Synthesis of a trans-fused tricyclic ether using a novel differentially protected glucal

Article abstract of DOI:10.1055/s-1999-3174

The construction of the trans-fused 7,6,6-ABC fragment (3) of ciguatoxin 3C, starting from the novel carbohydrate derivative 3-O-benzyl-4-O-tert- butyldimethylsilyl-6-O-trityl-D-glucal, is reported. The formation of the A- and C-rings can be effected by executing two individual ring-closing metathesis steps in a sequential or a one-pot procedure.

Full text of DOI:10.1055/s-1999-3174

LETTER
1945
Synthesis of a trans-Fused Tricyclic Ether Using a Novel Differentially
Protected Glucal
Michiel A. Leeuwenburgh, Camiel Kulker, Herman S. Overkleeft, Gijsbert A. van der Marel, Jacques H. van Boom*
Leiden Institute of Chemistry, P.O.Box 9502, 2300 RA Leiden, The Netherlands
Fax +31 71 5274307; E-mail: j_boom@chem.leidenuniv.nl
Received 30 August 1999
Abstract: The construction of the trans-fused 7,6,6-ABC fragment
(3) of ciguatoxin 3C, starting from the novel carbohydrate deriva-
tive 3-O-benzyl-4-O-tert-butyldimethylsilyl-6-O-trityl-D-glucal, is
reported. The formation of the A- and C-rings can be effected by ex-
ecuting two individual ring-closing metathesis steps in a sequential
or a one-pot procedure.
Key words: ring-closing metathesis, fused ethers, ciguatoxin 3C,
carbohydrate, glucal
Figure
Studies from our1 and other2 laboratories revealed that
sugars are useful starting compounds for the generation of
scaffolds featuring two olefin functions suitable for ring-
closing metathesis (RCM). The general usefulness of this
The synthesis of glucal 1b commences with the regiose-
lective benzylation of the allylic hydroxyl group of
known5 6-O-trityl-D-glucal 4. Thus, treatment of the stan-
nylidene acetal of 4 (see Scheme 2) with benzyl bromide
concept was nicely illustrated by us in the synthesis of
in the presence of cesium fluoride6 gave 3-O-benzyl de-
rivative 5. Silylation of HO-4 with t-butyldimethylsilyl
chloride (TBSCl), followed by stereoselective epoxida-
tion of fully protected 1b with 3,3-dimethyldioxirane,7 af-
forded the stable α-epoxide 6 in 65% yield (based on 4).8
Ring-opening of epoxide 6 under the influence of allyl-
magnesium bromide led, in contrast to expectation,9 to an
unacceptable α,β-mixture of both C-glucosides in a near
equal amount. It was therefore gratifying to establish that
the use of allylmagnesium chloride resulted in the main
formation (i.e. α/β = 1:9) of the required β-C-glucoside.10
Separation of the latter mixture could be readily effected
by silica gel chromatography to give the crucial interme-
diate 7 in 77% yield.
functionalised oxepines,1a spiroketals,1b as well as car-
bocycles.1c,d We also showed1e,f that tri-O-benzyl-D-glu-
cal (1a) could be converted into the trans-fused bicyclic
ether 2a via stereoselective epoxidation followed by the
installation of a trans-1-vinyl-2-O-allyl configuration and
subsequent RCM. It seemed evident that the masking of
HO-6 and HO-4 by an orthogonal set of temporary pro-
tecting groups as in the differentially protected3 glucal 1b
would open the way to the construction of an additional
trans-fused cyclic ether unit. For instance, removal of the
t-butyldimethylsilyl (TBS) group in the RCM product 2b
followed by sequential allylation of the secondary HO-
group and detritylation will provide 2c, the primary hy-
droxyl of which can be readily transformed into a terminal
alkene function. The viability of our concept will be dem-
onstrated in the synthesis of the trans-fused 7,6,6-tricyclic
fragment 3, which features the ABC ring framework of
ciguatoxin 3C,4 starting from glucal 1b.
Reagents and conditions: i. a) Bu2SnO, MeOH, reflux; b) BnBr, CsF,
DMF, 73%. ii. TBSCI, imidazole, DMF, 50 °C, 90%. iii. 3,3-dime-
thyldioxirane (1.2 equiv.), CH Cl2/acetone, 0 °C, 30 min, quant. iv.
2
allylmagnesium chloride (2 equiv.), THF, 10 min, 77%.
Scheme 1
Scheme 2
Synlett 1999, No. 12, 1945–1947 ISSN 0936-5214 © Thieme Stuttgart · New York

1946
M. A. Leeuwenburgh et al.
LETTER
The transformation of 7 into the target compound 3
(Scheme 3) starts with the allylation of HO-2 in 7. Subse-
quent RCM of the resulting trans-allyl-O-allyl setting in 8
using Grubbs’ catalyst (PCy3)2Cl2Ru=CHPh11 provided
the trans-fused 7,6-bicyclic system 2b in near quantitative
yield. Introduction of the second and similarly fused ring
could be realised by executing the following simple and
straightforward six-step procedure. Desilylation of 2b fol-
lowed by allylation of the secondary hydroxyl group gave,
after detritylation of 9, the primary alcoholic derivative
2c. Dess-Martin periodinane oxidation12 of 2c and subse-
quent Wittig olefination with methyltriphenylphosphoni-
um bromide in the presence of n-butyllithium led to the
isolation of RCM precursor 10. RCM of the latter deriva-
tive using the same ruthenium catalyst also proceeded
smoothly at room temperature to give the trans-fused tri-
cyclic ether 3,8 as evidenced by NOE-experiments, in
43% yield based on 7.
Reagents and conditions: i. TBAF, THF, 94%. ii. allyl bromide, NaH,
DMF, 87%. iii. TsOH, MeOH/CH2Cl2 (1:1), 92%. iv. a) Dess-Martin
periodinane, CH2Cl2; b) MePh3P+Br–, n-BuLi, THF, –40 °C to r.t.,
78% (two steps). v. Cl2(PCy3)2R=CHPh (5 mol%), 0.02 M diene
conc., CH2Cl2, 3h, 78%.
Scheme 4
The results presented in this paper clearly indicate that the
differentially protected glucal 1b is a valuable and versa-
tile building unit in the design and synthesis of trans-
fused cyclic ethers. Moreover, the protecting group strat-
egy described here can be easily adapted for the prepara-
tion of other appropriately protected glucal derivatives,
e.g., compound 1d in which the benzyl group is replaced
by a 4-methoxybenzyl (MPM) group. In this respect, it is
of interest to mention that glucal 1b may be an attractive
alternative for the preparation of the recently reported2g
intermediate 2 (n = 1, R1 = H, R2 = MPM, R3 = Bn). The
implementation of our strategy in the assembly of more
extended cyclic ether frameworks of ciguatoxin 3C and
other structurally related marine toxins will be reported in
due course.
Acknowledgement
The authors thank Fons Lefeber for recording the COSY and
NOESY spectra and Hans van den Elst for performing the mass
spectrometry.
Reagents and conditions: i. allyl bromide, NaH, DMF, 97%. ii.
Cl2(PCy3)2R=CHPh (5 mol%), 0.02 M diene conc., CH 2Cl2, 2h, 99%.
iii. TBAF, THF, 84%. iv. allyl bromide, NaH, DMF, 88%. v. TsOH,
References and Notes
MeOH/CH2Cl2 (1:1), 94%. vi. a) Dess-Martin periodinane, CH Cl2;
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2
b) MePh3P+Br–, n-BuLi, THF, –40 °C to r.t., 80%. vii.
Cl2(PCy3)2R=CHPh (5 mol%), 0.02 M diene conc., CH 2Cl2, 3h, 82%.
Overkleeft, H.S.; Van der Marel, G.A.; Van Boeckel, C.A.A.;
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Scheme 3
The relatively high efficacy of both metathesis steps (i.e.
8Æ2b and 10Æ3) urged us to explore whether the forma-
tion of 3 could be achieved in one step using the bis-O-al-
lyl derivative 14 (Scheme 4) as the substrate. The bis-O-
allyl ether functions could be easily installed (Scheme 4)
by desilylation of 7 (Æ11), allylation of both secondary
hydroxyl groups (11Æ12), detritylation of 12 and conver-
sion of 13 by the same sequence of events mentioned ear-
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overall yield.
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Synlett 1999, No. 12, 1945–1947 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthesis of a trans-Fused Tricyclic Ether Using a Novel Differentially Protected Glucal
1947
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3: 1H NMR (300 MHz, CDCl3): 7.44-7.26 (m, 5H), 5.88-5.71
(m, 4H), 4.93-4.82 (AB, 2H), 4.27 (dd, 1H, J1 = 15.7 Hz,
J2 = 5.5 Hz), 4.24 (dd, 2H), 3.98 (ddd, 1H, J = 5.3 Hz), 3.80
(app. d, 1H, J = 8.7 Hz), 3.57 (app. t, 1H, J1 = J2 = 8.8 Hz),
3.40-3.35 (m, 2H), 3.28 (t, 1H), 2.67 (ddd, 1H, J1 = 16.3 Hz,
J2 = 2.9 Hz), 2.35 (m, 1H). 13C NMR(75 MHz, CDCl3): 139.2,
131.1, 128.0, 126.4, 125.9, 128.1, 127.5, 127.3, 87.7, 81.9,
78.0, 77.2, 74.8, 71.6, 68.4, 66.0, 34.7.[ αD]+34.6 º (c 1,
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C
1b: 1H NMR (300 MHz, CDCl3): 7.58-7.18 (m, 20H), 6.49 (d,
1H, J = 6.6 Hz), 4.84 (dd, 1H, J = 2.9 Hz), 4.49 (AB, 2H),
4.18-4.07 (m, 1H), 3.92 (t, 1H), 3.82-3.76 (m, 1H), 3.47-3.36
(m, 2H), 0.70 (s, 9H), -0.16, -0.35 (s, 6H). 13C NMR (75 MHz,
Article Identifier:
1437-2096,E;1999,0,12,1945,1947,ftx,en;G21799ST.pdf
Synlett 1999, No. 12, 1945–1947 ISSN 0936-5214 © Thieme Stuttgart · New York