An expeditious route to eight- and nine-membered carbocycles based on a RCM-ring fragmentation strategy

Article abstract of DOI:10.1021/ol0063959

(matrix presented) The presence of a temporary one-atom internal tether in 1,9-deca- and 1,10-undecadienes allows their efficient ring-closing metathesis (RCM). Cleavage of the bridging tether of the resulting bicycles provides eight-or nine-membered carb

Full text of DOI:10.1021/ol0063959

ORGANIC
LETTERS
2000
Vol. 2, No. 20
3209-3212
An Expeditious Route to Eight- and
Nine-Membered Carbocycles Based on a
RCM-Ring Fragmentation Strategy†
J. Ramo´n Rodr´ıguez, Luis Castedo, and Jose´ L. Mascaren˜as*
Departamento de Qu´ımica Orga´nica y Unidad Asociada al CSIC, UniVersidad de
Santiago de Compostela, 15706 Santiago de Compostela, Spain
qojoselm@usc.es
Received July 31, 2000
ABSTRACT
The presence of a temporary one-atom internal tether in 1,9-deca- and 1,10-undecadienes allows their efficient ring-closing metathesis (RCM).
Cleavage of the bridging tether of the resulting bicycles provides eight- or nine-membered carbocycles, medium-sized rings that are difficult
to assemble using other currently available procedures.
The construction of medium-sized carbocycles, particularly
eight- and nine-membered ones, remains a major current
synthetic challenge owing to their being the main structural
motif of a growing number of natural products1 and the well-
known difficulties associated with their assembly via direct
cyclization routes.2 Several reports have shown that ring-
closing olefin metathesis (RCM) can be used to construct
these medium-sized rings; however its success is restricted
to substrates bearing some sort of conformational constraint
which bias the intra- over the intermolecular process.3,4
Previous attempts to cyclize conformationally flexible acyclic
dienes to eight-membered carbocycles were unsuccessful.5
We envisaged that the presence of a temporary one-atom
(3) These constraints have been achieved either by using a preexisting
ring or by introducing appropriate substituents in the acyclic precursors:
(a) Miller, S. J.; Kim, S. H.; Chen, R.; Grubbs, R. H. J. Am. Chem. Soc.
1995, 117, 2108. (b) Fu¨rstner, A.; Langemann, K. J. Org. Chem. 1996, 61,
8746. (c) Linderman, R. J.; Siedlecki, J.; O’Neill, S. A.; Sun, H. J. Am.
Chem. Soc. 1997, 119, 6919. (d) Marsella, M. J.; Maynard, H. D.; Grubbs,
R. H. Angew. Chem., Int. Ed. Engl. 1997, 36, 1101. (e) Paley, R. S.; Estroff,
L. A.; Gauguet, J.-M.; Hunt, D. K.; Newlin, R. C. Org. Lett. 2000, 2, 365.
(f) Paquette, L. A.; Tae, J.; Arrington, M. P.; Sadoun, A. H. J. Am. Chem.
Soc. 2000, 122, 2742 and references therein. (g) Maier, M. E. Angew. Chem.,
Int. Ed. 2000, 39, 2073. (h) Me´ndez-Andino, J.; Paquette, L. A. Org. Lett.
2000, 2, 1263.
(4) For recent reviews on RCM, see: (a) Schuster, M.; Blechert, S.
Angew. Chem., Int. Ed. Engl. 1997, 36, 2037. (b) Grubbs, R. H.; Chang, S.
Tetrahedron 1998, 54, 4413. (c) Armstrong, S. K. J. Chem. Soc., Perkin
Trans. 1 1998, 371. (d) Alkene Metathesis in Organic Synthesis; Fu¨rstner,
A., Ed.; Springer: Berlin, 1998. (e) Wright, D. L. Curr. Org. Chem. 1999,
3, 211. (f) Phillips, A. J.; Abell, A. D. Aldrichimia Acta 1999, 32, 75. (g)
Roy, R.; Das, S. K. Chem. Commun. 2000, 519.
† Dedicated to Prof. J. Barluenga on the occasion of his 60th birthday.
(1) For reviews, see: (a) Oishi, T.; Ohtsuka, Y. In Studies in Natural
Products Synthesis; Atta-ur-Rahman, Ed.; Elsevier: Amsterdam, 1989; Vol.
3, p 73. (b) Petasis, N. A.; Patane, M. A. Tetrahedron 1992, 48, 5757. (c)
Rousseau, G. Tetrahedron 1995, 51, 2777. (d) Molander, G. A. Acc. Chem.
Res. 1998, 31, 603. (e) Mehta, G.; Singh, V. Chem. ReV. 1999, 99, 881 and
references therein. For recent approaches to eight-membered rings, see: (f)
Paquette, L. A.; Sun, L.-Q.; Watson, T. J. N.; Friedrich, D.; Freeman, B.
T. J. Org. Chem. 1997, 62, 4908. (g) Li, C.-J.; Chen, D.-L, Lu, Y.-Q.;
Haberman, J. X.; Mague, J. T. Tetrahedron 1998, 54, 2347. (h) Paquette,
L. A.; Nakatani, S.; Zydowsky, T. M.; Edmonson, S. D.; Sun, L.-Q. Skerlj,
R. J. Org. Chem. 1999, 64, 3244. (i) Randall, M. L.; Lo, P. C-K;
Bonitatebus, P. J.; Snapper, M. L. J. Am. Chem. Soc. 1999, 121, 4534. (j)
Imai, A. E.; Sato, Y.; Nishida, M.; Mori, M. J. Am. Chem. Soc. 1999, 121,
1217. For recent approaches to nine-membered rings, see: (k) Boivin, J.;
Pothier, J.; Ramos, L.; Zard, S. Z. Tetrahedron Lett. 1999, 40, 9239. (l)
Rigby, J. H.; Fales, K. R. Tetrahedron Lett. 2000, 39, 1525.
(5) Kirkland, T. A.; Grubbs, R. H. J. Org. Chem. 1997, 62, 7310. See
also ref 3a.
(2) (a) Illuminati, G.; Mandolini, L. Acc. Chem. Res. 1981, 14, 95. (b)
Mandolini, L. AdV. Phys. Org. Chem. 1986, 22, 1. (c) Kreiter, C. G.; Lehr,
K.; Leyendecker, M.; Sheldrik, W. S.; Exner, R. Chem. Ber. 1991, 124, 3.
(d) Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds; John
Wiley and Sons: New York, 1994.
(6) The assembly of one-atom bridged bicycloalkenes by RCM of
monocyclic precursors has been shown to be feasible: Morehead, A., Jr.;
Grubbs, R. Chem. Commun. 1998, 275.
(7) Mascaren˜as, J. L.; Rumbo, A.; Castedo, L. J. Org. Chem. 1997, 62,
8620.
10.1021/ol0063959 CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/02/2000

internal tether in a diene precursor might decrease the
activation barrier of the ring closure and hence allow the
RCM to occur under relatively mild conditions (Scheme 1).6
Scheme 3
Scheme 1
Subsequent removal of the temporary bridge from the
resulting bicyclic systems would lead to the otherwise
difficult to assemble medium-sized rings. Herein we dem-
onstrate the validity of this “temporary bridge” concept for
the synthesis of eight- and nine-membered carbocycles.
Our exact plan, outlined in Scheme 2, was designed on
separated from the uncyclized trans isomer 3a by silica gel
chromatography.
We later found that removal of the silyl protecting group
from the mixture of 2a and 3a (TBAF, THF) does allow
chromatographic separation of the cis and trans isomers (2b
and 3b). Remarkably, whereas the RCM of 2a (obtained by
silylation of 2b) required heat (40 °C, 18 h, 5 nM in CH2-
Cl2) and gave only a 65% yield of 5a, alcohol 2b smoothly
cyclized at room temperature (20 °C, 9 h) to give the bicycle
5b in 95% yield. This notable rate difference can be attributed
to the equilibrium between A and B (see Table 1) being much
Scheme 2
Table 1. Difference in Steric Energy between the Two Chair
Conformations A and B
the basis of our recent results on the homologation of
oxabicyclic [5 + 2] pyrone-alkene cycloadducts to O-
bridged cyclonona- and cyclodecanoids.7 A key element of
the strategy is the use of an R-hydroxyketone as oxidatively
cleavable internal tether. Although the requisite R,R′-dialkyl-
R-silyloxycyclohexanones (2) could probably be readily
assembled from an R-silyloxycyclohexenone (1) by means
of an addition-silyl migration-enolate alkylation sequence,
the stereochemical outcome of this process was difficult to
predict.
entry
R
X
∆Ea
1
2
3
4
TBS
H
TBS
H
O
O
H, H
H, H
5.2
-0.3
4.5
2.9
Treatment of enone 1a8 with vinyllithium and subsequent
addition of allyl bromide (THF, -78 °C) led to the expected
addition-alkylation product, as a 6:4 mixture of cis (2a) and
trans (3a) isomers (83% combined yield, Scheme 3).9
Although it was not possible to separate these isomers by
simple chromatographic techniques, the viability of the
cyclization was proved when the mixture was subjected to
standard RCM conditions.4 Hence, heating of this mixture
in CH2Cl2 (approximately 0.05 M, 40 °C) for 12 h in the
presence of 5% of ruthenium catalyst 4 produced the desired
bicyclic derivative 5a (15% yield from 1a), which was easily
a Approximate difference in steric energy between conformer B and
conformer A (kcal/mol), calculated using the MM2 force field as imple-
mented in Chem3D (Chem3Dpro 4.0, CSC, 1997).
more in favor of the RCM-reactive conformation B when R
) H than when R ) TBS, which is in consonance with the
calculated steric energy difference between the two confor-
mations. A great part of this difference in energy must arise
from the existence of an intramolecular hydrogen bond which
considerably stabilizes conformer B in the case of the
R-hydroxycyclohexanone 2b (R ) H, X ) O). Indeed, when
R ) H but the hydrogen bond is prevented by the carbonyl
group being replaced by methylene (X ) H, H), the
conformer with the alkyl chains in a pseudoequatorial
position (A) is still largely preferred.
(8) Prepared in quantitative yield from commercially available 1,2-
cyclohexanedione using standard silylation conditions. See the Supporting
Information for details.
1
(9) The cis/trans ratio was deduced from the H NMR spectrum of the
mixture by integration of characteristic signals of each isomer, which could
be assigned owing to the feasibility of obtaining the trans isomer in pure
form after subjecting the mixture to the metathesis reaction (see discussion
that follows in the main text).
With 5b in hand we tested the feasibility of oxidative
cleavage of the bridge. Gratifyingly, treatment of this
3210
Org. Lett., Vol. 2, No. 20, 2000

compound with lead tetraacetate in MeOH induced instan-
taneous fragmentation of the bicycle to give the desired
cyclooctenone 6 in a satisfactory 84% yield.10
On the basis of the above results, the whole alkylation-
cyclization-fragmentation process was optimized to be
carried out in three simple steps (Scheme 4): (1) addition
The above results confirmed the validity of the cycliza-
tion-fragmentation tactic; however it was clearly desirable
to increase its efficiency by either improving the stereo-
selectivity of the initial addition-alkylation reaction or by
inducing in situ epimerization of the trans isomer 3 at the
metathesis stage. The epimerization of 3a or 3b was easily
promoted by treatment with catalytic amounts of KOtBu in
t-BuOH/CH2Cl2 (or of DBU in CH2Cl2),11 but these reagents
were unfortunately found to inhibit the metathesis reaction,
most probably by inactivating the catalyst. Use of an excess
of the ruthenium catalyst with respect to the base did allow
the RCM but suppressed the epimerization. On the other
hand, all attempts to induce the epimerization under acidic
conditions (AcOH or TfOH in aqueous CH2Cl2, or THF, or
p-TsOH in toluene) were unsuccessful.
Scheme 4
These failures, together with the finding that it is the
undesired trans epimer that predominates under thermody-
namic conditions (Table 2), led us to investigate the
of vinyllithium to 1d and trapping of the resulting enolate
with allyl bromide (THF, -78 °C), followed by in situ
desilylation by treatment with TBAF (73% yield); (2)
treatment of the resulting 2:1 mixture of 2b and 3b with the
ruthenium catalyst 4 (7%, CH2Cl2, 20 °C, 9 h; 64% yield,
95% based on 2b); (3) chromatographic purification of the
bicycle 512 and treatment with Pb(OAc)4 (MeOH, 20 °C, 5
min; 84% yield). Overall, the carbocycle 6 was obtained in
39% yield from commercially available 1,2-cyclohexane-
dione.
Table 2. Kinetic and Thermodynamic Ratios of 2:3
Importantly, the above approach is not limited to the
construction of cyclooctanoids. Hence, a slight change in
the synthetic sequence, the use of allyllithium instead of
vinyllithium in the initial alkylation reaction, allowed
preparation of the homologous nine-membered carbocycles
(Scheme 4). The diallylation reaction led to an approximately
2:1 mixture of the cis and trans isomers, which were
desilylated to give 7 and 8 in 81% combined yield.
Subjecting this mixture to the RCM conditions provided the
expected [4.3.1] bicyclic product 9 in 58% yield (87% based
on 7), in this case completion of the reaction requiring 15 h
at rt. The oxidative bridge cleavage proceeded efficiently
upon simple treatment of 9 with Pb(OAc)4 (MeOH, 20 °C),
affording the expected cyclononane 10 in 78% yield (37%
overall yield from 1d).
In summary, eight- and nine-membered carbocycles, which
are difficult to construct by standard cyclization methods,
can be expeditiously prepared in four simple steps from
commercially available 1,2-cyclohexanedione by appropri-
ately coupling a dialkylation, a cyclization, and a fragmenta-
tion reaction. The success of this approach relies on the use
of a temporary bridging connection to decrease the entropic
and enthalpic requirements of the cyclization step. Work to
extend the strategy to other types of cyclization, such as the
Pauson-Khand reaction, and to apply it to the synthesis of
natural products containing this type of medium-sized
carbocycles is now under way.
thermodynamic
ratio of 2:3b
entry
1
enone7
yield, %a
83
2:38
1a
2a :3a
(58:42)
2a :3a
(30:70)
2b:3b
2
3
4
1b
1c
1d
<10
76
(26:74)
2c:3c
(61:39)
2d :3d
2c:3c
(44:56)
2d :3d
78
(67:33)
(33:67)
a Combined isolated yield after chromatography. b Calculated after
stirring the kinetic mixture with NaOMe in MeOH for 12 h.
feasibility of improving the cis-stereoselectivity of the initial
vinyl addition-enolate allylation step. We reasoned that
increasing the bulk of the silyl migrating group might favor
the formation of the desired cis isomer 2 by hindering the
approach of the allyl bromide at the face bearing the silyloxy
group. Indeed, use of TIPS (triisopropylsilyl) as protecting-
migrating group slightly improved the cis/trans ratio, whereas
the introduction of a TBDPS (tert-butyldiphenylsilyl) allowed
us to obtain an acceptable proportion of the desired cis isomer
(2d:3d, 2:1, Table 2).
(10) Bridge cleavage in related bicyclo[3.3.1]nonane systems has been
based exclusively on Grob type of rearrangements: Hesse, M. Ring
Enlargement in Organic Synthesis; VCH Publishers: Weinheim, 1991; p
199. See also ref 2b, p 5796.
(11) Et3N, DABCO and 2,6-ditertbutylpyridine failed to promote the
epimerization.
(12) Most of the trans isomer 3b was recovered during chromatography.
Org. Lett., Vol. 2, No. 20, 2000
3211

Acknowledgment. Support of this research by the Span-
ish Ministry of Education and Culture under Grant PB97-
0524 is gratefully acknowledged. J.R.R. thanks the Spanish
Ministry of Education and Culture for a predoctoral research
grant. We also thank Armando Navarro for checking the
calculations and Prof. J. M. Sa´a for helpful discussions.
Supporting Information Available: Relevant experi-
mental procedures and main characterization data for 1a, 1c,
1d, 2b, 3b, 5b, 6, 8, 9, and 10. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL0063959
3212
Org. Lett., Vol. 2, No. 20, 2000