From galactose to highly functionalized seven- and eight-membered carbocyclic rings by ring-closing metathesis

Article abstract of DOI:10.1021/ol006182j

(equation presented) A short synthesis of highly functionalized seven- and eight-membered carbocyclic rings from galactose derivatives has been achieved. The key steps are a zinc-mediated reductive ring opening of 6-iodogalactopyranoses and a subsequent r

Full text of DOI:10.1021/ol006182j

ORGANIC
LETTERS
2000
Vol. 2, No. 17
2651-2654
From Galactose to Highly Functionalized
Seven- and Eight-Membered Carbocyclic
Rings by Ring-Closing Metathesis
,†
Issam Hanna* and Louis Ricard‡
Laboratoire de Synthe`se Organique associe´ au CNRS 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 9, 2000
ABSTRACT
A short synthesis of highly functionalized seven- and eight-membered carbocyclic rings from galactose derivatives has been achieved. The
key steps are a zinc-mediated reductive ring opening of 6-iodogalactopyranoses and a subsequent ring-closing olefin metathesis using Grubbs’
ruthenium catalyst.
Carbohydrate to carbocycle transformations offer an attrac-
tive route for the synthesis of optically active natural
products. Although a wide range of methods for producing
functionalized cyclohexane and cyclopentane derivatives
from sugars are available,1,2 few reports have been published
on the preparation of medium sized (seven- and eight-
membered) carbocyclic rings.3,4 The interest in the construc-
tion of such rings is largely due to their presence in an
increasing number of biologically active compounds.
In particular, cyclooctanoid natural products remain promi-
nent synthetic challenges owing to the difficulties associated
with cyclooctane chemistry.5
Ring-closing metathesis (RCM) has emerged as one of
the most popular methods for the construction of unsaturated
cyclic systems from acyclic dienes.6
Despite the unfavorable thermodynamic factors that im-
pede the preparation of eight-membered rings, this method
has been successfully applied to the synthesis of carbocyclic
rings of this size.7 Herein we describe the use of this reaction
in a flexible approach to unsaturated medium-carbocyclic
rings from readily available galactose derivatives, using
† Laboratoire de Synthe`se Organique associe´ au CNRS.
‡ Laboratoire “He´te´roe´le´ments et Coordination” associe´ au CNRS.
(1) For reviews see: (a) Dalko, D. I.; Sinay¨, P. Angew. Chem., Int. Ed.
1999, 38, 773. (b) Ferrier, R. J.; Middleton, S. Chem. ReV. 1993, 93, 2779.
(2) For recent examples, see: (a) Ackermann, L.; El Tom, D.; Fu¨rstner,
A. Tetrahedron 2000, 56, 2195. (b) Sollogoub, M.; Mallet, J.-M.; Sinay¨, P.
Angew. Chem., Int. Ed. 2000, 39, 362. (c) Kan, T.; Nara, S.; Ozawa, T.;
Shirahama, H.; Matsuda, F. Angew. Chem., Int. Ed. 2000, 39, 355. (d)
Collam, C. S.; Lowry, T. L. Org. Lett. 2000, 2, 167. (e) Hyldtof, L.; Poulsen,
C. S.; Madsen, R. Chem. Commun. 1999, 2101. (f) Kornienko, A.;
d’Alarcao, M. Tetrahedron: Asymmetry 1999, 10, 827. (g) Ovaa, H.; Code´e,
J. D. C.; Lastrager, B.; Overkleeft, H. S.; van der Marel, G.; van Boom, J.
Tetrahedron Lett. 1999, 40, 5063.
(5) For reviews, see: (a) Petasis, N. A.; Patane, M. A. Tetrahedron 1992,
48, 5757. (b) Mehta, G.; Singh, V. Chem. ReV. 1999, 99, 81.
(6) For recent reviews concernig ring-closure metathesis reactions, see
(a) Philips, A. J.; Abell, A. D. Aldrichimica Acta 1999, 32, 75. (b)
Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1 1998, 371. (c) Grubbs, R.
H.; Chang, S. Tetrahedron 1998, 54, 4413.
(7) For earlier examples of cyclooctene syntheses by RCM, see: ref 6.
For more recent applications, see: (a) Paquette, L. A.; Schloss, J. D.;
Efremov, I.; Fabris, F.; Gallou, F.; Me´ndez-Andino, J.; Yang, J. Org. Lett.
2000, 2, 1259. (b) Paquette, L. A.; Tae, J.; Arrington, M. P.; Sadoun, A. H.
J. Am. Chem. Soc. 2000, 122, 2742 and references therein. (c) Bourgeois,
D.; Pancrazi, A.; Ricard, L. P.; Prunet, J. Angew. Chem., Int. Ed. 2000, 39,
726. For recent reports on the syntesis of cyclic ethers of eight-membered
ring, see: Clark, J. S.; Mamelin, O. Angew. Chem., Int. Ed. 2000, 39, 372.
Crimmins, M. T.; Choy, A. L. J. Am. Chem. Soc. 1999, 121, 5653.
(3) For the synthesis of cycloheptane derivatives from carbohydrates,
see: (a) Marco-contelles, J.; de Opazo, E. Tetrahedron Lett. 1999, 40, 4445;
Tetrahedron Lett. 2000, 41, 2439. (b) Boyer, F.-D.; Lallemand, J.-Y.
Tetrahedron 1994, 50, 10443. (c) Duclos, O.; Dure´ault, A.; Depezay, J. C.
Tetrahedron Lett. 1992, 33, 1059 and 8061.
(4) For the synthesis of cyclooctane derivatives from sugars, see ref 2b
and Werschkum, B.; Thiem, J. Angew. Chem., Int. Ed. Engl. 1997, 36, 2793.
10.1021/ol006182j CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/27/2000

Grubbs’ commercially available ruthenium catalyst [(PCy3)2-
Cl2RudCHPh].
Scheme 2
The RCM precursors were prepared from either methyl
6-deoxy-6-iodo-3,4-isopropylidene-2-O-(tert-butyldimethyl-
silyl)-D-galactopyranoside 18 or from 6-deoxy-6-iodo-1,2:
3,4-di-O-isopropylidene-D-galactopyranoside 10.9
Zinc-mediated reductive ring opening of 1 under sonication
in aqueous THF in the presence of allyl bromide cleanly
afforded diene 2 in 93% yield as a mixture of syn and anti
(1.2:1) isomers separable by flash chromatography.10 On the
other hand, a one-pot reductive ring opening, amination, and
allylation of 1 was achieved with zinc dust in the presence
of benzylamine followed by the addition of allyl bromide in
anhydrous THF under sonication11 and led to amino diene 4
as a 6:1 mixture of diatereomers in 65% yield. In this
transformation, the intermediate aldehyde 7 was intercepted
with the amine prior to the alkylation. In fact, in the absence
of amine or the alkylating agent, reductive ring opening of
1 gave 7 in nearly quantitative yield. Treatment of this
compound with butenylmagnesium bromide at 0 °C afforded
alcohol 8 as a mixture of diastereomers (2:1 ratio, 77%
overall yield). Alcohols 2 and 8 and amine 4 were acetylated
respectively to 3, 5, and 9 under standard conditions (Scheme
1).
2. Reductive ring opening with zinc dust under sonication
converted 10 to the hitherto unknown hemiketal 11 as a
mixture of diastereomers, which was treated with allylmag-
nesium bromide to afford 12 as a 3:2 separable mixture of
diatereomers in 70% overall yield. The syn configuration of
the minor isomer was assigned later on the basis of the X-ray
structure of the RCM reaction product 25a. It is worthy of
note that when this transformation was perfomed in a one-
pot procedure under the Barbier conditions as above, a
mixture of products was obtained from which the desired
product 12 was isolated in low yield. This diol was converted
into diacetate 13 (Ac2O, Py, rt) or cyclic carbonate 14 (1,1′-
carbonyldiimidazole, THF, rt) in high yields.
Scheme 1
Similary, reaction of 11 with butenylmagnesium bromide
at 0 °C in ether gave diene 15 as a 3:1 mixture of
diastereomers in 71% yield from 10. In this case, the
stereochemistry of the vicinal diol in the major isomer has
been found to be anti on the basis of the X-ray structure of
cyclized products 28b and 29b.The diol moiety was then
protected either as diacetate 15 or the cyclic carbonate 16
as shown in Scheme 2.
The dienes prepared above were submitted to RCM using
5-7% Grubbs’ catalyst in CH2Cl2, and the results are
summarized in Table 1. In this study, the metathesis reaction
was carried out either separately on each diastereomer of
dienes or on the mixture. In the latter case, the sepration
was undertaken at this stage. Except for carbonates 14, both
diastereomers led to the cyclized products roughly in the
same yield. As expected,12 carbocyclization of dienes 2, 3,
5, 6, and 13 was readily achieved at room temperature with
5% catalyst to furnish substituted cycloheptenes in excellent
yield. Under these conditions, diol 12 and amino diene 4
failed to give any cyclization product (Table 1). Amino-
The seven- and eight-membered ring precursors 12-17
were constructed starting from 10 as illustrated in Scheme
(8) Compound 1 was prepared from methyl 3,4-O-isopropylidene-D-
galactopyranoside in two steps by iodation with PPh3-I2 reagent followed
by silylation with TBSOTf in 2,6-lutidine/CH2Cl2. Chiara, J. L.; Martinez,
S.; Bernabe´, M. J. Org. Chem. 1996, 61, 6488.
(9) Compound 10 is readily prepared by iodation of the commercially
available 1,2:3,4-di-O-isopropylidene-D-galactopyranose: Garegg, P. J.;
Johansson, R.; Ortega, C.; Samuelsson, B. J. Chem. Soc., Perkin Trans. 1
1982, 681.
(10) All new compounds were characterized by analytical and spectro-
scopic data. Yields are for isolated, chromatographically purified products.
(11) See ref 2e. We thank professor Robert Madsen for experimental
details for the preparation of amino diene 4.
(12) Table 2 in ref 6b points to the ease of closing seven-membered
monocycles as compared with the formation of cyclooctenes.
(13) See ref 3 and Pearson, A. J.; Katiyar, S. Tetrahedron 2000, 56,
2297. Johnson, C. R.; Bis, S. J. J. Org. Chem. 1995, 60, 615.
2652
Org. Lett., Vol. 2, No. 17, 2000

Table 1. Substituted Cycloheptenes and Cyclooctenes by RCM with Grubbs’ Catalyst in CH2Cl2
polyhydroxylated cycloheptanes such as 21 and 22 may be
used as intemediates in the synthesis of calystegines and
related tropane alkaloids.13
RCM reaction of cis and trans cyclic carbonates 14a and
14b gave the corresponding cycloheptenes 25a and 25b,
respectively, in high yield. However, while the conversion
of the syn isomer 14a was achieved after 2 h in the presence
of 5% catalyst, cyclization of the trans isomer needed 10%
catalyst and more than 24 h to be complete. The cis
configuration of 25a was deduced from detailed NMR studies
and confirmed by X-ray crystallographic analysis (Figure 1).
We turned next to the more problematic formation of the
eight-membered ring. Exposure of diene 8 containing a free
hydroxyl group to RCM conditions gave a mixture with
predominant formation of a dimer. In contrast, the corre-
sponding acetate 9 was successfuly converted into cy-
clooctene 27 (5 mol % of catalyst, 0.006 M in CH2Cl2 at
reflux) in 94% yield. Under these conditions, protected diols
Figure 1. X-ray structures of 25a and 28b.
Org. Lett., Vol. 2, No. 17, 2000
2653

16 and 17 led to cyclooctenes 28 and 29, respectively, in
excellent yield (Table 1). The structures of these compounds
were assigned on the basis of spectroscopic data, and the
relative stereochemistry of each was determined by X-ray
crystallographic analysis of diacetate 28b and cyclic carbon-
ate 29b (Figure 1 and Supporting Information).
In conclusion, we have described a rapid route to highly
functionalized cycloheptenes and cyclooctenes involving
zinc-mediated reductive ring opening of readily available
carbohyrate derivatives, followed by a ring-closing metathesis
reaction using the commercially available Grubbs’ catalyst.
Supporting Information Available: Spectroscopic data
for compounds and 19, 21, 22, 24a, 24b, 25a, 25b, 28b,
and 29b. X-ray crystal data for compounds 25a, 28b, and
29b. This material is free of charge via the Internet at
http://pubs.acs.org.
OL006182J
2654
Org. Lett., Vol. 2, No. 17, 2000