Cross-metathesis and ring-closing metathesis of olefinic monosaccharides

Article abstract of DOI:10.1016/S0040-4039(02)01617-9

Cross-metathesis (CM) of a variety of carbohydrate-based C-6 and olefins with related C-1 and C-6 carbohydrate-based olefins proved to be unselective. CM was selective when an unhindered straight chain olefin was coupled with a carbohydrate-based C-6 olefin. When related short chain alkenols were tethered, via a Me₂Si linker, to a suitably protected carbohydrate-based C-6 olefin, good yields of ring-closed products were obtained with the second-generation Grubbs catalyst 3. A few examples where two carbohydrate-based olefinic alcohols were tethered via a Me₂Si linker and subjected to ring-closing metathesis (RCM) have also been examined.

Full text of DOI:10.1016/S0040-4039(02)01617-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7095–7099
Cross-metathesis and ring-closing metathesis of olefinic
monosaccharides
Maarten H. D. Postema* and Jared L. Piper
Department of Chemistry, Wayne State University, Detroit, MI 48202, USA
Received 24 June 2002; revised 19 July 2002; accepted 22 July 2002
Abstract—Cross-metathesis (CM) of a variety of carbohydrate-based C-6 and olefins with related C-1 and C-6 carbohydrate-based
olefins proved to be unselective. CM was selective when an unhindered straight chain olefin was coupled with a carbohydrate-
based C-6 olefin. When related short chain alkenols were tethered, via a Me2Si linker, to a suitably protected carbohydrate-based
C-6 olefin, good yields of ring-closed products were obtained with the second-generation Grubbs catalyst 3. A few examples where
two carbohydrate-based olefinic alcohols were tethered via a Me2Si linker and subjected to ring-closing metathesis (RCM) have
also been examined. © 2002 Elsevier Science Ltd. All rights reserved.
Olefin metathesis has attracted a great deal of attention
from the synthetic community as evidenced by the large
number of papers and reviews1 that have appeared on the
subject. This has been due in large part to the availability
of a variety of catalysts2–5 with varying degrees of
stability and reactivity. Metathesis chemistry has become
quite popular in the realm of carbohydrate chemistry as
evidenced from two recent reviews on the subject.6,7
The cross-metathesis (CM)19 of a simple carbohydrate-
based olefin such as 5 with a variety of simple straight-
chain olefinic alcohols was initially examined using 20
mol% of 3.4 It was found that the hydroxyl group on the
straight-chain alcohol must be protected (entries 1–3
versus 5–8, Table 1) and used in a two-fold excess for
efficient CM to occur and the reaction proceeded best in
hot dichloromethane (entries 3 and 4 versus 5). The yields
with different olefinic alcohols (entries 5–8) were found
to be acceptable and, in all the cases, the trans isomer
was the major isomer produced.20
Our group has published several papers that involve an
esterification–RCM approach directed towards the syn-
thesis of C-disaccharides8–10 and C-glycosides11 and, in
this letter, we present our initial results of a tethering–
RCM metathesis approach towards stable C-saccharide-
type derivatives.12 These compounds have potential as
enzyme inhibitors and as stable carbohydrate mimics.
It was then surmised that the use of RCM might be one
way to improve the overall efficiency of the process. By
tethering21 the straight chain olefin alcohol to O-4 on the
sugar, the metathesis reaction now becomes intramolec-
ular. For this, access to alkene 11 was needed, and it was
readily prepared from 7 as shown in Scheme 1.
Our present approach to carbohydrate mimics is partly
inspired by the work of several groups13,14 and some of
which were even employed for the preparation of C-
disaccharides.15–18
A variety of tethered derivatives 12 were prepared as
shown (Table 2) and subjected to RCM with 10–15 mol%
Keywords: olefin; tethering; cross-metathesis; RCM; C-disaccharide.
* Corresponding author. E-mail: mpostema@chem.wayne.edu
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01617-9

7096
M. H. D. Postema, J. L. Piper / Tetrahedron Letters 43 (2002) 7095–7099
Table 1. CM of 5 with alkenyl acetatesa
and 15) and the simple dimer 16 began to appear in the
product distribution (Fig. 1).
Next, the cross-metathesis of several sugar-based olefins
was examined. Roy23 and others6 have carried out some
work in the area of metathetical-based sugar olefin
dimerization. We expected mixtures of compounds and
our expectations proved to be correct. Mixtures of
cross-coupled and dimerization products were formed
in roughly equal amounts, and Scheme 2 shows the
yields of the desired products. The CM was carried out
with 20 mol% of catalyst 3 and an equimolar amount of
each olefin. The trans isomer was the major isomer
formed in almost all of the cases we examined. It was
observed that compound 20 was formed in higher yield
than most of the other examples, and this is likely due
to the fact that one of the olefin coupling partners is
considerably less sterically hindered.
Entry
n
R
Temp. (°C)
Yieldc (%)
1
2
3
4
5
6
7
8
1
1
3
3
4
3
2
1
H
H
H
Ac
Ac
Ac
Ac
Ac
23
40
83b
23
40
40
40
40
13
15
7
17
66
56
49
69
a The reactions were carried out with 2 equiv. of the straight chain
olefin.
One way of circumventing this problem was to tether
the two olefins and carry out a RCM reaction in lieu of
a non-selective CM reaction. We decided to follow the
precedent for tethering established by Sinay¨.16 Com-
pound 11 was deprotonated with a slight excess of
n-butyllithium, and the formed lithium alkoxide was
quenched with an excess of Me2SiCl2. The reaction was
then concentrated under high vacuum and then exposed
to alcohol 22a in the presence of imidazole to give the
coupled product 23a24 in 67% yield. RCM with the
second-generation Grubbs catalyst 3, in hot
b Reaction carried out in 1,2-dichloroethane.
c Yields refer to chromatographically homogeneous materials.
of catalyst 3 at ambient temperature. In almost every
one of the cases, good yields of RCM products were
obtained with the cis-isomer predominating in all the
cases.
When the tether increased in length (entries 6 and 7,
Table 2), the head-to-tail dimerization product22 (14
Scheme 1.
Table 2. RCM of the tethered derivatives 12a
Entry
X
Yield of 12 (%)
Yield of 13c (%)
Ratio (Z:E)d
1
2
3
4
5
6
7
−CH2O-SiMe2−
−CH2CH2O-SiMe2−
−CH2CH2CH2O-SiMe2−
−CH2−
−CH2CH2−
−CH2CH2CH2−
−CH2CH2CH2CH2−
64b
64b
61b
95
8
91
74
81
84
90
96
79
40
1:0
4.8:1
3.6:1
1:0
1:0
1:tracee
2.1:1f
92
a Yields refer to chromatographically homogeneous materials.
b 15–25% of 11 was recovered from these reactions.
c Reaction carried out at 0.02 M in substrate.
d Determined from coupling constants in the 1H NMR spectra.
e The head to tail isomer 14 was isolated in 10% yield.
f The head to tail isomer 15 was isolated in 24% yield along with 14% of dimer 16.

M. H. D. Postema, J. L. Piper / Tetrahedron Letters 43 (2002) 7095–7099
7097
Figure 1.
Scheme 2.
Scheme 3.
Table 3. Tethering-RCM approach to (1“6)-C-disaccharidesa

7098
M. H. D. Postema, J. L. Piper / Tetrahedron Letters 43 (2002) 7095–7099
dichloromethane, gave an 87% yield of 24a25 as a single
trans-isomer. The protecting groups were removed
(TBAF followed by H2, Pd/C), and the resulting crude
tetrol was peracetylated to give the C-disaccharide-like
compound 25a in good overall yield (Scheme 3).
M. L. J. Mol. Catal. A: Chem. 1998, 133, 29–40; (g)
Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1 1998,
371–388; (h) Schuster, M.; Blechert, S. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 2036–2056; (i) Fu¨rstner, A. Top.
Catal. 1997, 4, 285–299; (j) Grubbs, R. H.; Miller, S. J.;
Fu, G. C. Acc. Chem. Res. 1995, 28, 446–452; (k)
Schmalz, H.-G. Angew. Chem., Int. Ed. Engl. 1995, 34,
1833–1836.
Given our success with the example shown in Scheme 3,
we decided to tether a more functionalized carbohy-
drate alcohol-olefin to 11 in order to prepare a (1“6)-
linked-C-disaccharide.26 Known alcohol 22b27 was
tethered with 11, but in this case, the tethering chem-
istry proceeded poorly giving 23b in only 30–35% yield
with the majority of the mass balance being recovered
alcohols 11 and 22b (entry 2, Table 3). Also, both the
1H and 13C NMR spectra of 22b showed the appear-
ance of extra signals indicating the presence of
rotamers.28 The crude material was nevertheless
exposed to catalyst 3 in the hope that a favorable
equilibrium would allow for the complete conversion of
the product 24b if the RCM was carried out at elevated
temperatures. The RCM reaction of 23b was very slug-
gish and proceeded to give 24b in only 35–40% yield
with reaction temperatures of 60°C and 30 mol% of 3
added in two to three portions over several hours. The
efforts made to optimize29 this sequence did not signifi-
cantly improve the overall yield of 24b, but did produce
enough material to allow for its full characterization
and conversion to 25b (entry 2, Table 3).
2. (a) Schrock, R. R.; Murdzek, J. S.; Bazan, G. C.; Rob-
bins, J.; DiMare, M.; O’Regan, M. J. Am. Chem. Soc.
1990, 112, 3875–3886; (b) Feldman, J.; Murdzek, J. S.;
Davis, W. M.; Schrock, R. R. Organometallics 1989, 8,
2260–2265.
3. (a) Fu, G. C.; Nguyen, S. T.; Grubbs, R. H. J. Am.
Chem. Soc. 1993, 115, 9856–9857; (b) Nguyen, S. T.;
Johnson, L. K.; Grubbs, R. H.; Ziller, J. W. J. Am.
Chem. Soc. 1992, 114, 3974–3975; (c) Nguyen, S. T.;
Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1993, 115,
9858–9859; (d) Schwab, P.; France, M. B.; Ziller, J. W.;
Grubbs, R. H. Angew. Chem., Int. Ed. Engl. 1995, 34,
2039–2041.
4. Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org.
Lett. 1999, 1, 953–956.
5. Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A.
H. J. Am. Chem. Soc. 2000, 122, 8168–8179.
6. Jørgensen, M.; Hadwiger, P.; Madsen, R.; Stutz, A. E.;
Wrodnigg, T. M. Curr. Org. Chem. 2000, 4, 565–588.
7. Roy, R.; Das, S. K. Chem. Commun. (Cambridge) 2000,
519–529.
8. Postema, M. H. D.; Calimente, D. Tetrahedron Lett.
1999, 40, 4755–4759.
9. Postema, M. H. D.; Calimente, D.; Liu, L.; Behrmann, T.
L. J. Org. Chem. 2000, 65, 6061–6068.
Similar results were obtained with the corresponding
b-vinyl derivative. Olefinic alcohol 22c30 was tethered to
11 to give 23c, once again as a mixture of compounds.
In this case, the RCM reaction (23c“24c) proved to be
even less efficient proceeding in only 10–15% yield with
30–40 mol% of 3 added portionwise over several hours
at 60°C (entry 3, Table 3).
10. Liu, L.; Postema, M. H. D. J. Am. Chem. Soc. 2001, 123,
8602–8603.
11. Postema, M. H. D.; Calimente, D. J. Org. Chem. 1999,
64, 1770–1771.
It is clear that a tethering approach to such carbohy-
drate mimics is superior to simple CM. The dimethyl-
silyl linker works well for relatively unhindered pyran
rings and simple olefin alcohols, but not with fully
oxygenated monosaccharides. We are currently screen-
ing a variety of linkers to try and improve the overall
efficiency of this tethering-RCM approach to both a-
and b-(1“6)-linked-C-disaccharides.
12. For reviews on C-glycoside synthesis, see: (a) M. H. D.
Postema and D. Calimente, In Glycochemistry: Principles,
Synthesis and Applications; Wang, P. G. and Bertozzi, C.
Eds. C-Glycoside Synthesis: Recent Developments and
Current Trends. Marcel Dekker, 2000; Chapter 4, pp.
77–131; (b) Du, Y.; Linhardt, R. J. Tetrahedron 1998, 54,
9913–9959; (c) Beau, J.-M.; Gallagher, T. Top. Curr.
Chem. 1997, 187, 1–54; (d) Nicotra, F. Top. Curr. Chem.
1997, 187, 55–83; (e) Togo, H.; He, W.; Waki, Y.;
Yokoyama, M. Synlett 1998, 700–717; (f) Postema, M.
H. D. C-Glycoside Synthesis; CRC Press: Boca Raton,
1995; (g) Levy, D. E.; Tang, C. The Chemistry of C-Gly-
cosides; Elsevier Science: Oxford, 1995; Vol. 13.
13. Fu, G. C.; Grubbs, R. H. J. Am. Chem. Soc. 1992, 114,
5426–5427.
Acknowledgements
We thank the NSF (CHE-0132770) for support of this
work.
14. Evans, P. A.; Murthy, V. S. J. Org. Chem. 1998, 63,
6768–6769.
15. Xin, Y. C.; Mallet, J.-M.; Sinay¨, P. J. Chem. Soc., Chem.
Commun. 1993, 864–865.
16. Mallet, A.; Mallet, J.-M.; Sinay¨, P. Tetrahedron: Asym-
metry 1994, 5, 2593–2608.
17. Rubinstenn, G.; Esnault, J.; Mallet, J.-M.; Sinay¨, P.
Tetrahedron: Asymmetry 1997, 8, 1327–1336.
18. Rubinstenn, G.; Mallet, J.-M.; Sinay¨, P. Tetrahedron
Lett. 1998, 39, 3697–3700.
References
1. For reviews on olefin metathesis chemistry, see: (a)
Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34,
18–29; (b) Fu¨rstner, A. Angew. Chem., Int. Ed. Engl.
2000, 39, 3012–3043; (c) Wright, D. L. Curr. Org. Chem.
1999, 3, 211–240; (d) Grubbs, R. H.; Chang, S. Tetra-
hedron 1998, 54, 4413–4450; (e) Ivin, K. J. J. Mol. Catal.
A: Chem. 1998, 133, 1–16; (f) Randall, M. L.; Snapper,

M. H. D. Postema, J. L. Piper / Tetrahedron Letters 43 (2002) 7095–7099
7099
19. For a listing of seminal papers in CM, see: Chatterjee, A.
K.; Sanders, D. P.; Grubbs, R. H. Org. Lett. 2002, 4,
1939–1942 and references cited therein.
NMR (125 MHz, CDCl3) l 139.0, 138.1, 136.7, 135.5,
128.4, 128.1, 128.1, 127.8, 127.4, 127.2, 118.1, 116.5, 97.9,
82.7, 81.4, 80.2, 75.2, 74.9, 73.2, 72.2, 71.2, 67.4, 55.2,
33.5, 25.4, −0.94, −1.49; HRMS (FAB): calcd for
C31H42O7Si (M+Na)+577.2592, found 577.2572.
1
20. All new compounds were fully characterized by H, 13C,
H–H COSY, DEPT and HMQC NMR, FT-IR, high-res-
olution mass spectroscopy and optical rotation.
21. For a review on silicon-tethered reactions, see: Bols, M.;
Skrydstrup, T. Chem. Rev. 1995, 95, 1253–1277.
22. This type of dimerization–RCM strategy has been used to
prepare symmetrical macrocycles in non-carbohydrate
systems; see for example: Lee, C. W.; Grubbs, R. H. J.
Org. Chem. 2001, 66, 7155–7158 and references cited
therein.
25. 24a: Catalyst 3 (5.1 mg, 6.0 mmol, 9.8 mol%) was added
to a solution of diene 23a (34 mg, 61.3 mmol) in
dichloromethane (3 ml). The reaction was heated to 40°C
for 4 h and then one more portion of 3 (5.2 mg, 6.1
mmol, 10 mol%) was added and the reaction heated for 4
h. At this point, the reaction was deemed complete by
TLC and was concentrated in vacuo. Flash chromatogra-
phy of the residue over silica gel (4×23 cm) with 10“40%
Et2O/hexanes/1% Et3N gave the olefin 24a (32.3 mg,
87%) as a pure (Rf=0.70, TLC silica, 50% EtOAc–hex-
anes; 1H NMR, 500 MHz) beige solid: mp=71–72°C;
[h]D=+93.7 (c 1.00, CH2Cl2); FT-IR (neat) 2961, 2932,
23. Roy, R.; Dominique, R.; Das, S. K. J. Org. Chem. 1999,
64, 5408–5412.
24. 23a: n-BuLi (386 ml, 1.43 M in hexanes, 0.551 mmol) was
added dropwise via syringe to a −78°C solution of olefin-
alcohol 11 (157 mg, 0.424 mmol) in THF (3 ml). The
resulting solution was stirred for 15 min at −78°C and
then Me2SiCl2 (153 ml, 1.27 mmol) was added in one
portion and the solution was allowed to warm to ambient
temperature and was stirred for 3 h. The solution was
carefully concentrated under high vacuum, diluted with
THF (3 ml) and a solution of olefin 22a (92 mg, 0.424
mmol) and imidazole (43 mg, 0.636 mmol) in THF (2 ml)
was rapidly added via cannula and the resulting solution
stirred at ambient temperature for 13 h. The reaction was
diluted with water (5 ml) and extracted with
dichloromethane (3×10 ml) and the combined organic
extracts dried and concentrated. Flash chromatography
of the residue over silica gel (4×23 cm) with 10“40%
Et2O/hexanes/1% Et3N gave olefin 23a (157 mg, 67%) as
1
2821, 1730, 1467, 1257, 1216, 1106, 1083, 1053 cm−1; H
NMR (500 MHz, CDCl3) l 7.35–7.24 (m, 10H, ArH),
5.54 (dd, 1H, J=16, 8.5 Hz, H-6), 5.45 (dd, 1H, J=16,
9.0 Hz, H-7), 4.83 (d, 1H, J=11 Hz, OCH2Ph), 4.79 (d,
1H, J=12.5 Hz, OCH2Ph), 4.74 (d, 1H, J=11 Hz,
OCH2Ph), 4.62 (d, 1H, J=11.5 Hz, OCH2Ph), 4.53 (d,
1H, J=3.5 Hz, H-1), 4.00 (dd, 1H, J=9.0, 9.0 Hz, H-1%),
3.90 (ddd, 1H, J=11, 4.0, 1.5 Hz, H-5%), 3.78 (dd, 1H,
J=9.0, 9.0 Hz, H-3), 3.53 (dd, 1H, J=8.5, 8.5 Hz, H-5),
3.45 (dd, 1H, J=9.5, 3.5 Hz, H-2), 3.37 (s, 3H, OCH3),
3.34 (dd, 1H, J=12, 2.5 Hz, H-5%), 3.21–3.14 (m, 2H,
H-4, H-2%), 2.02–1.94 (m, 1H, H-3%), 1.77–1.62 (m, 2H,
2×H-4%) 1.54–1.44 (m, 1H, H-3%), 0.10 (s, 3H, SiCH3),
0.07 (s, 3H, SiCH3); 13C NMR (125 MHz, CDCl3) l
138.8, 138.3, 132.4, 129.4, 128.4, 128.4, 128.3, 128.1,
127.9, 127.9, 127.5, 98.4, 84.6, 81.5, 79.6, 75.8, 74.6, 73.7,
73.6, 70.4, 67.4, 55.2, 32.6, 25.7, −.3.4, −3.9; HRMS
(FAB): calcd for C29H38O7Si (M+Na)+ 549.2279, found
549.2279.
1
a pure oil (Rf=0.21, TLC silica, 40% Et2O–hexanes; H
NMR, 500 MHz) oil: [h]D=+75.7 (c 1.00, CH2Cl2); FT-
IR (neat) 2935, 1454, 1410, 1371, 1256, 1194, 1035, 1007,
921, 903, 872, 851, 796, 734, 697 cm−1 1H NMR (500
;
26. For a comprehensive review on the synthesis of C-sac-
charides, see: Liu, L.; McKee, M.; Postema, M. H. D.
Curr. Org. Chem. 2001, 5, 1133–1167.
27. Rainier, J. D.; Cox, J. M. Org. Lett. 2000, 2, 2707–2709.
28. This premise is further supported by the presence of extra
peaks in the 1H NMR spectrum of the product that
results when 11 is dimerized with 0.5 equiv. of Me2SiCl2.
29. The use of catalyst 4 did not result in any improvement
in yield of 24 and we have not yet examined the RCM
reaction with catalyst 1.
MHz, CDCl3) l 7.37–7.23 (m, 10H, ArH), 5.92–5.83 (m,
2H, H-9, H-6), 5.35 (ddd, 1H, J=17, 1.5, 1.5 Hz,
CꢀCH2), 5.27 (ddd, 1H, J=17, 1.5, 1.5 Hz, CꢀCH2), 5.22
(d, 1H, J=11 Hz, CꢀCH2), 5.15 (ddd, 1H, J=11, 2.0, 2.0
Hz, CꢀCH2), 4.97 (d, 1H, J=11 Hz, OCH2Ph), 4.79 (d,
1H, J=11 Hz, OCH2Ph), 4.71 (d, 1H, J=12.5 Hz,
OCH2Ph), 4.59 (d, 1H, J=12.5 Hz, OCH2Ph), 4.58 (d,
1H, J=3.5 Hz, H-1), 3.98 (dd, 1H, J=9.5, 6.5 Hz,
H-10), 3.92–3.87 (m, 1H, H-14), 3.78 (dd, 1H, J=9.0, 9.0
Hz, H-3), 3.51–3.42 (bm, 3H, H-11, H-5, H-2), 3.40–3.28
(bm, 2H, H-14, H-4), 3.37 (s, 3H, OCH3), 2.10–2.03 (m,
1H, H-12), 1.64–1.56 (m, 2H, 2×H-13), 1.50–1.40 (m, 1H,
H-12), 0.05 (s, 3H, SiCH3); 0.04 (s, 3H, SiCH3); 13C
30. (a) Hanessian, S.; Liak, T. J.; Dixit, D. M. Carbohydr.
Res. 1981, 88, C14–C19; (b) Bellosta, V.; Czernecki, S.
Carbohydr. Res. 1993, 244, 275–284.