A general norbornyl based synthetic approach to carbasugars and 'confused' carbasugars

Article abstract of DOI:10.1016/S0040-4039(01)01454-X

The norbornyl system has been recognized simply as a 'locked' carbasugar and a short, general approach to carbasugars and their new siblings, 'confused' carbasugars, from readily available 7-ketonorbornanes is reported.

Full text of DOI:10.1016/S0040-4039(01)01454-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7663–7666
A general norbornyl based synthetic approach to carbasugars
and ‘confused’ carbasugars
Goverdhan Mehta,* Pinaki Talukdar and Narinder Mohal
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
Received 28 July 2001; accepted 7 August 2001
Abstract—The norbornyl system has been recognized simply as a ‘locked’ carbasugar and a short, general approach to
carbasugars and their new siblings, ‘confused’ carbasugars, from readily available 7-ketonorbornanes is reported. © 2001 Elsevier
Science Ltd. All rights reserved.
In the pursuit of scientific research, sometimes the most
obvious is either taken for granted or escapes attention.
The bicyclo[2.2.1]heptane (norbornyl) system has been
explored by generations of organic chemists in a myriad
ways ranging from mechanistic and stereochemical
probes to starting point for diverse syntheses.1 How-
ever, the C7-framework of the norbornyl system has not
been recognized as a simple ‘locked’ carbasugar from
which the six-membered C7-carbasugar skeleton can be
easily retrieved through ‘unlocking’ involving C1ꢀC7 or
C4ꢀC7 bond scission. Considering the current wide-
spread interest in the synthesis of carbasugars,2 we
regard our norbornyl approach as short, simple and
conceptually different. We demonstrate here that
indeed, a simple 7-norbornenone derivative like 1 can
be readily elaborated to a variety of carbasugars 2 and
to related new entities that we name ‘confused’ carba-
sugars 3. The ‘confused’ carbasugars 3 have the same
level of oxygenation on the cyclohexanoid framework
as the carbasugars, but the hydroxymethyl and the
‘para’ hydroxy groups are interchanged (see bold por-
tions in 2 and 3). In view of the well-established impor-
endo-2-Acetoxy-7-norbornenone 5 and its precursor
ketal 4, readily available through Diels–Alder reaction
between 5,5-dimethoxy-1,2,3,4-tetrachlorocyclopenta-
diene and vinyl acetate, followed by reductive dehalo-
genation,2b,3 were chosen as the starting points of our
projected syntheses.4 We recognized that dihydroxyla-
tion of the norbornene double bond and cleavage of the
C1ꢀC7 bond with amplification of functionality would
provide direct access to carbasugars. Consequently, 4
was subjected to OsO4-mediated dihydroxylation exclu-
sively from the exo-face to furnish 6. A one-pot cis-diol
protection and acetal deprotection in 6 delivered the
keto-acetonide 7 (Scheme 1). Baeyer–Villiger oxidation
of 7 led to a regioisomeric mixture of lactones 8 and 9
(13:87). LiAlH4 reduction of 8 and 9 yielded triols 10
and 11, respectively. Acetonide deprotection in 10 led
to the pseudo-a-DL-talopyranose carbasugar 12a (char-
acterized as the pentaacetate 12b4a,5). The same depro-
tection in 11 delivered the ‘confused’ carbasugar 13a
(characterized as the pentaacetate 13b6) quite easily
(Scheme 1).
tance of carbasugars
2
and its congeners in
To introduce stereochemical diversity in our synthetic
approach and to fine-tune the relative ratios of the
carba- and ‘confused’ carbasugar formation, an alter-
nate strategy was executed. Chemoselective Baeyer–Vil-
glycomimicry, the first time access to their new siblings,
the ‘confused’ carbasugars 3, should stimulate interest
in the evaluation of their biological activity profile.
hydroxylation
OH
O
OH
7
4
5
HO
HO
C1-C7 scission
C4-C7 scission
3
1
6
2
HO
OH
HO
OH
OH
X
OH
1 X = OH, OAc etc.
2
3
Carbasugar
'Confused' Carbasugar
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01454-X

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G. Mehta et al. / Tetrahedron Letters 42 (2001) 7663–7666
O
O
MeO
HO
MeO
OMe
O
O
OMe
O
O
O
O
i
ii
iii
HO
O
O
O
+
OAc
OAc
OAc
OAc
OAc
13 : 87
6
7
8
9
4
OH
OR
OR
OH
RO
RO
O
O
O
v
v
RO
RO
iv
iv
8
9
O
OR
OH
OH
OR
OH
10
OR
OH
12a R = H
b R = Ac
13a R = H
b R = Ac
11
Scheme 1. Reagents and conditions: (i) OsO4, NMMO (50% aq. solution, 4 equiv.), Me2CO–H2O (4:1), rt, 30 h, 80%; (ii)
Amberlyst-15, Me2CO, rt, overnight, 70%; (iii) MCPBA, NaHCO3, DCM, 0–5°C, 3–4 h, quant.; (iv) LAH, THF, 0–5°C, 2–3 h,
70%; (v) (a) Amberlyst-15, aq. MeOH, rt, overnight, (b) Ac2O, Py, rt, overnight, 72% (two steps).
liger oxidation of norbornenone 5 furnished the lac-
tones 14 and 15 (30:70) (Scheme 2). The minor lactone
14 was first subjected to LiAlH4 reduction to furnish
cyclohexene triol 16. OsO4-mediated dihydroxylation
on 16 was stereospecific from the face opposite to the
DL-mannopyranose 19a (characterized as the penta-
acetate 19b5,10) was the main product formed with only
traces of the regioisomeric pseudo-a-DL-idopyranose.11
In an analogous manner, the major lactone 15 from 5
was reduced with LiAlH4 to furnish two cyclohexene
triols 20 and 21 (75:25) (Scheme 3). Quite unexpectedly,
epimerization had occurred during the hydride reduc-
tion of 15, possibly at the intermediate aldehyde stage
and the hydroxymethyl group in 21 was cis to the
neighbouring hydroxyl group. Dihydroxylation of 20
with OsO4 proceeded stereoselectively to furnish the
‘confused’ carbasugar 22a (characterized as penta-
acetate 22b6). Epoxidation of 20 took a course analogous
to 16 and furnished the trans-epoxide 23.8,9 Acid-cata-
lyzed opening in 23 led to a new ‘confused’ carbasugar
allylic hydroxyl group and furnished pseudo-a-DL
-
altropyranose carbasugar 17a and was fully character-
ized as its pentaacetate 17b.7 In an alternate sequence,
16 was subjected to epoxidation with m-chloroperben-
zoic acid in aqueous medium to furnish trans-epoxide
18 in a stereoselective manner. Interestingly, the epoxi-
dation of 16 was dictated by steric considerations rather
than by the usually encountered directing influence of
the allylic hydroxyl group.8,9 Acid-catalyzed opening of
the epoxide ring in 18 was regioselective and pseudo-a-
O
O
O
O
O
i
+
OAc
OAc
OAc
5
30 : 70
15
14
ii
OR
OH
OR
OH
RO
RO
RO
RO
v
iv
iii
O
OR
OH
OR
OH
OR
OH
16
OR
17a R = H
b R = Ac
OH
18
19a R = H
b R = Ac
Scheme 2. Reagents and conditions: (i) MCPBA, Na2CO3, DCM, 0°C–rt, 4–5 h, 94%; (ii) LAH, THF, −15°C, 2 h, 70%; (iii) (a)
OsO4, NMMO (50% aq. solution, 4 equiv.), Me2CO–H2O (4:1), rt, overnight, (b) Ac2O, Py, rt, 36 h, 78% (two steps); (iv)
MCPBA, H2O, rt, 2 days, 75%; (v) (a) cat. HClO4 (70%), H2O, rt, 24 h, (b) Ac2O, Py, rt, 35 h, 73% (two steps).

G. Mehta et al. / Tetrahedron Letters 42 (2001) 7663–7666
7665
OH
OH
O
O
i
+
OH
OH
20
iii
OH
OH
OH
OAc
15
75 : 25
21
ii
OR
OR
RO
RO
RO
RO
iv
O
OR
OR
OR
OR
OH
OH
22a R = H
b R = Ac
24a R = H
b R = Ac
23
Scheme 3. Reagents and conditions: (i). LAH, THF, −15°C, 2 h, 70%; (ii) (a) OsO4, NMMO (50% aq. solution, 4 equiv.),
Me2CO–H2O (4:1), rt, overnight, (b) Ac2O, Py, rt, 36 h, 76% (two steps); (iii) MCPBA, H2O, rt, 2 days, 77%; (iv) (a) cat. HClO4
(70%), H2O, rt, 24 h, (b) Ac2O, Py, rt, 40 h, 72% (two steps).
24a (characterized as pentaacetate 24b6) in a regioselec-
tive manner (Scheme 3). Similar transformations, dihy-
droxylation and epoxidation ring opening could also be
executed on 21, thus providing additional diversity
among the ‘confused’ carbasugar family. We have car-
ried out preliminary studies of the glycosidase inhibi-
tion ability of ‘confused’ carbasugars 13a, 22a and 24a
towards a panel of six glycosidases. However, no sig-
nificant inhibition has been observed.
Commun. 1997, 2157; (d) Mehta, G.; Khan, F. A. J. Am.
Chem. Soc. 1990, 112, 6140; (e) Mehta, G.; Chan-
drasekhar, J. Chem. Rev. 1999, 99, 1437.
2. (a) Suami, T. Top. Curr. Chem. 1990, 154, 257; (b)
Ferrier, R. J. Chem. Rev. 1993, 93, 2779; (c) Hudlicky, T.;
Entwistle, D. A.; Pitzer, K. K.; Thorpe, A. J. Chem. Rev.
1996, 96, 1195; (d) Landais, Y. Chimia 1998, 52, 104.
3. (a) Jung, M. E.; Hudspeth, J. P. J. Am. Chem. Soc. 1977,
99, 5508; (b) Mehta, G.; Mohal, N. Tetrahedron Lett.
1999, 40, 5791.
4. For norbornyl based approach to cyclohexitols emanat-
ing from our laboratory, see: (a) Mehta, G.; Mohal, N.;
Lakshminath, S. Tetrahedron Lett. 2000, 41, 3505; (b)
Mehta, G.; Lakshminath, S. Tetrahedron Lett. 2000, 41,
3509.
In summary, we have delineated a new and exception-
ally simple approach to carbasugars and their siblings
the ‘confused’ carbasugars, which has built-in flexibility
to create stereochemical diversity. The ‘confused’ carba-
sugars being new entities, deserved to be evaluated
further and elaborated to their amino derivatives as
well as to oligomers. Efforts along these lines are in
progress.
5. Pingli, P.; Vandewalle, M. Synlett 1994, 228.
6. All compounds reported here were fully characterized on
the basis of their spectral (IR, 1H, 13C NMR, MS) and
analytical data. Selected spectral data. 13b: Mp=116–
117°C; IR (neat) wmax 1746 cm−1 1H NMR (300 MHz;
;
CDCl3) l 5.42–5.41 (m, 1H), 5.28–5.13 (m, 3H), 4.26 (dd,
1H, J=11.5, 6.0 Hz), 4.15 (dd, 1H, J=11.5, 8.1 Hz),
2.42–2.34 (m, 1H), 2.30–2.15 (m, 1H), 2.08 (s, 9H), 2.06
(s, 3H), 2.05 (s, 3H), 1.86–1.81 (m, 1H); 13C NMR (50
MHz; CDCl3) l 170.93, 170.00, 169.90, 169.85, 169.70,
69.57, 67.49, 67.28, 67.12, 60.79, 41.82, 29.43, 21.15,
20.92, 20.86, 20.82, 20.75; MS (EI, 70 eV) m/z 388 (M+,
<1%), 328 (5), 166 (90), 124 (70), 83 (74), 43 (100); anal.
found: C, 52.49; H, 6.26. C17H24O10 requires C, 52.57; H,
Acknowledgements
We thank Dr. M. Vairamani, IICT, Hyderabad for the
HRMS data and the SIF facility at IISc for the high
field NMR spectra. One of us (N.M.) thanks CSIR for
a research fellowship. Part of this was carried out at the
University of Hyderabad.
6.23. 22b: Mp=102–103°C; IR (thin film) wmax 1744 cm−1
;
1H NMR (300 MHz; CDCl3) l 5.31–5.27 (m, 1H), 5.17
(dd, 1H, J=11.3, 2.7 Hz), 5.13–5.03 (m, 2H), 4.19 (dd,
1H, J=11.7, 2.1 Hz), 4.12 (dd, 1H, J=11.7, 2.7 Hz),
2.36–2.17 (m, 1H), 2.23 (m, 1H), 2.15 (s, 3H), 2.13 (s,
3H), 2.10 (s, 3H), 2.06 (s, 3H), 2.02 (s, 3H), 1.89–1.80 (m,
1H); 13C NMR (75 MHz; CDCl3) l 170.91, 169.91,
169.79, 169.39, 169.27, 68.10, 67.40, 67.09, 66.29, 58.18,
40.34, 30.67, 21.04, 20.99, 20.83, 20.77, 20.69; MS (EI, 70
eV) m/z 388 (M+, <1%), 328 (20), 166 (44), 124 (66), 43
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7666
G. Mehta et al. / Tetrahedron Letters 42 (2001) 7663–7666
(100); anal. found: C, 52.61; H, 6.25. C17H24O10 requires
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1
1745 cm−1; H NMR (300 MHz; CDCl3) l 5.48–5.38 (m,
2H), 5.14 (dt, 1H, J=11.4, 4.5 Hz), 4.93 (dd, 1H, J=9.9,
3.3 Hz), 4.09 (d, 2H, J=3.0 Hz), 2.34 (td, 1H, J=13.8,
4.5 Hz), 2.16 (s, 3H), 2.08 (s, 3H), 2.07 (s, 3H), 2.07–2.05
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C
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169.62, 73.09, 67.28, 67.05, 65.97, 58.25, 44.95, 33.21,
20.99, 20.92, 20.69, 20.61 (2C); MS (EI, 70 eV) m/z 388
(M+), 328, 166, 124, 95, 43; anal. found: C, 52.74; H,
6.26. C17H24O10 requires C, 52.57; H, 6.23.