Atom-efficient assembly of 1,5-oxygen-bridged medium-sized carbocycles by sequential combination of a ru-catalyzed alkyne-alkene coupling and a Prins-type cyclization

Article abstract of DOI:10.1021/ja017804e

Ruthenium-catalyzed coupling of readily accessible 1-trimethylsilyl-1-alkyn-3-ols to allyl ethyl ether followed by in situ ketalization and Lewis-acid induced cyclization affords 1,5-oxygen-bridged eight- and nine-membered carbocycles, products which are

Full text of DOI:10.1021/ja017804e

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Atom-Efficient Assembly of 1,5-Oxygen-Bridged Medium-Sized Carbocycles
by Sequential Combination of a Ru-Catalyzed Alkyne-Alkene Coupling and a
Prins-Type Cyclization
Fernando Lo´pez, Luis Castedo, and Jose´ L. Mascaren˜as*
Departamento de Qu´ımica Orga´nica y Unidad Asociada al CSIC, UniVersidad de Santiago de Compostela,
15782, Santiago de Compostela, Spain
Received December 18, 2001
Table 1. Ruthenium-Catalyzed Coupling of 3 with Allyl Ethyl
Medium-sized carbocycles, particularly eight- and nine-mem-
bered ones, form the structural cores of numerous biologically
relevant natural products and are therefore important synthetic
targets.1 The well-known difficulty of their assembly by conven-
tional cyclization routes, which is due to unfavorable entropic and
enthalpic factors,2 makes the development of new, practical
approaches to these sized rings a major synthetic challenge.
We envisaged that the energy cost of the cyclization step might
be considerably decreased if it is templated by the introduction of
a temporary internal tether in the acyclic precursor. Thereby, a
Prins-type cyclization of a mixed acetal such as 2 could lead to
these sized carbocycles (1) because in effect the cyclization proceeds
to form a six- or seven-membered oxacycle (eq 1). The oxygen
Ethera
c
concn of allyl ether
4
(%)
ratio
5:3b
yield
(%)
entry
solvent
acetone
THF/acetone (10:1)
DMF
DMF
DMF
DMF
DMF/H2O (10:1)
DMF
3 (M)
(equiv)
1
2
3
4
5
6
7
8
9
0.1
0.1
0.2
1
1
1
1
1
10
10 1:4
10 1.6:1 48
10 2.3:1 66 (91)
15 (50)d
1
1
1
1
1
5
8
1.5:1 48 (72)
1
1
1
1
1.5
3
10 2.3:1 60 (85)
10 2.7:1 73 (98)
DMF
10 1:1
49 (97)
a All reactions were carried out by adding catalyst 4 to a solution of 3
and allyl ethyl ether, and were stopped after 2 h at room temperature.
b Calculated by 1H NMR after workup. c Isolated yield. d Yield based on
chromatographically recovered alkynol.
bridge of 1 was thought particularly interesting because it imposes
a high degree of conformational rigidity that might facilitate
stereoselective manipulations at the carbocycle prior to untethering.3
Herein we demonstrate that a ruthenium-catalyzed coupling of
1-trimethylsilyl-1-alkyn-3-ols to commercially available allyl ethyl
ether provides a rapid, atom-economical4 and versatile method for
preparing the required cyclization precursors. Lewis acid-induced
closure of the resulting products leads to the expected oxabicycles,
compounds that can be easily manipulated to unmask the underlying
eight- and nine-membered carbocycles.
Scheme 1. Synthesis of 10-Oxabicyclo[4.3.1]decanes
A key step in the genesis of the new procedure was the realization
that 5-hydroxy-1-enol ethers susceptible to straightforward conver-
sion to mixed acetals of type 2 might be obtained by using
1-trimethylsilyl-1-alkyn-3-ols and allyl ethers as reacting partners
in the recently developed ruthenium-catalyzed alkyne-alkene
coupling method.5 However, reaction of alkyne 3 and allyl ethyl
ether (1:1) with 10 mol % of catalyst 4, in acetone (0.1 M) at room
temperature,5a gave a quite complex mixture of products that
included no more than traces of the desired alcohol 5. In 5:1 THF/
acetone the reaction proceeded with low conversion to give a 15%
yield of 5, with mostly unreacted starting material (Table 1, entry
2). Other alkenes such as allyl acetate or allyl alcohol gave mixtures
of unwanted products in addition to unreacted starting material.
We later found that using DMF as solvent the reaction is much
more efficient,6 and even more so when higher concentrations of
the reactants were used (entry 4). Best results were obtained with
1.5 equiv of the allyl ether partner (entry 8). We have also observed
that the order of addition is important (Table 1, footnote a): adding
the allyl ether to a mixture of the catalyst and the alkynol in DMF
gave a significantly lower yield (about 30%).7
Once the alkynol-alkene coupling had been optimized, its
application to alkynols equipped with a nucleophilic alkene suitable
for carrying out the planned Prins cyclization8 was investigated.
Gratifyingly, the enynol resulting from the addition of trimethyl-
silyllithium acetylide to aldehyde 6a coupled efficiently with allyl
ethyl ether, giving the expected enol ether 7a. This product was
* Corresponding author. E-mail: qojoselm@usc.es.
9
4218
J. AM. CHEM. SOC. 2002, 124, 4218-4219
10.1021/ja017804e CCC: $22.00 © 2002 American Chemical Society

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C O M M U N I C A T I O N S
Scheme 2. Synthesis of 8-6 and 9-6 Fused Carbocyclic
Systems
bond-forming reaction and a Lewis acid-promoted Prins-like
cyclization. Since the oxygen bridge can be readily cleaved, and it
is presumably easy to prepare the starting 1-alkyn-3-ols in enan-
tiopure form, the new approach should provide for the straightfor-
ward synthesis of optically active medium-sized carbocycles. Work
in this direction is currently underway.
Acknowledgment. We thank the Spanish M.E.C. (project PB97-
0524) and the FEDER and MCyT (SAF2001-3120) for financial
support. F.L. thanks the MEC for a predoctoral fellowship.
Supporting Information Available: Experimental procedures,
including the preparation of the starting aldehydes when required, and
spectroscopic data for selected compounds (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
References
difficult to separate chromatographically from the starting alkynol,
but addition of a 100:1 mixture of MeOH and 10% aqueous HCl
to the reaction mixture smoothly converted it to acetal 8a that can
now be easily purified (58% yield from the alkynol, 77% based on
recovered starting material). As far as we knew, there were no
precedents for the assembly of 10-oxabicyclo[4.3.1]decane systems
via Prins-like cyclizations;9 however, we found that treatment of
8a with 1.5 equiv of SnCl4 at -78 °C gave a good yield (82%) of
the desired bicycle 9a as a 8:2 mixture of isomers at the tertiary
center. Remarkably, the same reaction with the trimethylsilylalkene
8b10 produced only one stereoisomer in 86% yield.11 This stereo-
selectivity confirms the potential of the bicyclic system for
stereocontrol of substitution on the underlying carbocycle.
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construction of oxygen-bridged eight-membered carbocycles we
preferred to use an aromatic system as the nucleophilic partner for
the final cyclization, not only for practical reasons related to the
handling of the starting alkenals, but also to find out whether the
route allows the assembly of fused bicarbocyclic systems. The
ruthenium-catalyzed coupling of alkynol 10a with allyl ethyl ether,
followed by in situ ketalization, gave the expected mixed acetal
11a in 67% yield (86% based on recovered alkynol). Reaction of
this compound with 1 equiv of SnCl4 promoted the desired Friedel-
Crafts reaction, affording tricycle 12a in excellent yield.12 When
the same protocol was used to assemble the homologous oxygen-
bridged 9-6 bicarbocyclic system, we found that compound 11b
failed to cyclize upon treatment with SnCl4; however, the Friedel-
Crafts reaction took place efficiently using the more electron-rich
aromatic system 11c10 (Scheme 2). Importantly, the exocyclic
double bond present in the tricyclic adducts 12, functionality created
in the Ru-catalyzed reaction, allows for facile reductive opening
of the oxygen bridge under electron-transfer conditions to give the
expected medium-sized carbocycles 13. In the case of the eight-
membered derivative, in addition to 13a we obtained a 43% yield
of a 1:1 isomeric mixture of vinylsilanes 14.
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(10) The synthesis of this compound is described in the Supporting Information.
(11) We have not detected NOE between the methyl groups of the TMS at
C-3 and H-1, suggesting that this TMS is anti to the epoxy bridge, though
a definitive stereochemical assignation requires further analysis.
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In summary, we have developed a simple, versatile, and atom-
economical protocol for rapidly assembling oxygen-bridged medium-
sized carbocycles from inexpensive, readily available materials (eq
2).13 The route involves a ruthenium-catalyzed alkyne-alkene C-C
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