Synthesis of 'molecular asterisks' via sequential cross-metathesis, sonogashira and cyclotrimerization reactions

Article abstract of DOI:10.1055/s-2000-6266

A series of suitably functionalized C-linked carbohydrate derivatives 9- 13 were prepared in good yields from alkenyl glycosides 1-4 by cross- metathesis reaction using Grubbs' catalyst [Cl₂(PCY₃)₂Ru=CHPh]. The reaction wa

Full text of DOI:10.1055/s-2000-6266

862
SPECIAL TOPIC
Synthesis of ‘Molecular Asterisks’ via Sequential Cross-Metathesis,
Sonogashira and Cyclotrimerization Reactions
Romyr Dominique, Bingcan Liu, Sanjoy K. Das, René Roy*
Department of Chemistry, University of Ottawa, Ottawa, Ontario, Canada K1N 6N5
Fax +1(613)5625170; E-mail: rroy@science.uottawa.ca
Received 25 March 2000
In view of the important role of multivalent carbohydrate
Abstract: A series of suitably functionalized C-linked carbohydrate
derivatives 9-13 were prepared in good yields from alkenyl glyco-
sides 1-4 by cross-metathesis reaction using Grubbs’ catalyst
[Cl2(PCy3)2Ru=CHPh]. The reaction was also applied to 6-O-allyl
derivatives in glycobiology, we recently initiated a pro-
gram toward the synthesis of carbohydrate-containing
clusters using various transition metals. We have shown
ether 5 and N-Cbz allylamine 6. C-Linked glycopeptide homologue the application of Grubbs’ catalyst for the first time to be
15 was prepared in 65% yield by cross-metathesis of perbenzylated
b-C-allyl mannopyranoside 1 and allyl glycine derivative 8. Finally,
an effective catalyst for the mild cyclotrimerization of ter-
minal alkynes toward aryl clustered glycosides.14 Sym-
amine-ending C-glycoside 11 was subjected to a sequence of depro-
metrical glycosylated alkynes have been converted into
tection, amidation with p-iodobenzoic acid (EDC, HOBt, DIPEA,
‘molecular asterisks’ by cyclotrimerization with dicobalt
r.t., 12 h), Sonogashira reaction [Pd(PPh3)2Cl2, Et3N, 65 °C, 6 h] and
octacarbonyl.15 Recently, C-glycosides have been shown
treatment with dicobalt octacarbonyl (60 °C, 6 h) to provide a ‘mo-
to be very important in carbohydrate, enzymatic, and met-
abolic chemistry because of the stability of the C-linkage
compared to that of O-glycosides.16 In order to synthesize
metabolically stable C-glycoside clusters with long spac-
ers, we required a convenient cross-metathesis route to
prepare carbohydrate derivatives having functionalized
aglycon. These extended glycosides can be further trans-
formed into ‘molecular asterisks’ using Grubbs’ catalyst
or dicobalt octacarbonyl. Herein we report the cross-met-
athesis reaction of various C-glycosides with olefins hav-
ing available amine or carboxylic acid derivatives. One of
these glycosides has been further transformed into a ‘mo-
lecular asterisk’ using cyclotrimerization reaction in 53%
yield. Thus, a sequence of transition metal catalyzed
transformation has led to the synthesis of interesting C-
linked glycoclusters.
lecular asterisk’ 21 in 53% yield.
Key words: cross-metathesis, carbohydrates, glycopeptides, Sono-
gashira reaction, cyclotrimerization, ruthenium
Introduction
Olefin metathesis has attracted much attention from syn-
thetic chemists in recent years.1,2 The importance of this
carbon-carbon bond construction method is evident from
the huge number of publications that have appeared with-
in a short span of time.3 Although ring-closing metathesis
has been successfully used for the synthesis of a variety of
carbo- and heterocyclic products and has proven to be the
key step in several natural products syntheses, the utility
of cross-metathesis reaction is somewhat more limited.4
Cross-metathesis has not found widespread application
due to the fact that general conditions which give rise to
high yields and stereoselectivity has not yet been discov-
ered since this procedure gives rise to large amount of
self-metathesis byproducts. With the development of
new, well-defined metal alkylidenes such as Schrock’s
Results and Discussion
The required starting material for the cross-metathesis re-
action, perbenzylated b-C-allyl mannopyranoside (1),
was prepared from commercially available 2,3,4,6-tetra-
O-benzyl-D-mannopyranose in a few steps by a known
procedure.17 Treatment of 1 and N-(benzyloxycarbon-
yl)allylamine (6)18 with 20 mol% of Grubbs’ catalyst in
refluxing dichloromethane under nitrogen provided
smooth conversion of the starting material into the cross-
metathesis product 9 in 56% yield as a 3:1 mixture of E-
and Z-isomers (Scheme 1). The remainder of the starting
material 1 was isolated along with trace amount of self-
metathesis product. The stereoisomers were separated by
silica gel column chromatography. To further explore the
scope and generality of this method, perbenzylated allyl
a-D-mannopyranoside (2) was prepared in 71% yield us-
ing allyltrimethylsilane and trimethylsilyl trifluo-
romethanesulfonate.19 The cross-metathesis reaction
under the same reaction conditions with 6 gave 10 in 50%
molybdenum
catalyst,5
PhMe2CCH=Mo=N-(2,6-
iPr2C6H3)[OCMe(CF3)2]2 and Grubbs’ ruthenium cata-
lyst,6 Cl2(PCy3)2Ru=CHPh, some examples of selective
cross-metathesis reactions have recently appeared in the
literature.7 The use of metathesis reactions in carbohy-
drate chemistry has also grown considerably.8 Schrock’s
and Grubbs’ catalysts have been used in carbohydrate-re-
lated ring-closing metathesis,9 cross-metathesis10 and
ring-opening11 metathesis reactions. Recently we have re-
ported that allyl O-glycosides can be easily homodimer-
ized in the presence of these catalysts in excellent yields.12
We have also reported an interesting application of cross-
metathesis reaction in the synthesis of C-linked pseudo-
disaccharides between two different sugar moieties using
a head to tail condensation procedure.13
Synthesis 2000, No. 6, 862–868 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Synthesis of ‘Molecular Asterisks’ via Sequential Cross-Metathesis
863
BnO
BnO
BnO
BnO
NHCbz
O
NHCbz
6
PCy3
Ru
Ph
H
Cl
Cl
BnO
BnO
BnO
BnO
9 (56%)
O
PCy3
CH2Cl2, reflux,
12h
BnO
BnO
1
NHCbz
O
BnO
BnO
NHCbz
CO2Bn
CO2Bn
8
15 (60%)
Scheme 1
yield (E/Z ratio = 4:1). In order to elaborate upon this biological conditions.25 In view of their importance, we
methodology, we prepared acetatylated and benzoylated have synthesized C-linked glycopeptidomimetics using
carbohydrate substrates such as peracetylated allyl a-D- this simple but efficient cross-metathesis procedure.
galactopyranoside 320 and perbenzoylated allyl a-D-man- Thus, the reaction between b-C-mannoside 1 and (R/S)-al-
nopyranoside 4,21 which are synthetically more useful in
carbohydrate chemistry. Treatment of 3 with 6 in the pres-
ence of 20 mol% of Grubbs’ catalyst gave 11 in 45% yield
as a single trans-isomer. The results are summarized in
Table Results of the Ruthenium-Catalyzed Cross-Metathesis of 1−
5 with 6 or 7
O
Grubbs' Cat., CH2Cl2
reflux, 12h
the Table. The cross-metathesis reaction between 4 and 6
under the same reaction conditions gave 12 in only 26%
yield. The yield could be improved to 57% by using 50
mol% of catalyst. The low reactivity of this cross-met-
athesis reaction could be explained by the low nucleophi-
licity (due to the presence of electron withdrawing
benzoyl group) of the ‘disarmed glycoside’ 11 and this is
consistent with the results obtained by Crowe et al.22 It is
also noteworthy to mention that the analogous O-alkenyl
glycosides gave generally higher yields than the actual C-
glycosides.13 This explanation is also supported by the
data in the Table where the electronically rich ‘armed gly-
coside’ 1 gave a higher yield in the cross-metathesis reac-
tion with 20 mol% of Grubbs’ catalyst.23 The low
reactivity of compound 4 could also be explained by a de-
creased reactivity of the catalyst originating from a better
‘coordinating’ ability of the benzoyl groups in the mole-
cule.
O
PO
X
+
PO
X
6 X = NHCbz
1-5
9-14
7 X = CH2CO2Bn
Entry Substrates 1−5
Alkene Product Yield (%)
(Ratio)
1
6
6
9
56 (3:1)
50 (4:1)
2
3
10
Once the reaction conditions were optimized for N-(ben-
zyloxycarbonyl)allylamine, the cross-metathesis reaction
was also extended to benzyl pent-4-enoate (7). The reac-
tion between 1 and 7 under the cross-metathesis reaction
conditions gave 13 (48% yield) having an ester group in
the aglycon moiety which can be further transformed into
neoglycoconjugates by known methods. In an another ex-
ample, 6-O-allyl-1,2:3,4-di-O-isopropylidene-a-D-galac-
topyranose (5) was reacted with 6 under the under cross-
metathesis reaction conditions to provide 14 in 82% yield
(E/Z = 2:1). Compound 14 is very useful from a synthetic
point of view and can be used as a readily accessible
source of chiral synthon possessing more functionality at
the C-6 position.
6
11
12
45 (100:0)
4
6a
57 (4:1)
5
6
1
7
6
13
14
48 (2:1)
82 (2:1)
O
O
O
O
Glycopeptides play an important role in a number of bio-
logical processes including tumor metastasis, immunosur-
veillance, and chemotaxis.24 Recently, much effort has
been invested into the synthesis of glycopeptides, espe-
cially C-linked glycopeptides that are more stable under
O
O
5
a Using 50 mol% Grubbs’ catalyst; 26% yield with 20 mol%.
Synthesis 2000, No. 6, 862–868 ISSN 0039-7881 © Thieme Stuttgart · New York

864
R. Dominique et al.
SPECIAL TOPIC
lyl glycine derivative 8 with 20 mol% Grubbs’ catalyst led yield when alkyne 20 was treated with dicobalt octacarbo-
to the formation of the homologous glycopeptidomimetic nyl in dioxane at 60 °C for 12 h (Scheme 3).28
15 in 60% yield as a separable mixture of E- and Z-iso-
mers (E/Z = 4:1) (Scheme 1). This demonstrates the utili-
ty of our strategy for the preparation of biologically Conclusion
important glycopeptidomimetics.
In conclusion, we have demonstrated the potential use of
In our continuing efforts towards the synthesis of multiva-
cross-metathesis reaction for the introduction of function-
lent neoglycoconjugates, it was deemed of interest to syn-
al groups on the aglycon moiety of C-linked glycosides.
thesize an aryl glycoside cluster having a long spacer arm.
Interestingly, C-allyl glycosides provided lower yields
As oligosaccharide mimetics, such molecules may find bi-
than the corresponding O-allyl glycosides under similar
ological utility as ‘cluster-type ligands’ and may help to
conditions.12-15 Moreover, benzyl ether protecting groups
elucidate binding specificity of multiple carbohydrate-
gave generally higher yields than perbenzoylated deriva-
tives. This observation can be ascribed to an “armed” and
protein interactions.26 The synthesis of such a ‘molecular
asterisk’ was initiated with a-C-galactopyranoside deriv-
“disarmed” effect toward the catalyst as seen previously
ative (11) which was converted into amine 16 (10% Pd/C,
between two differently protected carbohydrate residues
H2) in 92% yield. Amine 16 was coupled with p-iodoben-
zoic acid to afford aryl iodide 17 in 80% yield after chro-
matography (EDC, HOBt, DIPEA, r.t., 12h). The
upon cross-coupling.13 We have also reported the utility
of the cross-metathesis reaction towards the synthesis of a
novel C-linked glycopeptidomimetic. Finally, an aryl gly-
Sonogashira reaction between 17 and (trimethylsilyl)acet-
coside cluster, so called ‘molecular asterisk’ has been syn-
ylene gave 18 [Pd(PPh3)2Cl2, Et3N, 65 °C, 8 h], which
thesized from one of these extended glycosides by
upon treatment with tetrabutylammonium fluoride gave
sequential Sonogashira and cyclotrimerization reactions
the terminal alkyne 19 in 68% overall yield (Scheme 2).27
With compound 19, the next Sonogashira reaction was
carried out with 17 to afford acetylene dimer 20
in good overall yield. Further studies for the cluster effects
of this ‘molecular asterisk’ promise useful work ahead.
[Pd(PPh3)2Cl2, Et3N, 65 °C, 6h] in 73% yield (Scheme 2).
1H and 13C NMR spectra were recorded at 500 or 200 MHz and at
125 or 50 MHz respectively, with TMS as an internal reference.
TLC was performed using silica gel 60 F254 aluminium sheets (E.
Merck). Reagents used for developing plates include Ce(SO4)2 (1%
w/v) and (NH4)2SO4 (2.5% w/v) in 10% (v/v) aq H2SO4, I2, dil aq
KMnO4, and UV light. TLC plates were heated to approximately
150 °C when necessary. Purifications were performed by gravity or
With the key intermediate 20 in hand; the stage was set for
the crucial cyclotrimerization reaction. Unfortunately, the
cyclotrimerization of compound 20 with Grubbs’ catalyst
according to our recently published conditions was not
successful, perhaps due to steric hindrance. However, the
desired cyclotrimerized product 21 was isolated in 53%
AcO
OAc
AcO
OAc
Pd/C, H2
O
O
AcO
AcO
rt, 3 h, 92%
NHR
OAc
NHCbz
OAc
pIPhCO2H
11
16 R = H
HOBt, EDC
DIPEA, rt
12 h, 80%
17 R = COPhpI
(CH3)3SiC CH,
AcO
AcO
OAc
O
R
Et3N, [Pd(PPh3)2Cl2]
65 °C, 8 h; 75%
NH
OAc
O
18 R = TMS
19 R = H
TBAF, AcOH
rt, 1 h, 90%
AcO
OAc
O
[Pd(PPh3)2Cl2]
AcO
Et3N, 65 °C, 6 h
73%
NH
O
OAc
2
20
Scheme 2
Synthesis 2000, No. 6, 862–868 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Synthesis of ‘Molecular Asterisks’ via Sequential Cross-Metathesis
865
20
O
Co2(CO)8,
60 °C, 12 h
53%
O
OAc
OAc
AcO
2
AcO
O
OAc
OAc
O
NH
AcO
O
OAc
AcO
NH
2
AcO
O
OAc
O
O
N
H
2
OAc
OAc
O
AcO
AcO
H
N
O
OAc
AcO
2
AcO
O
OAc
HN
O
O
2
NH
OAc
AcO
2
AcO
O
OAc
AcO
21
Scheme 3
flash chromatography on silica gel 60 (230-400 mesh, E. Merck No.
9385). Solvents were evaporated under reduced pressure using
Buchi rotary evaporator connected to a water aspirator. All chemi-
cals used in experiments were of reagent grade. Solvents were puri-
fied by published procedure.
N-(Benzyloxycarbonyl)-4-(2,3,4,6-tetra-O-benzyl-a-D-manno-
pyranosyl)-1-but-2-enylamine (10)
Compound 10 was isolated as a syrup consisting of E/Z-isomers.
The E-isomer was separated from the isomeric mixture.
(E)-10
Syrup; [a]D25 +4.0 (c = 2.2, CHCl3).
Cross-Metathesis Reaction; General Procedure
1H NMR (500 MHz, CDCl3): d = 2.20-2.31 (m, 2 H, H-1’), 3.54
(dd, J = 3.1, 4.4 Hz, 1 H, H-2), 3.60-3.80 (m, 7 H, H-3, H-4, H-5,
H-6, H-4’), 3.96-3.99 (m, 1 H, H-1), 4.49-4.56 (m, 7 H, NH, 3 ×
CH2Ph), 4.68 (d, J = 11.2 Hz, 2 H, CH2Ph), 5.08 (d, J = 9.1 Hz, 2 H,
CH2Ph), 5.40 (dt, J = 6.0, 12.0 Hz, 1 H, H-3’), 5.48-5.52 (m, 1 H,
H-2’), 7.17-7.37 (m, 25 H, ArH).
To a 0.06 M solution of C-allyl glycoside in anhyd CH2Cl2 was add-
ed the appropriate terminal alkene (2 equiv) and Grubbs’ catalyst
(20 mol%). The reaction mixture was heated at reflux under N2 for
12 h. The solution was concentrated under reduced pressure, and the
residue was purified by silica gel column chromatography using
EtOAc and hexane as eluent.
13C NMR (125 MHz, CDCl3): d = 33.0, 42.9, 66.6, 69.2, 71.5, 72.2,
73.2, 73.6, 73.8, 75.0, 75.1, 127.5, 127.6, 127.7, 127.8, 127.9,
128.0, 128.3, 128.3, 128.4, 128.5, 128.6, 136.6, 138.1, 138.2, 138.3,
156.1
N-(Benzyloxycarbonyl)-4-(2,3,4,6-tetra-O-benzyl-b-D-manno-
pyranosyl)-1-but-2-enylamine (9)
Compound 9 was isolated as a syrup consisting of E/Z-isomers. The
E-isomer was separated from the isomeric mixture.
HRMS (FAB): m/z calcd for C46H50NO7 (M+ + H): 728.3587.
(E)-9
Found: 728.3571
Syrup; [a]D25 +2.2 (c = 2.75, CHCl3).
N-(Benzyloxycarbonyl)-4-(2,3,4,6-tetra-O-acetyl-a-D-galacto-
pyranosyl)-1-but-2-enylamine (11)
Compound 11 was isolated as a pure E-isomer.
1H NMR (500 MHz, CDCl3): d = 2.22-2.25 (m, 1 H, H-1’a), 2.41-
2.46 (m, 1 H, H-1’b), 3.27 (t, J = 6.8 Hz, 1 H, H-1), 3.42-3.46 (m,
1 H, H-5), 3.60 (dd, J = 2.6, 9.5 Hz, 1 H, H-3), 3.65-3.76 (m, 5 H,
H-2, H-4’, H-6), 3.89 (t, J = 9.5 Hz, 1 H, H-4), 4.50-4.80 (m, 3 ×
CH2Ph, NH, 7 H), 4.87-5.02 (2 d, J = 11.8 Hz, CH2Ph, 2 H), 5.09
(s, 2 H, OCH2), 5.38-5.39 (m, 2 H, H-2’, H-3’), 7.15-7.39 (m, 25
H, ArH).
13C NMR (125 MHz, CDCl3): d = 34.0, 42.9, 66.6, 69.7, 72.5, 73.4,
74.1, 74.4, 75.2, 75.4, 78.1, 79.8, 85.4, 127.4, 127.5, 127.6, 127.6,
127.8, 128.0, 128.1, 128.1, 128.2, 128.2, 128.3, 128.4, 128.5, 128.6,
128.7, 138.3, 138.4, 156.1.
(E)-11
Syrup; [a]D25 +59.4 (c = 1.9, CHCl3).
1H NMR (500 MHz, CDCl3): d = 1.99, 2.00, 2.04, 2.08 (4 s, 12 H,
OCOCH3), 2.16-2.21 (m, 1 H, H-1’a), 2.37-2.42 (m, 1 H, H-1’b),
3.75-3.76 (m, 2 H, H-4’), 3.97-4.05 (m, 2 H, H-5, H-6a), 4.20
(ddd, J = 4.6, 5.2, 14.9 Hz, 1 H, H-1), 4.25-4.29 (m, 1 H, H-6b),
4.90 (br s, 1 H, NH), 5.07 (s, 2 H, OCH2), 5.17 (dd, J = 2.9, 8.9 Hz,
1 H, H-3), 5.20 (dd, J = 4.6, 8.9 Hz, 1 H, H-2), 5.37 (t, J = 2.9 Hz,
1 H, H-4), 5.53-5.54 (m, 2 H, H-2’, H-3’), 7.27-7.33 (m, 5 H,
ArH).
Anal. calcd for C46H49NO7: C, 75.90; H, 6.78; N, 1.92. Found C,
75.60; H, 6.92; N, 1.92.
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866
R. Dominique et al.
SPECIAL TOPIC
13C NMR (125 MHz, CDCl3): d = 20.5, 20.6, 20.7, 29.5, 42.8, 61.6,
66.6, 67.3, 67.8, 68.3, 68.6, 71.2, 127.4, 128.0, 128.4, 129.3, 136.5,
156.1, 169.7, 169.8, 169.9, 170.5.
HRMS (FAB): m/z calcd for C26H34NO11 (M+ + H): 536.2132.
Found: 536.2168
Benzyl 6-(2,3,4,6-Tetra-O-benzyl-b-D-mannopyranosyl)-2-(N-
benzyloxycarbonyl)hex-4-enoate (15)
Compound 15 was obtained as a diastereoisomeric E/Z-mixture and
the E-isomers (R/S- at the amino acid residue) were isolated as a syr-
up.
1H NMR (500 MHz, CDCl3): d = 2.16-2.23 (m, 1 H, H-1’a), 2.36-
2.55 (m, 3 H, H-1’b, H-4’), 3.16-3.25 (m, 1 H, H-1), 3.40-3.42 (m,
1 H, H-3), 3.56-3.59 (m, 1 H, H-5), 3.66-3.69 (m, 1 H, H-6a),
3.71-3.75 (m, 2 H, H-2, H-6b), 3.90 (t, J = 9.6 Hz, 1 H, H-4), 4.41-
4.88 (m, 8 H, 3 × CH2Ph, NH, H-5’), 5.00-5.35 (m, 8 H, 3 × CH2Ph,
H-2’, H-3’), 7.16-7.39 (m, 30 H, ArH).
13C NMR (125 MHz, CDCl3): d = 30.2 (29.6), 35.4 (34.4), 53.7,
67.1 (66.9), 69.7, 72.4, (72.3), 73.4 (73.3), 74.3 (74.2), 74.6, 75.1,
75.4, 78.2 (78.1), 79.8, 85.4, 127.4, 127.5, 127.6, 127.8, 128.0,
128.1, 128.1, 128.2, 128.3, 128.4, 128.5, 128.5, 128.6, 135.3, 138.5,
138.8, 155.7, 155.8, 171.5.
N-(Benzyloxycarbonyl)-4-(2,3,4,6-tetra-O-benzoyl-a-D-manno-
pyranosyl)-1-but-2-enylamine (12)
Compound 12 was obtained as a syrup consisting of E/Z-isomers.
1H NMR (500 MHz, CDCl3): d = 2.57-2.62 (m, 1 H, H-1’a), 2.66-
2.72 (m, 1 H, H-1’b), 3.64-3.73 (m, 2 H, H-4’), 4.32-4.34 (m, 2 H,
H-1, H-5), 4.56-4.70 (m, 2 H, H-6), 4.94 (br s, 1 H, NH), 5.09 (s, 2
H, OCH2), 5.60-5.69 (m, 3 H, H-2, H-2’, H-3’), 5.76 (dd, J = 3.2,
8.9 Hz, 1 H, H-3), 5.94 (t, J = 8.9 Hz, 1 H, H-4), 7.26-7.57 (m, 17
H, ArH), 7.85-8.08 (m, 8 H, ArH).
13C NMR (125 MHz, CDCl3): d = 27.5 (C-1’Z), 32.2 (C-1’E), 38.1
(C-4’Z), 42.8 (C-4’E), 62.8, 66.6, 67.8, 69.7, 70.9, 71.0, 126.8,
127.9, 128.0, 128.0, 128.4, 128.4, 128.4, 128.5, 129.6, 129.7, 129.8,
133.1, 133.3, 133.5, 136.6, 156.1, 165.4, 165.6, 166.1.
HRMS (FAB): m/z calcd for C55H58NO9 (MH+) 876.0533, found:
876.3608.
HRMS (FAB): m/z calcd for C46H42NO11 (M+ + H): 784.2758.
Found: 784.3101
Compound 17
To a solution of compound 11 (90 mg, 0.172 mmol) in MeOH (10
mL) was added 10% Pd/C (10 mg). The reaction mixture was stirred
under H2 (1 atm) for 3 h at r.t. and then filtered through Celite. Re-
moval of the solvent in vacuo afforded compound 16 (62 mg, 92%)
as a syrup. To a solution of compound 16 (60 mg, 0.154 mmol) in
DMF (5 mL), were added p-iodobenzoic acid (46 mg, 0.185 mmol),
HOBt (25 mg, 0.185 mmol), N-ethyl-N-(3,3-dimethylamino)prop-
ylcarbodiimide (EDC, 35 mg, 0.185 mg) and diisopropylethylamine
(DIPEA, 54 mL, 0.309 mmol). The mixture was stirred at r.t. for 12
h and the solvent was evaporated under reduced presure. The re-
maining residue was purified by column chromatography (silica
gel, hexane/EtOAc, 1:1.5) to provide compound 17 as a syrup (78
mg) in 80% yield; [a]D25 +54.5 (c = 1 CHCl3).
1H NMR (500 MHz, CDCl3): d = 1.40-1.73 (m, 6 H, H-1’, H-2’, H-
3’), 1.96, 1.98, 2.03, 2.08 (s, 12 H, CH3CO2), 3.36-3.43 (m, 2 H,
H-4’), 3.98-4.02 (m, 2 H, H-5, H-6a), 4.14-4.17 (dt, J = 11, 3.9
Hz, 1 H, H-1), 4.23 (dd, J = 9.1, 13.2 Hz, 1 H, H-6b), 5.15 (dd,
J = 3.2, 9.1 Hz, 1 H, H-3), 5.20 (dd, J = 9.1, 3.9 Hz, 1 H, H-2), 5.36
(t, J = 3.2 Hz, 1 H, H-4), 6.35 (t, J = 5.3 Hz, 1 H, NH)), 7.45 (d,
J = 8.3 Hz, 2 H, ArH), 7.72 (d, J = 8.3 Hz, 2 H, ArH).
Benzyl 6-(2,3,4,6-Tetra-O-benzyl-b-D-mannopyranosyl)hex-4-
enoate (13)
Compound 13 was isolated as an inseparable mixture of E/Z-iso-
mers.
1H NMR (500 MHz, CDCl3): d = 2.25-2.51 (m, 6 H, H-1’, H-4’, H-
5’), 3.27 (dt, J = 7.0, 12.8 Hz, 1 H, H-1), 3.44-3.47(m, 1 H, H-3),
3.59-3.63 (m, 1 H, H-5), 3.67-3.72 (m, 1 H, H-6a), 3.76-3.79 (m,
2 H, H-2, H-6b), 3.90 (t, J = 9.5 Hz, 1 H, H-4), 4.53-4.81 (m, 6 H,
3 × CH2Ph), 4.88 (d, J = 10.8 Hz, 1 H, CH2Ph), 5.03 (d, J = 11.3 Hz,
1 H, CH2Ph), 5.11 (s, 2 H, OCH2), 5.26-5.44 (m, 2 H, H-2’, H-3’),
7.18-7.53 (m, 25 H, ArH).
13C NMR (125 MHz, CDCl3): d = 22.9 (C1’Z). 27.9 (C1’E), 29.3
(C4’Z), 34.1 (C4’E), 29.7 (C4’Z), 34.3 (C5’E), 66.1, 69.7, 72.4,
73.4, 74.2, 74.5, 75.0, 75.2, 75.5, 78.4, 79.8, 85.5, 127.2, 127.4,
127.4, 127.5, 127.6, 127.6, 127.9, 128.0, 128.0, 128.1, 128.2, 128.3,
128.4, 128.5, 129.6, 130.9, 136.0, 138.4, 138.4, 138.5, 138.8, 138.9,
172.8.
(FAB): m/z calcd for C47H51O7 (M+ + H): 727.905. Found:
727.9225.
13C NMR (125 MHz, CDCl3): d = 20.6, 20.7 (CH3CO), 20.7 (C-2’),
25.4 (C-1’), 29.1 (C-3’), 39.8 (C-4’), 61.3 (C-6), 67.4 (C-4), 67.9
(C-3), 68.2 (C-5), 68.5 (C-2), 71.7 (C-1), 98.2, 128.5, 134.0, 137.6
(ArH), 166.6, 169.8, 170, 170.5 (C=O).
HRMS (FAB): m/z calcd for C25H32NO10"K" (M+ + K): 672.0707.
Found: 672.1090.
Cross-metathesis Reaction Between 6-O-Allyl-1,2:4,5-di-O-iso-
propylidene-a-D-galactopyranose and Compound 6 to Give 14
Compound 14 was isolated as a syrup of E/Z-isomers. The E-isomer
was separated from the isomeric mixture.
(E)-14
Syrup; [a]D25 -33.2 (c = 5.1, CHCl3).
Synthesis of 18 by the Sonogashira Coupling Reaction Between
(Trimethylsilyl)acetylene and 17
1H NMR (500 MHz, CDCl3): d = 1.29, 1.30, 1.41, 1.50 (4s, 12 H,
CH3), 3.53 (dd, J = 6.8, 10.1 Hz, 1 H, H-6a), 3.61 (dd, J = 5.6, 10.1
Hz, 1 H, H-6b), 3.77-3.78 (m, 2 H, H-4’), 3.91-4.03 (m, 3 H, H-5,
H-1’), 4.20 (dd, J = 1.6, 7.9 Hz, 1 H, H-4), 4.26 (dd, J = 2.3, 5.1 Hz,
1 H, H-2), 4.55 (dd, J = 2.3, 7.9 Hz, 1 H, H-3), 4.91 (br s, 1 H, NH),
5.07 (s, 2 H, COOCH2), 5.50 (d, J = 5.1 Hz, 1 H, H-1), 5.69-5.70
(m, 2 H, H-2’, H-3’), 7.24-7.32 (m, 5 H, ArH).
13C NMR (125 MHz, CDCl3): d = 24.4, 24.8, 25.9, 26.0, 42.4, 66.6,
66.8, 69.0, 70.5, 70.6, 71.0, 71.1, 96.3, 108.5, 109.2, 128.0, 128.4,
128.5, 129.1, 136.5, 156.1.
To a solution of compound 17 (60 mg, 0.096 mmol) and trimethyl-
silylacetylene (27 mL, 0.192 mmol) in DMF/TEA (1:1, 3 mL) was
added Pd(PPh3)2Cl2 (3.4 mg, 5 mol%) and the mixture was stirred
under N2 at 65 °C for 8 h. The solvent and TEA were removed in
vacuo and the residue was purified by silica gel column chromatog-
raphy (hexane/EtOAc, 1:1) to provide compound 18 as a syrup (43
mg) in 75% yield; [a]D25 +51.0 (c = 1, CHCl3).
1H NMR (200 MHz, CDCl3): d = 0.22 [s, 9 H, Si(CH3)3], 1.41-1.75
(m, 6 H, H-1’, H-2’, H-3’), 1.97, 2.00, 2.04, 2.09 (s, 12 H, CH3CO2),
3.38-3.47 (m, 2 H, H-4’), 3.99-4.08 (m, 2 H, H-5, H-6a), 4.14-
4.17 (m, 1 H, H-1), 4.23 (m, 1 H, H-6b), 5.15 (dd, J = 3.2, 9.1 Hz,
1 H, H-3), 5.20 (dd, J = 9.1, 3.9 Hz, 1 H, H-2), 5.37 (t, J = 3.2 Hz,
1 H, H-4), 6.29 (t, J = 5.4 Hz, 1 H, NH), 7.47 (d, J = 8.5 Hz, 2 H,
ArH), 7.68 (d, J = 8.5 Hz, 2 H, ArH).
Anal. calcd for C24H33NO8: C, 62.19; H, 7.17; N, 3.02. Found: C,
62.13; H, 6.94; N, 3.25.
Synthesis 2000, No. 6, 862–868 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Synthesis of ‘Molecular Asterisks’ via Sequential Cross-Metathesis
867
13C NMR (50 MHz, CDCl3): d = 0.5, 21.3, 21.4, 23.3, 25.9, 29.8,
40.4, 62.0, 68.1, 68.5, 68.8, 69.0, 72.4, 97.5,104.6, 126.9, 127.3,
132.6, 134.7, 167.3, 170.5, 170.7, 171.3.
Acknowledgement
We gratefully acknowledge financial support from Natural Sciences
and Engineering Research Council (NSERC).
HRMS (FAB): m/z calcd for C30H41NO10Si"K" (M+ + K): 642.2137.
Found: 642.2112.
References
Desilylation of Compound 18 to Give 19
(1) (a) Grubbs, R. H. In Comprehensive Organometallic
Chemistry, Wilkenson, G.; Stone, G. A.; Abel, E. W., Eds.;
Pergamon: New York, 1982, Vol. 8, p 499.
(b) Feldman, J.; Schrock, R. R. Prog. Inorg. Chem. 1991, 39,
2.
(2) (a) Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res.
1995, 28, 446.
(b) Schrock, R. R. Acc. Chem. Res. 1990, 23, 158.
(3) For recent reviews, see:
To a solution of compound 18 (60 mg, 0.1 mmol) in THF (3 mL),
were added Bu4NF (0.3 mL, 3 equiv) and AcOH (2 drops). The re-
action mixture was stirred at r.t. for 1 h. The solvent was removed
under reduced pressure and the residue was purified by silica gel
column chromatography (hexane/EtOAc, 1:1) to give compound 19
as a syrup (50 mg) in 90% yield; [a]D25 +55.0 (c = 0.4, CHCl3).
1H NMR (200 MHz, CDCl3): d = 1.35-1.70 (m, 6 H, H-1’, H-2’, H-
3’), 1.97, 2.00, 2.04, 2.09 (s, 12 H, CH3CO2), 3.17 (s, 1 H, C∫C),
3.36-3.43 (m, 2 H, H-4’), 3.97-4.03 (m, 2 H, H-5, H-6a), 4.14-
4.23 (m, 2 H, H-1, H-6b), 5.18-5.21 (m, 2 H, H-2, H-3), 5.37 (t,
J = 3.2 Hz, 1 H, H-4), 6.30 (t, J = 5.3 Hz, 1 H, NH)), 7.50 (d, J = 8.5
Hz, 2 H, ArH), 7.70 (d, J = 8.5 Hz, 2 H, ArH).
13C NMR (50 MHz, CDCl3): d = 21.3, 21.4, 23.3, 26.0, 29.8, 40.4,
61.9, 68.1, 68.5, 68.8, 69.0, 72.4, 80.1, 83.3, 125.8, 127.4, 132.8,
135.2, 170.5, 170.7, 171.3.
HRMS (FAB): m/z calcd for C27H33NO10"K" (M+ + K): 570.1742.
Found: 570.2037.
(a) Schuster, M.; Blechert, S. Angew. Chem., Int. Ed. Engl.
1997, 36, 2036.
(b) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413.
(4) Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1 1998, 371.
(5) (a) Schrock, R. R.; Murdzek, J. S.; Bazan, G. C.; Robbins, J.;
Dimare, M.; O’Regan. M. J. Am. Chem. Soc. 1990, 112, 3875.
(b) Bazan, G. C. Khosravi, E.; Schrock, R. R.; Feast, W. J.;
Gibson, V. C.; O’Regan, M. B.; Thomas, J. K.; Davis, W. M.
J. Am. Chem. Soc. 1990, 112, 8378.
(6) Schwab, P.; France, M. B.; Ziler, J. W.; Grubbs, R. H. Angew.
Chem. Int. Ed. Engl. 1995, 34, 2039.
(7) (a) Biagini, S. C. G.; Gibson, S. E.; Keen, S. P. J. Chem. Soc.,
Perkin Trans. 1 1998, 2485.
Synthesis of Compound 20 by the Coupling Reaction Between
17 and 19
A solution of compound 20 (40 mg, 0.070 mmol), compound 19
(57mg, 0.091mmol), and Pd(PPh3)2Cl2 (2.5 mg, 5 mol%) in DMF/
TEA (1: 1, 3 mL) was stirred under N2 at 65 °C for 6 h. After com-
pletion of the reaction, the solvent and Et3N were removed in vacuo
and purified by silica gel column chromatography (hexane/EtOAc,
1:2) to give compound 20 as a syrup (53 mg, 73%); [a]D25 +63.8
(c = 1, CHCl3).
(b) Brummer, O.; Ruckert, A.; Blechert, S. Chem. Eur. J.
1997, 3, 441.
(c) Blackwell, H. E.; O’Leary, D. J.; Chatterjee, A. K.;
Washenfelder, R. A.; Bussmann, D. A.; Grubbs, R. H. J. Am.
Chem. Soc. 2000, 122, 58.
(8) For a recent review, see: Roy, R.; Das, S. K. Chem. Commun.
2000, 519.
1H NMR (200 MHz, CDCl3): d = 1.41-1.80 (m, 12 H, H-1’, H-2’,
H-3’), 1.98, 2.00, 2.04, 2.09 (s, 24 H, CH3CO2), 3.38-3.46 (m, 2 H,
H-4’), 3.99-4.05 (m, 4 H, H-5, H-6a), 4.14-4.24 (m, 4 H, H-1, H-
6b), 5.18-5.21 (m, 4 H, H-2, H-3), 5.38 (t, J = 2.8 Hz, 2 H, H-4),
6.36 (t, J = 5.3 Hz, 2 H, NH)), 7.55 (d, J = 8.6 Hz, 4 H, ArH), 7.74
(d, J = 8.6 Hz, 4 H, ArH).
13C NMR (50 MHz, CDCl3): d = 21.3, 21.4, 23.3, 26.0, 29.8, 40.5,
62.0, 68.1, 68.5, 68.7, 69.0, 70.4, 78.3, 126.5, 127.6, 132.4, 134.9,
167.3, 170.5, 170.7, 171.3.
(9) (a) Huwe, C. M.; Blechert, S. Tetrahedron Lett. 1995, 36,
1621.
(b) Ovaa, H.; Codée, J. D. C.; Lastdrager, B.; Overkleeft, H.
S.; van der Marel, G. A.; van Boom, J. H. Tetrahedron Lett.
1999, 40, 5063.
(10) (a) Feng, J.; Schuster, M.; Blechert, S. Synlett 1997, 129.
(b) O’Leary, D. J.; Blackwell, H. E.; Washenfelder, R. A.;
Grubbs, R. H. Tetrahedron Lett. 1998, 39, 7427.
(11) (a) Nomura, K.; Schrock, R. R. Macromolecules 1996, 29,
540.
HRMS (FAB): m/z calcd for C52H64NO20"K" (M+ + K): 1075.3690.
Found: 1075.3658.
(b) Fraser, C.; Grubbs, R. H. Macromolecules 1995, 28, 7248.
(c) Kanai, M.; Mortell, K. H.; Kiessling, L. L. J. Am. Chem.
Soc. 1997, 119, 9931.
Cyclotrimerization of Compound 20 to Give 21
(12) (a) Dominique, R.; Das, S. K. Roy, R. J. Chem. Soc.,Chem.
Commun. 1998, 2437.
(b) Das, S. K.; Dominique, R.; Smith, C.; Nahra, J.; Roy, R.
Carbohydr. Lett. 2000, 3, 361.
(13) Roy, R.; Dominique, R.; Das, S. K. J. Org. Chem. 1999, 64,
5408.
(14) Das, S. K.; Roy, R. Tetrahedron Lett. 1999, 40, 4015.
(15) Roy, R.; Das, S. K.; Dominique, R.; Trono, M. C.; Hernandez-
Mateo, F.; Santoyo-Gonzalez, F. Pure Appl. Chem. 1999, 71,
565.
(16) Du, Y.; Linhardt, R. J.; Vlahou, I. R. Tetrahedron 1998, 54,
9913.
(17) Lewis, M. D.; Cha, J. K.; Kishi, Y. J. Am. Chem. Soc. 1982,
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Lees, W.; Bednarski, M. D.; Whitesides, G. M. J. Org. Chem.
1988, 53, 3457.
A solution of compound 20 (40 mg, 0.039 mmol) and Co2(CO)8 (1.3
mg, 10 mol%) in anhyd 1,4-dioxane (3 mL) was stirred under N2 at
60 °C for 12 h. The solvent was removed under reduced pressure
and the remaining residue was purified by silica gel column chro-
matography (hexane/EtOAc, 1:5) to give compound 21 as a syrup
(21 mg, 53%); [a]D25 0.0 (c = 1, CHCl3).
1H NMR (500 MHz, CDCl3): d = 1.41-1.80 (m, 36 H, H-1’, H-2’,
H-3’), 2.00, 2.01, 2.06, 2.10 (s, 72 H, CH3CO2), 3.46 (br s, 6 H, H-
4’), 4.03 (br s, 12 H, H-5, H-6a), 4.18-4.33 (m, 12 H, H-1, H-6b),
5.19-5.22 (br d, 12 H, H-2, H-3), 5.39 (br s, 6 H, H-4), 6.23 (br s,
6 H, NH)), 7.58 (br s, 12 H, ArH), 7.75 (br s, 12 H, ArH).
13C NMR (125MHz, CDCl3): d = 21.3, 21.4, 23.3, 26.0, 29.8, 40.5,
62.0, 68.1, 68.5, 68.7, 69.0, 70.4, 78.3, 126.5, 127.6, 132.4, 134.9,
167.3, 170.5, 170.7, 171.3.
ESI-MS: m/z calcd. mass for C156H192N6O60: 3109.21; found:
1037.2 (M + 3 H)3+.
Synthesis 2000, No. 6, 862–868 ISSN 0039-7881 © Thieme Stuttgart · New York

868
R. Dominique et al.
SPECIAL TOPIC
(19) Hosomi, A.; Sakata, Y.; Sukurai, H. Carbohydr. Res. 1987,
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(21) Perbenzoylated allyl a-D-mannopyranoside was prepared
from the corresponding acetate derivative. Since a and b
anomers of peracetylated allyl D-mannopyranoside were not
separated by silica gel column chromatography,
perbenzoylated allyl a,b-D-mannopyranoside was prepared by
deacetylation and benzoylation. Allyl perbenzoylated a-D-
mannopyranoside and b-D-mannopyranoside were separated
by simple silica gel column chromatography.
(25) Debenham, S. D.; Debenham, J. S.; Burk, M. J.; Toone, E. J.
J. Am. Chem. Soc. 1997, 119, 9897, and references cited
therein.
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F.; Dam, T. K.; Brewer, C. F. Chem. Eur. J. 2000, in Press.
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(b) Trono, M. C.; Das, S. K.; Roy, R. unpublished results.
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5162.
(23) Fraser-Reid, B.; Udolong, U. E.; Wu, Z.; Ottosson, H.;
Merritt, J. R.; Rao, C. S.; Madsen, R. Synlett 1992, 927.
Article Identifier:
1437-210X,E;2000,0,06,0862,0868,ftx,en;C02500SS.pdf
Synthesis 2000, No. 6, 862–868 ISSN 0039-7881 © Thieme Stuttgart · New York