7
(Scheme 1b). Because of their complexity and presence of
multiple stereocenters, stereocontrolled routes to such
scaffolds are always desirable.
The idea stems from our earlier observation in which less
reactive nucleophiles such as unactivated alkynes were
observed to form C−C bond at the anomeric center of glycals
Received: January 25, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00234
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Organic Letters
Letter
from 3-methylstyrene and glucal triacetate and predictably
dihydroxylation occurred via attack at the less hindered β-face.
Scheme 1. (a) Present Work on the Generation of
Oxabicyclic Cores from Glycals and Styrenes in Different
Solvents. (b) Natural Products Containing Oxabicyclic
Rings
Scheme 2. Syn Dihydroxylation of Chiral
Cyclopenta[b]furan 2a
In order to enhance the yield of the cyclopenta[b]furan
product, we increased the concentration TfOH (Table 1,
entries 6 and 7) and screened other Lewis acids (Table 1,
entries 9−11). Summarizing the outcome of our optimization
study, the use of 2 equiv of TfOH at 0 °C in DCM (Table 1,
entry 7) proved to be the best condition for the formation of
cyclopenta[b]furan 2.
The substrate scope of the new reaction was examined by
using various substituted styrenes and glycals resulting in the
formation of the expected products in moderate yield with high
stereoselectivity (Scheme 3). Styrenes possessing either
electron-donating (Scheme 3, entries 2a and 2b) or -with-
drawing (Scheme 3, entries 2d−2j) groups undergo similar
type of conversion generating various cyclopenta[b]furan
scaffolds, but those with EDGs ensured somewhat better
yields. Moreover, no reaction occurs in the case of highly
electron-deficient styrenes like 4-cyano- and 4-nitrostyrenes,
whereas α-methylstyrene gives a complex mixture of products
which could not be resolved. A series of other glycals were also
examined under the standard reaction conditions.
Table 1. Reaction of Tri-O-acetyl-D-glucal with Styrene
under Various Lewis Acid Conditions
a
We also investigated the role of aromatic solvents which may
participate in the above transformation to trap the benzylic
carbocation initially generated from the glycosylation of
styrene with glycals and thereby initiate a new kind of cascade
reaction (Scheme 1a, path ii). Thus, we carried out the
reaction of tri-O-acetyl-D-glucal (1) with styrene in the
presence of TfOH (2 equiv) at 0 °C in benzene (Table 2,
entry 1). A new product different from 2 was obtained and
characterized as compound 7 by extensive NMR analysis and
mass spectroscopy (see the SI). The oxadecalin ring fusion
must be cis (J = 5.7 Hz), as a trans-fused ring will have both the
ring juncture protons axially oriented showing higher coupling
constant. Various non-nucleophilic Lewis acids in different
proportions were then screened under different conditions
(Table 2). The temperature and amount of TfOH played a
very important role on the yield of the reaction. From the
optimization study, addition of 30 mol % of TfOH at 0 °C to a
solution of tri-O-acetyl-D-glucal (1 equiv) and styrene (1
equiv) in benzene followed by the stirring of the reaction
mixture at 40 °C for 2 h were found to be the best conditions
(SI, Table 2, entry 8).
entry Lewis acid (equiv) temp (°C) time (h) product yield (%)
1
2
FeCl3 (1)
FeBr3 (1)
0
0
1
1
3
4
55
62
3
4
5
6
7
8
9
10
11
TfOH (0.2)
TfOH (0.5)
TfOH (0.5)
TfOH (1)
TfOH (2)
TfOH (1)
TMSOTf (1)
BF3·Et2O (1)
Cu(OTf)2 (1)
−30
−10
0
0
0
rt
0
0
0
1
6
60
0.5
0.5
0.5
0.5
0.5
0.5
1
5:6
2:5
2:5
2:5
ND
2:5:6
6
55:10
15:45
35:25
50:20
20:20:10
20
1
ND
a
Reactions were carried out using 1 (1 equiv) and 4-methylstyrene (1
equiv) in 3 mL of dichloromethane.
NOESY (see Figure 1 in the SI). The coupling constant of 5.5
Hz for an alkene proton confirms cyclopentene moiety.8
Finally, in order to find out the position of double bond in
cyclopenta[b]furan moiety we have conducted syn dihydrox-
ylation by OsO4−NMO of derivative 2a (Scheme 2) derived
The substrate scope of the new cascade reaction was
expanded by taking various substituted styrenes with tri-O-
acetyl-D-glucal (1) in aromatic solvents like benzene and
toluene to get the products in good yields (Scheme 4). In the
case of symmetrically substituted diaryl compounds, only one
B
DOI: 10.1021/acs.orglett.9b00234
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Scheme 3. Substrate Scope of the Reaction of Glycals with
Various Styrenes in Dichloromethane under Optimized
Reaction Conditions
Table 2. Reaction of Tri-O-acetyl-D-glucal with Styrene in
Benzene
a
a
entry
Lewis acid (equiv)
temp (°C)
time (h)
yield (%)
1
2
3
4
5
6
7
TfOH (2)
0
0
0
0
0
0
4
4
0.25
0.25
0.25
5
40
30
ND
ND
ND
45
TMSOTf (1)
ZnOTf (1)
CuOTf (1)
BF3.Et2O (1)
TfOH (0.5)
TfOH (0.1)
TfOH (0.3)
rt
0−40
2
2
40
73
b
8
a
Reactions were carried out using tri-O-acetyl-D-glucal (1 equiv) and
styrene (1 equiv) in 3 mL of benzene to which TfOH was added.
b
Addition of TfOH to a solution of glucal (1 equiv) and styrene (1
equiv) in benzene was done at 0 °C, then the reaction was stirred at
40 °C.
Scheme 4. Substrate Scope of the Reaction of Glycals with
Various Styrenes in Nucleophilic Solvents (Benzene and
a
Toluene) under Optimized Reaction Conditions
a
Reactions were carried out by using glycal (1 equiv), styrene (1
equiv), and TfOH (2 equiv) in 3 mL of CH2Cl2 at 0 °C for 30 min.
product was observed (Scheme 4, entries 7e and 7f). In the
case of unsymmetrically substituted diaryl products, a mixture
of two inseparable regioisomers was obtained (Scheme 4,
entries 7d and 7h−7k). Although four regioisomers are
possible in the case of products formed from unsymmetrically
substituted intermediates (taking into account the possibility
of o/p substitution in the intermolecular reaction), only two
regioisomeric products were formed in most of the cases as
1
confirmed by H NMR (Scheme 4, entries 7a, 7d, 7h−7k).
Interestingly, with 2-substituted styrenes (except 2-bromostyr-
ene in benzene), only single products were found, with either
the aryl ring of styrene or the solvent participating in the
second Friedel−Crafts reaction (Scheme 4, entries 7b, 7c, and
7g). Regioselectivity of the reaction was determined from the
HMBC (see the SI). Fortunately, when 2-bromostyrene was
reacted in benzene with tri-O-acetyl-D-glucal, we were able to
isolate both the regioisomers in a 5:1 ratio, the major one
being the product where solvent took part in a second
Friedel−Crafts alkylation (Scheme 4, entries 7a and 7a′).
a
Glycal (1 equiv), styrene (1 equiv), TfOH (30 mol %), solvent (3
b
c
mL). Both regioisomers were separated and characterized. Only
structures of major regioisomers were shown, and ratios were
determined from crude H NMR.
1
Since there is no literature precedent on these types of
cascade reactions, we wanted to gain some insight into the
C
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Letter
plausible mechanism by performing control and isotope-
labeling experiments. It is evident that the reaction starts with
initial protonation of the glucal to form oxocarbenium ion IV
(Scheme 5) followed by attack of styrene at the anomeric
Scheme 5. Plausible Mechanism for the Formation of the
Oxadecalins/Cyclopenta[b]furans from Glycals and
a
Styrene
Figure 1. (i) Reaction of tri-O-acetyl-D-glucal and styrene with
temperature variation. (ii) Isotopic-labeling experiments: (a) reaction
with normal benzene and deuterated benzene, (b) KIE plot.
*Reaction monitoring by HPLC using 0.1% formic acid in water
(A) and acetonitrile (B) in gradient, temp 35 °C, flow rate 1 mL/min,
at wavelength 210 nm in Column LiChrospher C18, 250 mm × 5 μm.
a
Mechanism of formation of 2c and 7 from 1.
disubstituted diphenyl derivatives, two regioisomers may be
observed depending upon which ring takes part in the second
Friedel−Crafts reaction controlled by cumulative effects of
activation or deactivation exerted by each substituent.
In addition we have carried out isotope labeling experiment
to find out the slowest step of these cascade reactions. For that
purpose, we installed two set of reactions in which glucal
triacetate and styrene were allowed to react in the presence of
normal benzene and deuterated benzene at 0 °C with the
addition of 0.03 mol % of TfOH at 30 min time intervals and
monitored it through HPLC up to 120 min. The kH/kD value
of 1.31 determined from the absolute rates of two set of
reactions showed that the glycosylation step is the slowest step
(Figure 1ii).
In conclusion, we have developed two new cascade reactions
in which bicyclic cis-fused oxabicylic scaffolds, namely,
benzannulated oxadecalins and cyclopenta[b]furans, were
synthesized from glycals and styrenes in a highly stereo-
selective fashion. The solvent played a major role in the
outcome of the reaction. Only TfOH has been used as a
catalyst to obtain such complex scaffolds without activation of
any of the starting materials. Isotope-labeling studies reveal
that glycosylation is the slowest step of the reaction sequence.
These metal-free domino reactions have allowed a fundamen-
tally new type of transformation to be discovered that has
significant potential in chemistry and chemical biology.
carbon from the α-side leading to the formation of a stable OH5
benzyl carbocation A. The attack of the styrene from the β-side
leads to the formation of a less stable 1,4B boat conformation
VI, making it less feasible. Intermediate A possibly undergoes
intramolecular cyclization following a 4-exo-trig process,
favored under Baldwin’s rules of cyclization forming V.
Subsequent 1,2-shift then leads to the formation of carbocation
VII, which is stabilized by the neighboring oxygen atom to
form oxiranyl cation VIII. Ring opening of the oxiranyl cation
with deprotonation gives cyclopenta[b]furan product 2c.
In presence of an external nucleophile like benzene, the
intermediate A is likely to undergo double displacement via
two consecutive Friedel−Crafts alkylation reactions to give the
oxadecalin core. In order to explain this, we carried out the
reaction of tri-O-acetyl-D-glucal with styrene at 0 °C in
benzene using 10 mol % of TfOH and quenched the reaction
at short intervals (after 15 min) to trap the likely intermediate
A. Indeed, we obtained a new product 7aa via Friedel−Crafts
alkylation of benzene with the carbocation A. Further reaction
of 7aa in the presence of TfOH at 40 °C via Friedel−Crafts
alkylation of the diphenyl derivative with the C-2 carbocation
of the pyran ring derived from the second acetyl elimination
ends up in the cyclized product 7 (Figure 1i). At this stage,
chemoselectivity is determined. In the case of unsymmetrically
D
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Org. Lett. XXXX, XXX, XXX−XXX

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Letter
(7) (a) Cutler, H. G.; Cutler, S. J.; Ross, S. A.; Sayed, K. El.; Dugan,
F. M.; Bartlett, M. G.; Hill, A. A.; Hill, R. A.; Parker, S. R. J. Nat. Prod.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00234.
■
S
(8) Solkan, V. N.; Sergeyev, N. M. Org. Magn. Reson. 1974, 6, 200.
Experimental procedures, 1H and 13C NMR spectra, and
characterization of all compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: dmukherjee@iiim.ac.in.
ORCID
Debaraj Mukherjee: 0000-0002-2162-7465
Author Contributions
§M.B. and F.R. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are thankful to DST-India (EMR-2016-004710)
and CSIR (HCP0008) for funding. M.B. and F.R. thank CSIR-
New Delhi for JRF and SRF. Publication No. IIIM/2187/
2019.
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