Ring-rearrangement metathesis of 3,6-dialkoxy-3,6-dihydro-2H-pyrans

Article abstract of DOI:10.1016/j.tetlet.2007.12.047

The first RCM-ROM-RCM sequence using a non-strained heterocycle as relay moiety is described. The course of the reaction strongly depends on the nature and relative configuration of the substituents in the starting trienic system. In addition, for a produ

Full text of DOI:10.1016/j.tetlet.2007.12.047

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1192–1195
Ring-rearrangement metathesis of 3,6-dialkoxy-3,6-dihydro-2H-pyrans
*
´
Morgan Donnard, Theophile Tschamber, Sandy Desrat, Karen Hinsinger, Jacques Eustache
Laboratoire de Chimie Organique et Bioorganique associe´ au CNRS, Universite´ de Haute-Alsace,
Ecole Nationale Supe´rieure de Chimie de Mulhouse. 3, rue Alfred Werner, F-68093, Mulhouse Cedex, France
Received 15 November 2007; revised 4 December 2007; accepted 7 December 2007
Available online 15 December 2007
Abstract
The first RCM–ROM–RCM sequence using a non-strained heterocycle as relay moiety is described. The course of the reaction
strongly depends on the nature and relative configuration of the substituents in the starting trienic system. In addition, for a productive
reaction to be observed, the site of initiation of the metathesis cascade is crucial. The compounds thus obtained may be useful for the
synthesis of unusual polydeoxydisaccharides.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Ring-rearrangement metathesis; Cascade metathesis; RCM; ROM
In the last decade, the olefin/alkyne metathesis reaction
has become a major synthetic tool for the preparation of
complex organic molecules. The intramolecular ring-closing
metathesis (RCM), and the intermolecular cross-metathesis
(CM) are now routinely used in organic synthesis. The
intermolecular ring-opening metathesis (ROM) of strained
cyclic olefins has been mainly used in polymer synthesis in
the so-called ring-opening metathesis polymerization
(ROMP).
( )m
( )m
X
X
( )l
RCM-ROM
( )l
A
( )
m Y
( )
mY
RCM-ROM-RCM
X
( )l
X
( )l
Z
( )n
Z
( )n
B
Relay
moiety
Known
:
X,Z = C, N, O; Y= C; l, n = 1, 2; m = 0-4.
In addition, a wide variety of ‘domino’ metatheses have
been developed (RCM–ROM, CM–ROM, RCM–ROM–
RCM, etc.) which increases the synthetic potential of this
reaction. For these combinations the collective term
‘ring-rearrangement metathesis’ (RRM) has been proposed
(Scheme 1).1
Among the various possible RRMs, the RCM–ROM–
RCM cascade (B, Scheme 1) which allows the stereocon-
trolled formation of bicyclic systems from relatively simple
monocyclic precursors is particularly useful. The method
can be used, for example, for the preparation of bicyclic
ethers2 and piperidine- and pyrrolidine-containing alka-
Unknown: Y= O, NR.
Scheme 1. Some synthetically useful metathetic cascades.
loids.3 To the best of our knowledge, however, there is
no example of type B RRM in which X, Y and Z are all
heteroatoms.4
We were intrigued by the possibility of achieving RRM
B using substrates in which X = Y = Z = O and m = 1.
Despite a superficial similarity, there are significant differ-
ences between such systems and their carbocyclic counter-
part (Y = C). In particular, an anomeric effect in the
former type of substrates may operate to stabilize certain
conformations.5 This, in turn is likely to influence (posi-
tively or negatively) the metathetic process. Apart from
*
Corresponding author. Tel.: +33 3 89 33 6855.
E-mail address: jacques.eustache@uha.fr (J. Eustache).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.12.047

M. Donnard et al. / Tetrahedron Letters 49 (2008) 1192–1195
1193
these mechanistic aspects, the product of the rearran-
gement is potentially useful as a versatile synthetic inter-
mediate in the preparation of unusual disaccharides.6 The
required metathesis substrates were readily prepared as
shown in Scheme 2: 3,4-bis(O-acetyl) rhamnal 3 was trea-
ted by but-3-en-1-ol in the presence of catalytic BF3ÁEt2O
to afford 4(R) glycoside 4,7 as a 6:1 mixture of a and b ano-
mers8 in agreement with the literature data.7 This was con-
verted in two steps into the 4-O-acryloyl 6a. The a and b
anomers could not be separated and our studies were pur-
sued using this mixture. Therefore, all subsequent products
will be obtained as mixtures of a major and a minor ano-
mer in a 6:1 ratio.
The first RCM–ROM–RCM sequence was then
attempted using acrylate 6a as the starting material. As
can be seen in Scheme 2, formation of the expected disac-
charide analogue 7a was not observed. Instead, using the
Grubbs ‘first generation’ catalyst 19 in the presence of
10
Ti(OiPr)4 the cross metathesis dimer 8a (ca. 30%) was
obtained along with starting material (ca. 50%). Using
OH
Olefin 3
O
O
O
O
COCl
BF3.Et2O
, NEt3
1
6
5
a
b
O
O
O
CH2Cl2, 20 °C,
1 h, 98%
2
CH2Cl2, 20 °C,
1 h, 97%
2
4
AcO
RO
3
Toluene,
O
OAc
O
4(R)
, NaH
R1
R2
Br
RCM 1
RCM 2
3
R1
60 °C, 6 h
DMF, 20 °C,
R2
4: R = Ac
5: R =H
MeONa/MeOH
20 °C, 6 h, 98%
6 h, 71%
Olefin 1
Olefin 2
6a: R1, R2 = (=O)
6b: R1 = R2 = H
7a: Not observed
7b: 8%
O
N
OiPr
PrOi
N
O
O
O
COCl, NEt3
CH2Cl2, 20 °C,
pNBzOH, PPh3
a
5
THF, 20 °C,
6 h,97%
RO
1 h, 84%
O
O
O
O
4(S)
, NaH
Br
b
c
2
DMF, 20 °C,
Toluene
O
6 h, 71%
O
10: R =pNBz
11: R = H
MeONa/MeOH
20 °C, 6 h, 98%
R1
R2
60 °C, 3-6 h
CH2=C=CHOMe
Pd(OAc)2, DPPP
R1
R2
12a-c
CH3CN, NEt3
13a: 8%
100 °C, 6 h, 41%
13b: 83%
12a: R1, R2= (=O)
12b: R1 = R2 =H
13c: No reaction
12c: R1 = OMe, R2 = H
O
O
O
O
2
Toluene
, Ag O
Br
2
O
O
O
60 °C, 120 h
60 °C, 3 h
14: 40%
15: 87%
11
COOH
2
O
O
O
O
AcO
Toluene
H2, Pd/C
DCC, DMAP
O
O
O
60 °C, 3 h
CH2Cl2, 20 °C,
16 h, 98%
AcOEt
O
20 °C, 16 h
R1
R2
AcO
16: R1, R2 = (=O)
17: R1 = H, R2 = OAc
19: 86%
18: 86%
a)DIBAL;b) Ac2O
CH2Cl2
0 °C, 86%
-78 °C
O
O
O
O
O
O
O
O
O
O
O
8a
O
O
O
9a
O
O
Scheme 2. RCM–ROM–RCM of 3,6-dialkoxy-3,6-dihydro-2H-pyrans.

1194
M. Donnard et al. / Tetrahedron Letters 49 (2008) 1192–1195
the Grubbs ‘second generation catalyst’ 2, we observed the
formation of macrocycle 9a (38%) along with dimer 8a
(7%) and starting material (50%).
In substrate 6a, initiation of the metathetic process
should occur at the more electron-rich olefin 1. If this is
the case, the first step of the cascade, RCM 1, (see Scheme
2), does not proceed. This was confirmed by the behaviour
of acetate 4 that was unchanged when submitted to the
same methathesis conditions (2, toluene, 60 °C).
went clean metathetic conversion into bis-dihydropyrane
15.
Finally, the mixed ketal 17 was obtained from 11 in two
steps: formation of the 4-O-3-butenoyl ester and reduction
of the latter with DIBAL then quenching with acetic anhy-
dride according to Rychnovsky16 (the success of this reac-
tion depends on the careful control of the experimental
conditions).13 We were very pleased to observe the clean
conversion of 17 to the bis-dihydropyrane 18 upon expo-
sure to catalyst 2. Reduction of the two olefinic double
bonds in 18 provided 19, the first disaccharide to be synthe-
sized by cascade metathesis.
Thus, we have described the first RCM–ROM–RCM
cascade using a non-strained, monocyclic heterocycle as a
relay moiety. We show that the success of the reaction cru-
cially depends on electronic and stereochemical factors. In
particular, our results suggest that, although a,b-unsatu-
rated ketals can participate in metathesis they cannot serve
as initiation site for the reaction. The structural pattern of
the newly formed compounds suggests that they could be
useful as valuable intermediates for the synthesis of
unusual disaccharides. This is illustrated by conversion of
bisacetal 18 into a simple polydeoxy-1,6-disaccharide.
The study of RRM using different heterocyclic relay
moieties is underway.
We then attempted to invert the sense of the sequence
(RCM 2?ROM?RCM 1) by allowing the initiation to
take place at the level of olefin 2. To this effect, the acrylate
ester was replaced by an allyl ether to afford 6b which was
submitted to standard metathesis conditions (catalyst 2,
toluene, 60 °C). Only limited (<8%) conversion to the
desired bicyclic ether 7b (obtained as a 6:1, mixture of a
1
and b anomers as determined by H NMR) was observed
and most of the starting material was recovered.
These results are markedly different from those reported
in earlier studies using carbocyclic relay moieties.2,3 A plau-
sible explanation is as follows: according to Chauvin’s
mechanism,11 a crucial step in the RCM catalytic cycle is
the formation of a strained bicyclic metallacyclobutane.
This is only possible when strict geometrical requirements
are met, including an adequate conformational organiza-
tion of the starting diene placing the two olefins in close
proximity while minimizing steric effects.12 In our case,
the central dihydropyran ring in 6 exists in a stable half
chair conformation (with an equatorial methyl group)
and this is probably detrimental to the formation of a bicy-
clic transition state regardless of the initiation site (olefin 1,
a or b anomer, or olefin 2).
Acknowledgments
`
We thank the French Ministere de la Jeunesse, de l’Edu-
cation Nationale et de la Recherche, and the CNRS for
financial support and for a fellowship for M.D.
Faced with these disappointing results, we decided to
examine the effect on metathesis of inverting the C-4 stereo-
chemistry (Scheme 2).
References and notes
Inversion of the 4-hydroxyl group in compound 5 was
achieved using the Mitsunobu procedure to afford 4 (S) gly-
coside 11, which was converted into the corresponding acry-
late ester 12a and allyl ether 12b. Compound 12a was only
poorly reactive but we could observe the formation (in low
yield) of the ring-rearranged product 13a. In contrast, the
allyl ether 12b reacted smoothly to afford bicyclic ether
13b13 (again as a 6:1 mixture of anomers) in excellent yield,
indicating that initiation took place mainly at olefin 2.
We also prepared the ethylene ketal 12c (Ref. 14b and
references cited therein) which, surprisingly, proved to be
non-reactive in the metathesis reaction. Inspection of the
literature indicates that allylic O,O-acetals do participate
in RCM14 but the results may be explained by these species
being involved in the propagation steps and we are not
aware of examples in which involvement of allylic O,O-ace-
tals at the initiation step has been shown. In our case, ini-
tiation must occur at the acrolein ketal moiety and our
results suggest that allylic O,O-acetals do not readily par-
ticipate in the initiation step of metathetic processes.15
The 4-O-allyl group was next replaced by a longer
homoallyl moiety. The resulting triene 14 readily under-
1. For a recent review on RRM, see: Holub, N.; Blechert, S. Chem.
Asian J. 2007, 2, 1064–1082.
2. (a) Zuercher, W. J.; Hashimoto, M.; Grubbs, R. H. J. Am. Chem. Soc.
1996, 118, 6634–6640; (b) Nicolaou, K. C.; Vega, J. A.; Vassilikog-
iannakis, G. Angew. Chem., Int. Ed. 2001, 40, 4441–4445.
3. Ru¨ckert, A.; Deshmukh, P. H.; Blechert, S. Tetrahedron Lett. 2006,
47, 7977–7981; and references cited therein.
4. A few examples of RCM–ROM–RCM of strained 7-oxa-bicy-
clo[2.2.1]hept-2-ene derivatives (Y = O, X, Z = C) are known. (a)
Sello, J. K.; Andreana, P. R.; Lee, D.; Schreiber, S. L. Org. Lett. 2003,
5, 4125–4127; (b) Winkler, J. D.; Asselin, S. M.; Shepard, S.; Yuan, Y.
Org. Lett. 2004, 6, 3821–3824.
5. Deslongchamps, P. Stereoelectronic Effects in Organic Chemistry;
Pergamon Press: Oxford, 1983.
6. Alternative approaches to classical saccharide synthesis may have
advantages for accessing rare disaccharides/oligosaccharides. For
examples, of recent non-classical disaccharide/oligosaccharide syn-
theses see: (a) Guo, H.; O’Doherty, G. A. Angew. Chem., Int. Ed.
2007, 46, 5206–5208; (b) O’Doherty, G. A.; Guo, H. J. Am. Chem.
Soc. 2004, 126, 3428–3429; Trost, B. M.; Rhee, Y. H. J. Am. Chem.
Soc. 2002, 124, 2528–2533.
7. For the sake of simplicity, rhamnal was chosen (instead of e.g., glucal)
as it contains only the hydroxyl groups necessary for the model
studies. Preparation of 3,4-di-(O-acetyl)-L-rhamnal and Ferrier rear-
rangement: Zhang, G.; Shi, L.; Liu, Q.; Wang, J.; Li, L.; Liu, X.
Tetrahedron 2007, 63, 9705–9711; and references cited therein.

M. Donnard et al. / Tetrahedron Letters 49 (2008) 1192–1195
1195
8. Established by hydrogenation to the corresponding 1-butoxy-tetra-
hydropyrane derivative and inspection of the 1H NMR spectra: the
major anomer shows two small coupling constants for the anomeric
proton.
5H), 4.12 (m, 1H), 3.67 (m, 3H), 2.52 (m, 2H), 2.36 (m, 2H), 2.09 (m,
3H), 1.27 (m, 3H).
13C NMR (CDCl3, 75 MHz) major isomer: d 170.5, 134.9, 131.5,
129.1, 127.4, 118.6, 116.2, 98.4, 94.0, 71.6, 67.3, 65.5, 39.2, 34.0, 21.2,
16.1.
9. Structure of the Grubbs catalysts used in this work:
HRMS: calcd for C16H24NaO5 319.1521; found, 319.1525. Analytical
1
data for ring-rearranged compounds 13b, 15, 18: Compound 13b: H
MesN
Cl
NMes
PCy3
NMR (CDCl3, 300 MHz) major isomer: d 6.02 (m, 2H), 5.86 (dq,
J = 2.3, 8.6 Hz, 1H), 5.72 (dtd, J = 1.3, 2.8, 10.1 Hz, 1H), 5.03 (t,
J = 1 Hz, 1H), 4.96 (m, 1H), 4.67 (m, 2H), 3.98 (m, 2H), 3.71 (ddt,
J = 1, 6.2, 11.1 Hz, 1H), 2.31 (m, 1H), 1.90 (dddt, J = 1, 4.1, 5.1,
17.8 Hz, 1H), 1.11 (d, J = 6.4 Hz,3H).
13C NMR (CDCl3, 75 MHz) major isomer: d 129.1, 128.1, 126.7,
126.1, 92.0, 88.5, 75.6, 74.1, 57.2, 24.7, 14.7. HRMS: calcd for
Cl
Cl
Ru CHPh
Ru CHPh
Cl
PCy3
PCy3
1
2
10. Furstner, A.; Langemann, K. Synthesis 1997, 792–803.
¨
11. Chauvin, Y.; Herrison, J.-L. Makromol. Chem. 1971, 41, 161–176.
12. Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1 1998, 371–388.
13. All new compounds have satisfactory analytical data (1H and
13NMR, MS and HRMS for key compounds). Experimental details
and analytical data for compound 17. Under argon, at À78 °C, to a
solution of ester 16 (228 mg, 0.87 mmol, 1 equiv) in dichloromethane
(7 mL), DIBAH (1.5 M in toluene, 1.16 mL, 1.74 mmol, 2 equiv) was
added slowly over a period of 15 min (caution! the internal temper-
ature must be kept below À72 °C). The solution was stirred for an
additional 45 min at À78 °C and pyridine (211lL, 2.61 mmol,
3 equiv) was added dropwise, while maintaining the temperature
below À76 °C. Then a solution of DMAP (214 mg, 1.74 mmol,
2 equiv) in dichloromethane (1.5 mL) was immediately added at a rate
such as to maintain the temperature below À72 °C. Finally, acetic
anhydride (492 lL, 5.22 mmol, 6 equiv) was added (again, the internal
temperature must be kept below À72 °C). The resulting light yellow
solution was stirred at À78 °C for 12 h, the mixture was warmed to
0 °C and stirred for an additional 30 min. The reaction was quenched
by the sequential addition of NH4Cl(aq) (5 mL) and saturated aqueous
sodium potassium tartrate (5 mL). The resulting emulsion was stirred
vigorously at 20 °C for one night. The resulting biphasic mixture was
extracted with dichloromethane (3 Â 10 mL). The organic layers were
combined, washed with brine, dried over anhydrous MgSO4 and
concentrated in vacuo. Purification by flash column chromatography
(triethylamine-deactivated silica gel, 10% EtOAc in cyclohexane with
3% Et3N) provided 220 mg (0.52 mmol, 86%) of the title compound as
a clear, colorless oil.
C
11H16NaO3 219.0992; found, 219.0976.
Compound 15: 1H NMR (CDCl3, 300 MHz) d 6.02 (dd, J = 6.0,
9.6 Hz, 1H), 5.94 (m, 1H), 5.73 (m, 2H), 5.01 (br s, 1H), 4.24 (m, 1H),
3.97 (m, 3H), 3.68 (m, 2H), 2.29 (m, 2H), 1.90 (m, 2H), 1.21 b, 1.14 a
(d, J = 6.4, 3H).
13C NMR (CDCl3, 75 MHz) major isomer: d 129.0, 127.1, 126.1 (2C),
92.23, 76.3, 73.9, 63.6, 57.2, 25.3, 24.7, 15.0. HRMS: calcd for
C
12H18NaO3 233.1154; found, 233.1149.
Compound 18: 1H NMR (CDCl3, 300 MHz) major isomer: d 6.31 (d,
J = 4.4 Hz, 1H), 6.03 (m, 1H), 5.84 (m, 2H), 5.70 (m, 1H), 5.01 (s,
1H), 4.46 (m, 1H), 3.95 (m, 2H), 3.70 (dd, J = 6.1, 11.1 Hz, 1H), 2.50
(m, 1H), 2.30 (m, 2H), 2.08 (s, 3H), 1.91 (m, 1H), 1.14 (d, J = 6.4 Hz,
3H).
13C NMR (CDCl3, 75 MHz) major isomer: d 169.1, 128.1, 125.0,
124.6, 120.7, 91.6, 89.6, 72.9, 70.2, 56.4, 28.7, 27.7, 23.7, 13.7. HRMS:
calcd for C14H20NaO5 291.1208; found, 291.1207.
14. See, for example, (a) Figueroa, R.; Hsung, R. P.; Guevarra, C. C.
Org. Lett. 2007, 9, 4857–4859; (b) Kinderman, S. S.; Doodeman, R.;
van Beijma, J. W.; Russcher, J. C.; Tjen, K. C. M. F.; Kooistra, T.
M.; Mohaselzadeh, H.; van Maarseveen, J. H.; Hiemstra, H.;
Schoemaker, H. E.; Rutjes, F. P. J. T. Adv. Synth. Catal. 2002, 344,
736–748; (c) Leeuwenburgh, M. A.; Appeldoorn, C. C. M.; van
Hooft, A. V.; Overkleeft, H. S.; van der Marel, G. A.; van Boom, J.
H. Eur. J. Org. Chem. 2000, 873–877.
15. This may be supported by earlier observations by van Boom et al. (see
Ref. 14c).
16. Kopecky, D. J.; Rychnovsky, S. D. J. Org. Chem. 2000, 65, 191–
198.
1H NMR (CDCl3, 300 MHz) major isomer: d 5.99 (m, 5H), 5.05 (m,