Exploiting the cross-metathesis reaction in the synthesis of pseudo-oligosaccharides

Article abstract of DOI:10.1039/b822989a

An approach to the synthesis of pseudo-oligosaccharides based on the cross-metathesis reaction between distinct sugar-olefins, followed by intramolecular cyclization of the obtained heterodimer, is presented. In particular, the relative efficiency of two

Full text of DOI:10.1039/b822989a

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Exploiting the cross-metathesis reaction in the synthesis of
pseudo-oligosaccharides†‡
Paolo Ronchi,a Stefano Vignando,a Sara Guglieri,b Laura Politoa and Luigi Lay*a
Received 5th January 2009, Accepted 30th March 2009
First published as an Advance Article on the web 5th May 2009
DOI: 10.1039/b822989a
An approach to the synthesis of pseudo-oligosaccharides based on the cross-metathesis reaction
between distinct sugar-olefins, followed by intramolecular cyclization of the obtained heterodimer, is
presented. In particular, the relative efficiency of two alternative approaches, the straightforward
cross-metathesis reaction and the two-step procedure (self-metathesis followed by cross- metathesis),
was explored and compared for diverse sugar-olefin substrates. Some representative examples of
intramolecular cyclization using iodine as an electrophilic promoter, are also reported.
metathesis products and the difficult control of the configuration
Introduction
at the newly formed double bond (E/Z ratio). Nonetheless, the
advent of the new ruthenium alkylidene complexes mentioned
above led to the increasing application of the CM reaction in
the total synthesis of natural products.4 It should be specifically
noticed that many applications of the CM reaction in the field
of carbohydrates are limited to the homodimerization of O-allyl
and C-allyl glycosides.11 On the other hand, the selective cross
coupling of unlike sugar partners is a very attractive process, since
the diversity of accessible carbohydrate derivatives would be much
higher than that obtained from simple homodimerization. We
therefore became interested in exploiting the CM reaction for the
synthesis of pseudo-oligosaccharides with potential application
as carbohydrate mimics. We were inspired by the paper of
Blechert and Schu¨rer12 who applied a sequence of yne-ene cross
metathesis and Diels-Alder reactions for the synthesis of pseudo-
trisaccharides.
As outlined in Scheme 1, we reasoned that by using suitable
monosaccharide derivatives of type A and B as cross-metathesis
partners, the construction of the new ring on type C heterodimer
could be achieved through an intramolecular cyclization promoted
by electrophilic activation of the C–C double bond, affording
tricyclic compounds of type D or E. We report herein our pre-
liminary investigations of this strategy exploring the CM reaction
of different substrates of type A and B (Scheme 1), and comparing
the efficiency and selectivity of the classical, straightforward
cross-metathesis with the two-step procedure (self-metathesis
followed by cross-metathesis) developed by Grubbs and co-
workers.13 Moreover the representative synthesis of some tricyclic
compounds of type D and E, using iodine as an electrophilic
promoter for the intramolecular cyclization, is also described.
Carbohydrates are primarily involved in many biological processes
and a wide number of cellular recognition phenomena.1 Because
of their biological importance and unique chemical features,
synthetic medicinal chemistry shows a growing interest towards
these molecules.2 Although excellent progress has been made by
modern carbohydrate chemistry, the development of saccharide-
based drugs using classical carbohydrate synthesis can be still a
difficult task.3 There is therefore a strong demand for general and
efficient approaches to sugar mimics endowed with very similar
biological properties, but structurally and synthetically simpler
than their natural counterparts.
During the last years transition metal catalyzed olefin metathe-
sis has undoubtedly gained a prominent role in modern synthetic
organic chemistry.4 In particular, the recent availability of robust
and well-defined ruthenium alkylidene-based pre-catalysts,5–7 en-
dowed with high reactivity, air-stability and impressive functional-
group tolerance has made olefin metathesis an extremely powerful
and versatile tool for the construction of carbon–carbon bonds
in the most diverse molecular architectures. Most applications
of olefin metathesis in synthetic organic chemistry employ the
more entropically favoured ring-closing metathesis (RCM), while
the intermolecular cross-metathesis (CM) has received much
less attention from the scientific community. This holds true in
the field of carbohydrate chemistry.8 Many reports describe the
application of the RCM reaction for the synthesis of carbocycles
and other carbohydrate derivatives,9 while there are relatively
few examples of CM applied to mono- and oligosaccharide
building blocks.10 The main reason is the poor selectivity often
exhibited by CM reactions, due to the formation of undesired self-
aDipartimento di Chimica Organica e Industriale and Centro Interdisci-
plinare Studi Bio-molecolari e Applicazioni Industriali (CISI), Universita`
degli Studi di Milano, Milano, Italy. E-mail: luigi.lay@unimi.it; Fax: +39
0250314061; Tel: +39 0250314062
Results and discussion
As highlighted in Scheme 1, a type A CM partner equipped with a
homoallylic alcohol function (n = 1) should lead to a heterodimer
apt to give five-membered ring closure. On the other hand, the
introduction of a hydroxyhexenyl appendage (n = 3) will give rise
to a dimer that, upon electrophilic activation, should cyclize to
form a six-membered ring, strongly preferred to a seven-membered
ring.
bIstituto di Chimica e Biochimica “G. Ronzoni”, Milano, Italy. E-mail:
nmrlab@ronzoni.it; Fax: +39 0270641634; Tel: +39 0270641627
† Dedicated to Prof. Giovanni Russo on the occasion of his 70th birthday.
‡ Electronic supplementary information (ESI) available: Experimental
procedures and full characterisation of compounds 3, 5a, 6a and
6b, and copies of NMR spectra of all new compounds. See DOI:
10.1039/b822989a
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Scheme 3 Synthesis of type A compounds. (a) Method A: AllMgBr,
Et2O, -78 ◦C (73%, 5a:5b = 60:40). Method B: AllMgBr, (+)-MeOB(Ipc)2,
-78 ◦C, Et2O, then 30% v/v H2O2, 3 N NaOH, reflux (73%, >95% of 5a);
(b) PentenylMgBr, Et2O, -78◦C (66%, 6a:6b = 58:42).
selective manner using Brown’s chemistry.18 Ligand exchange of
(+)-B-methoxydiisopinocampheylborane ((+)-MeOB(Ipc)2) with
AllMgBr followed by addition of aldehyde 4 afforded alcohols
5a/5b in 73% overall yield, with a satisfying d.e. (>95% of 5a,
as evidenced by NMR spectra). Addition of freshly prepared
pentenylMgBr to an ethereal solution of aldehyde 4 (Scheme 3)
afforded the hydroxy olefins 6a, 6b in moderate yield (66%) with
poor diastereoselectivity, that could not be improved even using
various Lewis acids as chelating agents. The two diastereoiso-
mers 6a and 6b were easily separated by flash chromatography
(diastereoisomeric ratio 58:42), and their absolute configurations
at C-7 were determined as described above for alcohols 5a and 5b,
and found to be R for 6a and S for 6b.
Scheme 1 Synthetic strategy.
Our investigation has been carried out using glucose-based
hydroxy olefins 5 and 6 as type A CM partners. Both compounds
have been obtained by alkylation of known aldehyde 4,14 which
in turn was synthesized in 6 steps from commercial methyl a-
glucoside 1 as described in Scheme 2.15
The structures of type B CM partners employed in the present
study are reported in Fig. 1. Allyl b-glycosides 719 and 820 were
synthesised by Zemple´n deacetylation (NaOMe, MeOH) and ben-
zylation (NaH, BnBr, DMF) of the corresponding peracetylated
Scheme 2 Synthesis of aldehyde 4. (a) PhCH(OMe)2, (+)-b-camphor-
sulphonic acid, CHCl3 (94%); (b) BnBr, NaH, DMF (96%); (c) PhBCl2,
Et3SiH, MS 4 A, CH2Cl2, -78 ◦C (95%); (d) I2, PPh3, imidazole;
˚
(e) 1,3-dithiane, BuLi 1.6 M in hexane, -20 ◦C, THF; (f) MeI, NaHCO3,
H2O/CH3CN (73% over 3 steps).
Allylation of 4 (Scheme 3) was carried out by treatment with
AllMgBr in Et2O affording a mixture of alcohol epimers 5a and
5b in a 3:2 diastereoisomeric ratio,16 and in 73% overall yield.
The absolute configuration of the newly formed stereogenic center
was determined, according to Mosher’s method,17 converting
both isomers of 5 into the corresponding esters of (R)- and
(S)-2-methoxy-2-phenyl-2-(trifluoromethyl) acetic acid (MTPA)
and analysing their NMR spectra. In this way we assigned
the R configuration at C-7 of the major isomer 5a and the
S configuration at the same carbon of the second isomer 5b.
Remarkably, almost pure 5a was obtained in a highly stereo-
Fig. 1 Structures of type B compounds and Hoveyda’s catalyst 16.
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Table 1 Synthesis of sugar heterodimers from alcohol 5a
allyl glycosides, while 9 was obtained by standard benzylation of
allyl a-D-galactopyranoside.21
Yield
Yield CM SM-CM
Allylation (NaH, AllBr, DMF) of known22 methyl 2,3,6-tri-
O-benzyl-a-D-glucopyranoside provided 4-O-allyl ether 10. C-
glucopyranosides 11 and 12 were prepared as reported in the
literature,23 while 13 was derived from chemoselective 2-O-
debenzylation of 1124 followed by standard 2-O-acetylation (Ac2O,
pyridine).
Finally, since glycosides of 2-amino-2-deoxy sugars occur
in the most important classes of glycoconjugates and biolog-
ically relevant oligosaccharides, we explored the behaviour of
the glucosamine derivatives 1425 and 15, the latter obtained
by allylation (KOH, 18-crown-6, AllBr, THF/H2O) of known
methyl 2-N-benzyloxycarbonyl-4,5-O-benzylidene-2-deoxy-a-D-
glucopyranoside.26
Entry Heterodimera
R
1
17
54%
42%
2
18
–
40%
3
19
45%
40%
After preliminary attempts using first and second generation
Grubbs’ catalysts, all the CM reactions described in this work have
been carried out with the phosphine-free Hoveyda’s catalyst 167
(Fig. 1) in CH2Cl2. Under these conditions, alcohol 5a reacted with
sugar-olefins 7 and 9–15 to give the corresponding heterodimers
17 and 19–25 (Scheme 4) with excellent stereoselectivities (only
E isomers were detected in the NMR spectra of the isolated
products), but in only moderate yields (25–62%), as summarized
in Table 1 (entries 1 and 3–9). In particular, the chemical
yields were eroded by the formation of substantial amounts of
homodimers derived from self-metatheses of the reaction partners
which is, as mentioned above, a typical drawback associated with
straightforward CM reactions.
4
5
20
21
37%
25%
80%
55%
6
7
22
23
34%
40%
64%
68%
8
9
24
25
62%
41%
45%
34%
Scheme 4 Straightforward CM reactions of alcohol 5a with sugar-olefins.
R are defined in Table 1. (a) 10 mol% of catalyst 16, CH2Cl2, rt.
In order to improve the general efficiency of our CM reactions,
we turned our attention to the two-step procedure developed by
Grubbs and co-workers.13 In this approach, a terminal olefin
is first homodimerized in a CM reaction (self-metathesis, SM),
and the internal olefin product (in excess) is then metathesized
with a second terminal olefin (CM step) to give cross-coupled
products. Since the homodimerization of 5a was the predominant
side-reaction in our previous experiments, we first carried out
the self-metathesis of 5a in the presence of 5 mol% of 16 in
refluxing CH2Cl2. The reaction proceeded smoothly providing the
dimer 26 as a mixture of E,Z isomers (E/Z ratio ª 3:1 on the
base of NMR spectra) in 85% yield (Scheme 5). Next, an excess
(2 eq.) of the symmetrical disubstituted olefin 26 was allowed to
react with type B sugar-olefins 7–15 in the presence of the same
catalyst (10 mol%), affording the corresponding heterodimers in
fair to good yields (34–80% over two steps, Table 1, entries 1–9)
and with excellent stereoselectivities (E/Z >95:5). Notably, the
E,Z mixture of 26 was employed without affecting the efficiency
and stereoselectivity of the following CM reaction. Moreover,
the unreacted homodimer was easily recovered and re-used in
subsequent CM reactions.
a In all cases, the E/Z ratio was higher than 95/5.
These results seem to indicate that the two-step procedure
is a favourable approach over the straightforward CM reaction
only when the relative homodimerization rates of the reaction
partners are markedly different.27 Sugar-olefins containing non-
anomerically linked O-allyl groups (10) or C-glycosides (11–13)
homodimerize at a much lower rate than 5a, and therefore they
were the best substrates for the SM-CM sequence.
Accordingly, the CM reaction of 26 with sugar-olefins 10–13 led
to the corresponding dimers 20–23, respectively, in much higher
yields than compared with the classical CM (Table 1, entries 4–7).
On the contrary, allyl glycosides 7–9 and 14, with a dimerization
rate comparable to 5a, showed poor selectivity in the CM reaction
and provided the corresponding heterodimers in statistical yields
(Table 1, entries 1–3 and 8), without significant changes on going
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the past few years, various research groups explored the non-
metathetic transformations catalysed by ruthenium carbene com-
plexes, presumably promoted by in situ formation of ruthenium
hydride species.32 For example, Snapper33 and Schmidt34 reported
the preparation of synthetically useful cyclic enol ethers via a
RCM/double bond isomerization tandem process.
Next, we applied the SM-CM sequence on 6a (Scheme 6). Ho-
modimerization of the hexenyl alcohol in the presence of 5 mol%
of 16 afforded a complex mixture of products (TLC). Besides
the desired homodimer 28, analysis of the mass spectra of the
crude mixture suggested the formation of various side-products
presumably derived from secondary metathesis events involving
constitutional isomers of 6a generated by one or more shifts of the
double bond from its initial terminal position. Moreover, the CM
of this mixture with 7 (10 mol% of 16 in refluxing CH2Cl2) gave the
expected heterodimer 29 in a very low yield (43%, E/Z ratio ª 9:1
on the base of NMR spectra), together with several by-products,
whereas no reaction occurred employing 10 as a coupling partner.
To test if the configuration at C-7 in the side chain of 6a/6b could
affect our results, we repeated the same series of experiments using
6b, but we did not observe any significant improvement.
Scheme 5 SM-CM sequence of alcohol 5a with sugar-olefins. R are
defined in Table 1. (a) 5 mol% of catalyst 16, CH2Cl2, reflux, (85%);
(b) 10 mol% of catalyst 16, CH2Cl2, reflux.
At this stage, we faced the intramolecular cyclization of het-
erodimers 17, 20 and 21 using iodine to promote the electrophilic
activation of the C–C double bond (Scheme 7). The results are
summarized in Table 2. As illustrated in Scheme 7, in each case
an inseparable mixture of anti-anti and syn-anti diastereoisomers
was obtained.
from the classical CM to the SM-CM sequence.28 Compound 15,
containing a 3-O-allyl group, was the only exception to this trend,
affording in both cases statistical yields of heterodimer 25 (Table 1,
entry 9). We conjectured that this behavior might be due to catalyst
trapping caused by unproductive coordination of the Cbz carbonyl
oxygen on the ruthenium-alkylidene intermediate.29
In a second series of experiments, hexenyl alcohol 6a was cross
metathesized with allyl glucoside 7 to obtain the heterodimer that
should lead to six-membered ring closure. However, no cross-
metathesis occurred under different reaction conditions (from
5 to 15 mol% of catalyst 16 in CH2Cl2, at room temperature
or reflux). In all cases, allyl isomerization occurred, leading to
propenyl glycoside 27 in almost quantitative yield (Scheme 6).
Roy and co-workers reported a similar isomerization of O-allyl
glycosides under the influence of Grubbs I catalyst.30 S. Hanessian
described the allyl to propenyl isomerization in functionally
diverse compounds in the presence of Grubbs II catalyst.31 Over
Scheme 7 Iodocyclization of heterodimers 17, 20 and 21. R are defined
in Table 1. (a) I2, THF, base (see text), rt.
The cyclization of dimer 17 with iodine in dry THF at room
35
temperature and in the presence of NaHCO3 afforded the
expected tricyclic compounds 30/31 in 92% overall yield (Table 2,
entry 1) and in a 1.5:1 ratio as determined by HPLC, while
stereoisomers 34/35 (2.9:1 ratio) were obtained in 79% yield
from 21 using CaCO3 as acidic scavenger (Table 2, entry 4). The
36
iodocyclization of dimer 20 was carried out in refluxing CH2Cl2
in the presence of CaCO3 giving the diastereoisomers 32/33 in 68%
yield (Table 2, entry 2) and in a 1.4:1 ratio. The chemical yield of
32/33 was raised to 87% when the iodocyclization of dimer 20 was
Table 2 Iodine promoted cyclization of heterodimers 17, 20 and 21
Entry
Heterodimer
Cyclic ether
Yield%
1
17
20
20
21
30/31
32/33
32/33
34/35
92
68
87
79
2a
3b
4
Scheme 6 Cross-metatheses of alcohol 6a. (a) compound 7, 5–15 mol%
of catalyst 16, CH2Cl2; (b) 5 mol% of catalyst 16, CH2Cl2, reflux;
(c) compound 7, 10 mol% of catalyst 16, CH2Cl2, reflux (43%).
a Reaction carried out in refluxing CH2Cl2. b Reaction carried out with
AgOTf at 0 ◦C in CH2Cl2.
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performed in the presence of silver trifluoromethanesulfonate at
0 ◦C in CH2Cl2 (Table 2, entry 3).
provided the two expected stereoisomers with poor stereoselectiv-
ity, thus implying that the monosaccharide units do not exert a
significant asymmetric induction on the reaction course. Further
investigations to explore the behavior of different electrophilic
promoters for the intramolecular cyclization, and to broaden the
scope and applicability of the described reactions are now in
progress.
The exclusive formation of 9,10-anti diastereoisomers is in
agreement with the widely accepted mechanism of electrophilic
addition to alkenes. The intramolecular nucleophilic attack of the
hydroxy group occurs by the back-side at the bridged iodonium
ion, giving overall anti addition. Since two diastereoisomeric
iodonium ions can be formed, the cyclization would lead in
principle to a couple of diastereoisomers, where the substituents
at C-9 and C-10 are in an anti relationship. This was confirmed by
NMR analyses of the product mixtures.
Experimental
General
Finally, we also tested the iodocyclization reaction on het-
erodimer 29. Using iodine and NaHCO3 in THF at room
temperature, an inseparable mixture of compounds 36/37 (1.4:1
ratio by HPLC) was obtained in a disappointing 40% yield (Fig. 2),
thus confirming the occurrence of the exclusive six-membered ring
closure.
NMR spectra were recorded on Bruker AC 300, Bruker Avance
400 and Bruker Avance 500 spectrometers at 298 K. In 13C NMR
spectra, signals corresponding to aromatic carbons are omitted.
Chemical shifts are reported on the d (ppm) scale and the coupling
constants are given in Hz. When possible, peaks assignments were
based on the analysis of 2D spectra (H,H-COSY and HSQC or
HMQC spectra). HRMS spectra were recorded in positive mode
on Bruker Daltonics APEXTM II (FT-ICR). Optical rotations
were measured at room temperature with a Perkin-Elmer 241
polarimeter. [a]D units are given in 10-1 deg cm2 g-1. HPLC
22
analyses were performed with Varian 9050. Column Lichrocart
125–4 RP-18 5 mm, flow rate 1 mL min-1, UV monitor l= 210 nm.
In all HPLC analyses, acetonitrile-water mixtures were used as
eluent. TLC and HPTLC were carried out on Merck Silica-gel
60 F-254 plates (0.25 mm and 0.2 mm thickness, respectively),
and spots were visualized by spraying with a solution containing
H2SO4 (31 mL), ammonium molybdate (21 g) and Ce(SO4)4 (1 g)
in 500 mL water, followed by heating at 110 ◦C for 5 min.
Column chromatography was performed by the flash procedure
using Merck Silica-gel 60 (230–400 mesh). Solvents were dried by
standard procedures.
Fig. 2 Structures of tricyclic compounds 36/37 obtained by iodocycliza-
tion of 29.
The iodocyclized compounds 30–35 can be seen as potential
precursors of carbohydrate mimics, via HI elimination followed
by functionalization of the C–C double bond. The low di-
astereoisomeric ratios obtained in the iodocyclization, however,
suggest a poor asymmetric induction from the sugar residues.
To overcome this problem, we are currently exploring different
electrophilic promoters that could improve the stereoselectivity of
the intramolecular cyclization.
Typical procedure for straightforward CM reaction (method
A). The proper reaction partners (allyl derivative and sugar
hydroxyolefin) were dissolved, under a N2 atmosphere, in dry
CH2Cl2 and nitrogen was bubbled through the solution for 15 min.
Catalyst 16 (10 mol%) was added in one portion and nitrogen was
bubbled through the solution for a further 15 min. The solution
was stirred overnight and the reaction was monitored by TLC.
The solvent was evaporated under reduced pressure and the crude
was purified by flash chromatography.
Conclusions
In conclusion, we have shown that our approach outlined in
Scheme 1 represents a promising methodology for the synthesis
of functionally diverse sugar heterodimers which can be employed
for the preparation of pseudo-oligosaccharides. These molecules
are useful scaffolds for the synthesis of mimics of naturally
occurring, biologically relevant carbohydrates. In particular, we
have explored and compared the straightforward cross-metathesis
reaction with the two-step procedure (self-metathesis followed by
cross-metathesis) developed by Grubbs et al.13 on diverse sugar-
olefin substrates.
Our results suggest that the relative efficiency of the two
approaches seems to depend on the relative homodimerization
rates of type A and type B substrates. Furthermore, we found
that hexenyl alcohols 6a/6b, apt to give a heterodimer leading to
six-membered ring closure, are poor substrates for both types of
cross-metathesis reaction.
Typical procedure for SM-CM reaction (method B). Homod-
imer 26 was dissolved under an argon atmosphere in dry CH2Cl2
(0.2 M) and the solution was warmed to 40 ◦C and argon was
bubbled through the solution for 10 min. Catalyst 16 (10 mol%)
was added. After 20 min a 0.1 M solution of allyl derivative in dry
CH2Cl2 was slowly added and the reaction was monitored by TLC.
After 6 h DMSO (20 mL) was added and stirring was continued
overnight. The solvent was removed under reduced pressure and
the crude was purified by flash chromatography.
(2R)-1-[Methyl-2,3,4-tri-O-benzyl-a-D-xilopyranosidyl]-6-[2,3,
4,6-tetra-O-benzyl-b-D-1-O-glucopyranosyl]-5-hexen-2-ol (17).
Finally, the results of intramolecular cyclizations performed on
heterodimers 17, 20, 21, and 29 using iodine as an electrophilic
promoter showed that, in all cases, the iodocyclization reaction
Method A. The allyl derivative 7 (202 mg, 0.348 mmol) and
alcohol 5a (150 mg, 0.289 mmol) were dissolved in CH2Cl2 (10 mL)
and were cross-metathesized as described above. After work-up,
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22
flash chromatography (hexane-AcOEt 7:3) afforded 17 (167 mg,
54% yield) as a white foam.
(35 mg, 40% yield over two steps) as a white foam. [a]D = +79.5
(c 0.6, CHCl3); dH (400 MHz, CDCl3) 7.40–7.25 (35H, m, H(Ar)),
5.71–5.66 (2H, m, 10-H, 9-H), 5.00–4.40 (16H, m, 14 ¥ CHHPh,
1-H, 1a-H), 4.10–3.94 (7H, m, 11-H, 11¢-H, 4a-H, 2a-H, 3a-H,
5a-H, 3-H), 3.83–3.79 (2H, m, 5-H, 7-H), 3.58–3.51 (3H, m, 2-H,
6a-H, 6a¢-H), 3.38 (3H, s, OCH3), 3.21 (1H, t, J 9.1, 4-H), 2.26–
2.13 (2H, m, 8-H, 8¢-H), 2.01–1.97 (1H, m, 6-H), 1.45–1.35 (1H,
m, 6¢-H); dC (100 MHz, CDCl3) 131.12 (2 ¥ CH, C-9 C-10), 98.10
(CH, C-1), 96.18 (CH, C-1a) 81.93 (CH, C4), 81.71 (CH, C-3),
76.89 (CH, C-2), 79.20 (CH, C-3a or C-4a), 76.55 (C-2a), 75.28
(CH, C-3a or C-4a), 75.80, 75.34, 74.36, 73.47, 73.28 (CH2Ph),
71.33 (CH, C-7 or C-5), 71.12 (CH, C-7 or C-5), 63.38 (CH, C-
5a), 69.09 (CH2, C-6a), 67.98 (CH2, C-11), 55.45 (OCH3), 40.48
(CH2, C-8), 37.83 (CH2, C-6); HRESIMS m/z 1093.5078 (100)
(C67H74O12Na [M + Na]+ requires 1093.5075).
Method B. Homodimer 26 (200 mg, 0.198 mmol) was cross-
metathesized with 7 (57 mg, 0.098 mmol) as described above. After
work-up, flash chromatography (hexane-AcOEt 7:3) afforded 17
22
(52 mg, 42% over two step) as a white foam. [a]D = +15.6 (c 0.5 in
CHCl3); dH (400 MHz, CDCl3) 7.41–7.25 (m, 35H, H(Ar)), 5.76–
5.71 (2H, m, 10-H, 9-H), 5.02–4.55 (15H, m, 14 ¥ CHHPh, 1-H),
4.46 (1H, d, J 7.8, 1a-H), 4.40 (1H, dd, J 12.3, J 7.0, 11-H), 4.17
(1H, dd, J 12.3, J 7.0, 11¢-H), 3.97 (t, 1H, J 9.2, 3-H), 3.81–3.69
(4H, m, 7-H, 5-H, 6a-H, 6a¢-H), 3.62–3.67 (2H, m, 4a-H, 3a-H),
3.54–3.51 (3H, m, 2-H, 2a-H, 5a-H), 3.40 (3H, s, OCH3), 3.24
(2H, m, 4-H, OH), 2.24–2.17 (2H, m, 8-H, 8¢-H), 2.13–1.96 (m,
1H, 6-H), 1.34–1.45 (m, 1H, 6¢-H); dC (100 MHz, CDCl3) 130.47
(CH, C-9), 128.70 (CH, C-10), 102.65 (CH, C-1a), 98.07 (CH,
C-1) 84.73 (CH, C-4a), 82.32 (CH, C-2a), 81.85 (CH, C-4), 81.69
(CH, C-3), 79.47 (CH, C-2) 77.87 (CH, C-2a) 75.87, 75.74, 75.38,
75.04, 75.88, 74.82, 73.50 (CH2Ph), 74.82 (CH, C-5a), 71.36(CH,
C-5 or C-7), 71.21 (CH, C-5 or C-7), 70.06 (CH2, C-11), 68.96
(CH2, C-6a), 55.47 (OCH3), 40.43 (CH2, C-8), 37.73 (CH2, C-
6); HRESIMS m/z 1093.5074 (C67H74O12Na [M + Na]+ requires
1093.5072).
(2R)-1-[methyl-2,3,4-tri-O-benzyl-a-D-xilopyranosidyl]-6-
[methyl-2,3,6-tri-O-benzyl-a-D-4-O-glucopyranosyl]-5-hexen-
2-ol (20).
Method A. allyl derivative 10 (177 mg, 0.351 mmol) and alcohol
5a (152 mg, 0.293 mmol) were dissolved in CH2Cl2 (10 mL) and
were cross-metathesized as described above. After work-up, flash
chromatography (hexane-AcOEt 75:25) afforded 20 (107 mg, 37%
yield) as a colourless oil.
(2R)-1-[Methyl 2,3,4-tri-O-benzyl-a-D-xilopyranosidyl]-6-[2,3,
4,6-tetra-O-benzyl-b-D-galactopyransyl(1–4)-2,3,6-tetra-O-benzyl-
b-D-glucopyranosyl]-5-hexen-2-ol (18).
Method B. Homodimer 26 (181 mg, 0.179 mmol) was cross-
metathesized with 10 (45 mg, 0.089 mmol) as described above. Af-
ter work-up, flash chromatography (hexane-AcOEt 7:3) afforded
20 (98 mg, 80% over two step) as a colourless oil. [a]D = +7.7 (c 0.5
Method B. Homodimer 26 (80 mg, 0.079 mmol) was cross-
metathesized with 8 (42 mg, 0.042 mmol) as described above. After
work-up, flash chromatography (hexane-AcOEt 75:25) afforded 18
22
in CHCl3); dH (400 MHz, CDCl3) 7.37–7.26 (30H, m, H(Ar)), 5.56
(1H, dt, J 15.4 J 7.0, 9-H), 5.51 (1H, dt, J 15.4 J 5.7, 10-H), 5.00
(1H, d, J 10.9, CHHPh), 4.94 (1H, d, J 10.9, CHHPh), 4.90 (1H,
d, J 11.0, CHHPh), 4.84–4.78 (4H, m, 4 ¥ CHHPh), 4.69–4.60
(4H, m, 3 ¥ CHHPh, 1-H), 4.61–4.49 (3H, m, 2 ¥ CHHPh, 1a-H),
4.24 (1H, dd, J 5.5 J 11.2, 11-H), 3.97 (2H, m, J 9.4, 3-H, 11¢-H),
3.91 (1H, t, J 9.4, 3a-H), 3.83–3.76 (2H, m, 5-H, 7-H), 3.71–3.62
(3H, m, 6a-H, 6a¢-H, 5a-H), 3.53 (2H, dd, J 5.5 J 11.2, 2a-H 2-H),
3.47 (1H, t, J 9.1, 4a-H), 3.41 (3H, s, OCH3), 3.40 (3H, s, OCH3),
3.21 (1H, t, J 9.3, 4-H), 3.13 (1H, bs, OH), 2.19–2.07 (2H, m,
8-H, 8¢-H), 1.96 (1H, dd, J 12.2, 6¢-H), 1.43–1.31 (1H, m, 6-H);
dC (100 MHz, CDCl3) 130.75–130.11 (2 ¥ CH, C-10, C-9), 98.89,
98.77 (2 ¥ CH, C-1 C-1a), 82.71, 82.59, 82.38 (3 ¥ CH, C-4 C-3a
C-3), 80.47 (2 ¥ CH, C-2 C-2a), 78.26 (CH, C-4a), 76.46, 76.33,
76.00 (CH2Ph), 74.17 (CH2, C-11 or CH2Ph), 74.06 (CH2, C-11 or
CH2Ph), 71.93 (CH, C-5 or C-7), 71.94 (CH, C-5 or C-7), 70.83
(CH, C-5a), 69.29 (CH2, C-6a), 56.11 (OCH3), 55.81 (OCH3),
41.10 (CH2, C-8), 38.58 (CH2, C-6); HRESIMS m/z 1017.4757
(100) (C61H70012Na1 [M + Na]+ requires 1017.4759).
22
(29 mg, 40% yield over two step) as a white foam. [a]D = +11.0
(c 0.4 in CHCl3); dH (400 MHz, CDCl3) 7.37–7.25 (50H, H(Ar)),
5.75–5.66 (2H, m, 10-H 9-H), 5.04–4.53 (18 H, m, 17 ¥ CHHPh
H-1), 4.58–4.26 (5H, m, 3 ¥ CHHPh 11-H 1a-H 1b-H), 4.07 (1H,
dd, J 12.4 J 5.8, 11¢-H), 3.94–3.91 (3H, m, 3-H 3a-H 4b-H), 3.78–
3.73 (5H, m, 2b-H 7-H 5-H 6b¢-H 6b-H), 3.58–3.52 (m, 3H, 4a-
H 2-H 6a-H), 3.41–3.35 (8H, m, 5b-H 5a-H 2a-H 6a¢-H OCH3
3b-H), 3.20 (1H, t, J 9.0, 4-H), 2.18–2.05 (2H, m, 8-H, 8¢-H),
1.98–1.95 (1H, m, 6-H), 1.40–1.36 (1H, m, 6¢-H); dC (100 MHz,
CDCl3): d (ppm) : 130.89–129.50 (2 ¥ CH, C-9 C-10), 103.46–
103.35 (2 ¥ CH, C-1a C-1b), 98.75 (CH, C-1), 83.69, 83.26, 82.56,
82.49, 82.37, 80.66, 80.50, 78.00, 75.85, 74.32, 73.66 (11 ¥ CH,
C-2a C-3a C-4a C-5a C-2b C-3b C-4b C-5b C-2 C-3 C-4), 76.46,
76.00, 75.65, 75.38, 74.07, 73.66, 73.26 (CH2Ph), 71.96 (CH, C-5
or C-7), 71.79 (CH, C-5 or C-7), 70.60 (CH2, C-11), 69.05 (CH2,
C-6b), 68.78 (CH2, C-6a), 56.20 (OCH3) 41.10 (CH2, C-8), 38.47
(CH2, C-6); HRESIMS m/z 1525.7008 (100) (C94H102O17Na [M +
Na]+ requires 1525.7009).
(2R)-1-[Methyl 2,3,4-tri-O-benzyl-a-D-xilopyranosidyl]-6-[2,3,
4,6-tetra-O-benzyl-a-D-1-O-galactopyranosyl]-5-hexen-
2-ol (19).
(2R)-1-[Methyl-2,3,4-tri-O-benzyl-a-D-xilopyranosidyl]-6-
[2,3,4,6-tetra-O-benzyl-1-deoxy-b-D-1-C-glucopyranosyl]-5-hexen-
2-ol (21).
Method A. Allyl derivative 9 (28 mg, 0.048 mmol) and alcohol
5a (20 mg, 0.039 mmol) were dissolved in CH2Cl2 (1 mL)
and were cross-metathesized as described above. After work-up,
flash chromatography (hexane-AcOEt 7:3) afforded compound 19
(19 mg, 45%) as a white foam.
Method A. Allyl derivative 11 (298mg, 0.528mmol) andalcohol
5a (232 mg, 0.447 mmol) were dissolved in CH2Cl2 (10 mL)
and were cross-metathesized as described above. After work-up,
flash chromatography (hexane-AcOEt 7:3) afforded compound 21
(117 mg, 25%) as a colourless oil.
Method B. Homodimer 26 (138 mg, 0.137 mmol) was cross-
metathesized with 9 (40 mg, 0.069 mmol) as described above. After
work-up, flash chromatography (hexane-AcOEt 7:3) afforded 19
Method B. Homodimer 26 (150 mg, 0.149 mmol) was cross-
metathesized with 11 (42 mg, 0.074 mmol) as described above. Af-
ter work-up, flash chromatography (hexane-AcOEt 7:3) afforded
2640 | Org. Biomol. Chem., 2009, 7, 2635–2644
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22
21 (49 mg, 55% over two steps) as a colourless oil. [a]D = +37.5 (c
Method B. Homodimer 26 (52 mg, 0.052 mmol) was cross-
metathesized with 13 (13 mg, 0.025 mmol) as described above. Af-
ter work-up, flash chromatography (hexane-AcOEt 7:3) afforded
23 (20 mg, 68% over two steps) as a white foam. [a]D = +52.7 (c
1.7 in CHCl3); dH (400 MHz, CDCl3) 7.37–7.26 (35H, m, H(Ar)),
5.52–5.48 (2H, m, 9-H, 10-H), 5.00 (1H, d, J 10.8, CHHPh), 4.95
(1H, d, J 10.9, CHHPh), 4.90 (1H, d, J 10.9, CHHPh), 4.84–
4.79 (5H, m, 5 ¥ CHHPh), 4.70–4.59 (4H, m, 4 ¥ CHHPh), 4.55
(1H, d, J 3.5, 1-H), 4.48 (1H, d, J 12.1, CHHPh), 4.47 (1H, d, J
10.6, CHHPh), 4.10–4.07 (1H, m, 1a-H), 3.96 (t, 1H, J 9.3, 3-H),
3.83–3.73 (4H, m, 2a-H, 3a-H, 5-H, 7-H), 3.63–3.58 (4H, m, 6a-H,
6a¢-H, 5a-H, 4a-H), 3.52 (1H, dd, J 3.6 J 9.7, 2-H), 3.40 (3H, s,
OCH3), 3.25 (1H, t, J 9.3, 4-H), 3.18 (1H, bs, OH), 2.48–2.44 (2H,
m, 11-H, 11¢-H), 2.16–2.13 (2H, m, 8-H, 8¢-H), 2.00 (dt, 1H, J
11.4, J 2.7, 6-H), 1.49–1.45 (m, 1H, 6¢-H). dC (100 MHz, CDCl3)
129.38 (CH, C-10), 129.00(CH, C-9), 98.05 (CH, C-1), 82.39 (CH,
C-3a), 82.05 (CH, C-4), 81.80 (CH, C-3), 80.12 (CH, C-2a), 79.90
(CH, C-2), 78.28 (CH, C-4a), 75.81, 75.47, 75.37, 75.11 (CH2Ph),
73.72 (CH, C-1a), 73.46, 73.20, 73.04 (CH2Ph), 71.07 (CH, C-5a),
70.75 (CH, C-7 C-5), 70.53 (CH, C-7 C-5), 69.04 (CH2, C-6a),
55.40 (OCH3), 40.89 (CH2, C-8), 32.83 (CH2, C-6), 28.73 (CH2,
C-11). HRESIMS m/z 1077.5126 (100) (C67H74O11Na [M + Na]+:
requires 1077.5123).
22
1, CHCl3); dH (400 MHz, CDCl3) 7.41–7.26 (m, 30H, CH(Ar)),
5.57–5.45 (2H, m, 10-H, 9-H), 5.01 (1H, dd, J 2.5 J 8.2, 2a-H),
4.99–4.51 (13H, m, 12 ¥ CHHPh, 1-H), 4.20–4.15 (1H, m, 1a-H),
3.98 (1H, t, 3-H), 3.87–3.81 (3H, m, 3a-H, 5-H, 7-H), 3.76–3.64
(4H, m, 5a-H, 6a-H, 6a¢-H, 4a-H), 3.54 (1H, dd, J 3.5 J 9.3, 2-H),
3.41 (3H, s, OCH3), 3.26 (1H, t, J 9.3, 4-H), 2.51–2.44 (1H, m,
11-H), 2.36–2.15 (3H, m, 8¢-H, 8-H, 11¢-H), 2.06 (3H, s, COCH3),
1.96 (1H, m, 6-H), 1.52–1.44 (1H, m, 6¢-H); dC (100 MHz, CDCl3)
170.01 (-COCH3), 129.70 (CH, C-9), 128.72 (CH, C-10), 98.08
(CH, C-1), 82.05 (CH, C-4), 81.78 (CH, C-3), 79.86 (2 ¥ CH,
C-2 C-3a), 77.54 (CH, C-4a), 75.82, 75.37, 75.02, 74.67, 74.47,
73.40 (CH2Ph), 72.63 (CH, C-2a), 71.91 (CH, C-1a or C-5a), 71.84
(CH, C-1a or C-5a), 70.90 (CH, C-5 or C-7), 70.95 (CH, C-5 or
C-7), 68.85 (CH2, C-6a), 55.42 (OCH3), 40.82 (CH2, C-8), 37.87
(CH2, C-6), 30.05 (CH2, C-11), 20.98 (CH3CO); HRESIMS m/z
1029.4752 (100) (C62H70012Na1 [M + Na]+ requires 1029.4759).
(2R)-1-[Methyl-2,3,4-tri-O-benzyl-a-D-xilopyranosidyl]-6-
[2,3,4,6-tetra-O-benzyl-1-deoxy-b-D-1-C-galactopyranosyl]-5-
hexen-2-ol (22).
(2R)-1-[Methyl-2,3,4-tri-O-benzyl-a-D-xilopyranosidyl]-6-
[3,4,6-tri-O-acetyl-2-azido-2-deoxy-b-D-glucopyranosyl]-5-hexen-
2-ol (24).
Method A. Allyl derivative 12 (71 mg, 0.126 mmol) and alcohol
5a (54 mg, 0.104 mmol) were dissolved in CH2Cl2 (5.2 mL) and
were cross-metathesized as described above. After work-up, flash
chromatography (hexane-AcOEt 75:25) afforded compound 22
(37 mg, 34%) as a colourless oil.
Method A. Allyl derivative 14 (34 mg, 0.092 mmol) and alcohol
5a (40 mg, 0.077 mmol) were dissolved in CH2Cl2 (5.2 mL)
and were cross-metathesized as described above. After work-up,
flash chromatography (hexane-AcOEt 7:3) afforded compound 24
(41 mg, 62%) as a colourless oil.
Method B. Homodimer 26 (100 mg, 0.0990 mmol) was cross-
metathesized with 12 (28 mg, 0.050 mmol) as described above. Af-
ter work-up, flash chromatography (hexane-AcOEt 7:3) afforded
22 (40 mg, 64% over two steps) as a colourless oil. [a]D = +46.3 (c
Method B. Homodimer 26 (103 mg, 0.102 mmol) was cross-
metathesized with 14 (18 mg, 0.051 mmol) as described above. Af-
ter work-up, flash chromatography (hexane-AcOEt 7:3) afforded
26 (23 mg, 45% over two steps) as a colourless oil. [a]D = +7.7 (c
22
22
0.1 in CHCl3); dH (400 MHz, CDCl3) 7.38–7.25 (35H, m, H(Ar)),
5.46–5.44 (2H, m, 9-H 10-H), 4.99 (1H, d, J 10.8, CHHPh), 4.89
(1H, d, J 10.8, CHHPh), 4.82 (1H, d, J 10.8, CHHPh), 4.80 (1H,
d, J 12.4, CHHPh), 4.75–4.51 (11H, m, 10 ¥ CHHPh, 1-H), 4.03–
3.93 (4H, m, 5a-H, 3-H, 1a-H, 4a-H), 3.85–3.71 (5H, m, 6a-H,
3a-H, 2a-H, 5-H, 7-H), 3.63 (1H, dd, J 4.8 J 10.4, 6a¢-H), 3.51
(1H, dd, J 3.6 J 9.6, 2-H), 3.38 (3H, s, OCH3), 3.22 (1H, t, J
9.2, 4-H), 2.42–2.30 (2H, m, 11-H, 11¢-H), 2.11–2.07 (2H, m, 8-
H, 8¢-H), 1.99 (1H, bd, J 12.0, 6-H), 1.46–1.37 (1H, m, 6¢-H); dC
(100 MHz, CDCl3) 131.85 (CH, C-9 or C-10), 127.48 (CH, C-9 or
C-10), 98.10 (CH, C-1), 82.03 (CH, C-4), 81.76 (CH, C-3), 79.88
(CH, C-2), 76.48 (2 ¥ CH, C2a C3a), 75.80, 75.37 (CH2Ph), 74.41
(CH, C-4a or C-1a), 73.45, 73.19, 73.03 (CH2Ph), 72.31 (CH, C-
5a), 71.39 (C1a or C4a), 70.97 (CH, C-5 or C-7), 70.86 (CH, C-5
or C-7), 67.49 (CH2, C-6a), 55.39 (OCH3), 40.83 (CH, C-8), 37.81
(CH2, C-6), 23.56 (CH2, C-11); HRESIMS m/z 1077.5127 (100)
(C67H74O12Na [M + Na]+ requires 1077.5123).
1.8 in CHCl3); dH (400 MHz, CDCl3) 7.38–7.27 (15H, m, H(Ar)),
5.80 (1H, dt, J 15.6 J 7.2, H-9), 5.70 (1H, dt, J 15.6 J 6.0, H-
10), 5.04–4.97 (m, 3H, 3a-H, 4a-H, CHHPh), 4.95 (1H, d, J 11.2,
CHHPh), 4.83 (1H, d, J 10.8, CHHPh), 4.82 (1H, d, J 12.4,
CHHPh), 4.68 (1H, d, J 12.0, CHHPh), 4.57 (1H, d, J 3.6, 1-H),
4.44 (1H, d, J 8, 1a-H), 4.37 (1H, dd, J 12.0 J 5.6, 11-H), 4.30
(1H, dd, J 12.4 J 5.2, 6a-H), 4.15–4.12 (2H, m, 6a¢-H, 11¢-H),
3.97 (1H, t, J 9.2, 3-H), 3.88–3.80 (2H, m, 5-H, 7-H), 3.69–3.63
(1H, m, 5a-H), 3.58–3.51 (2H, m, 2a-H, 2-H), 3.41 (3H, s, OCH3),
3.22 (1H, t, J 9.2, 4-H), 2.19–2.25 (2H, m, 8-H, 8¢-H), 2.10 (3H, s,
COCH3), 2.09 (3H, s, COCH3), 2.03 (3H, s, COCH3), 2.01–1.98
(1H, m, 6-H), 1.46–1.37 (1H, m, 6¢-H); dC (100 MHz, CDCl3)
170.65–170.01–169.62 (3 ¥ COCH3), 131.85 (CH, C-9), 127.48
(CH, C10), 100.87 (CH, C-1a), 98.10 (CH, C-1), 81.87, 81.68 (2 ¥
CH, C-3 C-4), 79.80 (CH, C-2), 75.84, 75.32, 73.48 (CH2Ph),
72.57 (CH, C-3a or C-4a), 71.75 (CH, C-5a), 71.75 (2 ¥ CH, C-5
C-7), 70.41 (CH2, C-6a), 68.43 (C-3a or C-4a), 61.93 (C-11); 55.48
(OCH3), 40.30 (CH2, C-8), 37.81 (CH2, C-6), 20.75–20.71–20.60
(3 ¥ CH3CO); HRESIMS m/z 884.3573 (100) (C45H55O14N3Na
[M + Na]+ requires 884.3576).
(2R)-1-[Methyl-2,3,4-tri-O-benzyl-a-D-xilopyranosidyl]-6-[2-
O-acetyl-3,4,6-tri-O-benzyl-1-deoxy-b-D-1-C-glucopyranosyl]-5-
hexen-2-ol (23).
(2R)-1-[Methyl-2,3,4-tri-O-benzyl-a-D-xilopyranosidyl]-6-
[methyl-2-amino-N-benzyloxycarbonyl-4,6-O-benzylidene-2-
deoxy-a-D-glucopyranoside]-5-hexen-2-ol (25).
Method A. Allyl derivative 13 (176mg, 0.341mmol)andalcohol
5a (152 mg, 0.293 mmol) were dissolved in CH2Cl2 (10 mL) and
were cross-metathesized as described above. After work-up, flash
chromatography (hexane-AcOEt 8:2) afforded 23 (118 mg, 40%
yield) as a white foam.
Method A. Allyl derivative 15 (38.5 mg, 0.088 mmol) and
alcohol 5a (40 mg, 0.078 mmol) were dissolved in CH2Cl2 (1.7 mL)
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and were cross-metathesized as described above. After work-up,
flash chromatography (hexane-AcOEt 7:3) afforded compound 25
(29 mg, 41%) as a colourless oil.
CH2Cl2 (2.3 mL) and the solution was warmed to 40 ◦C and
bubbled with argon for 10 min. Then Hoveyda catalyst (7 mg,
0.012 mmol) was added. The reaction was monitored by TLC
(dichloromethane-AcOEt 9:1). After 3 h DMSO (20 mL) was
added and stirring was continued overnight at room temperature.
The solvent was removed under reduced pressure and the crude
was filtered over a silica gel column affording a complex mixture
of isomers (106 mg), containing compound 28 as the major
component. A pure analytical sample of 28 was isolated during
chromatography and characterised by NMR. dH (400 MHz,
CDCl3): 7.36–7.26 (30H, m, H(Ar)), 5.44 (2H, m, 2 ¥ 11-H),
4.99 (2H, m, J 10.8, 2 ¥ CHHPh), 4.91 (2H, d, J 11.0, 2 ¥
CHHPh), 4.82 (2H, d, J 10.8, 2 ¥ CHHPh), 4.80 (2H, d, J 10.8,
2 ¥ CHHPh), 4.66 (2H, d, J 10.8, 2 ¥ CHHPh), 4.68–4.50 (4H,
m, 2 ¥ CHHPh 2 ¥ 1-H), 3.98 (2H, bt, J 9.3, 2 ¥ 3-H), 3.81 (2H,
bt, J 9.7, 2 ¥ 5-H), 3.75 (2H, m, 2 ¥ 7-H), 3.51 (2H, dd, J 3.5 J
11.0, 2 ¥ 2-H), 3.40 (6H, s, 2 ¥ OCH3), 3.20 (4H, m, J 9.1, 2 ¥ 4-H
2 ¥ OH), 1.99 (H, m, 2 ¥ 10-H 2 ¥ 10¢-H, 2 ¥ 6-H), 1.43–1.27 (5H,
m, 2 ¥ 6¢-H, 2 ¥ 8¢-H, 2 ¥ 8-H, 2 ¥ 9-H, 2 ¥ 9¢-H); dC (100 MHz,
CDCl3) 130.94 (CH, C-11), 98.78 (CH, C-1), 82.74 (CH, C-4),
82.37 (CH, C-3), 80.52 (CH, C-2), 76.48, 76.04, 74.13 (CH2Ph),
72.45 (2 ¥ CH, C-7 C-5), 56.10 (OCH3), 41.38 (CH2, C-6), 33.21
(CH2, C-10), 37.73 (CH2, C-8 or C-9), 26.02 (CH2, C-8 or C-9);
HRESIMS m/z 1087.5544 (C66H80N6012Na1 [M + Na]+ requires
1087.5542).
Method B. Homodimer 26 (118 mg, 0.117 mmol) was cross-
metathesized with 15 (24 mg, 0.054 mmol) as described above. Af-
ter work-up, flash chromatography (hexane-AcOEt 7:3) afforded
22
25 (20 mg, 34% over two steps) as a colourless oil. [a]D = +5.5 (c
0.5 in CHCl3); dH (400 MHz, CDCl3) 7.40–7.26 (20H, m, H(Ar)),
5.63–5.49 (3H, m, 9-H, 10-H, PhCH(O-)2), 5.18 (1H, d, J 12.0,
CHHPh), 5.10 (1H, d, J 12.0, CHHPh), 4.98 (1H, d, J 10.8,
CHHPh), 4.91 (1H, d, J 11.2, CHHPh), 4.83 (1H, d, J 10.8,
CHHPh), 4.82 (1H, d, J 12.4, CHHPh), 4.73 (1H, d, J 3.2, 1a-
H), 4.67 (1H, d, J 12.0, CHHPh), 4.60 (1H, d, J 11.2, CHHPh),
4.52 (1H, d, J 3.6, 1-H), 4.32–4.28 (2H, m, 6a-H, 11-H), 4.02–
3.91 (3H, m, 2a-H, 3-H, 11¢-H), 3.83–3.78 (4H, m, 6a¢-H, 5-H,
7-H, 5a-H), 3.66–3.62 (2H, m, 3a-H, 4a-H), 3.52 (1H, dd, J 9.6 J
3.2, H-2), 3.39 (3H, s, OCH3), 3.35 (3H, s, OCH3), 3.21 (1H,
t, J 9.2, 4-H), 2.12–2.09 (2H, m, 8-H, 8¢-H), 1.95 (1H, bd, J
3.6, 6-H), 1.40–1.37 (1H, m, 6¢-H); dC (100 MHz, CDCl3) 159.25
(-NHCOOCH2Ph), 130.89 (CH, C-9), 129.70 (CH, C-10), 101.25
(CH, PhCH(O-)2), 99.59 (CH, C-1a), 98.08 (CH, C-1), 82.43 (CH,
C-3a or C-4a), 81.96 (CH, C-4), 81.69 (CH, C-3), 79.85 (CH, C-2),
75.83 (CH2Ph), 75.43 (CH, C-3a or C-4a), 75.35 (CH2Ph), 71.28
(CH, C-5 or C-7), 71.06 (CH, C-5 or C-7), 69.09 (CH2, C-6a),
69.79 (CH2Ph), 62.73 (CH, C-5a), 55.39 (OCH3), 55.23 (OCH3),
54.71 (CH, C-2a), 40.57 (CH2, C-8), 38.16 (CH2, C-6); HRES-
IMS m/z 968.4189 (100) (C55H63O13NNa [M + Na]+ requires
968.4191).
The compound mixture containing 28 was directly employed in
the following cross-metathesis reaction.
(2R)-1-[Methyl 2,3,4-tri-O-benzyl-a-D-xilopyranosidyl]-8-[2,3,
(2R,7R) 1,8-bis-[Methyl 2,3,4-tri-O-benzyl-a-D-xilopyranosi-
dyl]-4-octen-2,7-diol (26). Compound 5a (370mg, 0.713 mmol)
was dissolved in dry CH2Cl2 (15 mL) and solution was warmed
to 40 ◦C and argon was bubbled through the solution for 10 min.
Then catalyst 16 (20mg, 0.033 mmol) was added. The reaction
was monitored by TLC (hexane-AcOEt 4:6). After 3 h DMSO
(20 mL) was added and stirring was continued overnight at room
temperature. The solvent was removed under reduced pressure
and the crude compound was purified by flash chromatography
(hexane-AcOEt 1:1) affording compound 26 (306 mg, 85% yield,
E/Z ratio ª 3:1 on the base of NMR spectra) as a white foam.
Major isomer (E): dH (400 MHz, CDCl3) 7.38–7.25 (30H, m,
H(Ar)), 5.49–5.45 (2H, m, 2 ¥ 9-H), 5.00 (2H, d, J 10.9, 2 ¥
CHHPh), 4.90 (2H, d, J 11.0, 2 ¥ CHHPh), 4.83 (2 H, d, J 10.8, 2 ¥
CHHPh), 4.81 (2H, d, J 12.0, 2 ¥ CHHPh), 4.67 (2H, d, J 10.9, 2 ¥
CHHPh), 4.60–4.58 (2H, m, 2 ¥ CHHPh), 4.55 (2H, d, J 3.5, 2 ¥ 1-
H), 3.96 (bt, 2H, J 9.3 J 9.2, 2 ¥ 3-H); 3.83–3.77 (4H, m, 2 ¥ 5-H, 2 ¥
7-H); 3.52 (2H, d, J 9.6 J 3.5, 2 ¥ 2-H), 3.39 (6H, s, 2 ¥ OCH3), 3.20
(2H, bt, J 9.3, 2 ¥ 4-H), 3.17 (2H, bs, OH), 2.14–2.09 (4H, m, 2 ¥
8-H, 2 ¥ 8¢-H), 2.02–1.98 (2H, bd, J 14.3, 2 ¥ 6-H), 1.42–1.38 (2H,
m, J 14.3, 2 ¥ 6¢-H); dC (100 MHz, CDCl3) 138.08 (CH, C-9), 98.09
(CH, C-1), 82.09 (CH, C-4), 81.71 (CH, C-3), 79.89 (CH, C-2),
75.79, 75.34, 73.46 (CH2Ph), 71.25 (CH, C-5 or C-7), 71.13 (CH,
C-5 or C-7), 55.42 (OCH3), 40.81 (CH2, C-8), 37.83 (CH2, C-6);
HRESIMS m/z 1031.4916 (100) (C62H72012Na1 [M + Na]+ requires
1031.4916).
4,6-tetra-O-benzyl-b-D-1-O-glucopyranosyl]-6-octen-2-ol
(29).
The compound mixture described above (28) (106 mg) was
dissolved under an argon atmosphere in dry CH2Cl2 (2 mL)
◦
and the solution was warmed to 40 C and bubbled with argon
for 10 min then catalyst 16 (6 mg, 9.6 mmol) was added. After
20 min a solution of compound 7 (56 mg, 0.096 mmol) in 1 mL
CH2Cl2 was added dropwise and the reaction was monitored by
TLC hexane:AcOEt 6:4). After 6 h DMSO (20 mL) was added
and stirring was continued overnight. The solvent was removed
under reduced pressure and the crude was purified by flash
chromatography (hexane-AcOEt 7:3) affording compound 29
22
(45 mg, 43%) as a colourless oil. [a]D = +26.9 (c 0.5, CHCl3);
major diastereoisomer (E): dH (400 MHz, CDCl3) 7.40–7.31 (35H,
m, H(Ar)), 5.76 (1H, m, 11-H), 5.65 (1H, m, 12-H), 5.02–4.45
(15H, m, 14 ¥ CHHPh 1-H), 4.46 (1H, d, J 7.8, 1a-H), 4.40 (1H,
d, J 12.2, 13-H), 4.12 (1H, d, J 12.2, 13¢-H), 3.98 (1H, bt, J 9.3,
3-H), 3.85–3.59 (6H, m, 5-H, 7-H, 6a-H, 6a¢-H, 4a-H, 3a-H),
3.55–3.47 (m, 3H, 2-H, 5a-H, 2a-H), 3.42 (s, 3H, OCH3), 3.21
(2H, m, 4-H, OH), 2.13–2.08 (2H, m, 10-H, 10¢-H), 1.96 (1H, bt,
J 14.3, 6-H), 1.72–1.29 (5H, m, 6¢-H, 8-H, 8¢-H, 9-H, 9¢-H); dC
(100 MHz, CDCl3) 134.71 (CH, C-11), 125.92 (CH, C-12), 102.57
(CH, C-1a), 98.08 (CH, C-1), 84.77 (CH, C-4a or C-3a), 82.33
(CH, C-2a), 82.04 (CH, C-4), 81.70 (CH, C-3), 79.82 (CH, C-2),
77.95 (CH, C-4a or C-3a), 75.84, 75.71, 75.38, 75.01 (CH2Ph),
74.89 (CH, C-5a), 74.82 (CH2Ph), 71.67 (2 ¥ CH, C-5 C-7),
70.26 (CH2, C-13), 69.06 (CH2, C-6a), 38.36 (CH2, C-6), 37.11
(CH2, C-8 or C-9), 32.31 (CH2, C-10), 24.85 (CH2, C-9 or C-8);
HRESIMS m/z 1121.5385 (C69H78012Na1 [M + Na]+ requires
1121.5386).
(2R,11R)-1,12-bis-[Methyl 2,3,4-tri-O-benzyl-a-D-xilopyranosi-
dyl]-5-dodecen-2,11-diol (28). Compound 6a (126 mg,
0.230 mmol) was dissolved under argon atmosphere in dry
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chromatography (hexane-AcOEt 9:1) afforded 32/33 (115 mg,
87% yield) as a mixture of diastereoisomers. A pure analytical
sample of a single diastereoisomer was isolated during column
chromatography. Major diastereoisomer: dH (400 MHz, CDCl3) :
7.32–7.15 (30H, m, H(Ar)), 4.95 (1H, d, J 10.8, CHHPh), 4.88–
4.82 (3H, m, 3 ¥ CHHPh), 4.79–4.72 (2H, m, 2 ¥ CHHPh), 4.63
(1H, d, J 4.6, 1-H), 4.64–4.49 (6H, m, 6 ¥ CHHPh), 4.45 (1H, d,
J 3.6, 1a-H), 4.12–4.07 (2H, m, 7-H, 11-H), 4.02 (1H, dd, J 2.0
J 9.9, 11¢-H), 3.94 (3H, m, 3-H, 3a-H, 9-H), 3.74 (1H, dd, J 2.0
J 9.9, 6a-H), 3.67–3.59 (1H, dd, H-6a¢), 3.60–3.54 (2H, m, 5-H,
5a-H), 3.52–3.42 (m, 3H, 2-H, 2a-H), 3.34 (3H, s, OCH3), 3.30
(3H, s, OCH3), 3.22 (1H, t, J 9.4, 4-H), 2.60–2.47 (1H, m, 8-H),
2.05–1.95 (1H, m, 8¢-H), 1.92–1.85 (2H, m, 6-H, 6¢-H). Maldi-Tof
m/z 1143.48 (100) (C67H73I012Na [M + Na]+ requires 1143.36).
2-{Methyl-[2,3,4,6-tetra-O-benzyl-b-D-glucopyranosyl]}-5-
{methyl-[methyl 2,3,4-tri-O-benzyl-a-D-xilopyranosidyl]}-3-iodo-
tetrahydrofuran (30/31). Compound 17 (20 mg, 0.018 mmol)
was dissolved in dry THF (1 mL) under an N2 atmosphere,
then NaHCO3 (3 mg, 0.04 mmol) and I2 (23 mg, 0.09 mmol)
were added and the solution was stirred at rt. The reaction
progress was monitored by TLC (hexane-AcOEt 7:3). After 3 h
the reaction mixture was diluted with CH2Cl2 (8 mL) and the
solution was washed with Na2S2O3 satd. sol. in water (3 ¥ 4 mL).
The aqueous phases were extracted with CH2Cl2 (2 ¥ 5 mL).
The organic layers were collected, dried over Na2SO4, filtered and
the solvent was removed under reduced pressure. Purification by
flash chromatography (hexane-AcOEt 9:1) afforded 30/31 (20 mg,
92% yield) as an inseparable mixture of diastereoisomers. A
diastereomeric ratio of 1:1.5 was determined by HPLC analysis
(CH3CN:H2O 85:15). Major diastereoisomer: dH (400 MHz,
CDCl3) 7.40–7.18 (m, 35H, H(Ar)), 5.00–4.58 (14H, m, 14 ¥
CHHPh), 4.54 (1H, bs, 1-H), 4.48 (d, 1H, J 7.2, 1a-H), 4.25–
4.20 (3H, m, 10-H, 9-H, 7-H), 4.20–4.12 (1H, m, 11-H), 4.04 (1H,
dd, J 10.8 J 2.0, 11¢-H), 3.94 (1H, t, J 9.2, 3-H), 3.77–3.72 (2H, m,
6a-H, 6a¢-H), 3.65–3.62 (3H, m, 3a-H, 4a-H, 5-H), 3.49–3.42 (3H,
m, 2-H, 2a-H, 5a-H), 3.32 (3H, s, OCH3), 3.25 (1H, t, J 9.3, 4-H),
2.56–2.53 (1H, m, 8-H), 2.10–2.03 (1H, m, 8¢-H), 1.97–1.88 (1H, m,
6-H, 6¢-H); dC (100 MHz, CDCl3) 103.67 (CH, C-1a); 97.93 (CH,
C-1), 85.67 (CH, C-10), 84.72 (CH, C-4a), 82.20 (CH, C-2a), 81.99
(CH, C-4), 81.77 (CH, C-3), 80.05 (CH, C-2), 77.80 (CH, C-3a),
76.50 (CH, C-7), 75.74, 75.65, 75.22, 74.83 (CH2Ph), 73.80 (CH,
C-5a), 73.56, 73.35 (CH2Ph), 68.80 (CH2, C-6a), 68.05 (CH, C-5),
67.04 (CH2, C-11), 55.33 (OCH3), 45.04 (CH2, C-8), 37.44 (CH2,
C-6), 17.24 (CH, C-9). Maldi-Tof m/z 1220.4 (100)(C67H73IO12Na
[M + Na]+ : requires 1220.2).
2-{Methyl-[2,3,4,6-tetra-O-benzy l-1-deoxy-b-D-1-C-glucopy-
ranosil]}-5-{methyl[methyl 2,3,4-tri-O-benzyl-a-D-xilopyranosi-
dyl]}-3-iodo-tetrahydrofuran (34/35). Compound 21 (30 mg,
0.028 mmol) was dissolved, under a N2 atmosphere, in dry THF
(1.5 mL) and iodocyclized at rt with I2 (35 mg, 0.14 mmol)
in the presence of CaCO3 (4 mg, 0.028 mmol). After 3 h the
reaction mixture was diluted with CH2Cl2 (8 mL) and the solution
was washed with Na2S2O3 satd. sol. in water (3 ¥ 4 mL). The
aqueous phases were extracted with CH2Cl2 (2 ¥ 5 mL). The
organic layers were collected, dried over Na2SO4, filtered and
the solvent was removed under reduced pressure. Purification
by flash chromatography (hexane-AcOEt 9:1) afforded 34/35
(26 mg, 79% yield) as an inseparable mixture of diastereoisomers.
A diastereomeric ratio of 1:2.9 was determined by HPLC analysis
(CH3CN:H2O 85:15). Major diastereoisomer: dH (400 MHz,
CDCl3) 7.34–7.27 (35H, m, H(Ar)), 4.99 (1H, d, J 10.9, CHHPh),
4.95 (1H, d, J 10.6, CHHPh), 4.92 (1H, d, J 10.4, CHHPh),
4.85–4.77 (4H, m, 4 ¥ CHHPh), 4.69–4.59 (5H, m, 5 ¥ CHHPh),
4.54 (1H, d, J 3.5, 1-H), 4.51–4.39 (3H, m, 2 ¥ CHHPh, 10-H),
4.31–4.21 (3H, m, 1a-H, 7-H, 9-H), 3.96 (1H, t, J 9.4, 3-H),
3.83–3.64 (6H, m, 2a-H, 3a-H, 4a-H, 5a-H, 6a-H, 6a¢-H), 3.51
(1H, dd, J 3.5 J 9.7, 2-H), 3.36 (3H, s, OCH3), 3.30 (1H, t,
J 9.3, H-4), 2.64–2.58 (1H, m, H-8), 2.12–2.10 (2H, m, 11-H,
11¢-H), 2.06–1.98 (1H, m, 8¢-H), 1.97–1.90 (2H, m, 6-H, 6¢-H);
dC (100 MHz, CDCl3) 98.01 (C-1), 84.64 (CH, C-7), 82.03 (CH,
C-3), 82.03 (CH, C-4), 80.10 (CH, C-2); 82,36, 79.54, 77.88, 71.62,
67.99 (5 ¥ CH, C-2a C-4a C-3a C-5a C-5), 75.97 (CH, C-1a),
75.74, 75.44, 75.19, 75.09, 73.55, 73.35, 72.51 (Ch2Ph), 70.50
(CH, C-10), 68.88 (CH2, C-6a), 55.29 (OCH3), 45.01 (CH2, C-8),
38.00 (CH2, C-6), 23.99 (CH, C-11), 21.86 (CH, C-9). Maldi-Tof
m/z 1220.40 (C67H73I012Na [M + Na]+ requires 1220.22).
2-{Methyl-[2,3,6-tri-O-benzyl-a-D-4-O-glucopyranosyl]}-5-
{methyl-[methyl 2,3,4-tri-O-benzyl-a-D-xilopyranosidyl]}-3-iodo-
tetrahydrofuran (32/33).
Method C. Compound 20 (118 mg, 0.119 mmol) was dissolved
in dry CH2Cl2 (5 mL) under an N2 atmosphere. CaCO3 (12 mg,
0.12 mmol) and I2 (180 mg, 0.71 mmol) were subsequently added
and the reaction heated at 40 ◦C. The reaction was monitored by
TLC (hexane-AcOEt 7:3). After 3 h, the reaction was diluted with
CH2Cl2 (12 mL) and the solution was washed with Na2S2O3 satd.
sol. in water (3 ¥ 10 mL). The aqueous phases were extracted
with CH2Cl2 (2 ¥ 10 mL). The organic layers were collected,
dried over Na2SO4, filtered and the solvent was removed under
reduced pressure. Purification by flash chromatography (hexane-
AcOEt 9:1) afforded 32/33 (91 mg, 68% yield) as a mixture of
diastereoisomers. A diastereomeric ratio of 1:1.4 was determined
by HPLC analysis (CH3CN:H2O 85:15).
2-{1-Iodo-2-[2,3,4,6-tetra-O-benzyl-b-D-glucopyranosyl] ethyl}-
6-{methyl-[methyl 2,3,4-tri-O-benzyl-a-D-xilopyranosidyl]}-tetra-
hydro-2H-pyran (36/37). Compound 29 (10 mg, 0.0091 mmol)
was dissolved in dry THF (1 mL) under an N2 atmosphere, then
NaHCO3 (2 mg, 0.024 mmol) and I2 (11 mg, 0.043 mmol) were
added and the solution stirred at rt. The reaction was monitored
by TLC (hexane-AcOEt 7:3). After 3 h the reaction was diluted
with CH2Cl2 (4 mL) and the solution was washed with Na2S2O3
satd. sol. in water (3 ¥ 2 mL). The aqueous phases were extracted
with CH2Cl2 (2 ¥ 3 mL). The organic layers were collected, dried
over Na2SO4, filtered and the solvent was removed under reduced
pressure. Purification by flash chromatography (hexane-AcOEt
9:1) afforded 36/37 (4 mg, 40% yield) as an inseparable mixture of
Method D. Compound 20 (118 mg, 0.119 mmol) was dissolved
in dry CH2Cl2 (3 mL) under an inert atmosphere and CaCO3 (6 mg,
0.06 mmol) and AgOTf (6 mg, 0.023 mmol) were successively
added. The mixture was cooled to 0 ◦C, stirred for 10 min and
I2 (55 mg, 0.217 mmol) was added. The reaction was stirred
at 0 ◦C for 3 h, then warmed at rt and stirred for 1 h. The
reaction was diluted with CH2Cl2 (10 mL) and the solution
was washed with Na2S2O3 satd. sol. in water (3 ¥ 5 mL). The
aqueous phases were extracted with CH2Cl2 (2 ¥ 5mL). The
organic layers were collected, dried over Na2SO4, filtered and the
solvent was removed under reduced pressure. Purification by flash
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Org. Biomol. Chem., 2009, 7, 2635–2644 | 2643
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diastereoisomers. A diastereomeric ratio of 1:1.4 was determined
by HPLC analysis (CH3CN:H2O 93:7). Major diastereoisomer: dH
(500 MHz, CDCl3) 7.46–7.16 (35H, m, H(Ar)), 4.90–4.86 (2H, m,
2 ¥ CHHPh), 4.81–4.76 (3H, m, 3 ¥ CHHPh), 4.70–4.60 (7H, m,
7 ¥ CHHPh), 4.54–4.49 (m, 3H, 2 ¥ CHHPh, 1-H), 4.43 (1H, d,
J 8.2, 1a-H), 4.31–4.26 (m, 1H, 12-H), 4.25–4.20 (1H, m, 13-H),
3.99–3.96 (1H, m, 3-H), 3.92–3.86 (2H, m, 13¢-H, 5-H), 3.73–3.60
(m, 4H, 6a-H, 6a¢-H, 4a-H, 3a-H), 3.56–3.53 (1H, m, 7-H), 3.48
(1H, dd, J 3.6, J 9.5, 2a-H), 3.44–3.40 (2H, m, 2-H, 5a-H), 3.33
(3H, s, OCH3), 3.17–3.09 (2H, m, 11-H, 4-H), 2.03–2.01 (1H, m,
6-H), 1.84–1.81 (1H, m, 10-H), 1.32–1.27 (1H, m, 6¢-H), 1.27–1.16
(5H, m, 10¢-H, 8-H, 8¢-H, 9-H, 9¢-H); dC (100 MHz, CDCl3) 103.10
(CH, C-1a), 98.07 (CH, C-1), 84.52 (CH, C-4a), 82.57 (CH, C-4),
81.90 (CH, C-2a), 81.76 (CH, C-3), 80.54 (CH, C-2), 77.9 (CH,
C-3a), 77.13 (CH, C-11), 77.00 (CH, C-5a), 75.67, 75.62 (CH2Ph),
75.00 (CH, C-5), 74.80, 74.90, 74.76 (CH2Ph), 74.23 (CH, C-7),
73.19, 73.40 (CH2Ph), 72.00 (CH2, C-13), 69.12 (CH2, C-6a), 55.34
(OCH3), 38.98 (CH2, C-6), 29.97 (CH2, C-10), 34.12 (CH2, C-8 or
C-9), 28.63 (CH2, C-8 or C-9), 19.53 (CH, C-12). HRESIMS m/z
1247.4355 (100) (C69H77012INa1 [M + Na]+ requires 1247.4352).
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15 Wong and co-workers reported the synthesis of aldehyde 4 from the
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16 The diastereoisomeric ratio was determined by complete separation of
the two epimers by flash chromatography.
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Acknowledgements
We gratefully acknowledge financial support from MUR-Italy
(FIRB RETI, prot. RBPR05NWWC) and Italian National Re-
search Council (CNR).
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27 We performed competition experiments to compare the relative homod-
imerization rates of alcohol 5a and some representative sugar-olefins,
such as compounds 7–11. We found that alcohol 5a homodimerizes
in 3–4 hours in refluxing CH2Cl2, and very similar reaction times are
required for allyl glycosides 7–9, while the dimerization of 4-O-allyl
ether 10 and C-glycoside 11 occurs in 24–48 hours.
28 Straightforward CM reaction was not performed on allyl lactoside 8.
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2644 | Org. Biomol. Chem., 2009, 7, 2635–2644
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