Polycyclic scaffolds from fructose

Article abstract of DOI:10.1016/S0040-4039(01)02393-0

Iodocyclisation of polybenzylated allyl α-C-fructofuranoside 1 afforded the bicyclic iodoether 2 through debenzylation at C-1; treatment of 2 with zinc and acetic acid restored the allylic group with concomitant deprotection of the hydroxyl group at C-1, which was oxidised to the corresponding aldehyde 4. Reaction of 4 with vinylmagnesium bromide afforded diene 5, whose double bonds were reacted regioselectively in order to obtain, upon iodocyclisation under different experimental conditions, bicycles 6 or 7, or tricycle 8.

Full text of DOI:10.1016/S0040-4039(01)02393-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1355–1357
Polycyclic scaffolds from fructose
Eleonora Forni,a Laura Cipolla,a Enrico Caneva,b Barbara La Ferla,a Francesco Peria and
Francesco Nicotraa,*
aDepartment of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza 2, I-20126 Milano, Italy
bDepartment of Organic and Industrial Chemistry, University of Milano, Via Venezian 21, I-20133 Milano, Italy
Received 1 February 2001; revised 2 April 2001; accepted 20 December 2001
Abstract—Iodocyclisation of polybenzylated allyl a-C-fructofuranoside 1 afforded the bicyclic iodoether 2 through debenzylation
at C-1; treatment of 2 with zinc and acetic acid restored the allylic group with concomitant deprotection of the hydroxyl group
at C-1, which was oxidised to the corresponding aldehyde 4. Reaction of 4 with vinylmagnesium bromide afforded diene 5, whose
double bonds were reacted regioselectively in order to obtain, upon iodocyclisation under different experimental conditions,
bicycles 6 or 7, or tricycle 8. © 2002 Elsevier Science Ltd. All rights reserved.
Carbohydrates are of great interest, due to their unique
characteristics as polyfunctional molecules which are
enantiomerically pure and conformationally rigid.
These features make this class of compounds particu-
larly attractive as scaffolds for combinatorial chem-
istry,1 and for the design of novel peptidomimetics. For
example, carbohydrates have been used as a rigid back-
bone on which aminoacidic side chains were intro-
duced,2 or as mimics of peptide loops, such as b-turns,
which induce conformational rigidity once included
into bioactive peptides.3
In this context, we are interested in the synthesis of
carbohydrate-derived scaffolds with enhanced confor-
mational rigidity compared to the parent monosaccha-
ride. One possible way to reduce the molecular
flexibility is the introduction of a second, and possibly
a third ring on the sugar backbone. Towards this aim,
BnO
BnO
BnO
BnO
BnO
O
BnO
O
BnO
O
BnO
O
O
OH
OBn
O
(a)
(b)
(c)
CH2I
BnO
BnO
BnO
BnO
3
4
2
1
BnO
BnO
O
CH2I
O
BnO
BnO
BnO
O
CH2I
O
O
O
OH
BnO
(d)
6
CH2I
BnO
BnO
8
5
OH
O
BnOH2C
CH2I
O
H
BnO
7
Scheme 1. (a) I2, dry THF; (b) Zn, AcOH, Et2O/EtOH 1/1; (c) DMSO/Ac2O 2/1; (d) vinylmagnesium bromide, dry THF, 0°C;
(e) I2, dry THF; (f) I2, dry DCM.
* Corresponding author. Tel.: +39.02.64483457; fax: +39.02.64483565; e-mail: francesco.nicotra@unimib.it
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02393-0

1356
E. Forni et al. / Tetrahedron Letters 43 (2002) 1355–1357
then the benzyloxy group at C-3 is involved in a 5-exo
cyclisation with the b-allylic substituent, affording the
bicyclic compound 7 (70% yield based on both
diastereoisomers, in a 6:1 ratio in favour of isomer 7, as
we developed a procedure that allows bi- and tricyclic
compounds to be obtained starting from fructose, one
of the most abundant natural sugars, which does
present interesting features: it possesses two ‘arms’ on
the furanosidic ring, the C-1 and C-6 hydroxymethylene
groups, and offers the possibility of inserting an addi-
tional appendage at the anomeric centre. These arms
can be exploited in the formation of the second and the
third ring, and in further functionalisations.
1
determined by H NMR). It is worth noting that differ-
ent rigid bicyclic structures can be obtained just by
switching the reaction medium. Both these bicyclic
compounds 6 and 7 can undergo further iodocyclisation
in dichloromethane, affording the tricyclic compound 8
as a mixture of diastereomers (66% yield). The full
characterisation of compounds 6 and 7 was performed
Methyl fructofuranoside was benzylated according to
the classical method (NaH, BnBr, DMF, quantitative
yield), and an allylic appendage was then introduced at
the anomeric position by treatment with allyltrimethyl-
silane in the presence of boron trifluoride etherate as
Lewis acid catalyst4 (57% yield). The spatial relation-
ship between the double bond and the oxygen at C-1 in
the polybenzylated allyl a-C-fructoside 1 is such that a
5-exo cyclisation/debenzylation can occur upon treat-
ment with I2 (1.2 equiv.) in THF (Scheme 1). This
reaction afforded the spiro-compound 2 (as a mixture
of diastereomers) in 98% yield. Treatment of compound
2 with zinc in acetic acid gave derivative 3, having the
C-1 hydroxyl group selectively deprotected and the
double bond re-established (80% yield). This selective
deprotection was exploited for the introduction of a
second double bond which, upon treatment with iodine,
gave raise to a further cyclisation.
1
by H NMR and COSY experiments on a 400 MHz
spectrometer (Bruker Avance). The absolute configura-
tions of the new stereocentres were determined by
NMR NOESY experiments, using mixing time values
optimised for these bicyclic structures; the analysis of
NOE cross peak correlations also allowed the acquire-
ment of fundamental information about the whole con-
formational arrangement of the bicyclic scaffolds to be
acquired. In compound 6 the fructose furan oxygen
points upward and the oxygen of the second ring points
downwards. In compound 7, the fructofuranose ring is
essentially planar, while in the second ring the furano-
sidic oxygen is orientated below the plane.
The formation of the third cycle confirmed the (R)
stereochemistry of the stereocentre formed at C-1 in the
Grignard reaction since only in this diastereomer is the
double bond properly orientated for the cyclisation
with the benzyloxy group at C-3. The stepwise intro-
duction of two electrophilic functional groups (the
iodides), and the presence of two differentiable benzyl-
oxy groups (a primary and a secondary) make this
tricyclic scaffold extremely flexible for further
elaborations.
In more detail (Scheme 1), oxidation of alcohol 3
(DMSO–Ac2O, 83% yield) afforded the corresponding
aldehyde 4, which reacted stereoselectively with vinyl-
magnesium bromide (2 equiv., THF) giving the (R)
allylic alcohol 5 in 75% yield and 98% d.e. (determined
by HPLC). The high stereoselectivity of this reaction
can be ascribed to the formation of a Cram-chelated
intermediate where the magnesium ion coordinates the
carbonyl group and the furanosidic oxygen, as depicted
in Fig. 1. Attack of the nucleophile is allowed only on
the re face of the carbonyl group of this intermediate,
the benzyloxy group at C-3 preventing the attack on
the si face.
Acknowledgements
We thank the Ministero dell’Universita` e della Ricerca
Scientifica e Tecnologica (MURST) for the financial
support.
Compound 5 can be transformed into two different
bicyclic structures. If the double bond of the a-allylic
substituent is activated by I2 (1 equiv.) in THF as
solvent, a 5-exo cyclisation occurs with the unprotected
OH derived from the Grignard reaction, affording
bicyclic compound 6 (89% yield based on both
diastereoisomers, in a 6:1 ratio in favour of isomer 6, as
References
1. (a) Sofia, M. J.; Hunter, R.; Chan, T. Y.; Vaughan, A.;
Dulina, R.; Wang, H.; Gange, D. J. Org. Chem. 1998, 63,
2802; (b) Wunberg, T.; Kallus, C.; Opaz, T.; Henke, S.;
Schmidt, W.; Kunz, H. Angew. Chem., Int. Ed. 1998, 37,
2503; (c) Kallus, C.; Opaz, T.; Wumberg, T.; Schmidt, W.;
Henke, S.; Kunz, H. Tetrahedron Lett. 1999, 40, 7783; (d)
Hanessian, S.; Saavedra, O. M.; Xie, F.; Arnoldi, N.;
Battistini, C. Bioorg. Med. Chem. Lett. 2000, 10, 439; (e)
Wong, C.-H.; Ye, X.-S.; Zang, Z. J. Am. Chem. Soc. 1998,
120, 7137.
2. (a) Hirschmann, R.; Nicolau, K. C.; Pietranico, S.;
Salvino, J.; Laehy, E. M.; Splengeler, P. A.; Furst, G.;
Smith, A. B., III; Strader, C. D.; Cascieri, M. A.; Cande-
lore, M. R.; Donaldson, C.; Vale, W.; Maechler, L. J. Am.
Chem. Soc. 1992, 114, 9217; (b) Hirschmann, R.; Nicolau,
K. C.; Pietronico, S.; Leay, E. M.; Salvino, J.; Arison, B.;
1
determined by H NMR). When the iodocyclisation is
performed with 1 equiv. of iodine in dichloromethane,
RMgX
Mg
O
re face
O
BnO
H
BnO
OBn
4
Figure 1.

E. Forni et al. / Tetrahedron Letters 43 (2002) 1355–1357
1357
Cichy, M. A.; Spoors, P. G.; Shakespeare, W. C.; Spren-
geler, P. A.; Hamley, P.; Smith, A. B., III; Reisine, T.;
Raynor, K.; Maechler, L.; Donaldson, C.; Vale, W.;
Freidinger, R. M.; Cascieri, M. R.; Strader, C. D. J. Am.
Chem. Soc. 1993, 115, 12550.
Fleet, G. W. J. J. Chem. Soc., Chem. Commun. 1998, 2041;
(e) Lohof, E.; Planker, E.; Mang, C.; Burkhart, F.;
Dechantsreiter, M. A.; Haubner, R.; Wester, H.-J.;
Schwaiger, M.; Ho¨lzemann, G.; Goodman, S. L.; Kessler,
H. Angew. Chem., Int. Ed. 2000, 39, 2761; (f) Overkleeft,
H. S.; Verhelst, S. H. L.; Pieterman, E.; Meeuwenoord, N.
J.; Overhand, M.; Cohen, L. H.; van der Marel, G. A.; van
Boom, J. H. Tetrahedron Lett. 1999, 40, 4103; (g) Peri, F.;
Cipolla, L.; La Ferla, B.; Nicotra, F. J. Chem. Soc., Chem.
Commun. 2000, 2303.
3. (a) Graf von Roedern, E.; Kessler, H. Angew. Chem., Int.
Ed. 1994, 33, 687; (b) Graf von Roedern, E.; Lohof, E.;
Hessler, G.; Hoffmann, M.; Kessler, H. J. Am. Chem. Soc.
1996, 118, 10156; (c) Smith, M. D.; Long, D. D.; Mar-
quess, D. G.; Claridge, T. D. W.; Fleet, G. W. J. J. Chem.
Soc., Chem. Commun. 1998, 2039; (d) Smith, M. D.;
Claridge, T. D. W.; Tranter, G. E.; Sansom, M. S. P.;
4. Nicotra, F.; Panza, L.; Russo, G. J. Org. Chem. 1987, 52,
5627.