Carbohydrate-based oxepines: Ring expanded glycals for the synthesis of septanose saccharides

Article abstract of DOI:10.1016/S0040-4039(03)00849-9

A ring-closing metathesis (RCM) approach to a family of carbohydrate-based oxepines is described. A variety of readily accessible, protected monosaccharide derived dienes were used to demonstrate the utility of the synthetic sequence and to investigate ho

Full text of DOI:10.1016/S0040-4039(03)00849-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4057–4061
Carbohydrate-based oxepines: ring expanded glycals for the
synthesis of septanose saccharidesꢀ
Mark W. Peczuh* and Nicole L. Snyder
Department of Chemistry, The University of Connecticut, 55 North Eagleville Road, Storrs, CT 06269-3060 USA
Received 4 March 2003; revised 31 March 2003; accepted 1 April 2003
Abstract—A ring-closing metathesis (RCM) approach to a family of carbohydrate-based oxepines is described. A variety of
readily accessible, protected monosaccharide derived dienes were used to demonstrate the utility of the synthetic sequence and to
investigate how factors such as rigidification and deoxygenation mediate RCM using the Grubbs or Schrock catalyst. The
seven-membered cyclic enol ethers are ring expanded glycals to be used in the synthesis of septanose carbohydrates. © 2003
Elsevier Science Ltd. All rights reserved.
Natural carbohydrates exist almost exclusively in the
furanose or pyranose form. Larger ring saccharides,
such as seven-membered ring septanoses, hold tremen-
dous potential as probes of carbohydrate structure and
function and as starting materials for the synthesis of
natural products and designed structures. We have
initiated a program to synthesize and characterize car-
bohydrates composed in whole or in part of septanose
monomers. In this letter, we report a three-step
sequence—Wittig olefination, vinyl ether formation,
and ring-closing metathesis (RCM)—to synthesize car-
bohydrate based seven-membered cyclic enol ethers
from protected pyranose lactols. The resulting enol
ethers will serve as glycosyl donors in the synthesis of
septanose-based carbohydrates.
tionally dynamic nature of selected polysaccharide
sequences by replacing the flexible monosaccharide with
a septanose monosaccharide. The objective is to
approximate natural structure and function with the
unnatural carbohydrate in an effort to understand how
conformational flexibility is used by nature in protein–
carbohydrate interactions. Eventually we would like to
incorporate conformationally dynamic monosaccha-
rides to give unnatural oligosaccharides with a pre-
dictable function.
Our inspiration for the investigation of septanose
carbohydrates1 is based on work that has focused on
pyranose based nucleic acids2 and peptides derived
from b-amino acids.3 These examples share a common
feature in that the natural biopolymer monomer units
are homologated by one carbon. We anticipate that the
homologation of pyranose monosaccharides will lead to
biologically interesting unnatural carbohydrates. The
ability of a furanose or pyranose monosaccharide
within an oligosaccharide to access more than one low
energy conformation has an effect on a carbohydrate’s
biological activity.4 We intend to mimic the conforma-
Drawing inspiration from glycal (1) chemistry,5 the
seven-membered ring cyclic enol ether 2 presented itself
as a promising starting point toward the synthesis of
septanose carbohydrates. The ring expanded glycal
(septanal) should have a reactivity profile similar to
that of glycals themselves. Glycals have proven to be
formidable glycosyl donors and can also be used in the
generation of other types of donors through simple
transformations.6 As such, we expect septanals to
undergo glycosylations to form 2-oxo,7 2-amino,8 and
2-deoxy9 septanosides. Access to this family of cyclic
enol ethers is a prerequisite to understanding the selec-
tivity of subsequent glycosylation reactions.
Keywords: septanose carbohydrate; oxepine; ring-closing metathesis;
glycal.
ꢀ Supplementary data associated with this article can be found at
doi:10.1016/S0040-4039(03)00849-9
Oxepines derived from carbohydrates have recently
been described. One notable synthetic approach was the
dihalocyclopropanation of a glycal followed by nucle-
* Corresponding author. E-mail: mark.peczuh@uconn.edu
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00849-9

4058
M. W. Peczuh, N. L. Snyder / Tetrahedron Letters 44 (2003) 4057–4061
ophilic ring expansion to give the corresponding 2-
halooxepine 3.10 A second example involved Wittig
homologation of a protected furanose followed by for-
mation of an allyl ether and ring-closing metathesis to
give molecules such as 4.11 The key factor of these
reported syntheses is that they are not directly
amenable to subsequent glycosylation reactions. The
strategy described here provides precursors that can
directly utilize precedented procedures in the formation
of glycosidic linkages.
using the less expensive and more easily handled
Grubbs catalyst 9 (Table 1).
Dienes 11–14 were synthesized from known lactols23 via
olefination and vinyl ether formation as described for
tetra-O-benzyl glucose. These RCM precursors were
used to address different properties of the diene that we
thought might contribute to successful cyclization using
9. For example, dienes 11 and 12 were derived from
Table 1. RCM of monosaccharide derived dienes
Demonstrations of synthetic routes to seven membered
cyclic enol ethers have employed either a cyclization–
elimination procedure of hydroxy acetals12 or the ring-
closing metathesis of olefin enol ethers.13 Our approach
was driven by the success of RCM for preparation of
cyclic enol ethers in systems with similar functional-
ity.13a,b,14 No examples of the RCM of carbohydrate
derived enol ethers in the formation of oxepines have
yet been reported. We were mindful that formation of
six-membered cyclic enol ethers by RCM of olefin enol
ethers had shown various substituent effects.15,16 We
have established that the RCM strategy can be imple-
mented in the presence of highly demanding functional-
ity inherent in the carbohydrate systems described here
to form oxepines.
Diene
Cyclic enol ether
% Yield
9§
10†
NR
92
10
25
71
89
Our three-step synthetic strategy is demonstrated in
Scheme
1 using tetra-O-benzyl glucose (5). The
sequence is initiated by known Wittig olefination17 of 5
with concomitant release of the C5 (glucose numbering)
hydroxyl group. Recently reported conditions for vinyl
ether formation, using Pd(II) in the presence of phenan-
throline,18 provided enol ether 719 in modest yield.
Compound 7 was heated in an appropriate solvent in
the presence of each of the commercially available
RCM catalysts 9 and 10. No product formation was
observed using Grubbs catalyst 9 under a range of
reaction conditions.20 Schrock catalyst 1021 cleanly con-
verted the diene 7 to the tetra-benzyl oxepine 822 in 92%
yield.
NR
27
82
86
Encouraged by the successful formation of oxepine 8, a
series of diene precursors with varying protecting
groups or sites of deoxygenation were synthesized (i) to
probe the generality of the approach and (ii) to identify
protecting groups that would allow for cyclization
§ 0.005 M diene, 20 mol% 9 in DCM under N2, reflux overnight.
† 0.002 M diene, 20 mol% 10 in toluene 60°C, 4 h. Diene 11 was
reacted for 12 h for complete conversion.
Scheme 1.

M. W. Peczuh, N. L. Snyder / Tetrahedron Letters 44 (2003) 4057–4061
4059
Scheme 2.
groups. Access to preferred conformations by internal
cyclic constraint13a,b,c and acyclic steric effects27 are well
documented. Deoxygenation allows greater accessibility
to the vinyl ether 13 or to the alkene 14 relative to 7.
The results show that increased access to the vinyl ether
disfavors cyclization (presumably by favoring forma-
tion of G), while access to the alkene favors reactivity
(via B) at the cost of formation of glucal as a side
product. The use of diene 14, which is deoxygenated at
the allylic position of the olefin was motivated by
reports that alkoxy substituents at this position slow
the rate of metathesis or completely inhibit reaction.24
Removal of the inductive effect from the alkoxy sub-
stituent also contributes to the increased reactivity of
14. The more reactive Schrock catalyst gave con-
sistently good yields with all diene precursors. The
insensitivity of Schrock catalyst 10 to diene
electronics observed here mirrors results from other
systems.13a,b,c,14
4,6-O-benzylidene glucose and mannose diacetonide,
respectively. They incorporated acetal protecting
groups that rigidified the diene in comparison to 7.
Deoxygenated derivatives 13 and 14 allowed for greater
accessibility to nearby olefins (based on the site of
deoxygenation). The 2-deoxyglucose derived diene 14
was especially interesting because it tested the influence
of the alkoxy substituent in the allylic position of the
diene for cyclization.24
Cyclization using the 4,6-benzylidene protected precur-
sor 11 (glucose numbering) showed limited formation
of product using 9 (Table 1). The mannose derived
precursor 12 showed slightly greater yields of the cyclic
enol ether 16 and indicated that RCM efficiency using
9 could be affected by changing the nature of the
protecting groups. Diene 13, synthesized from tri-O-
benzyl xylose, showed no reaction in the presence of 9.
Deoxygenated precursor 14 gave a modest yield using
9 and formation of a side product was also observed
(18:side product ratio 3:1). After column chromato-
In summary, we have introduced a convenient and
concise route to ring expanded glycals from protected
pyranose sugars. The method allows for the synthesis of
a range of carbohydrate derived oxepines via a three
step sequence from the protected reducing sugar. The
approach provides a better understanding of sub-
stituent contributions in the RCM reaction of enol
ethers using Grubbs catalyst. Current work is aimed at
demonstrating that the carbohydrate-derived cyclic enol
ethers are functional analogs of glycals and can serve as
glycosyl donors in the synthesis of septanose
carbohydrates.
1
graphy, this side product was identified by H and 13C
NMR as tri-O-benzyl glucal 1 (where R=Bn). The
formation of this product could occur via a ruthenium
mediated 1,3-hydrogen shift or through reductive elimi-
nation of a ruthenium hydrido species followed by
RCM of the truncated diene.25 High yields of oxepines
15–18 were observed using Schrock catalyst 10 (Table
1).
The reactivity profile of the RCM substrates can be
rationalized by considering the proposed reaction
mechanism (Scheme 2). A few examples of RCM reac-
tions involving enol ethers using Grubbs catalyst have
been reported.13a,b,d Of critical importance is the forma-
tion of Fisher-type carbenes such as G (Scheme 2,
Route II). Recent reports have shown that this carbene
species, generated from electron-rich olefins, can be
reactive in specific metathesis reactions, but is otherwise
unreactive.20,26 Our findings suggest that the features
critical to RCM using 9 are: (i) the preorganization or
rigidity of the diene, (ii) the steric accessibility of the
vinyl ether or the alkene, and (iii) the alkoxy sub-
stituent allylic to the alkene. In comparing diene 7 to 11
and 12, there is a progression toward fewer allowed
bond rotations by virtue of the acetal protecting
Acknowledgements
The authors thank Martha Morton for help with NMR
spectroscopy, the University of Connecticut, and the
UConn Research Foundation for support of this
project.
References
1. (a) Tran, T. Q.; Stevens, J. D. Aust. J. Chem. 2002, 55,
171–178 and references cited therein; (b) Paluski, Z.
Polish J. Chem. 1996, 70, 667–707.

4060
M. W. Peczuh, N. L. Snyder / Tetrahedron Letters 44 (2003) 4057–4061
Chem. 2001, 9, 1269–1278; (b) Qioa, L.; Vederas, J. C. J.
2. Eschenmoser, A. Science 1999, 284, 2118–2124.
Org. Chem. 1993, 58, 3480–3482.
3. (a) Gellman, S. H. Acc. Chem. Res. 1998, 31, 173–180; (b)
Gademan, K.; Ernst, M.; Hoyer, D.; Seebach, D. Angew.
Chem., Int. Ed. 1999, 38, 1223–1226; (c) Porter, E. A.;
Wang, X.; Lee, H.-S.; Weisblum, B.; Gellman, S. H.
Nature 2000, 404, 585.
4. (a) Gordon, M. T.; Lowary, T. L.; Hadad, C. M. J. Am.
Chem. Soc. 1999, 121, 9682–9692; (b) Ernst, S.;
Venkataraman, G.; Sasisekharan, V.; Langer, R.;
Cooney, C. L.; Sasisekharan, R. J. Am. Chem. Soc. 1998,
120, 2099–2107.
18. (a) Weintraub, P. M.; King, C-H. R. J. Org. Chem. 1997,
62, 1560–1562; (b) Handerson, S.; Schlaf, M. Org. Lett.
2002, 4, 407–409; (c) Vinyl ether formation at this
hydroxyl group using Hg(OAc)2 in ethylvinyl ether was
inefficient; in fact, Sinay¨ has shown that Hg(OAc)2 in
THF can efficiently mediate cyclization to form the mer-
curicmethyl C-glycoside, see: Pougny, J. R.; Nassr, M. A.
M.; Sinay¨, P. J. Chem. Soc., Chem. Commun. 1981,
375–376.
19. 7: Into a roundbottom flask under N2 atmosphere were
sequentially added 6 mL dry DCM and 20 mL ethylvinyl
ether followed by 1,10-phenanthroline (6 mg, 0.03 mmol)
and Pd(OAc)2 (7 mg, 0.03 mmol). This was allowed to
stir at room temperature for 10–15 min and a yellow
suspension was observed. To this solution was added 6
(111 mg, 0.205 mmol) in 2 mL dry DCM. The flask was
fitted with a reflux condensor, maintained under N2
atmosphere and heated to reflux for 72 h. The reaction
mixture slowly turned black, indicating formation of
palladium black. The reaction was cooled to room tem-
perature and the solvent removed under reduced pres-
sure. The resulting oil was purified by column
chromatography (silica, 15 mm×100 mm) eluting with
20% EtOAc/Pet. Ether to give 37 mg of 7 (32%, 80%
based on recovered starting material) as a clear colorless
oil. Starting material eluted second and was also recov-
ered (66 mg). Yields up to 49% could be obtained with
longer reaction times. Rf (25% EtOAc/pet. ether)=0.92
1H NMR 400 MHz (CDCl3) l 7.31–7.23 (m, 20H), 6.23
(dd, J=14.0, 6.5 Hz, 1H), 5.86 (ddd, J=17.5, 10.3, 7.4
Hz, 1H), 5.28 (dd, J=10.3, 1.2 Hz, 1H), 5.20 (d, J=17.5,
1H), 4.78 (d, J=11.2 Hz, 1H), 4.70–4.58 (m, 3H), 4.48 (s,
2H), 4.36 (dd, J=14.3, 1.6 Hz, 1H), 4.15 (ddd, J=5.3,
5.3, 3.4 Hz, 1H) 4.10 (dd, J=6.8, 6.8 Hz, 1H), 3.99 (dd,
J=6.5, 1.6 Hz, 1H), 3.97 (dd, J=5.0, 5.0 Hz, 1H), 3.84
(dd, J=10.7, 3.3 Hz, 1H), 3.69 (dd, J=6.3, 5.0 Hz, 1H),
3.66 (dd, J=10.7, 5.8 Hz, 1H); 13C NMR 100 MHz
(CDCl3) l 151.3, 138.9, 138.4, 138.3, 135.5, 128.5 (2),
128.4 (2), 128.3, 128.2, 127.9 (2), 127.7, 127.6 (2), 119.4,
89.4, 81.7, 81.5, 79.3, 79.0, 76.9, 75.3, 74.3, 73.5, 70.8,
69.1. FAB MS m/z (M++H) calcd 565.2954, found
565.2944.
20. Heating to 60°C or to reflux in toluene in the presence of
20 mol% 9 showed no reaction. Temperature dependence
for RCM has been noted elsewhere, see: Majumder, U.;
Cox, J. M.; Rainier, J. D. Org. Lett. 2003, 5, 913–916.
21. Schrock, R. R. Tetrahedron 1999, 55, 8141–8153 and
references cited therein.
22. 8: (In a glovebox) To a solution of 7 (94 mg, 0.166 mmol)
in 15 mL dry toluene was added catalyst 10 (32 mg, 0.042
mmol) in 2 mL toluene. The reaction was sealed in a
airfree screw-top roundbottom and removed from the
glovebox. The reaction mixture was put on an oil bath
and heated at 60°C for 4 h. The reaction was then
allowed to cool to room temperature and exposed to air.
The solvent was removed under reduced pressure and the
resulting dark brown oil was purified by column chro-
matography (silica, 15 mm×85 mm) using 25% EtOAc/
pet. ether as eluent to give a clear colorless oil (82 mg,
92%). Rf (25% EtOAc/pet. ether)=0.63; [h]D=+68.8° (c
1.7, CHCl3); 1H NMR 400 MHz (CDCl3) l 7.56–7.06 (m,
20H), 6.51 (d, J=6.9 Hz, 1H), 4.80 (dd, J=6.8, 6.8 Hz,
5. Danishefsky, S. J.; Bilodeau, M. T. Angew. Chem., Int.
Ed. Engl. 1996, 35, 1380–1419.
6. (a) Seeberger, P. H.; Eckhardt, M.; Gutteridge, C. E.;
Danishefsky, S. J. J. Am. Chem. Soc. 1997, 119, 10064–
10072; (b) Plante, O.; Seeberger, P. H. J. Org. Chem.
1998, 63, 9150–9151.
7. Halcomb, R. L.; Danishefsky, S. J. J. Am. Chem. Soc.
1989, 111, 6661–6666.
8. (a) Griffith, D. A.; Danishefsky, S. J. J. Am. Chem. Soc.
1990, 112, 5811–5819; (b) Di Bussolo, V.; Liu, J.; Huff-
man, L. G., Jr.; Gin, D. Y. Angew. Chem., Int. Ed. 2000,
39, 204–207; (c) Liu, J.; Gin, D. Y. J. Am. Chem. Soc.
2002, 124, 9789–9797.
9. Friesen, R. W.; Danishefsky, S. J. J. Am. Chem. Soc.
1989, 111, 6656–6660.
10. (a) Ramana, C. V.; Murali, R.; Nagarajan, M. J. Org.
Chem. 1997, 62, 7694–77703; (b) Hoberg, J. O. J. Org.
Chem. 1997, 62, 6615–6618; (c) Hoberg, J. O.; Bozell, J. J.
Tetrahedron Lett. 1995, 38, 6831–6834.
11. Ovaa, H.; Leeuwenburgh, M. A.; Overkleeft, H. S; van
der Marel, G. A.; van Boom, J. Tetrahedron Lett. 1998,
39, 3025–3028.
12. (a) Rainier, J. D.; Allwein, S. P.; Cox, J. M. J. Org.
Chem. 2001, 66, 1380–1386; (b) Rainier, J. D.; Allwein, S.
P. Tetrahedron Lett. 1998, 39, 9601–9604.
13. (a) Allwein, S. P.; Cox, J. M.; Howard, B. E.; Johnson,
H. W. B.; Rainier, J. D. Tetrahedron, 2002, 58, 1997–
2009; (b) Rainier, J. D.; Cox, J. M.; Allwein, S. P.
Tetrahedron Lett. 2001, 42, 179–181; (c) Clark, J. S.;
Kettle, J. G. Tetrahedron 1999, 55, 8231–8248. In this
example the oxepine was not able to be separated from
other products of the reaction. (d) Chatterjee, A. K.;
Morgan, J. P.; Scholl, M.; Grubbs, R. H. J. Am. Chem.
Soc. 2000, 122, 3783–3784; (e) A tandem RCM/olefin
isomerization sequence has recently been introduced, see:
Sutton, A. E.; Seigal, B. A.; Finnegan, D. F.; Snapper,
M. L. J. Am. Chem. Soc. 2002, 124, 13390–13391.
14. (a) Calimente, D.; Postema, M. H. D. J. Org. Chem.
1999, 64, 1770–1771; (b) Postema, M. H. D.; Calimente,
D.; Liu, F.; Berhman, T. L. J. Org. Chem. 2000, 65,
6061–6068.
15. Sturino, C. F.; Wong, C. Y. Tetrahedron Lett. 1998, 39,
9623–9626.
16. Substituted six and seven membered enol ethers have
been synthesized using a tandem methylenation-metathe-
sis approach, see: (a) Nicolaou, K. C.; Postema, M. H.
D.; Claiborne, C. F. J. Am. Chem. Soc. 1996, 118,
1565–1566; (b) Nicolaou, K. C.; Postema, M. H. D.; Yue,
E. W.; Nadin, A. J. Am. Chem. Soc. 1996, 118, 10335–
10336.
17. (a) Martin, O. R.; Saavedra, O. M.; Xie, F.; Liu, L.;
Picasso, S.; Vogel, P.; Kizu, H.; Asano, N. Bioorg. Med.

M. W. Peczuh, N. L. Snyder / Tetrahedron Letters 44 (2003) 4057–4061
4061
1H), 4.67–4.55 (m, 8H), 4.50 (d, J=11.2 Hz, 1H), 4.09 (dd,
J=5.9, 5.9 Hz, 1H), 3.96 (dd, J=4.5, 4.5 Hz, 1 Hz), 3.87
(dd, J=9.4, 3.8 Hz, 1H), 3.78 (d, J=3.2 Hz, 2H); 13C NMR
100 MHz (CDCl3) l 149.4, 138.6, 138.4(2), 128.6, 128.5,
128.0(2), 127.9(2), 127.8, 127.7(2), 123.0, 103.8, 82.8, 81.2,
80.3, 73.6(2), 73.5, 72.8, 70.9, 70.4; FAB MS m/z (M+−H)
calcd 535.2484, found 535.2455.
Refs. 13e, 24. We envision the glucal arising from RCM
of a truncated diene that comes about by 1,3 hydrogen shift
followed by reductive elimination. See also: Miller, S. J.;
Blackwell, H. E.; Grubbs, R. H. J. Am. Chem. Soc. 1996,
118, 9606–9614; (b) A similar trunctation using Schrock
catalyst has also been reported, see: Joe, D.; Overman, L.
E. Tetrahedron Lett. 1997, 38, 8635–8638.
26. (a) Louie, J.; Grubbs, R. H. Organometallics 2002, 21,
2153–2164; (b) Sanford, M. S.; Love, J. A.; Grubbs, R. H.
J. Am. Chem. Soc. 2001, 123, 6453–6554; (c) Grubbs, R.
H.; Chang, S. Tetrahedron 1998, 54, 4413–4450.
27. Crimmins, M. T.; Choy, A. L. J. Am. Chem. Soc. 1999, 121,
5653–5660.
23. (a) Drew, K. N. J. Org. Chem. 1991, 56, 509–513; (b) Wang,
H.; Sun, L.; Glazebnik, S.; Zhao, K. Tetrahedron Lett. 1995,
36, 2953–2956; (c) Reed, L. A.; Ito, Y.; Masamune, S.;
Sharpless, K. B. J. Am. Chem. Soc. 1982, 104, 6468–6470.
24. Hoye, T. R.; Zhao, H. Org. Lett. 1999, 1, 1123–1125.
25. (a) Ruthenium-hydrido species of this type are known. See