A sequential Claisen/ring-closing metathesis approach to the synthesis of spirocyclic cyclopentanes and cyclohexanes

Article abstract of DOI:10.1016/j.tetlet.2003.09.190

A new method for the formation of spirocycles is described using a sequential Ireland-Claisen/Metathesis strategy to construct spirocyclic systems. Optimization of the Ireland-Claisen conditions provides the key metathesis substrates. The metathesis reactions were highly regioselective by virtue of steric hindrance in the substrate olefins.

Full text of DOI:10.1016/j.tetlet.2003.09.190

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8883–8885
A sequential Claisen/ring-closing metathesis approach to the
synthesis of spirocyclic cyclopentanes and cyclohexanesꢀ
Patrick Beaulieu and William W. Ogilvie*
Department of Chemistry, University of Ottawa, 10 Marie Curie, Ottawa, Ontario, Canada K1N 6N5
Received 20 August 2003; revised 18 September 2003; accepted 19 September 2003
Abstract—A new method for the formation of spirocycles is described using a sequential Ireland–Claisen/Metathesis strategy to
construct spirocyclic systems. Optimization of the Ireland–Claisen conditions provides the key metathesis substrates. The
metathesis reactions were highly regioselective by virtue of steric hindrance in the substrate olefins.
© 2003 Elsevier Ltd. All rights reserved.
gave allylic alcohols 7 that were acylated to afford
esters 8. These transformations proceeded extremely
well providing esters 8 in 61 to 86% overall yields.
The formation of carbonꢀcarbon bonds in an asymmet-
ric manner is a central goal of modern synthetic chem-
istry. Many methods have been developed, however the
asymmetric formation of quaternary carbons is still a
formidable challenge.1 Spirocycles, found in many nat-
ural products, represent a special case with added syn-
thetic difficulties2 because of the requirements for ring
formation and facial selectivity during the creation of a
quaternary carbon. In this paper we report a methodol-
ogy based on ring-closing metathesis that produces
spirocyclopentanes and -hexanes. The formation of the
quaternary center is set by an Ireland–Claisen rear-
rangement,3,4 thus controlling the configuration of the
quaternary center by virtue of suprafacial migration.
We then proceeded to optimize the rearrangement.8
The use of KHMDS9 was essential to realize syntheti-
cally useful yields (Table 1, entry 4). LDA, LiHMDS or
NaHMDS gave significantly decreased recoveries
(entries 1–3). Attempts to form the silyl ethers using
TIPS triflate and Hunig’s base resulted in decomposi-
tion (entry 5).
In our strategy, the configuration of the quaternary
carbon would be dictated by the configuration of the
starting alcohol 4 (Scheme 1). The enantioselective pro-
duction of products such as 4 is well precedented5 and
provides stereochemical information to set the absolute
configuration of the spiro center. Acylation of 4 would
give compounds such as 3. Ireland–Claisen
rearrangement6 of the derived silyl enol ethers would
produce products such as 2. These compounds could be
cyclized to spirocycles 1 using olefin metathesis.7
Scheme 1.
The allylic alcohols required for this work were pre-
pared as shown in Scheme 2. Addition of allylmagne-
sium chloride to enol ethers 5 gave the a,b-unsaturated
ketones 6. Selective reductions using NaBH4/CeCl3
ꢀ Supplementary data associated with this article can be found at
doi:10.1016/j.tetlet.2003.09.190
* Corresponding author. Tel.: +1-613-562-5800; fax: +1-613-562-5170;
e-mail: wogilvie@science.uottawa.ca
Scheme 2.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.190

8884
P. Beaulieu, W. W. Ogil6ie / Tetrahedron Letters 44 (2003) 8883–8885
Table 1. Effect of base on the Ireland–Claisen rearrange-
ment of 8a
recoveries. Among the silyl reagents used, the combina-
tion of TMS-Cl/TEA gave the best yields and
reproducibility.
Surprisingly, TBS-Cl gave no product at all and only
starting material was recovered (entry 5). Improve-
ments in reproducibility were achieved using a slight
excess of TIPSOTf as the silylating agent (entry 6). The
TIPS silyl ketene acetals proved to be stable toward
flash chromatography allowing us to purify the inter-
mediates (in quantitative yield) if warranted. Brief
exposure to HF in CH3CN was required in these cases
after the rearrangement in order to obtain the desired
carboxylic acids.
Entry
Base
Yield (%)
dr
1
2
3
4
5
LDA
0
12
44
76
0
LiHMDS
NaHMDS
KHMDS
2.1:1
1.4:1
3:2
Using KHMDS and TMS-Cl in toluene, we were able
to rearrange substrates 8 to obtain the acids 11 in good
yields and verify the effect of the R group on yield and
selectivity (Table 3). The rearrangement of substrates
incorporating no substituent proceeded in excellent
yield and modest diastereoselectivity. We investigated
the reactions of 8c and 8f incorporating bromo sub-
stituents as a possible means to increase diastereoselec-
tivity. Substrate 8f gave improved selectivity over 8d.
However only a small effect was observed for derivative
8c.
DIPEA/TIPSOTf
Table 2. Effect of solvent and silyl reagent on the Ireland–
Claisen rearrangement of 8a
Entry
Solvent
Silyl reagent
Yield (%)
dr
1
2
3
4
5
6
THFa
TMS-Cl/Et3N
TMS-Cl/Et3N
TMS-Cl/Et3N
TMS-Cl/Et3N
TBS-Cl
47
79
76
44
0
4.5:1
2:1
3:2
4:1
–
The rearrangements of 8d and 8e proved to be challeng-
ing. Both substrates were unstable and quickly decom-
posed under the mildly acidic conditions required for
isolation. The former substrate 8d could be converted
to 9d if the rearrangement was carried out immediately
after the isolation of 8d. Compound 8e proved to be
too unstable and could not be rearranged.
Ethera
Toluene
THF/HMPAb
Toluene
Toluene
TIPS-OTf
79c
2:1
a Solvent for silyl ether formation. Rearrangement performed in
toluene.
b LDA was used as base.
With substrates 11 in hand we then explored the ring-
closing metathesis to obtain the various spirocyclic
cores. After treating the substrates 11 with excess di-
azomethane, we subjected the methyl esters to metathe-
sis. The metathesis reactions proceeded extremely
rapidly and cleanly giving the desired products 10 in
82–97% yields (Table 4). In all cases except 9d the
endocyclic olefins of the starting materials were
untouched and we obtained the desired spirocycles
only. Compound 9d gave a mixture of products result-
ing from opening of the five-membered ring.10 This was
c Yield after deprotection of the TIPS ester with aqueous HF in
CH3CN.
Table 3. Results of the Ireland–Claisen rearrangement of
various substrates
Entry
Substrate
Yield (%)
dr
3:2
1.6:1
1.9:1
1.3:1
–
Table 4. Ring-closing metathesis of various substrates
1
2
3
4
5
6
8a
8b
8c
8d
8e
8f
76
51
47
74
0
41
4.6:1
Entry
Substrate
Catalyst loading (mol%)
Yield (%)
Toluene was superior as a rearrangement solvent (Table
2, entry 3). Selectivity was slightly higher when the silyl
ether was formed in THF or ether. In these cases, the
ethereal solvent was removed in vacuo and the rear-
rangement was completed in refluxing toluene (entries
1–3). The use of HMPA did not invert the ratio of
products obtained (entry 4, see below) and led to lower
1
2
3
4
5
9a
9b
9c
9d
9f
7
7
10
5
97
91
82
–
5
96

P. Beaulieu, W. W. Ogil6ie / Tetrahedron Letters 44 (2003) 8883–8885
8885
Acknowledgements
Financial support from the University of Ottawa,
NSERC, Canada Foundation for Innovation and the
Ontario Innovation Trust is gratefully acknowledged.
References
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Scheme 3.
unexpected given the proximity of the endocyclic olefin
to the quaternary center and the excellent regioselectiv-
ity observed for all the other substrates. Substrate 9f,
possessing a more sterically hindered endocyclic double
bond, did not suffer ring-opening under the conditions
employed (entry 5).
4. For other applications of Claisen rearrangements in the
formation of spiro systems, see: (a) Srikrishna, A.; Vijayku-
mar, D.; Jagadeeswar Reddy, T. Tetrahedron 1997, 53,
1439–1446; (b) Dickson, J. K.; Tsang, R., Jr.; Llera, J. M.;
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McIntosh, M. C. Tetrahedron 2002, 58, 2905–2928; (b)
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9. Fukuzaki, T.; Kobayashi, S.; Hibi, T.; Ikuma, Y.; Ishihara,
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10. Metathesis of 9d was complete in less than 2 min at 0°C.
Reaction at −78°C gave 64% conversion after 10 min with
the same distribution of ring-opened products.
11. This was consistent with NMR observations on the subse-
quent metathesis product 10a. The proton a to the ester
in the spectrum of the minor isomer shows couplings of 9.9
Hz and 5.4 Hz. The same hydrogen in the major product
gives 6.6 and 6.8 Hz couplings. NOE measurements are
consistent with this assignment.
We explored the possibility of cyclizing the TIPS ester
products as isolated directly after the rearrangement.
The reactions proceeded extremely rapidly, however
small amounts of side products, that were difficult to
remove, were formed. We therefore found it prudent to
hydrolyze the TIPS esters and convert the resulting
acids to the methyl esters for metathesis.
The rearrangement of pure enolates to give mixtures of
diastereomers is not unknown for other cyclic sub-
strates.3,6 Calculations performed by Houk6b indicate
that this is a consequence of the rearrangements occur-
ring through both chair and boat-like transition states.
We were able to confirm this by experiments performed
using substrate 8a. Treatment of 8a with KHMDS and
TIPSOTf resulted in exclusive formation of the E eno-
late 12 as evidenced by the characteristic chemical shift
of the enolate carbon (85 ppm as opposed to 75 ppm
for the Z enolate).3 Rearrangement of this compound
gave a 2:1 mixture of products in favor of epimer 1511
(Scheme 3). This suggests that the rearrangement was
proceeding via both boat- and chair-like transitions
states in agreement with calculations performed by
Houk.6b
The described method provides a rapid and reliable
way to assemble spirocycles. Using the Claisen proto-
col, one can set the configuration of the spiro carbon by
virtue of the well-precedented3,6 suprafacial migration.
By exploiting the steric hindrance of the endocylcic
double bond, ring-closing metathesis proceeds
extremely selectively, affording in all cases studied
except one, the desired compounds in excellent yield.
We are currently exploring this method in the synthesis
of natural products.