Synthesis of polyoxygenated bicyclic systems containing medium-sized rings from carbohydrates via tandem metathesis of dienynes.

Article abstract of DOI:10.1021/ol016329m

[reaction: see text] Highly functionalized (5-7), (5-8), and (6-8) ring systems have been prepared from carbohydrates via tandem ring-closing metathesis of dienynes.

Full text of DOI:10.1021/ol016329m

ORGANIC
LETTERS
2001
Vol. 3, No. 20
3095-3098
Synthesis of Polyoxygenated Bicyclic
Systems Containing Medium-Sized
Rings from Carbohydrates via Tandem
Metathesis of Dienynes
Franc¸ois-Didier Boyer,† Issam Hanna,* and Louis Ricard§
,‡
Unite´ de Phytopharmacie et Me´diateurs Chimiques, I.N.R.A., Route de Saint-Cyr,
F-78026 Versailles, France, and Laboratoire de Synthe`se Organique and Laboratoire
“He´te´roe´le´ments et Coordination” associe´ au CNRS, Ecole Polytechnique,
F-91128 Palaiseau Cedex, France
hanna@poly.polytechnique.fr
Received June 22, 2001
ABSTRACT
Highly functionalized (5-7), (5-8), and (6-8) ring systems have been prepared from carbohydrates via tandem ring-closing metathesis of dienynes.
Bridged and fused bicyclic systems containing medium-sized
rings are widely found in biologically active natural products,
and development of new synthetic approaches to these
skeletons continues to be an important goal.1,2
Since the pioneering work by the groups of Grubbs and
Schrock, the ring-closing metathesis (RCM) reaction of
dienes3 and to a lesser extent of enynes4 has become a
powerful tool for the synthesis of a variety of cyclic
structures, especially for medium-sized and macrocyclic ring
systems, which would be difficult to achieve, if at all, using
traditional methods.5 In comparison, the tandem dienyne
metathesis reaction leading to bicyclic compounds is less
well documented. The few examples reported are confined
to the assembly of compounds containing unsubstituted or
alkyl-substituted dienynes.6 An account describing the for-
mation of a bicyclic system incorporating an eight-membered
ring by RCM of dienynes has only recently been reported.7
Our previous work on the preparation of polyoxygenated
medium-sized carbocycles from carbohydrates8 led us to
focus on the construction of polyfunctionalized carbobicyclic
products that contain seven- and eight-membered rings by
tandem RCM of dienynes using Grubbs’ ruthenium catalysts
19 and 210 as indicated in Figure 1.
† Unite´ de Phytopharmacie et Me´diateurs Chimiques, I.N.R.A.
‡ Laboratoire de Synthe`se Organique associe´ au CNRS, Ecole Polytech-
nique.
§ Laboratoire “He´te´roe´le´ments et Coordination” associe´ au CNRS, Ecole
Polytechnique.
(1) For reviews on eight-membered ring carbocycle construction see:
(a) Petasis, N. A.; Patane, M. A. Tetrahedron 1992, 48, 5757-5821. (b)
Mehta, G.; Singh, V. Chem. ReV. 1999, 99, 881-930.
(2) For recent approaches to the (5-7) ring system see: Deak, H. L.;
Stokes, S. S.; Snapper, M. L. J. Am. Chem. Soc. 2001, 123, 5152-5153.
Trost, B. M.; Shen, H. C. Angew. Chem., Int. Ed. 2001, 40, 2313-2316.
Wender, P. A.; Fuji, M.; Husfeld, C. O.; Love, J. A. Org. Lett. 1999, 1,
137-139 and references therein.
(3) For recent reviews concernig ring-closure metathesis reactions see
(a) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18-29. (b)
Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012-3043. (c) Armstrong,
S. K. J. Chem. Soc., Perkin Trans. 1 1998, 371-388. (d) Grubbs, R. H.;
Chang, S. Tetrahedron 1998, 54, 4413-4450
(4) For recent examples on the enynes RCM see: Renaud, J.; Graf, C.-
D.; Oberer, L. Angew. Chem., Int. Ed. 2000, 39, 3101-3104. Ackermann,
L.; Bruneau, C.; Dixneuf, P. H. Synlett 2001, 397-399. Mori, M.; Kitamura,
T.; Sato, Y. Synthesis 2001, 654-664.
(5) For recent reviews see: Maeir, M. E. Angew. Chem., Int. Ed. 2000,
39, 2073-3077. Yet, L. Chem. ReV. 2000, 100, 2963-3007.
(6) Kim, S.-H.; Zuercher, W. J.; Bowden, N. B.; Grubbs, R. H. J. Org.
Chem. 1996, 61, 1073-1081. Zuercher, W. J.; Scholl, M.; Grubbs, R. H.
J. Org. Chem. 1998, 63, 4291-4298.
(7) Codesido, E. M.; Castedo, L.; Granja, J. R. Org. Lett. 2001, 3, 1483-
1486.
(8) (a) Hanna, I.; Ricard, L. Org. Lett. 2000, 2, 2651-2654. (b) Boyer,
F.-D.; Hanna, I. Tetrahedron Lett. 2001, 42, 1275-1277. (c) Boyer, F.-D.;
Hanna, I.; Nolan, S. L. J. Org. Chem. 2001, 66, 4094-4096.
10.1021/ol016329m CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/07/2001

Scheme 2
Figure 1.
The polyoxygenated dienynes used in this study were
readily prepared from (+)-glucose and (+)-ribose as il-
lustrated in Schemes 1 and 2. Reductive ring-opening with
zinc dust under sonication converted 3 to aldehyde 4 in nearly
quantitative yield. Treatment of 4 with butenylmagnesium
bromide at -60 °C followed by Dess-Martin oxidation of
the resulting crude alcohols furnished 5 in 65-75% overall
yield from 48c (Scheme 1). Ketone 5 reacted with excess
ethynylmagnesium bromide in THF at room temperature,
presumably via a chelation-controlled transition model, to
give 6 as the only isolated diastereomer. The configuration
of the hydroxyl group at the newly created chiral center in
6 was tentatively assigned to be syn in agreement with the
stereochemical outcome of the addition of Grignard reagents
to R-alkoxy carbonyl compounds.11 Addition of propargyl-
magnesium bromide to 5 was less stereoselective, affording
8 as a mixture of diastereomers in a 80:20 ratio. Hydroxyl
groups of 6 and 8 were then protected as the triethylsilyl
ethers 7 and 9 in 87% and 90% overall yields, respectively.
Dienyne precursors to the (5-8) and (6-8) ring systems
were prepared as depicted in Scheme 2. Zinc-mediated
reductive ring opening of 1012 in aqueous THF followed by
treatment of the resulting aldehyde with methyl bromoacetate
under the Reformatsky reaction conditions led to 11 as a
diastereomeric mixture (7:1) in 64% yield. These isomers
could be separated by flash column chromatography, and
the syn configuration of the major isomer was assigned as
above and confirmed later on the basis of the RCM reaction
product (vide infra). The major diastereomer was used for
the rest of the synthetic sequence. This â-hydroxy ester was
uneventfully converted to the Weinreb amide13 12 in the
Scheme 1
(9) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc 1996,
118, 100-110.
(10) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953-956.
(11) For a review on chelation control in addition reactions see: Reetz,
M. T. Angew. Chem., Int. Ed. Engl. 1984, 23, 556-569.
(12) Garegg, P. J.; Samuelsson, B. J. Chem. Soc., Perkin Trans. 1 1980,
2866-2869.
(13) Levin, J. I.; Weinreb, S. M. Synth. Commun. 1982, 12, 989-993.
3096
Org. Lett., Vol. 3, No. 20, 2001

Table 1. Ring-Closing Metathesis of Dienynes
usual manner in 71% yield. Treatment of 12 with butenyl-
magnesium bromide or pentenylmagnesium bromide at 0 °C
in THF afforded ketones 13 and 14, respectively. Addition
of ethynylmagnesium bromide to these ketones gave alcohols
15 and 16 as easily separable mixtures of diastereomers in
1.6:1 and 1.2:1 ratios, respectively, in good overall yields.
These alcohols were then protected as their triethylsilyl ethers
17 and 18.
The dienynes prepared above were subjected to RCM
reactions using commercially available catalysts 1 or 214 as
3.5 × 10-3 M solutions in refluxing dichloromethane or
benzene; the results are summarized in Table 1.
ether 7 using catalysts 1 or 2 (entries 1-4). As expected,
the tandem RCM reaction using catalyst 2 proceeded much
faster than with its parent complex 1 and converted 6 and 7
to the corresponding bicyclic[5.3.0] compounds 19 and 20
in significantly improved yields.15
A more dramatic illustration of the difference in RCM
activity of complexes 1 and 2 was observed during the
construction of fused (5-8) and (6-8) bicyclic cores. Initial
attempts on dienyne 17a (the major isomer) using catalyst 1
(20%) in either refluxing CH2Cl2 or benzene for 17 h failed
to give the corresponding polyoxygenated fused bicyclic
compound. Instead the monocyclic compound 23 was
obtained as the only isolated product in 85% yield (entry
As shown in the Table, the fused (5-7) ring system could
be obtained either from alcohol 6 or from its triethylsilyl
(15) Whereas triethylsiyl ether 20 is stable enough to be stored in the
refrigerator for weeks, the free alcohol 19 was found to be rather labile
and easily decomposed.
(14) Catalysts 1 and 2 were purchased from Strem Chemicals, Inc.
Org. Lett., Vol. 3, No. 20, 2001
3097

Figure 2. X-ray structures of 22 and 33.
5). In contrast, the use of catalyst 2 (10% in refluxing CH2Cl2
for 24 h) converted 17a into the desired bicyclic[6.3.0]
derivative 22 in 94% yield. This bicyclic structure was
assigned on the basis of spectroscopic data, and the con-
figurations of OTBS (R) and OTES (â) groups were obtained
by X-ray crystallographic analysis (Figure 2). Under the same
conditions the minor isomer 17b underwent the tandem
cyclization affording 25 (R-OTES) in 96% yield. Interest-
ingly, the corresponding free alcohol 15b was also success-
fully converted to the bicyclic compound 24, albeit in lower
yield (entry 7).
Construction of the fused (6-8) ring systems was next
investigated. Treatment of dienyne 18a (the major isomer)
with catalyst 2 (10 mol %) in refluxing dichloromethane or
benzene for 3 days gave an inseparable mixture of 26 and
28. For separation purpose the TES ether was selectively
cleaved (TBAF, THF, rt) leading to the easily separated
bicyclic alcohol 29 and the cyclohexene derivative 27 (1:1
ratio) in 87% overall combined yield (entry 10). Under the
same conditions, the corresponding free alcohol 16a gave
27 (66%) together with the starting material (21%). In sharp
contrast, the minor isomer 18b, on treatment with catalyst 2
(10%) in refluxing CH2Cl2 for only 5 h smoothly underwent
the tandem RCM reaction leading to the fused (6-8) bicyclic
product 32 in an almost quantitative yield. This substrate
was readily desilylated (TBAF, THF, rt) to furnish diol 33
as a crystalline compound that was confirmed by X-ray
analysis (Figure 2).
Attempts at tandem RCM reaction on the free alcohol 16b
with catalyst 2 in refluxing CH2Cl2 for a prolonged time led
to the bicyclic compound 30 together with the cyclohexene
derivative 31 in 53% and 36% yields, respectively (entry
11).
The notable difference in reactivity of dienyne 18a in
comparison to its epimer 18b toward the tandem RCM
reaction is unclear at present. However, it is likely that the
formation of the (6-8) bicyclic product 26 from 18a is
thermodynamically unfavorable. Molecular model of this
compound showed severe transannular interactions due to
the bulky OTES group in the â position. Such an effect does
not exist in the corresponding R-OTES compound 32 (Figure
2).
In summary, we have shown that highly functionalized
carbobicyclic systems containing seven- and eight-membered
rings can be prepared in very good yields from carbohyrates
via tandem ring-closing metathesis of dienynes. Further
studies on the application of these results to target orientated
synthesis are currently under investigation.
Supporting Information Available: Characterization
data for compounds 6, 7, 9, 15-25, 27, 29, 31-33 and X-ray
crystal data for compounds 22 and 33. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL016329M
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Org. Lett., Vol. 3, No. 20, 2001