'Off-template site' intramolecular nitrone cycloaddition (INC) reactions on sugar-derived allylic ethers - A study on the substituent effect and synthesis of furano-pyrans

Article abstract of DOI:10.1016/S0040-4039(01)01889-5

Sugar-derived allylic ethers having one or two substituents on the terminal olefinic carbon centre were subjected to intramolecular nitrone cycloaddition (INC) reactions resulting in bicyclo[4.3.0] systems. The exclusiveness of product formation may be attributed to the effect of substituents.

Full text of DOI:10.1016/S0040-4039(01)01889-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8893–8896
‘Off-template site’ intramolecular nitrone cycloaddition (INC)
reactions on sugar-derived allylic ethers—a study on the
substituent effect and synthesis of furano-pyrans†
G. V. M. Sharma,a,* K. Ravinder Reddy,a A. Ravi Sankarb and A. C. Kunwarb
aD-211, Discovery Laboratory, Organic Chemistry Division III, Indian Institute of Chemical Technology,
Hyderabad 500 007, India
bNMR Group, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 8 June 2001; revised 6 September 2001; accepted 5 October 2001
Abstract—Sugar-derived allylic ethers having one or two substituents on the terminal olefinic carbon centre were subjected to
intramolecular nitrone cycloaddition (INC) reactions resulting in bicyclo[4.3.0] systems. The exclusiveness of product formation
may be attributed to the effect of substituents. © 2001 Published by Elsevier Science Ltd.
Cycloaddition reactions, in particular 1,3-dipolar
cycloaddition1 reactions, play a prominent role in
organic synthesis since the newly generated ring systems
are highly amenable for further transformations leading
to versatile intermediates. Fused O-heterocycles, such
as furano- and pyrano-pyrans, being constituents of
bioactive compounds,2 are targets for synthetic organic
chemists. Sugar based 1,3-dipolar cycloaddition prod-
ucts, either of intra- or intermolecular reactions, are
highly useful chiral systems both for further elaboration
and biological evaluation. Our recent work on the
intramolecular oxime–olefin cycloaddition (IOOC) pro-
tocol, resulted in a new sugar-derived furano-pyran
isoxazolidine,3 the first sugar based isoxazolidine auxil-
iary. On the other hand, using the intramolecular
nitrone cycloaddition (INC) protocol on
D-glucose-
derived 3-O-allyl ethers, Collins4 and Bhattacharya5,6
reported the synthesis of oxepane systems.7 In continu-
ation of our efforts8–13 on the synthesis of new ‘glyco-
substances’ from monosaccharides, herein we describe
the results of the INC protocol on
D-glucose-derived
3-O-allylic ethers and the effect of allylic substituents
on the product formation (Eq. (1)).
D
-glucose-derived 3-O-prenyl ether, through the
CH3
OHC
O
R
N
HH
O
H
CH3NHOH.HCl
O
R'
O
O
(1)
Et3N, Toluene
Reflux, 5 h
R'
O
O
R
O
O
CH3
HH
CH3
HH
OHC
N
N
O
H
O
O
H
Me(3)
(4)Me
O
O
b
CH3NHOH.HCl
8 d
1
5
4
+
6
c
O
O
Et3N, Toluene
Reflux, 5 h
51%
O
O
a O
O
3
2
7
O
Me(1)
O
O
(S)H
H(R)
1
2
Me(2)
3
Scheme 1.
* Corresponding author. E-mail: esmvee@iict.ap.nic.in
† IICT Communication No. 4789.
0040-4039/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0040-4039(01)01889-5

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G. V. M. Sharma et al. / Tetrahedron Letters 42 (2001) 8893–8896
Accordingly, 1 (Scheme 1) derived3 from
D-glucose was
sively and (b) unlike the case of the IOOC reaction of
3-O-prenyl ethers, the corresponding INC reaction
resulted in cis- and trans-fused isoxazolidines. These
results could well be attributed to the steric effect of the
methyl groups that are present on the allylic double
bond.
subjected to an INC reaction with MeNHOH·HCl and
Et3N in toluene to afford a separable (silica gel, 60–120
mesh; ethyl acetate:petroleum ether, 1:9) mixture of 2
1
and 3 (2:1). The H and 13C NMR study indicated that
2 and 3 are fused rather than bridgehead isoxazolidines,
since chemical shift of protons corresponding to a
bridgehead methine were absent. Unlike our earlier
results on IOOC reactions of 1 the two products
Having observed disparities in the IOOC and INC
reactions on 1 giving cis- and cis/trans-fused products,
the study was extended to the mono substituted allylic
ethers 12–14, prepared from diacetone glucose 4.
Accordingly, 4 on reaction (Scheme 2) with crotyl and
cinnamyl chlorides gave the corresponding ethers 6 and
7, respectively, while the known14 allyl ether 5, was
subjected to ozonolysis and Wittig olefination
(Ph3PꢀCHꢁCO2Me, benzene, D) to give 8. Hydrolysis
of 6–8 (60% aq. AcOH) and oxidative cleavage of diols
9–11 with NaIO4 gave 12–14, respectively.
1
obtained here should be epimeric at C (6). In the H
NMR spectrum of 2, the coupling constant of 11.7 Hz
for JH6–H7 (pro-R) indicates a 1,2-diaxial disposition in a
chair conformation, while JH4–H5=1.8 Hz suggests that
H5 is trans to H4 with the (S)-configuration at C5.
Small values of the couplings involving the protons at
the centres of ring fusion are consistent with the cis
stereochemistry for all the three five-membered rings a,
b and d. The inter ring NOE shown in Fig. 1 confirmed
the envelope conformation for rings a and d. The
flagpole–flagpole and 1,3-diaxial proximities between
H3–H6, H4–H6 and H5–H7 (pro-S) in the NOE stud-
ies on 3 (Fig. 1) amply indicate a distorted boat struc-
ture for the pyran ring and infer a trans-fused
isoxazolidine ring unlike that in 2. The coupling con-
stants JH5–H6=12.8 Hz, JH6–H7 (pro-R)=8.3 Hz and
JH6–H7 (pro-S)=11.2 Hz agree well with the pro-
posed configuration.
Compound 14 on an IOOC reaction (Scheme 3) with
NH21OH·HCl and Et3N in ethanol gave 15. From exten-
sive H and 13C spectral analysis it was evident that 15
is neither a fused nor a bridged isoxazolidine, but an
oxazepine derivative. The observation of an NOE
between H3–H8 (pro-R) as well as between H5–H7
implies their diaxial disposition, while the vicinal cou-
pling JH7–H8 (pro-R)=11.4 Hz and JH7–H8 (pro-S)=4.2 Hz
suggests that H7 and H8 (pro-R) are trans to each
other. This unambiguously indicates that H3 and H8
(pro-R) are on one side, while H5 and H7 are on the
opposite side of the seven-membered ring, which takes
a deformed chair structure. The other characteristic
NOEs which further support the structure are shown in
Fig. 2. Thus the formation of 15 is the result of a
Michael addition and concomitant cyclisation reaction
of NH2OH.
Thus, from extensive NMR studies it was evident that
(a) unlike the case of the 3-O-allyl ether, the INC
reaction of 3-O-prenyl ether gave furano-pyrans exclu-
N
N
O
H
H
O
H
O
H
H
O
O
H
H
O
H
H
O
H
O
H
H
O
H
O
H
H
H
Aldehyde 14, when subjected to an INC reaction with
MeNHOH·HCl–Et3N in toluene at reflux, afforded a
mixture of 16 and 17 (59%; 2:1), which were found to
be fused isoxazolidines similar to 2 and 3. The cou-
2
3
Figure 1.
R=H
O
O
O
1. O3, CH2Cl2
-78oC, 1 h
O
O
O
O
R
Br
R
O
O
O
O
O
2. Ph3P=CHCO2Me
Benzene, 5 h,
NaH, DMF
O
HO
O
0oC to rt, 1 h
O
O
4
MeO2C
Reflux
78%
O
5 R=H (96%)
6 R=Me ( 87%)
7 R=Ph (83%)
8
HO
HO
O
OHC
O
O
60% aq.CH3COOH
rt, 12 h
NaIO4, aq NaHCO3
6,7,8
O
O
O
O
CH2Cl2, 0oC to rt, 5 h
R
O
R
12 R=Me (89%)
13 R=Ph (91%)
14 R=CO2CH3 (93%)
9 R=Me (86%)
10 R=Ph (89%)
11 R=CO2CH3 (87%)
Scheme 2.

G. V. M. Sharma et al. / Tetrahedron Letters 42 (2001) 8893–8896
8895
HO
H
HO
O
1
5
H
4
NH2OH.HCl
9
N6
14
O
O
Et3N. EtOH,
7
3
2
8
H3CO2C H
(S)H
O
10 to 15oC, 1 h
69%
H(R)
15
CH3
CH3
CH3
HH
N
HH
N
HH
N
O
H
O
H
O
H
O
O
O
CH3NHOH.HCl
H
R
H
2, 13, 14
+
Et3N, Toluene
Reflux, 5 h
+
O
O
O
O
H
O
O
R
R
O
O
O
16 R=CO2CH3
18 R=Ph (61%)
19 R=Me
17 R=CO2CH3
20 R=Me
Scheme 3.
N
H
OH
N
H
OO
H
H
H
OO
H
O
H
H
O
O
HO
H
O
O
H
N
O
H
H
H
H
H
Me
O
O
O
H
H
H
O
O
O
H
H
H
O
H
H
O
H
H
O
O
H
H
H
15
17
16
Figure 2.
under INC conditions, the furano-pyrans are obtained
as exclusive products, rather than the oxepanes, which
may be attributable to the steric effect of the sub-
stituents. Similarly, the IOOC reaction on the allylic
ether (with CO2Me) gave an oxazepine ring while an
isoxazolidine was obtained from the INC reaction. The
substituent effect is clearly evident in the exclusive
formation of fused isoxazolidines, where additional
stereocentres can be incorporated for further manipula-
tions. Additional work on the synthesis of fused isoxa-
zolidines as chiral linkers is in progress in our
laboratories.
plings and NOE results for 16 were very similar to
those of 2 with the NOE of H8 with H7 (pro-S) and H7
(pro-R), indicating H8 to be trans to H6 with the
(S)-configuration at C8 (Fig. 2). The results from 17
were similar to those of 3. The presence of an H8–H5
NOE supports the (R)-configuration at C8, H8 being
trans to H6 (Fig. 2). Further confirmation was obtained
from the NOE between H8 and H7 (pro-S).
Similarly, the INC reaction on 13 (R=Ph) gave 18 as
the exclusive product, which was identified from exten-
sive spectroscopic data, while 12 (R=Me) afforded a
mixture of 19 and 20 (66%) in a 9:1 ratio. The ring
junction stereochemistry was unambiguously assigned
from NMR data. Adduct 19 has a structure similar to
that of 16, whereas 20 is the epimer of 19 at C-8.
Additional NOEs between Me-3 with H5 in 19 and
Me-3 with H7 (pro-R), H7 (pro-S) in 20, further sup-
ported the assigned stereochemistry.
Acknowledgements
One of the authors (K.R.R.) is thankful to the CSIR,
New Delhi, for financial support.
The regiochemical outcome of the present study with
the exclusive formation of bicyclo[4.3.0] systems may be
attributed to the flexibility in the transition state (Fig.
3). In the preferred transition state (A), due to the
presence of substituent(s) at the terminal olefinic car-
bon, the formation of the exo isomer is highly favoured
due to steric reasons.
N
N
O
O
O
O
R
R'
O
R'
O
O
O
O
O
R
A (exo)
Thus, in conclusion we have reported substituent effects
on the intramolecular 1,3-dipolar cycloaddition of 3-O-
allylic ethers, where unlike in the case of an allyl ether,
B (endo)
Figure 3.

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G. V. M. Sharma et al. / Tetrahedron Letters 42 (2001) 8893–8896
8. Sharma, G. V. M.; Hymavathi, L.; Radha Krishna, P.
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