Diastereoselective synthesis of five- and seven-membered rings by [2+2+1], [3+2], [3+2+2], and [4+3] carbocyclization reactions of β-substituted (alkenyl)(methoxy)carbene complexes with methyl ketone lithium enolates

Article abstract of DOI:10.1002/chem.200500164

β-Substituted alkenylcarbene complexes react with methyl ketone lithium etiolates to give different carbocyclization products depending on the structure of the lithium enolate, on the metal of the carbene complex, and on the reaction media. Thus, the reac

Full text of DOI:10.1002/chem.200500164

FULL PAPER
Diastereoselective Synthesis of Five- and Seven-Membered Rings by
[2+2+1], [3+2], [3+2+2], and [4+3] Carbocyclization Reactions of b-
Substituted (Alkenyl)(methoxy)carbene Complexes with Methyl Ketone
Lithium Enolates
JosØ Barluenga,* Jorge Alonso, and Francisco J. FaÇanµs[a]
Abstract: b-Substituted alkenylcarbene
complexes react with methyl ketone
lithium enolates to give different car-
bocyclization products depending on
the structure of the lithium enolate, on
the metal of the carbene complex, and
on the reaction media. Thus, the reac-
tions of aryl and alkyl methyl ketone
lithium enolates with b-substituted al-
kenyl chromium and tungsten carbene
complexes in diethyl ether afford 1,3-
cyclopentanediol derivatives derived
from a formal [2+2+1] carbocycliza-
tion reaction. However, the lithium
enolates of acetone and tungsten com-
plexes furnish formal [3+2+2] carbo-
cyclization products. In the case of al-
kynyl methyl ketone lithium enolates,
competitive formal [2+2+1] and [3+2]
carbocyclization reactions occur and
1,3-cyclopentanediol and 3-cyclopente-
nol derivatives are formed. Conversely,
alkenyl methyl ketone lithium enolates
react with alkenylcarbene complexes
under the same reaction conditions to
form 2-cycloheptenone derivatives by a
formal [4+3] carbocyclization reaction.
Finally, when the reaction was per-
formed in the presence of a coordinat-
ing medium, the [3+2] carbocyclization
pattern was observed independently of
the nature of the methyl ketone lithium
enolate used.
Keywords: carbenes · carbocycles ·
cyclization · enolates
Introduction
diverse examples in which these compounds act as a C3 com-
ponent for the formation of five- and seven-membered
rings. Thus, reactions of alkenylcarbene complexes with al-
kynes,[4c,6] electronically neutral 1,3-dienes,[7] electron-rich
1,3-dienes,[8] 1-amino-1-aza-1,3-dienes,[9] electron-poor al-
kenes,[10] enamines,[11] ynamines,[12] imines,[13] and isoni-
triles[14] give rise to five-membered rings by a formal [3+2]
cyclization process. In this last case, if the isonitrile stoichi-
ometry is changed, a new cyclopentane ring can also be
formed by a formal [3+1+1] cyclization reaction.[14,15] The
participation of alkenylcarbene complexes as a C1 compo-
nent in the formation of five-membered rings is rather un-
common. Thus, when these complexes react with electroni-
cally neutral 1,3-dienes[7] or 1-amino-1-azadienes,[9] cyclo-
pentene and pyrrole derivatives arising from a formal [4+1]
cyclization reaction are obtained. Nevertheless, 1,3-diamino-
1,3-dienes and chromium alkenylcarbene complexes can
also undergo a [4+1] cyclization reaction.[16] Alkenylcarbene
complexes can also take part in the construction of seven-
membered rings, generally as a C3 component. Certainly,
they react with both electron-rich[17] and electron-poor
dienes[18] or azadienes[19] to give the corresponding [4+3]
cyclization adducts. Recently,[20] a nickel-mediated [3+2+2]
The design of new methods for the selective synthesis of
medium-size carbocycles continues to be of great interest
for organic chemists[1] due to the importance of carbocyclic
skeletons in biologically relevant compounds.[2] Organome-
tallic compounds have considerably contributed in the de-
velopment of important processes for the construction of
cyclic products with different ring sizes.[3] In this context,
Fischer carbene complexes, which have been revealed as ex-
traordinarily useful tools for synthesizing a wide variety of
complex molecules,[4] have turned out to be a solid asset for
the preparation of cyclization products.[5] In particular, stabi-
lized Group 6 alkenylcarbene complexes are recognized as
valuable building blocks for the preparation of five- and
seven-membered carbo- and heterocycles. In fact, there are
[a] Prof. Dr. J. Barluenga, Dr. J. Alonso, Dr. F. J. FaÇanµs
Instituto Universitario de Química Organometµlica “Enrique Moles”
Unidad Asociada al CSIC, Universidad de Oviedo
Juliµn Clavería 8, 33006 Oviedo (Spain)
Fax : (+34)985-103-450
E-mail: barluenga@uniovi.es
Chem. Eur. J. 2005, 11, 4995 – 5006
DOI: 10.1002/chem.200500164
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4995

cyclization reaction of alkenyl chromium carbene complexes
and alkynes has been described in which the carbene com-
plexes act as a C3 unit. Alternatively, while lithium enolates
add to a,b-unsaturated carbene complexes in a Michael
fashion,[21] Casey and Brunsvold[21a] described only an exam-
ple in which the lithium enolate of acetone added to these
complexes through 1,2-nucleophilic attack to furnish a,b-un-
saturated ketones. In this context, we have recently[22] re-
ported the novel and solvent-controlled diastereoselective
[3+2] and [4+1] cyclization reactions of a,b-substituted
(alkenyl)(methoxy)carbene complexes and methyl ketone
lithium enolates to form five-membered carbocyclic rings.
Herein, we present the reaction of b-substituted (alkenyl)-
(methoxy)carbene complexes and lithium enolates derived
from methyl ketones to afford five- and seven-membered
Scheme 1. Reaction of carbene complexes 1 or 2 with aryl methyl ketone
lithium enolates 3a–c to give 1,3-cyclopentanediol derivatives 6a–e.
LDA=lithium diisopropylamide, TMS=trimethylsilyl.
carbocyclic rings in
a
diastereoselective way. Formal
Aryl methyl ketones—Formal [2+2+1] cyclizations: When
b-substituted (alkenyl)(methoxy)carbene complexes 1 (M =
Cr) or 2 (M = W) were treated with two equivalents of aryl
methyl ketone lithium enolates 3a–c, generated by the reac-
tion of the corresponding silyl enol ethers 5 with butyllithi-
um at 08C, in diethyl ether at temperatures of 0–208C, 1,3-
cyclopentanediol derivatives 6a–e were obtained, after hy-
drolysis with silica gel, in moderate yield and as single dia-
stereoisomers (Scheme 1 and Table 1). Compounds 6a–e
can be considered as the result of a three-component,
formal [2+2+1] carbocyclization reaction, in which three
quaternary stereogenic centers have been generated with
complete diastereoselectivity. The structure and relative
configuration of the stereogenic centers of compounds 6a–e
were determined by 2D NMR spectroscopic analysis
(COSY, HMQC, HMBC, and NOESY).
[2+2+1], [3+2], [3+2+2], and [4+3] cyclization reactions
are observed and the reaction outcome depends on the
nature of the substituent on the lithium enolate, the metal
of the carbene complex, and the presence or absence of a
strong coordinating cosolvent in the reaction medium.
Results and Discussion
Since the results of the reaction of b-substituted alkenyl car-
bene complexes 1, 2 and lithium enolates 3 are highly de-
pendent on the nature of the R group of the enolate, the re-
sults and discussion have been systematized according to the
structure of the methyl ketones 4, which are the precursors
of the lithium enolates 3 (Scheme 1).
It is interesting to note that the use of one equivalent of
the lithium enolate 3a–c under the same reaction conditions
led to the formation of compounds 6a–e in lower yields and
the recovery of almost half of the carbene complexes 1. Re-
markably, the reaction only works when the lithium enolates
3 were prepared from silyl enol ethers 5 and with diethyl
ether as solvent. When the same reaction was carried out
with tetrahydrofuran (THF) as the solvent, a mixture of un-
identified products was observed. When enolates 3 were
formed by deprotonation of the corresponding aryl methyl
ketones 4 with LDA in THF and were then treated with car-
bene complexes 1 or 2, the open-chain adducts, derived
from a 1,2-addition reaction, were formed.[20a] Probably, the
presence of diisopropylamine in the reaction medium inhib-
ited the progress of the reaction. With regard to the carbene
complex, both chromium and tungsten derivatives were
competent in this chemistry, although the yields obtained
with the former were slightly higher. In particular, the most
noticable difference was observed in the reaction with the
lithium enolate 3c. Although compound 6c could be ob-
tained in low yield from carbene complex 1a, the same reac-
tion did not proceed with the tungsten carbene complex 2a.
Abstract in Spanish: Los complejos alquenilcarbeno b-susti-
tuidos reaccionan con enolatos de litio de metil cetonas para
dar diferentes productos de carbociclación dependiendo de la
estructura del enolato de litio, del metal del complejo carbeno
y del medio de reacción. Así, la reacción de enolatos de litio
de aril y alquil metil cetonas con complejos alquenilcarbeno
de cromo y wolframio b-sustituidos en dietil eter origina deri-
vados de 1,3-ciclopentanodiol, derivados de una reacción de
carbociclación formal [2+2+1]. Sin embargo, el enolato de
litio de la acetona y complejos de wolframio dan lugar a pro-
ductos de carbociclación formal [3+2+2]. En el caso de eno-
latos de litio de alquinil metil cetonas, se observa la forma-
ción de una mezcla de derivados de 1,3-ciclopentanodiol y 3-
ciclopentenol derivados de reacciones de carbociclación
formal [2+2+1] y [3+2] competitivas. Por el contrario, los
enolatos de litio de alquenil metil cetonas reaccionan con
complejos alquenilcarbeno en las mismas condiciones de
reacción para generar derivados de 2-cicloheptenona a travØs
de una reacción de carbociclación formal [4+3] Finalmente,
cuando la reacción se lleva a cabo en presencia de PMDTA,
un medio coordinante, se observa el modelo de carbocicla-
ción formal [3+2], independientemente de la naturaleza del
enolato de litio utilizado.
Alkyl methyl ketones—Formal [2+2+1] and [3+2+2] cycli-
zations: Taking into account the results described above for
the aryl methyl ketone lithium enolates 3a–c, we decided to
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Carbocyclization Reactions
FULL PAPER
Table 1. Synthesis of 1,3-cyclopentanediol derivatives 6a–e from carbene complexes 1 and 2 and aryl methyl
ketone lithium enolates 3a–c.
oxabicyclo[3.2.1]octane deriva-
tives 8, generated by simple dis-
solution of the former in
chloroform containing hydro-
gen chloride. Both products 7b
and 8 were obtained as unique
diastereoisomers, as deduced
from the 2D NMR spectrosco-
py analysis (Scheme 2). The
global reaction can be consid-
ered as formal [3+2+2] cycliza-
tion of three components. Un-
fortunately, attempts to extend
this transformation to other
alkyl methyl ketone lithium
Carbene complex
Ar
Enolate[a]
Ar’
Product
Yield [%][b]
1a
2a
1a
2a
1a
1b
2b
1b
2b
Ph
Ph
Ph
Ph
3a
3a
3b
3b
3c
3a
3a
3b
3b
Ph
Ph
6a
6a
6b
6b
6c
6d
6d
6e
6e
51
49
55
43
28
52
52
42
34
4-MeOC6H4
4-MeOC6H4
2-furyl
Ph
Ph
Ph
2-furyl
2-furyl
2-furyl
2-furyl
4-MeOC6H4
4-MeOC6H4
[a] Enolates 3 were generated by reaction of the corresponding silyl enol ether 5 with butyllithium at 08C.
[b] Yield after product isolation and based on starting carbene complexes 1 or 2.
investigate the behavior of alkyl methyl ketone lithium eno-
lates towards carbene complexes 1 and 2. The reaction of
two equivalents of lithium enolates 3d–f with chromium car-
bene complexes 1 in diethyl ether at 208C gave rise, after
hydrolysis, to 1,3-cyclopentanediol derivatives 6 f–k in mod-
erate yields and as a mixture of diastereoisomers (Scheme 2
and Table 2).
A different reaction outcome was observed when tungsten
carbene complexes 2 were used. Treatment of carbene com-
plexes 2 with the lithium enolate of acetone, 3d, under the
same reaction conditions as those described above led, after
hydrolysis, to cycloheptenediol derivatives 7, which could be
isolated in the case of 7b in moderate yield. In general, cy-
cloheptenediol derivatives 7 were characterized as the 8-
enolates failed and the corresponding cycloheptenediol de-
rivatives were not formed.
Alkynyl methyl ketones—Formal [2+2+1] and [3+2] cycli-
zations: Considering the influence of the nature of the R
group of the lithium enolate and the metal of the carbene
complex, we decided to study further the behavior of lithi-
um enolates derived from alkynyl methyl ketones in this
chemistry. Treatment of carbene complexes 1 or 2 with lithi-
um enolates 3g or 3h under the same reaction conditions as
those described before led to separable mixtures of the cor-
responding 1,3-cyclopentanediol derivatives 6l–p and 3-cy-
clopentenol derivatives 9a–e, both as single diastereoisomers
(Scheme 3and Table 3). The former compounds correspond,
as before, to a formal [2+2+1]
cyclization of three components
and the latter products indicate
a formal [3+2] cyclization of
two components.
It is difficult to explain the
influence of the R1 substituent
of the alkynyl lithium enolate
and the metal of the carbene
complex in the product distri-
bution.
Remarkably,
com-
pounds 6 are obtained as Z/E
mixtures in different ratios in
almost all the cases (Table 3,
entries 6–8 and 10).
Scheme 2. Reaction of carbene complexes 1 or 2 with alkyl methyl ketone lithium enolates 3d–f to give 1,3-cy-
clopentanediol derivatives 6 f–k, 5-cycloheptene-1,3-diols 7, and 8-oxabicyclo[3.2.1]octanes 8.
Alkenyl
methyl
ketones—
Formal [4+3] cyclizations:[23]
Finally, we have applied the re-
action of b-substituted alkenyl
carbene complexes 1 and 2 to
Table 2. Synthesis of 1,3-cyclopentanediol derivatives 6 f–k from chromium carbene complexes 1 and alkyl
methyl ketone lithium enolates 3d–f.
Carbene complex
Ar
Enolate[a]
R
Product
Yield [%][b]
de [%]
1a
1b
1b
1c
1c
1c
Ph
2-furyl
2-furyl
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
3d
3d
3e
3d
3e
3 f
Me
Me
Ph(CH2)2
Me
Ph(CH2)2
iBu
6 f
6g
6h
6i
6j
6k
3
6
90
alkenyl methyl ketone lithium
44
40
42
3
80
67
50
8
90
enolates. When the reaction
was performed with enolates
3i–l, 2-cycloheptenone deriva-
95
tives 10 were obtained in mod-
erate yields and as single dia-
stereoisomers (Scheme 4 and
41
[a] Enolates 3 were generated by reaction of the corresponding silyl enol ether 5 with butyllithium at 208C.
[b] Yield after product isolation and based on starting carbene complexes 1.
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J. Barluenga et al.
Table 3. Synthesis of 1,3-cyclopentanediol derivatives 6l–p and 3-cyclopentenol derivatives 9a–e from carbene
complexes 1 and 2 and alkynyl methyl ketone lithium enolates 3g and 3h.
and diethyl ether was used
when the enolate was formed
by treatment of the correspond-
ing silyl enol ether with butyl-
lithium. The solvent does not
seem to have an influence on
the formation of the final prod-
uct 10, either in the diastereose-
lectivity or the chemical yield,
when the Ar, R2, or R3 groups
do not have heteroatoms
(Table 4, entries 4, 5). However,
when either the carbene com-
plex or the lithium enolate con-
tain a heteroatom at certain po-
sitions in their structure, an in-
teresting reaction variation was
noticed as a function of the re-
Entry Carbene complex Ar
Enolate[a] R1
Product 6 (yield [%])[b] Product 9 (yield [%])[b]
1
2
3
4
5
6
7
8
1a
2a
1a
2a
1b
2b
1c
2c
1c
2c
Ph
Ph
Ph
Ph
3g
3g
3h
3h
3h
3h
Bu
Bu
TMS
6l (14)
6l (9)
–
9a (52)
9a (61)
9b[c] (80)
9b (59)
9c[d] (69)
9c (19)
9d (52)
9d (20)
9e (68)
9e (42)
TMS 6m (11)
TMS
2-furyl
2-furyl
4-MeOC6H4 3g
4-MeOC6H4 3g
4-MeOC6H4 3h
4-MeOC6H4 3h
–
TMS 6n[e] (54)
Bu
Bu
6o[f] (19)
6o[f] (63)
–
9
10
TMS
TMS 6p[g] (20)
[a] Enolates 3 were generated by reaction of the corresponding silyl enol ether 5 with butyllithium at 08C.
[b] Yield after product isolation and based on starting carbene complexes 1 or 2. [c] Obtained as a separable
88:12 mixture of diastereoisomers. [d] Obtained as a separable 94:6 mixture of diastereoisomers. [e] Obtained
as a nonseparable 1.3:1 mixture of Z/E diastereoisomers. [f] Obtained as a nonseparable 1:1.4 mixture of Z/E
diastereoisomers. [g] Obtained as a nonseparable 1:2 mixture of Z/E diastereoisomers.
action conditions. For example, in the reaction of tungsten
carbene complex 2a with lithium enolate 3l, containing a di-
hydropyran moiety in its structure, cycloheptenone 10d was
not formed when the reaction was performed in THF, while
in diethyl ether product 10d was obtained in 52% yield
(Table 4, entries 6, 7). In a similar way, cycloheptenone 10e
Scheme 3. Reaction of carbene complexes 1 or 2 with alkynyl methyl
ketone lithium enolates 3g,3h to give 1,3-cyclopentanediol derivatives
6l–p and 3-cyclopentenols 9a–e.
Table 4). The relative cis configuration of product 10 was
determined on the basis of the coupling constant (JH5,H6
=
5.5 Hz) and NOESY experiments. In a similar way, the b,b-
disubstituted carbene complex 11 reacted with the lithium
enolate 3i to give, after hydrolysis, the 2-cycloheptenone de-
rivative 12 in 41% yield (Scheme 4). The formation of com-
pounds 10 and 11 can be considered as a formal [4+3] cycli-
zation reaction, in which two
Scheme 4. Synthesis of 2-cycloheptenone derivatives 10 and 12 by reac-
tion of carbene complexes 1, 2, or 11 with alkenyl methyl ketone lithium
enolates 3i–l.
carbon–carbon bonds and two
or three stereogenic centers
have been generated.
Table 4. Synthesis of 2-cycloheptenone derivatives 10 from carbene complexes 1 and 2 and alkenyl methyl
ketone lithium enolates 3i–l.
From the results summarized
in Table 4, the following conclu-
sions can be extracted. The re-
action outcome does not
depend on the nature of the
metal of the carbene complex
and the yields of the reactions
are comparable (Table 4 en-
tries 1, 2). The solvent used de-
pended on the method used for
the formation of the enolate.
Thus, THF was used when the
lithium enolate was generated
by deprotonation of the corre-
Entry Carbene complex
M
Ar
Cr Ph
Ph
Enolate[a] R2
R3
Solvent Product Yield [%][b]
1
2
3
4
5
6
7
8
1a
2a
1a
1a
1a
2a
2a
1b
2b
2b
1c
1c
3i
3i
3j
3k
3k
3l
H
H
H
H
H
H
H
Me
Ph
Ph
THF
THF
THF
THF
Et2O
THF
Et2O
THF
THF
Et2O
THF
THF
10a
10a
10b
10c
10c
46
48
44
51
53
W
Cr Ph
Cr Ph
Cr Ph
W
W
Cr 2-furyl
W
W
[c]
Ph
Ph
O(CH2)3
O(CH2)3
–
3l
10d
53
[c]
3k
3k
3k
H
Ph
Ph
Ph
H
–
9
2-furyl
2-furyl
H
H
H
H
10e
10e
10 f
10g
6
10
11
12
46
52
43
Cr 4-MeOC6H4 3i
Cr 4-MeOC6H4 3k
Ph
[a] Enolates 3 were generated by deprotonation of the corresponding ketone 4 with LDA when the reaction
was carried out in THF and by treatment of the corresponding silyl enol ether 5 with butyllithium at 08C
when the reaction was performed in diethyl ether. [b] Yield after product isolation and based on starting car-
sponding ketone 4 with LDA bene complexes 1 and 2. [c] No defined product was observed.
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Carbocyclization Reactions
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was not formed when the chromium carbene complex 1b
(Ar = 2-furyl) reacted with the lithium enolate 3k, and
only a 6% yield of 10e was obtained from the tungsten car-
bene 2b when the reaction was performed in THF (Table 4,
entries 8, 9). However, the seven-membered ring 10e was
obtained in 46% yield when the reaction was carried out in
diethyl ether (Table 4, entry 10). It seems that both the sol-
vent and/or the presence of diisopropylamine in the reaction
medium could be responsible for the different result of the
reaction. In this context, we carried out an experiment in
the absence of diisopropylamine by treating carbene com-
plex 1b with lithium enolate 3k, generated by the reaction
of silyl enol ether 5k and butyllithium, in THF under the
same reaction conditions, but unfortunately an intractable
mixture of compounds was obtained and the 2-cyclohepte-
none derivative 10e was not observed.
Given the complete diatereoselectivity for 10 in all the
cases examined, we carried out a reaction with the homochi-
ral enolate derived from ketone 4m (Scheme 5), which is
easily obtained by treatment of (ꢀ)-myrtenal with methyl-
lithium and further Swern oxidation of the resulting mixture
of diastereoisomeric alcohols. The reaction of the enolate
3m with chromium carbene complex 1a at ꢀ78 to 208C fol-
lowed by hydrolysis at ꢀ788C with a solution of ammonium
chloride afforded the fused tricyclic compound 13 in 41%
yield with diastereoselectivity higher than 99%. The struc-
ture and absolute configuration of the new stereogenic cen-
ters were unequivocally determined by 2D NMR spectrosco-
py analysis.
and on the solvent. Thus, when R is an alkyl, aryl, or alkynyl
group and the reaction is carried out in diethyl ether, the
lithium atom could coordinate to the oxygen atoms of the
carbonyl and methoxy groups, thereby increasing the rigidity
of intermediates 14 or 14’ and the electrophilic character of
the carbonyl group. In these circumstances, addition of a
second molecule of lithium enolate 3 to the carbonyl group
of intermediates 14 or 14’, giving the new intermediates 15
or 15’, could be preferred over an intramolecular ring clos-
ing. A nucleophilic attack of the g-carbon atom of the allyl-
pentacarbonylmetallate on the carbonyl group in intermedi-
ates 15 would lead to the cyclic systems 16, which after hy-
drolysis, would give rise to the 1,3-cyclopentanediol deriva-
tives 6. Alternatively, compounds 6 could be formed by an
attack of the a-carbon atom of the allyl metallate moiety of
intermediates 15’ on the carbonyl group. However, the for-
mation of compounds 6 as Z/E isomers in some cases (see
Table 3) supports the former proposal rather than the latter.
On the other hand, in cases where R = Me and M = W,
the evolution would be from intermediates 15’, which would
undergo a cyclization reaction induced by a 1,2-migration[25]
of the pentacarbonyltungsten fragment to afford the seven-
membered intermediate 17. Further elimination of the metal
moiety would furnish, after hydrolysis and metal decoordi-
nation, the cycloheptenediol derivatives 7. The reason why
the last reaction only works with R = Me and evolves in a
different manner to the other cases is not clear. Possibly, the
difference could be attributed to steric effects hindering the
addition of a second molecule of alkyl enolate to tungsten
intermediates 14 or 14’. On the other hand, the formation of
seven-membered rings in the reaction of the lithium enolate
of acetone and tungsten complexes could be due to the
greater steric volume of the tungsten fragment favoring the
formation of intermediates 15’ over 15. Moreover, the high
diastereoselectivity found in the formation of compounds 6
and 7 could be attributed to transition states with the same
geometric disposition as intermediates 15 and 15’, respec-
tively, in which the coordination of the three oxygen atoms
to the lithium atom would favor these dispositions.
Alternatively, and only when R is an alkynyl group
(R = ꢁꢀR1) due to its shorter size compared with the alkyl
and aryl groups, intermediates 14 could undergo a cycliza-
tion reaction promoted by an 1,2-migration of the pentacar-
bonylmetal fragment to give the five-membered ring inter-
mediates 18, which after elimination of the metal moiety,
hydrolysis, and metal decoordination would afford the 3-cy-
clopentenol derivatives 9 (Scheme 6). The formation of a
unique diastereoisomer of 9 is a consequence of the more
favorable trans disposition of the aryl and alkynyl groups in
the lithium-coordinated intermediate 14, which would avoid
the steric interactions between these groups.
Finally, when the R substituent is an alkenyl group (R =
C(R2)=CHR3), the evolution is also different and, in this
case, intermediates 14 undergo a cyclization induced by a
1,2-migration of the pentacarbonylmetal group, in which a
Michael addition is involved, thereby furnishing the seven-
membered intermediates 19. Subsequent elimination of the
Scheme 5. Synthesis of tricyclic compound 13 from homochiral lithium
enolate 3m, derived from (ꢀ)-myrtenal, and chromium carbene complex
1a.
Mechanistic proposals: In Scheme 6, tentative mechanisms
to rationalize the different results obtained in the reaction
of b-substituted alkenylcarbene complexes 1 or 2 with
methyl ketone lithium enolates 3 are presented. We assume
that a 1,2-addition of the lithium enolates 3 to the carbene
complexes 1 or 2 occurs first to form intermediates 14,
which could be in equilibrium with 14’ derived from an 1,3-
migration[24] of the pentacarbonylmetal. The evolution of
these intermediates depends on the nature of the R group
of the lithium enolate, on the metal of the carbene complex,
Chem. Eur. J. 2005, 11, 4995 – 5006
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J. Barluenga et al.
atom has been proposed as a key feature for the diastereo-
selective formation of the final products. In order to verify
the validity of this statement, we carried out a set of reac-
tions with carbene complex 2a and lithium enolates 3, gen-
erated from the reaction of the corresponding silyl enol
ethers 5 and butyllithium, in diethyl ether at temperatures
of 0–208C and in the presence of N,N,N’,N’,N’’-pentamethyl-
diethylenetriamine (PMDTA). In these cases, the formal
[3+2] cyclization products 9 were formed in moderate yields
and as single diastereoisomers, independently of the nature
of the R substituent of the lithium enolate 3 used (Scheme 7
and Table 5).
Scheme 7. Reaction of carbene complex 2a with lithium enolates 3 in the
presence of PMDTA to give 3-cyclopentenol derivatives 9 and a proposal
for the mechanism of product formation.
Table 5. Synthesis of 3-cyclopentenol derivatives 9 from carbene com-
plex 2a and lithium enolates 3 in the presence of PMDTA.
Enolate[a]
R
Product
Yield [%][b]
3a
3d
3 f
3h
3k
Ph
Me
iBu
9 f
53
64
51
61
20
9g[c]
9h
Scheme 6. Mechanistic proposal for the formation of compounds 6, 7, 9,
and 10.
C=CTMS
(E)-PhCH=CH
9b[d]
9i
[a] Enolates 3 were generated by reaction of the corresponding silyl enol
ether 5 with butyllithium at 08C. [b] Yield after product isolation and
based on starting carbene complex 2a. [c] A small amount of compound
6 f was also obtained (22%, >95% de). [d] Obtained as a separable 95:5
mixture of diastereoisomers.
metal fragment followed by hydrolysis, metal decoordina-
tion, and double bond isomerization, gives rise to 2-cyclo-
heptenone derivatives 10 (Scheme 6). The generation of the
cis diastereoisomers can be explained by invoking a chair-
like transition state, derived from 14 and presumably fa-
vored by the internal coordination of the oxygen atoms to
the lithium atom. The importance of this coordination in the
outcome of the reaction is manifested by the fact that the
presence of other heteroatoms, either in the carbene com-
plex or lithium enolate, influences the result of the reaction
and the fact the seven-membered rings 10 are formed in di-
ethyl ether but not, or in very low yields, in THF. The coor-
dination of the lithium atom to the other heteroatoms or to
THF could disfavor the chairlike conformation of intermedi-
ate 14 and, therefore, the ring closing. Furthermore, the
presence of diisopropylamine in the reaction medium could
lead to decomposition of intermediate 14.
In order to prove the influence of the metal in the reac-
tion outcome, a reaction was carried out with the chromium
carbene complex 1a and the lithium enolate 3d under the
same reaction conditions and compound 9g was obtained in
55% yield and also as a single diastereoisomer.
The formation of 9 when PMDTA was used can be ration-
alized in terms of coordination of the lithium atom to the
triamine; this coordination lowers the rigidity of the transi-
tion structure derived from 14’’, thereby favoring the ap-
proach of the allylic carbon atom of the s-allyltungsten
moiety to the carbonyl atom and giving the cyclization inter-
mediates 20. The elimination of the metal fragment and the
final hydrolysis would furnish the 3-cyclopentenol deriva-
tives 9. The diastereoselectivity found can also be under-
As stated in all the mechanistic proposals presented
above, the coordination of the oxygen atoms to the lithium
5000
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Chem. Eur. J. 2005, 11, 4995 – 5006

Carbocyclization Reactions
FULL PAPER
assigned by DEPT techniques. Two-dimensional NMR experiments
(COSY, HMQC, HMBC, and NOESY) were recorded on a Bruker
AMX-400 (400 MHz) instrument. High-resolution mass spectra were de-
termined on a Finnigang MAT95 spectrometer. Elemental analyses were
carried out on a Perkin–Elmer 2400 microanalyzer.
stood by assuming that the phenyl and the R groups would
adopt a trans disposition in the transition structure to avoid
steric interactions.
Materials: Butyllithium (1.6n in hexanes) was purchased from Acros Or-
ganics; methyl ketones 4, silyl enol ethers 5a and 5d, diisopropylamine,
and PMDTA were purchased from Aldrich and used without further pu-
rification, except PMDTA, which was dried prior to use. The other silyl
enol ethers 5 were prepared in a similar way to the literature proce-
dures.[26] (Alkenyl)(methoxy)carbene complexes 1, 2,[27] and 11[28] were
prepared according to literature procedures. Ketones 4g and 4l were pre-
pared by addition of the corresponding organocuprate to acetyl bro-
mide.[29]
Conclusion
We have described the reaction of b-substituted alkenylcar-
bene complexes and methyl ketone lithium enolates. The re-
action outcome is highly dependent on the structure of the
lithium enolate, on the metal of the carbene complex, and
on the reaction medium. Thus, in
a noncoordinating
General procedure for the preparation of compounds 6 and 7: In a
flame-dried round-bottomed flask, enolates 3 were prepared by treat-
ment of silyl enol ethers 5 (1 mmol) with BuLi (0.63mL, 1.6 n in hexanes,
1 mmol) in diethyl ether (10 mL), at room temperature for 30 min for
silyl enol ethers 5d and 5 f, and at 08C for 30 min for the rest of the silyl
enol ethers 5. Carbene complexes 1 or 2 (0.4 mmol) were then added at
08C and the mixture was warmed to room temperature and stirred for
30 min. The reaction mixture was quenched with a small amount of silica
gel, solvents were removed, and the resulting residue was purified by
flash column chromatography on silica gel (hexanes/ethyl acetate 10:1!
3:1) to give compounds 6 and 7.
medium, aryl and alkyl methyl ketone lithium enolates react
with b-substituted alkenyl chromium and tungsten carbene
complexes to give 1,3-cyclopentanediol derivatives derived
from a formal [2+2+1] carbocyclization reaction. Only for
the lithium enolate of acetone with tungsten complexes was
a formal [3+2+2] carbocyclization reaction observed. Both
carbocyclization reactions involve two equivalents of alkyl
or aryl lithium enolates and one equivalent of carbene com-
plex. In the case of alkynyl lithium enolates, competitive for-
mation of five-membered rings by formal [2+2+1] and
[3+2] carbocyclization reactions occurs. Conversely, alkenyl
methyl ketone lithium enolates react with alkenylcarbene
complexes under the same reaction conditions to form
seven-membered carbocycles by formal [4+3] carbocycliza-
tion reactions. This last cyclization pattern has been success-
fully applied in the diastereoselective transformation of a
natural product, (ꢀ)-myrtenal. On the other hand, when the
reaction is performed in a coordinating medium, in the pres-
ence of PMDTA, the [3+2] carbocyclization pattern was ob-
served, independently of the nature of the methyl ketone
lithium enolate used. Mechanistic proposals for all cycliza-
tion patterns, taking into account all the factors above men-
tioned, have also been discussed herein. Finally, it is impor-
tant to point out the simplicity of the starting materials,
methyl ketones and Fischer-type carbene complexes. Investi-
gations to clarify the mechanism of the reactions, the appli-
cation of this method to organic synthesis, and the search
for a version leading to enantiopure products are underway
in our laboratories.
(1R*,3R*,4S*)-4-Methoxy-1,3-diphenyl-4-[(E)-styryl]-1,3-cyclopentane-
diol (6a): Silyl enol ether 5a (192 mg, 1 mmol), BuLi (0.63mL, 1.6 n in
hexanes, 1 mmol), and carbene complex 1a (135 mg, 0.4 mmol) or 2a
(188 mg, 0.4 mmol) afforded 6a (79 mg, 51% from 1a; 76 mg, 49% from
2a) as a colorless oil. 1H NMR (300 MHz, C6D6): d=7.96–7.18 (m, 15H;
ArH), 6.43(d, J=16.5 Hz, 1H; =CHPh), 5.19 (d, J=16.5 Hz, 1H; =
CHC), 5.39 (s, 1H; OH), 4.70 (t, J=1.7 Hz, 1H; OH), 3.07 (dd, J=14.3,
1.7 Hz, 1H; PhCCHHCPh), 2.55 (dd, J=14.3, 1.7 Hz, 1H;
PhCCHHCPh), 2.98 (d, J=15.2 Hz, 1H; CHHCOMe), 2.72 (d, J=
15.2 Hz, 1H; CHHCOMe), 2.91 ppm (s, 3H; OMe); 13C NMR
(75.5 MHz, C6D6): d=146.9, 141.7, 136.2, 133.0, 130.0, 128.7, 128.3, 128.1,
127.8, 127.3, 127.0, 126.8, 126.6, 125.7, 89.3, 86.5, 78.9, 51.9, 49.6,
48.7 ppm; HRMS (70 EV, EI): m/z: calcd for C25H21O: 337.1592; found:
337.1579 [MꢀH2OꢀMeO]+; elemental analysis calcd (%) for C26H26O3:
C 80.80, H 6.78; found: C 80.98, H 6.59.
(1R*,3R*,4S*)-4-Methoxy-1,3-bis(4-methoxyphenyl)-4-[(E)-styryl]-1,3-cy-
clopentanediol (6b): Silyl enol ether 5b (222 mg, 1 mmol), BuLi
(0.63mL, 1.6 n in hexanes, 1 mmol), and carbene complex 1a (135 mg,
0.4 mmol) or 2a (188 mg, 0.4 mmol) afforded 6b (98 mg, 55%, from 1a;
77 mg, 43% from 2a) as a colorless oil. 1H NMR (300 MHz, C6D6): d=
7.85, 7.49, 6.87 (3d, J=8.8 Hz, 6H; ArH), 7.11–7.02 (m, 7H; ArH), 6.49
(d, J=16.5 Hz, 1H; =CHPh), 5.81 (d, J=16.5 Hz, 1H; =CHC), 5.38, 4.70
(2s, 2H; 2”OH), 3.48, 3.38, 2.98 (3s, 9H; 3”OMe), 3.09 (d, J=14.2 Hz,
1H; ArCCHHCAr), 2.62 (d, J=14.2 Hz, 1H; ArCCHHCAr), 3.04 (d,
J=15.1 Hz, 1H; CHHCOMe), 2.79 ppm (d, J=15.1 Hz, 1H;
CHHCOMe); 13C NMR (75.5 MHz, C6D6): d=159.2, 159.0, 139.2, 136.3,
133.9, 133.0, 130.3, 128.7, 128.1, 128.0, 126.9, 126.6, 113.7, 113.2, 89.4,
86.3, 78.6, 54.7, 54.5, 51.9, 49.6, 49.1 ppm; HRMS (70 EV, EI): m/z: calcd
for C28H26O3: 410.1882; found: 410.1884 [Mꢀ2H2O]+.
(1R*,3S*,4S*)-1,3-Bis(2-furyl)-4-methoxy-4-[(E)-styryl]-1,3-cyclopentane-
diol (6c): Silyl enol ether 5c (182 mg, 1 mmol), BuLi (0.63mL, 1.6 n in
hexanes, 1 mmol), and carbene complex 1a (135 mg, 0.4 mmol) afforded
6c (41 mg, 28%) as a colorless oil. 1H NMR (300 MHz, C6D6): d=7.18–
7.05 (m, 5H; ArH), 7.03, 6.97 (2d, J=1.8 Hz, 2H; 2”=CHO), 6.63(d,
J=16.2 Hz,1H; =CHPh), 5.85 (d, J=16.2 Hz, 1H; =CHC), 6.55, 6.03
(2d, J=3.3 Hz, 2H; 2”CHCH=CHO), 6.09, 5.96 (2dd, J=3.3, 1.8 Hz,
2H; 2”CH=CHO), 4.44, 4.37 (2s, 2H; 2”OH), 3.08, 3.07, 2.49, 2.46 (4d,
J=14.4 Hz, 4H; 2”CH2), 2.86 ppm (s, 3H; OMe); 13C NMR (75.5 MHz,
C6D6): d=158.5, 155.0, 142.6, 141.2, 136.8, 133.1, 129.3, 128.6, 128.1,
126.7, 110.6, 110.1, 107.1, 105.4, 89.3, 83.2, 76.8, 51.9, 47.9, 46.6 ppm;
HRMS (70 EV, EI): m/z: calcd for C22H18O3: 330.1250; found: 330.1252
[Mꢀ2H2O]+.
Experimental Section
General: All reactions involving organometallic species were carried out
under an atmosphere of dry N2 by using oven-dried glassware and syring-
es. THF and Et2O were distilled from sodium/benzophenone under N2
immediately prior to use. TLC was performed on aluminum-backed
plates coated with silica gel 60 with F254 indicator (Scharlau). Flash
column chromatography was carried out on commercial and deactivated
silica gel 60 (230–240 mesh). (Deactivated silica gel was prepared as fol-
lows: Silica gel (125 g) was stirred with a 4% aqueous solution of
K2HPO4 (500 mL) for 3h. After filtration, the resulting solid was oven-
dried at 1008C for 2 d.) 1H NMR (200, 300 MHz) and 13C NMR (50.5,
75.5 MHz) spectra were measured at room temperature on Bruker AC-
200, AV-300, and DPX-300 instruments, with tetramethylsilane (d=
0.0 ppm, 1H NMR) and CDCl3 (d=77.0 ppm, 13C NMR) or C6D6 (d=
127.8 ppm, 13C NMR) as internal standards. Carbon multiplicities were
Chem. Eur. J. 2005, 11, 4995 – 5006
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J. Barluenga et al.
(1R*,3R*,4S*)-4-[(E)-2-(2-Furyl)ethenyl]-4-methoxy-1,3-diphenyl-1,3-cy-
clopentanediol (6d): Silyl enol ether 5a (192 mg, 1 mmol), BuLi
(0.63mL, 1.6 n in hexanes, 1 mmol), and carbene complex 1b (131 mg,
0.4 mmol) or 2b (184 mg, 0.4 mmol) afforded 6d (76 mg, 52% from 1b;
76 mg, 52% from 2b) as a colorless oil. 1H NMR (400 MHz, C6D6): d=
7.92–7.06 (m, 10H; ArH), 6.91 (d, J=1.9 Hz, 1H; =CHO), 6.18 (d, J=
16.4 Hz, 1H; 2-FuCH=), 5.84 (d, J=16.4 Hz, 1H; =CHC), 6.02 (dd, J=
3.3, 1.9 Hz, 1H; CH=CHO), 5.90 (d, J=3.3 Hz, 1H; CHCH=CHO), 5.39,
4.65 (2s, 2H; 2”OH), 3.03 (dd, J=14.3, 1.9 Hz, 1H; PhCCHHCPh), 2.55
(dd, J=14.3, 1.9 Hz, 1H; CPhCHHCPh), 2.88 (s, 3H; OMe), 2.84 (d, J=
15.2 Hz, 1H; CHHCOMe), 2.70 ppm (dd, J=15.2, 1.2 Hz, 1H;
CHHCOMe); 13C NMR (100.6 MHz, C6D6): d=152.0, 147.0, 142.4, 141.6,
128.3, 127.8, 127.7, 127.3, 126.9, 126.8, 125.6, 121.5, 111.3, 108.7, 89.2,
86.6, 78.8, 51.9, 49.9, 49.1 ppm; HRMS (70 EV, EI): m/z: calcd for
C24H20O2: 340.1463; found: 340.1471 [Mꢀ2H2O]+; elemental analysis
calcd (%) for C24H24O4: C 76.57, H 6.43; found: C 76.80, H 6.19.
CDCl3, major diastereomer): d=151.7, 142.7, 142.3, 128.3, 127.6, 125.6,
120.3, 111.4, 108.7, 88.7, 84.8, 77.8, 52.4, 47.9, 47.1, 43.9, 37.8, 30.6,
30.4 ppm; HRMS (70 EV, EI): m/z: calcd for C28H32O4: 432.2301; found:
432.2286 [M]+.
(1S*,3R*,4S*)-4-Methoxy-4-[2-(4-methoxyphenyl)ethenyl]-1,3-dimethyl-
1,3-cyclopentanediol (6i): Silyl enol ether 5d (144 mg, 1 mmol), BuLi
(0.63mL, 1.6 n in hexanes, 1 mmol), and carbene complex 1c (147 mg,
0.4 mmol) afforded 6i (49 mg, 42%, 50% de) as a colorless oil 1H NMR
(300 MHz, CDCl3): d=7.38 (d, J=8.8 Hz, 2H; ArH, minor diastereom-
er), 7.36 (d, J=8.8 Hz, 2H; ArH, major diastereomer), 6.89 (d, J=
8.8 Hz, 4H; ArH, both diastereomers), 6.58, 6.03(2d, J=16.5 Hz, 2H;
CH=CH, minor diastereomer), 6.47, 5.95 (2d, J=16.4 Hz, 2H; CH=CH,
major diastereomer), 3.82 (s, 6H; 2”MeO, both diastereomers), 3.28 (s,
6H; 2”MeO both diastereomers), 3.75, 3.71 (s, 2H; 2”OH, minor dia-
stereomer), 3.62, 3.53 (s, 2H; 2”OH, major diastereomer), 3.28 (s, 3H;
MeO, major diastereomer), 3.12 (s, 3H; MeO, minor diastereomer),
2.38–1.90 (m, 8H; 4CH2, both diastereomers), 1.40, 1.34 (2s, 6H; 2”Me,
minor diastereomer), 1.39, 1.18 ppm (2s, 6H; 2”Me, major diastereom-
er); 13C NMR (75.5 MHz, CDCl3, major diastereomer): d=159.5, 132.0,
127.7, 127.6, 126.3, 114.0, 88.9, 82.7, 75.5, 55.2, 53.4, 51.8, 45.7, 28.2,
23.1 ppm; HRMS (70 EV, EI): m/z: calcd for C17H24O4: 292.1675; found:
292.1674 [M]+.
(1R*,3R*,4S*)-4-[(E)-2-(2-Furyl)ethenyl]-4-methoxy-1,3-bis(4-methoxy-
phenyl)-1,3-cyclopentanediol (6e): Silyl enol ether 5b (222 mg, 1 mmol),
BuLi (0.63mL, 1.6 n in hexanes, 1 mmol), and carbene complex 1b
(131 mg, 0.4 mmol) or 2b (184 mg, 0.4 mmol) afforded 6e (73mg, 42%
from 1b; 59 mg, 34% from 2b) as a colorless oil. 1H NMR (200 MHz,
C6D6): d=7.74, 7.32, 6.94, 6.76 (4d, J=8.9 Hz, 8H; ArH), 6.79 (d, J=
1.8 Hz, 1H; =CHO), 6.18 (d, J=16.4 Hz, 1H; 2-FuCH=), 5.88 (d, J=
16.4 Hz, 1H; =CHC), 5.91 (dd, J=3.3, 1.8 Hz, 1H; CH=CHO), 5.82 (d,
J=3.3 Hz, 1H; CHCH=CHO), 5.29 (s, 1H; OH), 4.53(brs, 1H; OH),
3.38, 3.26 (2s, 6H; 2”OMe), 2.98 (d, J=14.1 Hz, 1H; ArCCHHCAr),
2.53(d, J=14.1 Hz, 1H; ArCCHHCAr), 2.83(s, 3H; OMe), 2.82 (d, J=
15.1 Hz, 1H; CHHCOMe), 2.68 ppm (d, J=15.1 Hz, 1H; CHHCOMe);
13C NMR (75.5 MHz, C6D6): d=159.1, 158.9, 152.1, 142.3, 139.3, 133.8,
128.2, 128.1, 126.8, 121.4, 113.7, 113.2, 111.3, 108.7, 89.4, 86.3, 78.5, 54.6,
54.4, 51.9, 49.8, 49.5 ppm; HRMS (70 EV, EI): m/z: calcd for C24H24O4:
400.1675; found: 400.1692 [Mꢀ2H2O]+.
(1R*,3S*,4S*)-4-Methoxy-1,3-dimethyl-4-[(E)-styryl]-1,3-cyclopentane-
diol (6 f): Silyl enol ether 5d (144 mg, 1 mmol), BuLi (0.63mL, 1.6 n in
hexanes, 1 mmol), and carbene complex 1a (135 mg, 0.4 mmol) afforded
6 f (38 mg, 36%, 90% de) as a colorless oil. 1H NMR (300 MHz, C6D6,
major diasteromer): d=7.22–7.08 (m, 5H; ArH), 6.36 (d, J=16.4 Hz,
1H; =CHPh), 5.98 (d, J=16.4 Hz, 1H; =CHC), 3.61 (brs, 1H; COH-
COMe), 3.34 (s, 1H; CH2COHCH2), 2.89 (s, 3H; OMe), 2.19 (d, J=
14.8 Hz, 1H; CHHCOMe), 1.98 (d, J=14.8 Hz, 1H; CHHCOMe), 2.05
(d, J=14.2 Hz, 1H; MeCCHHCMe), 1.69 (2d, J=14.2 Hz, 2H;
MeCCHHCMe), 1.36 (s, 3H; CH2CMeCH2), 1.10 ppm (s, 3H; CMe-
COMe); 13C NMR (75.5 MHz, C6D6, major diasteromer): d=136.5, 132.4,
129.5, 128.7, 128.1, 126.6, 88.9, 82.7, 75.1, 53.4, 51.4, 46.3, 28.6, 22.9 ppm;
HRMS (70 EV, EI): m/z: calcd for C16H22O3: 262.1569; found: 262.1565
[M]+.
(1S*,3R*,4S*)-4-Methoxy-4-[2-(4-methoxyphenyl)ethenyl]-1,3-dipheneth-
yl-1,3-cyclopentanediol (6j): Silyl enol ether 5e (220 mg, 1 mmol), BuLi
(0.63mL, 1.6 n in hexanes, 1 mmol), and carbene complex 1c (147 mg,
0.4 mmol) afforded 6j (72 mg, 38%, >95% de) as
a colorless oil.
1H NMR (300 MHz, CDCl3): d=7.38–7.19 (m, 12H; ArH), 6.90 (d, J=
8.8, 2H; ArH), 6.49 (d, J=16.3Hz, 1H; =CHAr), 5.98 (d, J=16.3Hz,
1H; =CHC), 4.07, 3.62 (2brs, 2H; 2”OH), 3.86, 3.31 (2s, 6H; 2OMe),
3.04–1.58 ppm (m, 12H; CH2CCH2, 2CH2CH2Ph); 13C NMR (75.5 MHz,
CDCl3): d=159.5, 142.7, 131.6, 128.7, 128.3, 127.7, 126.8, 125.7, 114.0,
88.9, 84.7, 77.8, 55.2, 52.4, 48.0, 46.6, 43.8, 37.9, 30.6, 30.3 ppm; HRMS
(70 EV, EI): m/z: calcd for C31H36O4: 472.2614; found: 472.2598 [M]+.
(1S*,3R*,4S*)-1,3-Diisobutyl-4-methoxy-4-[2-(4-methoxyphenyl)ethenyl]-
1,3-cyclopentanediol (6k): Silyl enol ether 5 f (172 mg, 1 mmol), BuLi
(0.63mL, 1.6 n in hexanes, 1 mmol), and carbene complex 1c (147 mg,
1
0.4 mmol) afforded 6k (62 mg, 41%, 90% de) as a colorless oil. H NMR
(300 MHz, CDCl3): d=7.38 (d, J=8.5 Hz, 2H; ArH), 6.91 (d, J=8.5 Hz,
2H; ArH), 6.53(d, J=16.5 Hz, 1H; =CHAr), 5.92 (d, J=16.5 Hz, 1H; =
CHC), 4.02, 3.36 (2s, 2H; 2”OH), 3.83, 3.23 (2s, 6H; 2”OMe), 2.31–
1.14 (m, 10H; CH2CCH2 and 2”CH2CH), 1.07–0.88 ppm (m, 12H;
4Me); 13C NMR (75.5 MHz, CDCl3): d=159.4, 131.2, 129.0, 127.6, 127.5,
114.0, 89.2, 85.3, 78.4, 55.3, 52.2, 50.3, 49.1, 47.5, 43.9, 24.8, 24.7, 24.6,
24.5, 24.3ppm; HRMS (70 EV, EI): m/z: calcd for C23H36O4: 376.2614;
found: 376.2601 [M]+.
(1S*,3R*,4R*)-4-(2-Furyl)-1,3-dimethyl-6-methoxy-5-cycloheptene-1,3-
diol (7b): Silyl enol ether 4d (144 mg, 1 mmol), BuLi (0.63mL, 1.6 n in
hexanes, 1 mmol), and carbene complex 1b (184 mg, 0.4 mmol) afforded
7b (56 mg, 56%) as a colorless oil. 1H NMR (400 MHz, C6D6): d=7.16
(d, J=1.0 Hz, 1H; =CHO), 6.22 (dd, J=3.0, 1.0 Hz, 1H; CH=CHO),
6.19 (d, J=3.0 Hz, 1H; CHCH=CHO), 4.76 (d, J=5.2 Hz, 1H; CH=),
3.52 (d, J=5.2 Hz, 1H; CH), 3.41, 3.25 (2s, 2H; 2”OH), 3.17 (s, 3H;
OMe), 2.48 (d, J=14.5 Hz, 1H; CHHCOMe), 2.34 (dt, J=14.5, 2.0 Hz,
1H; CHHCOMe), 1.84 (dd, J=14.5, 2.0 Hz, 1H; COHCHHCOH), 1.28
(d, J=14.5 Hz, 1H; COHCHHCOH), 1.07 (s, 3H; CH2CMeCH2),
0.91 ppm (s, 3H; CHCMe); 13C NMR (100.6 MHz, C6D6): d=158.4,
157.4, 140.6, 110.3, 106.1, 96.2, 73.3, 69.5, 55.0, 54.0, 46.0, 45.2, 32.7,
30.3 ppm; HRMS (70 EV, EI): m/z: calcd for C14H20O4: 252.1362; found:
252.1359 [M]+; elemental analysis calcd (%) for C14H20O4: C 66.65, H
7.99; found: C 66.79, H 7.86.
(1S*,3R*,4S*)-4-[2-(2-Furyl)ethenyl]-4-methoxy-1,3-dimethyl-1,3-cyclo-
pentanediol (6g): Silyl enol ether 5d (144 mg, 1 mmol), BuLi (0.63mL,
1.6n in hexanes, 1 mmol), and carbene complex 1b (131 mg, 0.4 mmol)
afforded 6g (44 mg, 44%, 80% de) as
a
colorless oil. 1H NMR
(300 MHz, CDCl3, major diastereomer): d=7.38 (d, J=2.0 Hz, 1H; =
CHO), 6.41 (dd, J=3.1, 2.0 Hz, 1H; CH=CHO), 6.34 (d, J=16.3Hz, 1H;
2-FuCH=), 6.03(d, J=16.3Hz, 1H; =CHC), 6.29 (d, J=3.1 Hz, 1H;
CHCH=CHO), 3.64, 3.45 (2brs, 2H; 2”OH), 3.22 (s, 3H; OMe), 2.33
(d, J=14.8 Hz, 1H; CHHCOMe), 2.19 (d, J=14.8 Hz, 1H; CHHCOMe),
2.04 (d, J=14.5 Hz, 1H; MeCCHHCMe), 1.88 (d, J=14.5 Hz, 1H;
MeCCHHCMe), 1.34, 1.13 ppm (2s, 6H; 2”Me); 13C NMR (75.5 MHz,
CDCl3, major diastereomer): d=151.9, 142.2, 127.4, 120.7, 111.4, 108.5,
88.6, 82.9, 75.5, 53.0, 52.1, 46.4, 28.3, 22.9 ppm.
(1S*,3R*,4S*)-4-[2-(2-Furyl)ethenyl]-4-methoxy-1,3-diphenethyl-1,3-cy-
clopentanediol (6h): Silyl enol ether 5e (220 mg, 1 mmol), BuLi
(0.63mL, 1.6 n in hexanes, 1 mmol), and carbene complex 1b (131 mg,
General procedure for the preparation of compounds 8: The reaction de-
scribed before to obtain compound 7 was performed. The resulting resi-
due was filtered through a small amount of silica gel (hexanes/ethyl ace-
tate 2:1). The solvents were removed, and the resulting mixture was dis-
solved in CHCl3 (3mL) and left for 24 h. The solvent was then removed,
and the residue was purified by flash column chromatography on silica
gel (hexanes/ethyl acetate 10:1!5:1).
1
0.4 mmol) afforded 6h (69 mg, 40%, 67% de) as a colorless oil. H NMR
(300 MHz, CDCl3, major diastereomer): d=7.42–7.16 (m, 11H; ArH and
=CHO), 6.42 (dd, J=3.1, 1.9 Hz, 1H; CH=CHO), 6.38 (d, J=16.3Hz,
1H; 2-FuCH=), 6.04 (d, J=16.3Hz, 1H; =CHC), 6.32 (d, J=3.1 Hz, 1H;
CHCH=CHO), 4.10, 3.58 (2brs, 2H; 2”OH), 3.31 (s, 3H; OMe), 3.04–
1.66 ppm (m, 12H; CH2CCH2 and 2CH2CH2Ph); 13C NMR (75.5 MHz,
5002
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2005, 11, 4995 – 5006

Carbocyclization Reactions
FULL PAPER
(1S*,3S*,5S*,6S*)-1-Methoxy-3,5-dimethyl-6-phenyl-8-oxabicyclo-
[3.2.1]octan-3-ol (8a): Silyl enol ether 4d (144 mg, 1 mmol), BuLi
(0.63mL, 1.6 n in hexanes, 1 mmol), and carbene complex 1a (188 mg,
C18H22O2: 270.1620; found: 270.1610 [M]+; elemental analysis calcd (%)
for C18H22O2: C 79.96, H 8.20; found: C 80.10, H 8.01.
(1R*,3R*,4S*)-4-Methoxy-1,3-bis(trimethylsilylethynyl)-4-[(E)-styryl]-
1,3-cyclopentanediol (6m) and (1R*,2R*)-4-methoxy-1-(trimethylsilyle-
thynyl)-2-phenyl-3-cyclopentenol (9b): Silyl enol ether 5h (170 mg,
1 mmol), BuLi (0.63mL, 1.6 n in hexanes, 1 mmol), and carbene complex
1a (135 mg, 0.4 mmol) or 2a (188 mg, 0.4 mmol) afforded 6m (19 mg,
11% from 2a) and 9b (92 mg, 80%, 76% de from 1a; 68 mg, 59% from
2a) as colorless oils.
0.4 mmol) afforded 8a (48 mg, 46%) as
a
colorless oil. 1H NMR
(300 MHz, C6D6): d=7.33–7.14 (m, 5H; ArH), 3.46 (s, 3H; MeO), 2.78
(dd, J=9.2, 4.3Hz, 1H; C HPh), 2.54 (brs, 1H; OH), 2.47–2.39 (m, 2H;
MeOCHH, CHHCH), 2.26 (dd, J=13.9, 9.2 Hz, 1H; CHHCH), 1.85 (d,
J=13.9 Hz, 1H; MeCCHHCMe), 1.73(d, J=13.7 Hz, 1H; MeOCHH),
1.51 (d, J=13.9 Hz, 1H; MeCCHHCMe), 1.31, 0.98 ppm (2s, 6H; 2”
Me); 13C NMR (75.5 MHz, C6D6): d=144.5, 128.8, 128.6, 126.5, 106.0,
81.8, 69.7, 52.6, 52.1, 50.0, 47.7, 45.1, 29.9, 25.6 ppm.
1
Compound 6m: H NMR (200 MHz, C6D6): d=7.59–7.12 (m, 5H; ArH),
6.97 (d, J=16.0 Hz, 1H; =CHPh), 6.66 (d, J=16.0 Hz, 1H; =CHC), 3.69,
3.28 (2s, 2H; 2”OH), 3.22–2.53 (m, 4H; 2”CCH2C), 0.22, 0.16 ppm (2s,
18H; 6”Me); HRMS (70 EV, EI): m/z: calcd for C24H34O3Si2: 426.2046;
found: 426.2042 [M]+.
Compound 9b: 1H NMR (200 MHz, C6D6): d=7.59–7.19 (m, 5H; ArH),
4.48 (s, 1H; CHPh), 4.33 (s, 1H; =CH), 3.28 (s, 3H; OMe), 3.23 (d, J=
16.3Hz, 1H; C HH), 3.06 (d, J=16.3Hz, 1H; CH H), 1.47 (s, 1H; OH),
0.27 ppm (s, 9H; 3”Me); 13C NMR (75.5 MHz, C6D6): d=159.5, 138.2,
129.4, 128.3, 128.1, 109.9, 93.7, 87.6, 72.5, 60.6, 56.0, 47.9, ꢀ0.3ppm;
HRMS (70 EV, EI): m/z: calcd for C17H22O2Si: 286.1389; found: 286.1391
[M]+.
(1S*,3S*,5S*,6R*)-6-(2-Furyl)-1-methoxy-3,5-dimethyl-8-oxabicyclo-
[3.2.1]octan-3-ol (8b): Silyl enol ether 4d (144 mg, 1 mmol), BuLi
(0.63mL, 1.6 n in hexanes, 1 mmol), and carbene complex 1b (184 mg,
0.4 mmol) afforded 8b (48 mg, 48%) as
a
colorless oil. 1H NMR
(300 MHz, CDCl3): d=7.36 (d, J=1.7 Hz, 1H; =CHO), 6.33 (dd, J=3.1,
1.7 Hz, 1H; CH=CHO), 6.13(d, J=3.1 Hz, 1H; CHCH=CHO), 3.51 (s,
3H; MeO), 3.19 (dd, J=9.5, 5.3Hz, 1H; 2-FuC H), 2.65 (brs, 1H; OH),
2.43(dd, J=14.0, 5.3Hz, 1H; C HHCH), 2.24 (dd, J=14.0, 9.5 Hz, 1H;
CHHCH), 2.21 (dd, J=14.0 Hz, 1H; MeOCHH), 1.93(d, J=14.0 Hz,
1H; MeCCHHCMe), 1.94 (d, J=14.0 Hz, 1H; MeOCHH), 1.82 (d, J=
14.0 Hz, 2H; MeCCHHCMe), 1.40, 1.03ppm (2s, 6H; 2”Me); 13C NMR
(75.5 MHz, C6D6): d=156.4, 141.4, 110.0, 106.5, 105.5, 81.3, 70.0, 51.8,
50.0, 48.7, 45.5, 39.0, 29.8, 24.4 ppm; HRMS (70 EV, EI): m/z: calcd for
C14H20O4: 252.1362; found: 252.1351 [M]+.
(1R*,3R*,4S*)-4-[(Z/E)-2-(2-Furyl)ethenyl]-4-methoxy-1,3-bis(trimethyl-
silylethynyl)-1,3-cyclopentanediol (6n) and (1R*,2S*)-2-(2-furyl)-4-me-
thoxy-1-(trimethylsilylethynyl)-3-cyclopentenol (9c): Silyl enol ether 5h
(170 mg, 1 mmol), BuLi (0.63mL, 1.6 n in hexanes, 1 mmol), and carbene
complex 1b (131 mg, 0.4 mmol) or 2b (184 mg, 0.4 mmol) afforded 6n
(90 mg, 54%, cis:trans 1.3:1 from 2b) and 9c (76 mg, 69%, 88% de from
1b; 21 mg, 19% from 2b) as colorless oils.
Compound 6n: 1H NMR (300 MHz, C6D6): d=7.13(d, J=1.7 Hz, 1H; =
CHO, trans diastereomer), 6.99 (d, J=1.7 Hz, 1H; =CHO, cis diaster-
eomer), 6.96 (d, J=3.4 Hz, 1H; CHCH=CHO, cis diastereomer), 6.79,
6.72 (2d, J=16.5 Hz, 2H; CH=CH, trans diastereomer), 6.60, 5.80 (2d,
J=13.1 Hz, 2H; CH=CH cis diastereomer), 6.31 (d, J=3.4 Hz, 1H;
CHCH=CHO, trans diastereomer), 6.20–6.16 (m, 2H; CH=CHO), 3.70,
3.65, 3.38, 3.26 (4brs, 4H; 4”OH), 3.20–2.38 (m, 8H; 2”CH2CCH2),
3.19 (s, 3H; OMe, cis diastereomer), 2.91 (s, 3H; OMe, trans diastereom-
er), 0.25, 0.20 (2s, 18H; 6”MeSi, trans diastereomer), 0.18, 0.14 ppm (2s,
18H; 6”MeSi, cis diastereomer); 13C NMR (75.5 MHz, C6D6): d=152.5,
151.1, 142.4, 142.3, 128.1, 125.1, 122.7, 113.2, 112.1, 111.5, 110.0, 109.9,
109.1, 108.9, 106.0, 105.0, 90.5, 90.3, 88.4, 88.3, 86.6, 79.3, 77.9, 71.3, 71.2,
54.6, 53.6, 53.5, 52.4, 52.1, 48.6, ꢀ0.3, ꢀ0.4, ꢀ0.5, ꢀ0.6 ppm.
(1S*,3S*,5S*,6S*)-1-Methoxy-6-(4-methoxyphenyl)-3,5-dimethyl-8-
oxabicyclo[3.2.1]octan-3-ol (8c): Silyl enol ether 4d (144 mg, 1 mmol),
BuLi (0.63mL, 1.6 n in hexanes, 1 mmol), and carbene complex 1c
1
(200 mg, 0.4 mmol) afforded 8c (54 mg, 46%) as a colorless oil. H NMR
(400 MHz, CDCl3): d=7.17, 6.83(2d, J=8.8 Hz, 4H; ArH), 3.80, 3.51
(2s, 6H; 2”MeO), 2.97 (dd, J=9.1, 4.1 Hz, 1H; CH), 2.74 (brs, 1H;
OH), 2.48 (dd, J=13.9, 9.1 Hz, 1H; CHHCH), 2.32 (d, J=13.9 Hz, 1H;
O2CCHHC), 2.28 (dd, J=13.9, 4.1 Hz, 1H; CHHCH), 1.93(d, J=
14.0 Hz, 1H; CMeCHHCMe), 1.89 (d, J=13.9 Hz, 1H; O2CCHHC), 1.79
(d, J=14.0 Hz, 1H; CMeCHHCMe), 1.39, 0.92 ppm (2s, 6H; 2”Me);
13C NMR (100.6 MHz, C6D6): d=158.1, 135.9, 129.4, 113.4, 105.9, 82.0,
70.4, 55.1, 51.8, 51.7, 50.5, 47.6, 45.0, 29.5, 25.5 ppm; HRMS (70 EV, EI):
m/z: calcd for C17H24O4: 292.1675; found: 292.1673[ M]+; elemental anal-
ysis calcd (%) for C17H24O4: C 69.84, H 8.27; found: C 69.95, H 8.21.
General procedures for the preparation of compounds 6l–p and 9a–e:
These compounds were prepared by using the method described before
for compounds 6a–k. The only difference was the amount of lithium eno-
late, as 0.8 mmol were generated from silyl enol ethers 4 (0.8 mmol) and
BuLi (0.5 mL, 1.6n in hexanes, 0.8 mmol).
Compound 9c: 1H NMR (300 MHz, C6D6, major diastereomer): d=7.16
(d, J=1.8 Hz, 1H; =CHO), 6.23(d, J=3.1 Hz, 1H; CHCH=CHO), 6.18
(dd, J=3.1, 1.8 Hz, 1H; CH=CHO), 4.56–4.53, 4.27–4.25 (2m, 2H;
CHCH-2-Fu), 3.18 (s, 3H; OMe), 3.14 (d, J=15.9 Hz, 1H; CHH), 3.03
(d, J=15.9 Hz, 1H; CHH), 2.02 (brs, 1H; OH), 0.22 ppm (s, 9H; 3”
Me); 13C NMR (75.5 MHz, C6D6, major diastereomer): d=159.3, 153.3,
142.3, 110.4, 109.8, 108.2, 92.0, 87.1, 72.3, 55.9, 54.8, 47.9, ꢀ0.3ppm;
HRMS (70 EV, EI): m/z: calcd for C15H20O3Si: 276.1182; found: 276.1184
[M]+.
(1R*,3R*,4S*)-1,3-Bis(1-hexynyl)-4-methoxy-4-[(E)-styryl]-1,3-cyclopen-
tanediol (6l) and (1R*,2R*)-1-(1-hexynyl)-4-methoxy-2-phenyl-3-cyclo-
pentenol (9a): Silyl enol ether 5g (157 mg, 1 mmol), BuLi (0.63mL, 1.6 n
in hexanes, 1 mmol), and carbene complex 1a (135 mg, 0.4 mmol) or 2a
(188 mg, 0.4 mmol) afforded 6l (22 mg, 14% from 1a; 14 mg, 9% from
2a) and 9a (56 mg, 52% from 1a; 66 mg, 61% from 2a) as colorless oils.
Compound 6l: 1H NMR (300 MHz, C6D6): d=7.46–7.02 (m, 5H; ArH),
6.88 (d, J=16.4 Hz, 1H; =CHPh), 6.57 (d, J=16.4 Hz, 1H; =CHC), 3.63,
3.38 (2s, 2H; 2”OH), 2.98 (d, J=14.6 Hz, 1H; HOCCHHCOH), 2.77
(d, J=14.6 Hz, 1H; HOCCHHCOMe), 2.70 (d, J=14.6 Hz, 1H;
HOCCHHCOH), 2.48 (d, J=14.6 Hz, 1H; HOCCHHCOMe), 2.03, 1.93
(2t, J=6.9 Hz, 4H; 2”CH2Pr), 1.31–1.19 (m, 8H; 2”CH2CH2Me), 0.72,
0.66 ppm (2t, J=7.4 Hz, 6H; 2”Me); 13C NMR (75.5 MHz, C6D6): d=
136.8, 129.9, 128.7, 128.1, 126.8, 88.6, 86.5, 84.5, 83.2, 80.0, 79.2, 71.2, 54.4,
52.0, 48.9, 30.9, 30.7, 22.0, 21.9, 18.4, 13.5, 13.4 ppm; HRMS (70 EV, EI):
m/z: calcd for C26H34O3: 394.2508; found: 394.2501 [M]+.
Compound 9a: 1H NMR (200 MHz, C6D6): d=7.58–7.17 (m, 5H; ArH),
4.47 (s, 1H; CHPh), 4.40 (s, 1H; =CH), 3.31 (s, 3H; OMe), 3.27 (d, J=
17.7 Hz, 1H; CHHCOH), 3.11 (d, J=17.7 Hz, 1H; CHHCOH), 2.12 (t,
J=6.5 Hz, 2H; CH2Pr), 1.49 (s, 1H; OH), 1.44–1.28 (m, 4H;
CH2CH2Me), 0.89 ppm (t, J=6.9 Hz, 3H; Me); 13C NMR (75.5 MHz,
C6D6): d=159.7, 138.7, 129.7, 128.3, 127.5, 94.0, 84.2, 83.9, 72.5, 60.8, 56.0,
48.3, 30.8, 22.0, 18.4, 13.5 ppm; HRMS (70 EV, EI): m/z: calcd for
(1R*,3R*,4S*)-1,3-Bis(1-hexynyl)-4-methoxy-4-[(Z/E)-2-(4-methoxyphe-
nyl)ethenyl]-1,3-cyclopentanediol (6o) and (1R*,2R*)-1-(1-hexynyl)-4-
methoxy-2-(4-methoxyphenyl)-3-cyclopentenol (9d): Silyl enol ether 5g
(157 mg, 1 mmol), BuLi (0.63mL, 1.6 n in hexanes, 1 mmol), and carbene
complex 1c (147 mg, 0.4 mmol) or 2c (200 mg, 0.4 mmol) afforded 6o
(32 mg, 19%, cis:trans 1:1.4 from 1c; 107 mg, 63%, cis:trans 1:1.4 from
2c) and 9d (62 mg, 52% from 1c; 24 mg, 20% from 2c) as colorless oils.
Compound 6o: 1H NMR (300 MHz, C6D6): d=7.59 (d, J=8.7 Hz, 2H;
ArH, cis diastereomer), 7.58, 6.94 (2d, J=8.7 Hz, 4H; ArH, trans diaster-
eomer), 6.88, 6.50 (2d, J=16.4 Hz, 2H; CH=CH, trans diastereomer),
6.83–6.74 (m, 6H; ArH), 6.61, 5.98 (2d, J=13.1 Hz, 2H; CH=CH, cis di-
astereomer), 3.71–3.48 (m, 4H; 4”OH), 3.32, 3.28, 3.24, 2.98 (4s, 12H;
4”MeO), 3.30–2.50 (m, 8H; 2”CH2CCH2), 2.08–0.63ppm (m, 18H; 2”
Bu); 13C NMR (75.5 MHz, C6D6): d=160.0, 159.7, 134.7, 133.2, 131.8,
129.6, 128.1, 126.5, 114.2, 113.6, 88.7, 88.0, 86.5, 84.6, 83.2, 81.0, 79.3, 78.1,
71.2, 54.6, 54.5, 54.3, 51.9, 48.9, 30.9, 30.7, 30.5, 22.0, 21.9, 18.5, 18.3,
13.5 ppm.
Chem. Eur. J. 2005, 11, 4995 – 5006
www.chemeurj.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5003

J. Barluenga et al.
Compound 9d: 1H NMR (300 MHz, C6D6): d=7.42, 6.83(2d, J=8.8 Hz,
4H; ArH), 4.39, 4.31 (2s, 2H; ArCH, =CH), 3.31, 3.22 (2s, 6H, 2”
MeO), 3.18 (d, J=15.9 Hz, 1H; CHHCOMe), 3.03 (d, J=15.9 Hz, 1H;
CHHCOMe), 2.02 (t, J=6.8 Hz, 2H; CH2Pr), 1.37–1.24 (m, 5H;
CH2CH2Me, OH), 0.75 ppm (t, J=6.9 Hz, 3H; Me); 13C NMR
(75.5 MHz, C6D6): d=159.6, 130.4, 130.2, 113.9, 94.3, 84.4, 83.8, 72.4,
60.1, 56.0, 54.5, 48.2, 30.9, 21.9, 18.4, 13.5 ppm; HRMS (70 EV, EI): m/z:
calcd for C19H24O3: 300.1725; found: 300.1730 [M]+.
(135 mg, 0.4 mmol) afforded compound 10c (60 mg, 51%) as a colorless
oil.
Method A: Silyl enol ether 5k (174 mg, 0.8 mmol), BuLi (0.50 mL, 1.6n
in hexanes, 0.8 mmol), and carbene complex 1a (135 mg, 0.4 mmol) af-
forded 10c (62 mg, 53%) as a colorless oil. 1H NMR (300 MHz, CDCl3):
d=7.18–6.73(m, 10H; ArH), 5.62 (s, 1H; CH =), 3.93–2.67 (m, 6H;
CH2CHCHCH2), 3.73 ppm (s, 3H; OMe); 13C NMR (75.5 MHz, CDCl3):
d=200.8, 175.5, 142.0, 140.8, 128.1, 127.8, 127.7, 126.3, 126.2, 105.4, 55.8,
46.7, 46.4, 45.0, 36.8 ppm; HRMS (70 EV, EI): m/z: calcd for C20H20O2:
292.1463; found: 292.1472 [M]+.
(1R*,3R*,4S*)-4-Methoxy-4-[(Z/E)-2-(4-methoxyphenyl)ethenyl]-1,3-
bis(trimethylsilylethynyl)-1,3-cyclopentanediol (6p) and (1R*,2R*)-2-me-
thoxy-2-(4-methoxyphenyl)-1-(trimethylsilylethynyl)-3-cyclopentenol
(9e): Silyl enol ether 5h (170 mg, 1 mmol), BuLi (0.63mL, 1.6 n in hex-
anes, 1 mmol), and carbene complex 1c (147 mg, 0.4 mmol) or 2c
(200 mg, 0.4 mmol) afforded 6p (36 mg, 20%, cis:trans 1:2 from 2c) and
9e (86 mg, 68% from 1c; 53mg, 42% from 2c) as colorless oils.
Compound 6p: 1H NMR (300 MHz, C6D6): d=7.66, 6.85 (2d, J=8.4 Hz,
4H; ArH, cis diastereomer), 7.58, 6.94 (2d, J=8.4 Hz, 4H; ArH, trans di-
astereomer), 6.98, 6.62 (2d, J=16.4 Hz, 2H; CH=CH, trans diastereom-
er), 6.68, 6.01 (2d, J=13.1 Hz, 2H; CH=CH, cis diastereomer), 3.39, 3.22
(2s, 6H; 2”MeO, cis diastereomer), 3.36, 2.99 (2s, 6H; 2”MeO, trans di-
astereomer), 3.35–2.42 (m, 12H; 4”OH and 2”CH2CCH2), 0.24, 0.20
(2s, 18H; 6”MeSi, trans diastereomer), 0.21, 0.18 ppm (2s, 18H; 6”
MeSi, cis diastereomer).
Compound 9e: 1H NMR (300 MHz, C6D6): d=7.38, 6.81 (2d, J=8.4 Hz,
4H; ArH), 4.38, 4.24 (2s, 2H; ArCH, =CH), 3.30, 3.18 (2s, 6H; 2”
OMe), 3.13 (d, J=15.9 Hz, 1H; CHH), 2.96 (d, J=15.9 Hz, 1H; CHH),
1.48 (s, 1H; OH), 0.16 ppm (s, 9H; 3”MeSi); 13C NMR (75.5 MHz,
C6D6): d=159.7, 159.4, 130.4, 129.8, 114.0, 110.1, 94.0, 87.4, 72.5, 59.9,
56.1, 54.5, 47.7, ꢀ0.2 ppm; HRMS (70 EV, EI): m/z: calcd for C18H24O3Si:
316.1495; found: 316.1483 [M]+.
(4aR*,5R*,9aR*)-3,4,4a,5,6,9a-Hexahydro-7-methoxy-5-phenyl-2H-cyclo-
hepta[b]pyran-9-one (10d): Method A: Silyl enol ether 5l (158 mg,
0.8 mmol), BuLi (0.50 mL, 1.6n in hexanes, 0.8 mmol), and carbene com-
plex 2a (188 mg, 0.4 mmol) in diethyl ether (10 mL) afforded 10d
(58 mg, 53%) as a colorless oil. 1H NMR (400 MHz, C6D6): d=7.22–6.84
(m, 5H; ArH), 5.56 (s, 1H; CH=), 4.41 (d, J=4.2 Hz, 1H; OCH), 3.84–
3.78 (m, 1H; CHHO), 3.53–3.47 (m, 1H; CHHO), 3.32–3.26 (m, 1H;
CHHCHPh), 3.17 (dd, J=12.7, 3.7 Hz, 1H; CHPh), 3.06 (s, 3H; OMe),
2.48 (d, J=16.6 Hz, 1H; CHHCHPh), 2.25–2.21 (m, 1H; CHCHPh),
1.52–1.04 ppm (m, 4H; OCH2CH2CH2); 13C NMR (100.6 MHz, C6D6):
d=197.1, 173.8, 144.6, 128.5, 127.3, 126.4, 103.8, 85.3, 65.2, 54.8, 44.0,
41.4, 36.3, 24.6, 22.1 ppm; HRMS (70 EV, EI): m/z: calcd for C17H20O3:
272.1412; found: 272.1416 [M]+; elemental analysis calcd (%) for
C17H20O3: C 74.97, H 7.40; found: C 75.09, H 7.24.
cis-5-(2-Furyl)-3-methoxy-6-phenyl-2-cycloheptenone (10e): Method B:
Ketone 4k (64 mg, 0.44 mmol), LDA (0.44 mmol), and carbene complex
2b (184 mg, 0.4 mmol) afforded compound 10e (7 mg, 6%) as a colorless
oil.
Method A: Silyl enol ether 5k (174 mg, 0.8 mmol), BuLi (0.50 mL, 1.6n
in hexanes, 0.8 mmol), and carbene complex 2b (184 mg, 0.4 mmol) af-
forded 10e (52 mg, 46%) as a colorless oil. 1H NMR (400 MHz, C6D6):
d=7.11–6.66 (m, 5H; ArH), 6.89 (d, J=1.8 Hz, 1H; =CHO), 5.86 (dd,
J=3.3, 1.8 Hz, 1H; CH=CHO), 5.51 (s, 1H; =CHCOMe), 5.44 (d, J=
3.3 Hz, 1H; CHCH=CHO), 2.98 (s, 3H; OMe), 3.47–2.83 (m, 5H;
CH2CHCHCH2), 2.46 ppm (ddd, J=16.2, 4.2, 1.3Hz, 1H;
CH2CHCHCH2); 13C NMR (100.6 MHz, C6D6): d=199.0, 171.4, 155.1,
142.2, 141.0, 127.9, 127.5, 126.3, 109.9, 106.7, 105.1, 55.0, 46.3, 43.5, 40.2,
35.9 ppm; HRMS (70 EV, EI): m/z: calcd for C18H18O3: 282.1256; found:
282.1259 [M]+; elemental analysis calcd (%) for C18H18O3: C 76.57, H
6.43; found: C 76.69, H 6.29.
General procedures for the preparation of compounds 10 and 12: Meth-
od A: The compounds were prepared following the procedure described
before for compounds 9a–e.
Method B: Alternatively, when chromium carbene complexes were used,
compounds 10 were prepared by treatment of ketones 4 (0.44 mmol)
with LDA (1 equiv) at ꢀ308C for 30 min in THF (10 mL). Carbene com-
plexes 1 (0.4 mmol) were then added, and the mixture was warmed to
room temperature and stirred for 1 h. The reaction was quenched with
water (10 mL) and extracted with diethyl ether (3”50 mL). The solvents
were removed, and the residue was dissolved in hexanes/ethyl acetate
(5:1; 25 mL). Air was bubbled through the mixture, and the solution was
exposed to direct sunlight for 3h. The resulting suspension was filtered
through Celite, the solvents removed, and the obtained residue was puri-
fied by flash column chromatography on silica gel (hexanes/ethyl acetate
5:1!2:1) to give compounds 10 or 12. Compounds 10d and 10e were pu-
rified on deactivated silica gel (hexanes/ethyl acetate 10:1!5:1).
3-Methoxy-5-(4-methoxyphenyl)-2-cycloheptenone (10 f): Method B:
Ketone 4i (31 mg, 0.44 mmol), LDA (0.44 mmol), and carbene complex
1c (147 mg, 0.4 mmol) afforded compound 10 f (51 mg, 52%) as a color-
less oil. 1H NMR (200 MHz, CDCl3): d=7.12, 6.87 (2d, J=6.9 Hz, 4H;
ArH), 5.49 (s, 1H; CH=), 3.83, 3.65 (2s, 6H; 2”OMe), 3.23–1.86 ppm
(m, 7H; CH2CHCH2CH2); 13C NMR (50.5 MHz, CDCl3): d=202.1,
175.0, 158.1, 138.1, 127.5, 114.0, 105.3, 55.8, 55.2, 41.1, 40.7, 40.0,
30.1 ppm; HRMS (70 EV, EI): m/z: calcd for C15H18O3: 246.1256; found:
246.1255 [M]+.
3-Methoxy-5-phenyl-2-cycloheptenone (10a): Method B: Ketone 4i
(31 mg, 0.44 mmol), LDA (0.44 mmol), and carbene complex 1a (135 mg,
0.4 mmol) or 2a (188 mg, 0.4 mmol) afforded compound 10a (40 mg,
cis-3-Methoxy-5-(4-methoxyphenyl)-6-phenyl-2-cycloheptenone
(10g):
46%, from 1a; 42 mg, 48% from 2a) as
a
colorless oil. 1H NMR
Method B: Ketone 4k (64 mg, 0.44 mmol), LDA (0.44 mmol), and car-
bene complex 1c (147 mg, 0.4 mmol) afforded compound 10g (55 mg,
43%) as a colorless oil. 1H NMR (200 MHz, CDCl3): d=7.16–6.66 (m,
9H; ArH), 5.59 (s, 1H; CH=), 3.73, 3.70 (2s, 6H; 2”OMe), 3.53–3.19
(m, 4H; CHHCHCHCHH), 2.90 (dd, J=15.3, 3.1 Hz, 1H; CHHCH),
2.70 ppm (d, J=17.0 Hz, 1H; CHCHH); 13C NMR (50.5 MHz, CDCl3):
d=201.2, 175.5, 157.9, 141.2, 134.2, 128.9, 128.1, 127.8, 126.4, 113.1, 105.3,
55.8, 55.2, 46.4, 45.9, 45.1, 37.3 ppm; HRMS (70 EV, EI): m/z: calcd for
C21H22O3: 322.1569; found: 322.1550 [M]+.
(200 MHz, CDCl3): d=7.36–7.19 (m, 5H; ArH), 5.48 (s, 1H; CH=), 3.65
(s, 3H; OMe), 3.26–1.91 ppm (m, 7H; C H2CHPhCH2CH2); 13C NMR
(50.5 MHz, CDCl3): d=202.1, 175.1, 145.9, 128.6, 126.5, 126.4, 105.3, 55.8,
41.5, 40.8, 39.7, 30.0 ppm; HRMS (70 EV, EI): m/z: calcd for C14H16O2:
216.1150; found: 216.1165 [M]+.
cis-3-Methoxy-6-methyl-5-phenyl-2-cycloheptenone (10b): Method B:
Ketone 4j (57 mg, 0.44 mmol), LDA (0.44 mmol), and carbene complex
1a (135 mg, 0.4 mmol) afforded compound 10b (40 mg, 44%) as a color-
1
less oil. H NMR (400 MHz, CDCl3): d=7.35–7.05 (m, 5H; ArH), 5.45 (s,
3-Methoxy-5,5-dimethyl-6-phenyl-2-cycloheptenone
(12):
Method B:
1H; CH=), 3.62 (s, 3H; OMe), 3.29 (ddd, J=11.0, 5.5, 2.2 Hz, 1H;
CHPh), 3.11 (dd, J=16.9, 11.0 Hz, 1H; CHHCOMe), 2.68–2.56 (m, 3H;
CH2CO, CHHCOMe), 2.37–2.28 (m, 1H; CHMe), 0.68 ppm (d, J=
6.8 Hz, 3H; Me); 13C NMR (100.6 MHz, CDCl3): d=201.0, 176.8, 143.3,
128.2, 127.5, 126.3, 105.4, 55.7, 49.8, 46.0, 35.4, 33.0, 16.4 ppm; HRMS
(70 EV, EI): m/z: calcd for C15H18O2: 230.1307; found: 230.1299 [M]+.
Ketone 4k (64 mg, 0.44 mmol), LDA (0.44 mmol), and carbene complex
11 (169 mg, 0.4 mmol) afforded compound 12 (47 mg, 48%) as a colorless
oil. H NMR (200 MHz, CDCl3): d=7.32–7.02 (m, 5H; ArH), 5.43 (d, J=
2.2 Hz, 1H; CH=), 3.70 (s, 3H; OMe), 3.04 (dd, J=16.6, 11.3Hz, 1H;
CHCHH), 2.87 (d, J=11.3Hz, 1H; CH), 2.83 (d, J=14.6 Hz, 1H;
CHHCMe2), 2.71 (d, J=16.6 Hz, 1H; CHCHH), 2.20 (dd, J=14.6,
2.2 Hz, 1H; CHHCMe2), 1.05, 0.65 ppm (2s, 6H; 2”Me); 13C NMR
(50.5 MHz, CDCl3): d=203.5, 173.5, 142.3, 129.2, 127.6, 126.2, 103.7, 55.8,
1
cis-3-Methoxy-5,6-diphenyl-2-cycloheptenone (10c): Method B: Ketone
4k (64 mg, 0.44 mmol), LDA (0.44 mmol), and carbene complex 1a
5004
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2005, 11, 4995 – 5006

Carbocyclization Reactions
FULL PAPER
49.1, 46.6, 46.5, 35.0, 27.9, 25.5 ppm; HRMS (70 EV, EI): m/z: calcd for
C16H20O2: 244.1463; found: 244.1465 [M]+; elemental analysis calcd (%)
for C16H20O2: C 78.65, H 8.25; found: C 78.50, H 8.13.
colorless oil. 1H NMR (300 MHz, C6D6): d=7.47–7.05 (m, 10H; ArH),
4.44–4.40 (m, 2H; =CH, CHPh), 3.39 (s, 3H; OMe), 3.17 (d, J=16.3Hz,
1H; CHH), 3.01 (d, J=16.3Hz, 1H; CH H), 1.61 ppm (s, 1H; OH);
13C NMR (50.5 MHz, C6D6): d=159.7, 147.5, 138.6, 129.0, 128.4, 128.0,
127.4, 126.6, 125.4, 94.4, 80.6, 61.6, 56.1, 50.0 ppm; HRMS (70 EV, EI):
m/z: calcd for C18H18O2: 266.1307; found: 266.1302 [M]+.
1-{(1R,5S)-6,6-Dimethylbicyclo[3.1.1]hept-2-en-2-yl}ethanone
(4m):
MeLi (1 equiv, 6.7 mL, 1.5m in diethyl ether) was added dropwise to a so-
lution of (ꢀ)-myrtenal (1.52 g, 10 mmol) in diethyl ether (20 mL) at
ꢀ788C, thereby warming the mixture to room temperature; it was then
stirred for 10 min. The reaction was quenched with water (20 mL) and
extracted in diethyl ether (3”20 mL). After removing solvents, the ob-
tained crude residue was used in the next step without further purifica-
tion. Dimethyl sulfoxide (4 equiv, 3.12 g, 40 mmol) was added dropwise
to a solution of oxalyl chloride (2 equiv, 2.54 g, 20 mmol) in CH2Cl2
(20 mL) at ꢀ788C. After the reaction mixture had been stirred for 5 min,
a solution of the residue from the previous step in CH2Cl2 (30 mL) was
added dropwise and the resulting mixture was stirred for 30 min. Tri-
ethylamine (6.5 equiv, 9 mL, 65 mmol) was then added and the reaction
was warmed to room temperature. After stirring for 12 h, the reaction
was quenched with water (30 mL) and extracted with diethyl ether. The
solvents were removed, and the resulting residue was purified by flash
column chromatography on silica gel (hexanes/ethyl acetate 10:1!5:1)
to afford compound 4m as a pale yellow oil (1.26 g, 76%). [a]2D0 =ꢀ29.7
(c=0.77, CH2Cl2); 1H NMR (300 MHz, CDCl3): d=6.68–6.64 (m, 1H;
CH=), 2.86–1.98, 0.98–0.94 (2m, 6H; CH2CHCH2CH), 2.18 (s, 3H;
MeCO), 1.21, 0.62 ppm (2s, 6H; 2”Me); 13C NMR (75.5 MHz, CDCl3):
d=196.9, 149.4, 137.5, 40.0, 39.1, 37.1, 32.3, 30.9, 25.6, 24.7, 20.6 ppm;
HRMS (70 EV, EI): m/z: calcd for C11H16O: 164.1201; found: 164.1195
[M]+.
(1S,2S,7R,8R,10S)-5-Methoxy-11,11-dimethyl-7-phenyltricyclo[8.1.1.02,8]-
dodec-4-en-3-one (13): Ketone 4m (73mg, 0.44 mmol) was added to a so-
lution of lithium diisopropylamide (0.44 mmol) in THF (10 mL) at
ꢀ408C and the mixture was stirred for 30 min and then cooled to ꢀ788C.
A solution of carbene complex 1a (188 mg, 0.4 mmol) in THF (5 mL)
was added dropwise and the reaction mixture was slowly warmed over-
night. The reaction mixture was cooled again to ꢀ788C and a saturated
solution of ammonium chloride (5 mL) was added. The mixture was
warmed to room temperature and extracted with diethyl ether (3”
20 mL). Solvents were removed and the resulting crude residue was dis-
solved hexanes/ethyl acetate (5:1, 20 mL). Air was bubbled through the
mixture and the solution was exposed to direct sunlight for 1 h. The ob-
tained suspension was filtered on celite, the solvents were removed, and
the resulting residue was purified by flash column chromatography on
silica gel (hexanes/ethyl acetate 20:1!5:1) to afford compound 13 as a
colorless oil (51 mg, 41%). [a]2D0 =ꢀ59.3( c=0.44, CH2Cl2); 1H NMR
(400 MHz, CDCl3): d=7.34–7.17 (m, 5H; ArH), 5.57 (s, 1H; CH=), 3.62
(s, 3H; OMe), 3.53–3.41 (m, 2H; CHHCHPh), 3.11 (dd, J=10.2, 5.1 Hz,
1H; CHCO), 2.83(apparent q, J=5.7 Hz, 1H; CHPhCH), 2.74 (q, J=
10.2 Hz, 1H; CH2CHCHCO), 2.65 (d, J=16.2 Hz, 1H; CHHCHPh),
(1R*,2R*)-4-Methoxy-1-methyl-2-phenyl-3-cyclopentenol (9g): Silyl enol
ether 5d (144 mg, 0.8 mmol), BuLi (0.50 mL, 1.6n in hexanes, 0.8 mmol),
and carbene complex 2a (188 mg, 0.4 mmol) afforded 9g (52 mg, 64%)
as a colorless oil along with compound 6 f (22 mg, 22%, >95% de).
1H NMR (300 MHz, C6D6): d=7.28–7.20 (m, 5H; ArH), 4.44 (brs, 1H;
CH=), 3.88 (brs, 1H; CHPh), 3.48 (s, 3H; OMe), 2.63 (d, J=16.1 Hz,
1H; CHH), 2.58 (d, J=16.1 Hz, 1H; CHH), 1.61 (brs, 1H; OH),
0.91 ppm (s, 3H; Me); 13C NMR (75.5 MHz, C6D6): d=158.5, 142.2,
128.2, 126.6, 95.8, 79.4, 61.0, 55.7, 47.7, 25.6 ppm; HRMS (70 EV, EI): m/
z: calcd for C13H16O2: 204.1150; found: 204.1159 [M]+.
(1R*,2R*)-1-Isobutyl-4-methoxy-2-phenyl-3-cyclopentenol (9h): Silyl
enol ether 5a (138 mg, 0.8 mmol), BuLi (0.50 mL, 1.6n in hexanes,
0.8 mmol), and carbene complex 2a (188 mg, 0.4 mmol) afforded 9h
(50 mg, 51%) as a colorless oil. 1H NMR (300 MHz, C6D6): d=7.26–7.16
(m, 5H; ArH), 4.46 (ddd, J=3.3, 2.6, 0.8 Hz, 1H; CH=), 3.70 (d, J=
2.6 Hz, 1H; CHPh), 3.37 (s, 3H; OMe), 2.80 (dd, J=16.1, 3.3 Hz, 1H;
CCHHC), 2.52 (dd, J=16.1, 0.8 Hz, 1H; CCHHC), 1.91–1.82 (m, 1H;
CHMe2), 1.75 (brs, 1H; OH), 1.28 (dd, J=14.4, 5.3Hz, 1H; C HHCH),
1.03(dd, J=14.4, 6.4 Hz, 1H; CHHCH), 0.88 (d, J=6.7 Hz, 3H; Me),
0.86 ppm (d, J=6.3Hz, 3H; Me); 13C NMR (75.5 MHz, C6D6): d=160.0,
142.3, 128.6, 128.3, 126.6, 96.6, 81.8, 63.2, 55.9, 46.7, 45.8, 24.7, 24.3 ppm;
HRMS (70 EV, EI): m/z: calcd for C16H22O2: 246.1620; found: 246.1619
[M]+.
(1R*,2R*)-4-Methoxy-2-Phenyl-1-[(E)-styryl]-3-cyclopentenol (9i): Silyl
enol ether 5k (174 mg, 0.8 mmol), BuLi (0.50 mL, 1.6n in hexanes,
0.8 mmol), and carbene complex 2a (188 mg, 0.4 mmol) afforded 9i
(23mg, 20%) as a colorless oil. 1H NMR (300 MHz, C6D6): d=7.35–7.06
(m, 10H; ArH), 6.63(d, J=15.9 Hz, 1H; =CHPh), 6.41 (d, J=15.9 Hz,
1H; =CHCOH), 4.42 (s, 1H; =CHCOMe), 4.04 (s, 1H; CHPh), 3.39 (s,
3H; OMe), 3.28 (s, 1H; OH), 2.90 (d, J=15.8 Hz, 1H; CHH), 2.82 ppm
(d, J=15.8 Hz, 1H; CHH); 13C NMR (75.5 MHz, C6D6): d=160.3, 142.1,
137.3, 135.6, 130.0, 129.2, 126.7, 94.5, 79.8, 58.7, 56.1, 46.8 ppm.
Acknowledgements
Financial support for this work was provided by the Ministerio de Cien-
cia y Tecnología (project BQU2001-3853) and Junta del Principado de
Asturias (project PR-01-GE-9) of Spain.
2.20–2.14
(m,
1H;
CHPhCHCHH),
1.98–1.84
(m,
2H;
CHPhCHCH2CHCHH), 1.51–1.36 (m, 2H; CHPhCHCHHCHCHH),
1.18, 0.76 ppm (2s, 6H; 2”Me); 13C NMR (100.6 MHz, C6D6): d=202.5,
172.8, 144.9, 128.6, 128.5, 125.9, 106.8, 54.6, 54.6, 46.3, 44.0, 40.0, 39.4,
35.8, 34.8, 28.1, 26.3, 23.1, 22.3 ppm; HRMS (70 EV, EI): m/z: calcd for
C21H26O2: 310.1933; found: 310.1939 [M]+; elemental analysis calcd (%)
for C21H26O2: C 81.25, H 8.44; found: C 81.33, H 8.35.
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General procedures for the preparation of compounds 9b,f–i: BuLi
(1 equiv) was added to
a solution of silyl enol ethers 5a,d,f,h,k
(0.8 mmol) in diethyl ether (10 mL) at 208C for silyl enol ethers 5d,f or
at 08C for silyl enol ethers 5a,h,k, and the reaction mixture was then
stirred for 30 min. PMDTA (0.50 mL, 2.4 mmol) was then added at 08C,
and the mixture was stirred for further 10 min. Carbene complex 2a
(188 mg, 0.4 mmol) was then added and the reaction was warmed to
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Chem. Eur. J. 2005, 11, 4995 – 5006
www.chemeurj.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5005

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Received: February 15, 2005
Please note: Minor changes have been made to this manuscript since its
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