Observation of a 1,5-silyl-migration on fructose

Article abstract of DOI:10.1055/s-2005-872660

During synthetic studies involving fructose, an unexpected silyl migration was observed - resulting in a sterically more crowded product. 1,4-Silyl migrations have been observed previously taking place in several different carbohydrate derivatives. Howeve

Full text of DOI:10.1055/s-2005-872660

LETTER
2385
Observation of a 1,5-Silyl-Migration on Fructose
Observation
o
t
f
a
1,5-
e
S
ilyl-Migra
f
tion on F
a
ructose n Furegati, Andrew J. P. White, Andrew D. Miller*
Imperial College Genetic Therapies Centre, Department of Chemistry, Flowers Building, Armstrong Road, Imperial College London,
London SW7 2AZ, UK
Fax +44(20)75945803; E-mail: a.miller@imperial.ac.uk
Received 15 June 2005
Abstract: During synthetic studies involving fructose, an unex-
pected silyl migration was observed – resulting in a sterically more
crowded product. 1,4-Silyl migrations have been observed previ-
ously taking place in several different carbohydrate derivatives.
However, here we report for the first time an apparent base-assisted
1,5-silyl migration in fructose, identified by evidence from X-ray
crystallography and 2D-NMR spectroscopy. This novel migration
is related to the Brook rearrangement, and appears to be mediated
via an anionic, cyclic transition state involving pentavalent silicon.
Key words: carbohydrates, fructose, protecting groups, regioselec-
tivity, silyl migration
In order to investigate the biological behavior of unsym-
metrically substituted fructose-1,6-bisphosphates we real-
ized the need to combine D-fructose with different
substituents at O(1) and O(6), and hence the need for syn-
thetic intermediates with differential protection. Whereas
for many carbohydrates the protecting group chemistry is
well elaborated, this is surprisingly not the case for fruc-
tose. As part of our chosen route to products, we intended
to prepare 1a (Scheme 1) by initial protection of both
primary hydroxyl groups of D-fructose with TBDMS
groups followed by benzylation to give 3a, desilylation to
yield 4a, and mono-tritylation giving rise to 1a ready for
controlled functionalization.
Scheme 1 Expected route towards synthetic intermediate product
1a using orthogonal protecting groups.
2D 1H NMR and 13C NMR spectroscopic analysis at 60°
C revealed that in fact the product was 1b, against all our
reasonable expectations. This unexpected product imme-
diately suggested to us the possibility of protecting group
migration during the synthetic scheme leading to 1b. We
also recognized the possibility of furanose to pyranose
transformation when D-fructose was silylated leading to
alternative protection products.
Trityl chloride has been used typically to regioselectively
protect O(1) – or both primary hydroxyl groups – of D-
fructose.1 However, we elected to use TBDMSCl instead
owing to the formation of complex mixtures when 1-O-
trityl-D-fructofuranose was subjected to benzylation. Ini-
In order to investigate these possibilities, a crystal
structure of the first di-O-(tert-butyldimethylsilyl)-b-D-
fructofuranose intermediate product2 was obtained. The
solid-state structure (Figure 1) revealed the presence of
two independent molecules (A and B) with identical
absolute configurations and very similar conformations;
excluding the disordered tert-butyldimethylsilyl groups,
the rms fit of the two molecules was ca. 0.018 Å. Despite
the disorder in both silyl moieties, the crystallographic
data were of sufficient quality to prove that the func-
tionalization and absolute configuration of the first di-O-
(tert-butyldimethylsilyl)-b-D-fructofuranose intermediate
product was consistent with the expected structure 2a
(Figure 1).
tially,
a di-O-(tert-butyldimethylsilyl)-b-D-fructofura-
nose product (85%)2 was obtained as fine, colorless
needles (thought to be 2a) after recrystallization from hex-
ane. This was then subjected to benzylation affording a
colorless oil comprising tri-O-benzyl-di-O-(tert-bu-
tyldimethylsilyl)-b-fructofuranose (43%)3 as the main in-
termediate product (thought to be 3a). Thereafter we
performed a desilylation reaction yielding a tri-O-benzyl-
b-D-fructofuranose (84%)4 intermediate product (as-
sumed to be 4a) that was then monotritylated after some
optimization to give a wax-like tri-O-benzyl-O-trityl-b-D-
fructofuranose intermediate product (74%).5 This final in-
termediate product was thought to be 1a, but exhaustive
Therefore, having excluded the possibility of pyranose
forms, we considered that the only reasonable explanation
for the formation of unexpected product 1b starting from
expected intermediate product 2a, was protecting group
SYNLETT 2005, No. 15, pp 2385–2387
Advanced online publication: 08.08.2005
DOI: 10.1055/s-2005-872660; Art ID: D16205ST
© Georg Thieme Verlag Stuttgart · New York
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2386
S. Furegati et al.
LETTER
It would be desirable to explain why the observed migra-
tion takes place when 2b appears more sterically crowded
than 2a, and therefore apparently less desirable. After
some consideration, ab initio calculations of the ground
states of the 20 possible configurations of the silyl groups
on di-O-(tert-butyldimethylsilyl)-D-fructofuranose (10 b-
anomers and 10 a-anomers) were not performed given the
expectation that energies would be too similar to segre-
gate one from the other. Transition state analyses were not
expected to be of much value either given the uncertainty
of sodium ion involvement in the transition state and the
extra possibility of dimerization adding further computa-
tional complications.7 A simple molecular mechanics8
comparison was performed demonstrating that 2a was in-
deed 15.4 kJ/mol more stable than 2b taking into account
only steric considerations. However, 2b may be rendered
more stable through the formation of more extensive in-
tramolecular b-face hydrogen bonding interactions in-
volving b-face hydroxyl functional groups, than are
feasible in 2a.
Figure 1 The molecular structure of one (A) of the two independent
molecules present in the crystals of 2a.
migration either through the formation of tri-benzylated
intermediate product 4a that transmutes into 4b, or
through the interconversion of intermediate 2a into 2b via
a 1,5-silyl migration (Scheme 2), followed by tri-benzyl-
ation to give 3b and desilylation to form 4b.
Analogous base-assisted silyl migrations have been re-
ported within the last few years in various carbohydrate
systems,9 but not in fructose. Moreover, all these exam-
ples are 1,4-silyl migrations. In our case, we would sug-
gest that for the first time we have amassed sufficient
evidence to propose a novel base-assisted 1,5-silyl migra-
tion. All these migrations seem to be related to the base-
catalyzed migration of silyl groups from carbon to oxygen
in a-, b- and g-silyl alcohols yielding silyl ethers. This
type of rearrangement, known as the Brook rearrange-
ment,10 is clearly driven by Si–O bond formation.
While benzyl group migration is a possibility via some
form of benzyl-cation migration, 1,5-silyl migration in 2a
leading to 2b was considered to be a more logical expla-
nation. Benzylation of 2a requires NaH treatment to gen-
erate oxy-anions that are subsequently trapped by addition
of benzyl bromide. The use of NaH clearly opens up the
possibility of general base-assisted 1,5-silyl migration to
give 2b (Scheme 2). Proof of this possibility was obtained
by the treatment of intermediate product 2a with NaH,
leading to the isolation of pure 1,4-di-O-(tert-butyldi-
methylsilyl)-b-D-fructofuranose (2b, 42%).6
In conclusion we have reported for the first time an unex-
pected 1,5-silyl migration in fructose resulting in the for-
mation of a more sterically crowded product, stabilized
through other means such as intramolecular hydrogen
bonding.
Anhydrous solvents were used for the reactions, which were carried
out under argon. The crude products were subjected to flash column
chromatography (SiO2) for purification/separation, except from 1,
which could be crystallized.
Acknowledgment
This work was supported by the Swiss National Science Foundation
and IC-Vec.
References
(1) (a) Bredereck, H.; Henning, I.; Zinner, H. Chem. Ber. 1953,
86, 476. (b) Bredereck, H.; Protzer, W. Chem. Ber. 1954, 87,
1873.
(2) D-Fructose: [a]D22 –90.9 (c 10.34, H2O).
Analytical data of 2a: [a]D22 +5.4 (c 5.00, MeOH);
mp = 91.5–93.5 °C; Rf = 0.62 (SiO2, EtOAc). 1H NMR (400
MHz, CDCl3): d = –0.03–0.01 (12 H, m, CH3–Si), 0.78–0.82
(18 H, m, CH3–C–Si), 3.72–4.34 (10 H, m, 2 CH2, 3 CH, 3
OH). 13C NMR (100.4 MHz, CDCl3, two conformations):
d = –5.63, –5.62, –5.59, –5.53, –5.46, –5.39, –5.37, –5.30 (4
C, CH3–Si), 18.4, 18.5 (2 C, C–Si), 25.81, 25.90, 25.94 (6 C,
Scheme 2 Reagents and conditions: (a) TBDMSCl (2.0 equiv), pyri-
dine, r.t.; (b) NaH (3.3 equiv), DMF, 0 °C; (c) BnBr (3.3 equiv),
Bu4NI (0.3 equiv), r.t.; (d) TBAF (2.2 equiv), THF, r.t.; (e) trityl
chloride (10 equiv), pyridine, 60 °C.
Synlett 2005, No. 15, 2385–2387 © Thieme Stuttgart · New York

LETTER
CH3–C–Si), 63.6, 64.0 (CH2), 64.6, 66.8 (CH2), 77.5, 78.8
Observation of a 1,5-Silyl-Migration on Fructose
2387
CH2-6), 3.92–3.95 (1 H, m, CH-5), 4.12–4.23 (1 H, m, CH-
4), 4.28 (1 H, d, J = 7.8 Hz, CH-3), 4.56 (6 H, s, 3 × CH2–
Ph), 5.50 (1 H, d, J = 5.6 Hz, OH–CH-4), 7.12–7.50 (30 H,
m, arom. H). 13C NMR (100.4 MHz, DMSO-d6, 60 °C, the
only fructose derivative found here displaying only one
conformation): d = 63.7 (CH2–Ph), 66.2 (CH2-1), 70.3 (CH2-
6), 71.7 (CH2–Ph), 72.4 (CH2–Ph), 74.7 (CH-4), 80.0 (CH-
5), 85.0 (CH-3), 103.8 (C-2), 126.5, 126.9, 126.95, 127.0,
127.1, 127.2, 127.25, 127.3, 127.4, 127.5, 127.7, 127.8,
127.9, 128.0, 128.05, 128.1, 128.3, 128.4 (30 arom. CH),
138.5, 138.9, 143.5, 147.8 (6 arom. C). The assignment of
the 1H- and 13C NMR spectra was based on COSY, HSQC
and HMBC spectra (unsuccessful for CPh3 though). NOESY
cross peaks between CH-3 and both CH2-1 proved that the b-
anomer was present. MS (ESI): m/z (%) = 715 (19) [M +
Na]+, 243 (26) [Ph3C]+, 186 (100).
(CH), 78.9, 79.0 (CH), 85.7, 87.8 (CH), 104.2, 106.3 (C-2).
MS (ESI): m/z (%) = 431 (100) [M + Na]+. Crystal data:
crystal derived from toluene, C18H40O6Si2, M = 408.68,
trigonal, P31 (no. 144), a = 17.0933 (13) Å, c = 15.5690 (16)
Å, V = 3939.5 (6) Å3, Z = 6 (2 independent molecules),
Dc = 1.034 g cm–3, m(Cu-Ka) = 1.433 mm–1, T = 293 K,
colorless needles, Oxford Diffraction Xcalibur PX Ultra
diffractometer; 8947 independent measured reflections, F2
refinement, R1 = 0.094, wR2 = 0.252, 4167 independent
observed reflections [|Fo| > 4s(|Fo|), 2qmax = 143°], 592
parameters. The absolute structure of 2a was determined by
a combination of R-factor tests [R1+ = 0.0935, R1– = 0.0960]
and by use of the Flack parameter [x+ = +0.00(8)]. CCDC
270727.
(3) Analytical data of 3b: [a]D22 –12.9 (c 0.500, MeOH);
Rf = 0.21 (SiO2, hexane–Et2O 19:1). 1H NMR (400 MHz,
CDCl3): d = –0.10–0.00 (12 H, m, CH3–Si), 0.77–0.85 (18 H,
m, CH3–C–Si), 3.46–4.80 (13 H, m, 5 CH2, 3 CH), 7.12–7.31
(15 arom. H). 13C NMR (100.4 MHz, CDCl3, two
(6) Analytical data of 2b. Acid quenching or warming to r.t. lead
to an exothermic reaction resulting in complex mixtures.
Isolation of 2b – the main product whereas no 2a was found
– was only successful when the cold mixture was subjected
to column chromatography very quickly: [a]D22 ca. 0 (c 1.05,
MeOH); Rf = 0.13 (SiO2, EtOAc–hexane 1:2). 1H NMR (400
MHz, CDCl3): d = 0.03–0.19 (12 H, m, CH3–Si), 0.86–0.95
(18 H, m, CH3–C–Si), 3.49–4.25 (10 H, m, 2 CH2, 3 CH, 3
OH). 13C NMR (100.4 MHz, CDCl3, two conformations):
d = –4.9, –4.8, –4.6, –4.5, –3.6 (4 C, CH3–Si), 17.8, 17.9,
18.3, 18.4 (2 C, C–Si), 25.6, 25.6, 25.7, 25.8 (6 C,
conformations): d = –5.31, –5.27, –5.24, –5.18, –4.92, –4.21
(4 C, CH3–Si), 17.9, 18.3, 18.4 (2 C, C–Si), 25.7, 25.8,
25.83, 25.9, 26.0 (6 C, CH3–C–Si), 63.0, 64.7, 64.8, 66.9,
67.6, 69.4, 72.2, 72.6, 72.9, 73.4 (5 C, CH2), 76.5, 80.1, 80.2,
82.8, 84.5, 85.5 (3 C, CH), 104.7, 104.8 (C-2), 127.1, 127.2,
127.5, 127.52, 127.6, 127.67, 127.7, 127.8, 127.85, 127.9,
128.0, 128.1, 128.2, 128.23, 128.3, 128.4, 128.5 (15 arom.
CH), 138.3, 138.4, 138.43, 138.5, 138.6 (3 arom. C). MS
(ESI): m/z (%) = 701 (100) [M + Na]+, 517 (35).
CH3–C–Si), 63.2, 63.4 (CH2), 64.5, 65.7 (CH2), 77.2, 77.6
(CH), 79.1, 79.2 (CH), 84.4, 86.9 (CH), 103.3, 107.2 (2-C).
MS (ESI): m/z (%) = 431 (100) [M + Na]+.
(4) Analytical data of 4b: [a]D22 –17.6 (c 1.07, MeOH);
Rf = 0.21 (SiO2, EtOAc–hexane 3:2). 1H NMR (400 MHz,
CDCl3): d = 2.38–4.84 (15 H, m, 5 CH2, 3 CH, 2 OH), 7.18–
7.39 (15 arom. H). 13C NMR (100.4 MHz, CDCl3, two
conformations): d = 63.5, 64.4, 64.7, 64.9, 65.2, 70.9, 72.8,
72.9, 73.0, 73.6 (5 C, CH2), 76.5, 79.6, 80.5, 82.7, 84.8, 84.9
(3 C, CH), 104.8, 105.1 (C-2), 127.4, 127.45, 127.5, 127.6,
127.7, 127.8, 127.82, 127.86, 127.9, 128.0, 128.1, 128.16,
128.2, 128.3, 128.49, 128.50, 128.53, 128.7 (15 arom. CH),
137.8, 137.9, 138.0, 138.3, 138.7. 138.9 (3 arom. C). MS
(ESI): m/z (%) = 473 (20) [M + Na]+, 186 (100).
(7) Oral communication by Henry Rzepa.
(8) Molecular mechanics (MM2) of Chem3D Ultra 9.0: for 2a
the X-ray data of the conformation yielding the lower energy
were used whereas for 2b several conformations were tried
and again the one resulting in the lowest energy was chosen.
(9) (a) Yoon, S. J. Korean Chem. Soc. 2002, 46, 590. (b) Arias-
Pérez, M. S.; López, M. S.; Santos, M. J. J. Chem. Soc.,
Perkin Trans. 2 2002, 1549. (c) Li, Y.; Horton, D.;
Barberousse, V.; Samreth, S.; Bellamy, F. Carbohydr. Res.
1999, 316, 104. (d) Akai, S.; Nishino, N.; Iwata, Y.;
Hiyama, J.; Kawashima, E.; Sato, K.; Ishido, Y. Tetrahedron
Lett. 1998, 39, 5583.
(5) Analytical data of 1b: [a]D22 –3.9 (c 1.07, MeOH); Rf = 0.17
(SiO2, Et2O–hexane 1:1). 1H NMR (400 MHz, DMSO-d6, 60
°C): d = 3.03, 3.26 (2 H, 2 d, J = 9.5 Hz, CH2-1), 3.62 (1 H,
dd, J = 11.1, 6.0 Hz, CH2-6), 3.77 (1 H, dd, J = 11.1, 2.4 Hz,
(10) (a) Brook, A. G. J. Am. Chem. Soc. 1958, 80, 1886.
(b) Brook, A. G. Acc. Chem. Res. 1974, 7, 77.
Synlett 2005, No. 15, 2385–2387 © Thieme Stuttgart · New York