New cationic olefin cyclization-pinacol reactions. Ring-expanding cyclopentane annulations that directly install useful functionality in the cyclopentane ring

Article abstract of DOI:10.1021/jo025927r

Two new tandem cationic olefin cyclization-pinacol reactions that provide cyclopentane-fused cycloalkanone products are described. Treatment of cis-1-[2-alkenyl-2-(triethylsiloxy)cycloalkyl]-but-3-en-2-ol derivatives 21-24 with triflic anhydride at -78 °C affords cycloalkanones 31-34 in 54-90% yields with diastereoselectivities of typically >20:1. In this unusual transformation, the starting cycloalkanone is ring-expanded and fused to a 2-alkenylcyclopentane fragment. Reaction of cis-(2-siloxy-2-alkenylcycloalkyl)pyrrolidin-1-ylethanones 15-17 with triflic anhydride and 2,6-di-tert-butyl-4-methylpyridine (DTBMP) at -20 to +65 °C followed by hydrolysis of the intermediate iminium salts 64 with aqueous KHCO₃ affords cycloalkanediones 46-48 in moderate yield and high diastereoselectivity (>20:1). These are the first examples of ring-expanding cyclopentane annulations that directly introduce a carbon side chain or carbonyl functionality at the cyclopentane C2 position. The high diastereoselectivities observed in these reactions are believed to arise from reaction through highly organized cyclic transition states.

Full text of DOI:10.1021/jo025927r

New Ca tion ic Olefin Cycliza tion -P in a col Rea ction s.
Rin g-Exp a n d in g Cyclop en ta n e An n u la tion s Th a t Dir ectly In sta ll
Usefu l F u n ction a lity in th e Cyclop en ta n e Rin g
Larry E. Overman* and J ohn P. Wolfe
Department of Chemistry, 516 Rowland Hall, University of California, Irvine, California 92697-2025
leoverma@uci.edu
Received May 10, 2002
Two new tandem cationic olefin cyclization-pinacol reactions that provide cyclopentane-fused
cycloalkanone products are described. Treatment of cis-1-[2-alkenyl-2-(triethylsiloxy)cycloalkyl]-
but-3-en-2-ol derivatives 21-24 with triflic anhydride at -78 °C affords cycloalkanones 31-34 in
54-90% yields with diastereoselectivities of typically >20:1. In this unusual transformation, the
starting cycloalkanone is ring-expanded and fused to a 2-alkenylcyclopentane fragment. Reaction
of cis-(2-siloxy-2-alkenylcycloalkyl)pyrrolidin-1-ylethanones 15-17 with triflic anhydride and 2,6-
di-tert-butyl-4-methylpyridine (DTBMP) at -20 to +65 °C followed by hydrolysis of the intermediate
iminium salts 64 with aqueous KHCO3 affords cycloalkanediones 46-48 in moderate yield and
high diastereoselectivity (>20:1). These are the first examples of ring-expanding cyclopentane
annulations that directly introduce a carbon side chain or carbonyl functionality at the cyclopentane
C2 position. The high diastereoselectivities observed in these reactions are believed to arise from
reaction through highly organized cyclic transition states.
In tr od u ction
ring-expanding cyclopentane annulation has been ex-
ploited to synthesize a number of natural products
including the lycopodium alkaloid magellaninone (1)7 and
the diterpene shahamin K (2).8
For some years, our group has been involved in the
development of tandem Prins cyclization-pinacol reac-
tions for the synthesis of carbocyclic and heterocyclic
products.1 These reactions typically exhibit excellent
levels of stereocontrol, as they are believed to occur
through highly organized six-membered chairlike transi-
tion states. A wide variety of monocyclic and fused
polycyclic compounds1,2 as well as attached ring systems3
and spirocycles4 can be constructed in this way. One
variant of this chemistry, the ring-expanding cyclopen-
tane annulation, involves treatment of a 2-[(2,2-dialkoxy)-
ethyl]-1-alkenylcycloalkanol silyl ether with a Lewis acid.
The resulting oxonium ion engages the tethered alkene
in a 6-endo Prins cyclization, which is followed by a
pinacol rearrangement of the resulting cyclic carbenium
ion to provide cycloalkanones that have been expanded
by one carbon and fused to a 2-alkoxycyclopentane ring
(Figure 1). Analogous ring-expanding cyclopentene5 and
cyclohexane6 annulations have been described also. The
The 2-alkoxycyclopentane unit introduced in ring-
expanding cyclopentane annulations is not converted
easily into congeneric 2-alkyl or 2-alkenyl derivatives.
However, a number of natural products exhibiting po-
tentially important biological activities contain a 2-al-
kenylcyclopentane fragment fused to various carbocyclic
rings. For example, cylindramide (3) is cytotoxic toward
B16 melanoma cells,9a geodin A (4) is a potent nemato-
cide,9d and SS-8201B (5) exhibits antibacterial activity.9e
Our interest in these compounds, coupled with the
opportunity they provide to further expand the scope of
the ring-expanding cyclopentane annulations, led us to
explore the use of other functional groups as initiators
for pinacol-terminated cationic cyclization reactions. In
particular, we wished to examine initiating groups that
would directly install alkenyl or carbonyl functionality
at the C2 position of the newly formed cyclopentane ring.
Herein we describe the use of allyl cations and keten-
(1) For brief reviews, see: (a) Overman, L. E. Aldrichim. Acta 1995,
28, 107-120. (b) Overman, L. E. Acc. Chem. Res. 1992, 25, 352-359.
(c) Overman, L. E. In Selectivities in Lewis Acid-Promoted Reactions;
NATO ASSI Series 289; Schinzer, D., Ed.; Kluwer Academic: Dor-
drecht, The Netherlands, 1989; pp 1-20.
(2) (a) Hirst, G. C.; Howard, P. N.; Overman, L. E. J . Am. Chem.
Soc. 1989, 111, 1514-1515. (b) Gahman, T.; Overman, L. E. Tetrahe-
dron 2002, 58, in press.
(7) Hirst, G. C.; J ohnson, T. O., J r.; Overman, L. E. J . Am. Chem.
Soc. 1993, 115, 2992-2993.
(8) Lebsack, A. D.; Overman, L. E.; Valentekovich, R. J . J . Am.
Chem. Soc. 2001, 123, 4851-4852.
(9) (a) Kanazawa, S.; Fusetani, N.; Matsunaga, S. Tetrahedron Lett.
1993, 34, 1065-1068. (b) Gunasekera, S. P.; Gunasekera, M.; McCar-
thy, P. J . Org. Chem. 1991, 56, 4830-4833. (c) Shigemori, H.; Bae,
M.; Yazawa, K.; Sasaki, T.; Kobayashi, J . J . Org. Chem. 1992, 57,
4317-4320. (d) Capon, R. J .; Skene, C.; Lacey, E.; Gill, J . H.;
Wadsworth, D.; Friedel, T. J . Nat. Prod. 1999, 62, 1256-1259. (e)
Kouichi, Y. J apanese patent J P59151896, Aug 30, 1984; Chem. Abstr.
1985, 102, 94328.
(3) Overman, L. E.; Pennington, L. P. Can. J . Chem. 2000, 78, 732-
738.
(4) Minor, K. P.; Overman, L. E. Tetrahedron 1997, 53, 8927-8940.
(5) J ohnson, T. O.; Overman, L. E. Tetrahedron Lett. 1991, 32,
7361-7364.
(6) Ando, S.; Minor, K. P.; Overman, L. E. J . Org. Chem. 1997, 62,
6379-6387.
10.1021/jo025927r CCC: $22.00 © 2002 American Chemical Society
Published on Web 08/08/2002
J . Org. Chem. 2002, 67, 6421-6429
6421

Overman and Wolfe
F IGURE 1.
SCHEME 1a
iminium ions as initiators for ring-expanding cyclopen-
tane annulations.
a
Key: (a) 1-(chloroacetyl)pyrrolidine; (b) RLi or RMgBr/CeCl3;
(c) TES-Cl, DMAP, pyridine; (d) Ti(Oi-Pr)4, Ph2SiH2; (e) R′Li or
R′MgBr.
Resu lts
treated with an alkenyllithium or alkenylcerium15 re-
agent to afford tertiary allylic alcohols 12-14. Diaste-
reoselection in the alkenylmetal additions ranged from
3-5:1 for cyclopentanone substrates 12a -c to 5-10:1 for
cyclohexanone precursors 13a -c and 10-20:1 for cyclo-
heptanone amides 14a ,b.16,17 Protection of the tertiary
alcohols as triethylsilyl ethers,18 followed by reduction
of the amide functionality to the aldehyde oxidation state
with Ti(O-i-Pr)4/Ph2SiH2 provided siloxyalkenyl alde-
hydes 18-20.19 Reaction of these intermediates with an
Allyl Ca tion -In itia ted Ta n d em Cycliza tion -P i-
n a col Rea ction s. Since the pioneering investigations of
J ohnson,10 allylic alcohols have proven to be highly
efficacious initiators of cationic cyclization reactions.11,12
We anticipated that generation of an allylic cation from
a 1-[2-alkenyl-2-(trialkylsiloxy)cycloalkyl]alk-3-en-2-ol (21-
27) would initiate ring-expanding cyclopentane annula-
tion to provide a bicyclo[n.3.0]alkanone product contain-
ing a 2-alkenyl side chain on the cyclopentane fragment.
Accordingly, substrates 21-27 were prepared as shown
in Scheme 1. Alkylation of enamines 6-813 with 1-(chlo-
roacetyl)pyrrolidine14 gave keto amides 9-11, which were
(13) Stork, G.; Brizzolara, A.; Landesman, H.; Szmuszkovicz, J .;
Terrell, R. J . Am. Chem. Soc. 1963, 85, 207-222.
(14) Seguin, H.; Gardette, D.; Moreau, M.-F.; Madelmont, J .-C.;
Gramain, J .-C. Synth. Commun. 1998, 28, 4257-4272.
(15) Imamoto, T.; Takiyama, N.; Nakamura, K.; Hatajima, T.;
Kamiya, Y. J . Am. Chem. Soc. 1989, 111, 4392-4398.
(16) The tertiary alcohol products were often accompanied by 15-
30% of unreacted starting material, presumably due to competitive
deprotonation of the ketone substrates. The amount of unreacted
starting material was minimized by the use of alkenylcerium reagents.
(17) Diastereomer ratios were determined by 1H NMR analysis.
(18) Roush, W. R.; Russo-Rodriquez, S. J . Org. Chem. 1987, 52, 598-
603.
(10) (a) J ohnson, W. S.; Lunn, W. H.; Fitzi, K. J . Am. Chem. Soc.
1964, 86, 1972-1978. (b) J ohnson, W. S.; J ensen, N. P.; Hooz, J .;
Leopold, E. J . J . Am. Chem. Soc. 1968, 90, 5872-5881.
(11) Reviews: (a) Bartlett, P. A. Asymm. Synth. 1984, 3, 341-409.
(b) Sutherland, J . K. In Comprehensive Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 3, pp 341-377.
(c) Harmata, M. Tetrahedron 1997, 53, 6235-6280.
(12) For representative recent examples, see: (a) Gassman, P. G.;
Riehle, R. J . J . Am. Chem. Soc. 1989, 111, 2319-2320. (b) Collins, M.
P.; Mann, J .; Finch, H. J . Chem. Soc., Perkin Trans. 1 1991, 239-240.
(c) Doyle, T. J .; VanDerveer, D.; Haseltine, J . Tetrahedron Lett. 1995,
36, 6197-6200.
(19) Bower, S.; Kreutzer, K. A.; Buchwald, S. L. Angew. Chem., Int.
Ed. Engl. 1996, 35, 1515-1516.
6422 J . Org. Chem., Vol. 67, No. 18, 2002

Cationic Olefin Cyclization-Pinacol Reactions
SCHEME 2a
TABLE 1. Ta n d em Allyl Ca tion -Olefin Cycliza tion /
P in a col Rea r r a n gem en ts
a
Key: (a) NaOH, EtOH, H2O, 70 °C; (b) Mukaiyama’s salt,
Et3N, DMF; (c) TBAF; (d) TPAP, NMO, MeCN, H2O.
appropriate vinyllithium or vinyl Grignard reagent gave
secondary allylic alcohols 21-27 as ∼1:1 mixtures of
alcohol epimers.
The relative configuration of the side chains of 21-27
was assigned by conversion of amides 12-14 or alde-
hydes 18 to the corresponding bicyclic lactones (Scheme
2), either by hydrolysis of the amides followed by lacton-
ization with Mukaiyama’s salt20 or by desilylation of 18
followed by TPAP/NMO oxidation of the resulting lac-
1
tols.21 Analysis by H NMR NOE confirmed the relative
configuration of lactones 28-30; diagnostic NOE signals
were observed between the angular C3a hydrogen and
the R or cis-â hydrogen(s) of the alkene substituent.
In our preliminary experiments, we found that treat-
ment of cis-1-[2-isopropenyl-2-(triethylsiloxy)cyclohexyl]-
4-methyl-pent-3-en-2-ol (21b) with 1.3 equiv of triflic
anhydride at -78 °C in dichloromethane12a led to the
formation of 3a-methyl(2-methylpropenyl)octahydroazu-
len-4-one (31b) in 64% yield as a 1.5:1 mixture of epimers
at the carbon bearing the alkenyl side chain (eq 1). Both
epimers had a cis ring fusion, with the major epimer
having the 2-methylpropenyl side chain oriented on the
more sterically congested concave â face. We reasoned
that incorporation of an additional methyl group at C3
of the allyl side chain should increase the diastereose-
lectivity of the conversion (see below). Accordingly, cis-
1-[2-isopropenyl-2-(triethylsiloxy)cyclohexyl]-3,4-dimeth-
ylpent-3-en-2-ol (23b) was allowed to react with triflic
anhydride to provide a 90% yield of (1,2-dimethylprope-
nyl)-3a-methyloctahydroazulen-4-one (32b) as a 10:1
mixture of epimers (eq 1). As observed in the reaction of
21b, the major epimer has a cis ring fusion and the
alkenyl side chain is oriented on the concave face. The
configuration of 32b was assigned by 1H NMR NOE
studies; irradiation of the C2 hydrogen led to small NOE
a
This material contained ∼5% of an unidentified isomeric
product.
enhancements of both the C7a hydrogen and the C3a
methyl substituent.
To probe the scope and limitations of the allyl cation-
initiated ring expanding cyclopentane annulations, allylic
alcohol substrates 22-24 were prepared and allowed to
react with triflic anhydride at -78 °C. As summarized
in Table 1, products 32-34 were obtained in good to
(20) Funk, R. L.; Abelman, M. M.; J ellison, K. M. Synlett 1989, 36-
37.
(21) Paquette, L. A.; Kang, H.-J .; Ra, C. S. J . Am. Chem. Soc. 1992,
114, 7387-7395.
J . Org. Chem, Vol. 67, No. 18, 2002 6423

Overman and Wolfe
excellent yields (54-90%).22 In all cases, the bi- or
tricyclic ketone product had a cis ring fusion; in all
reactions but one, the alkenyl side chain was incorporated
SCHEME 3
1
with >20:1 stereocontrol as judged by H NMR and/or
GC analysis of crude reaction mixtures.23 Substrates
bearing a weakly nucleophilic vinyl group (22a -24a ), as
well as those containing a more reactive 2-propenyl
(22b-23b) or 1-cyclopentenyl (22c-23c) unit were trans-
formed in good yields.24 Disubstitution at the terminus
of the allylic initiator was required for successful trans-
formation, as substrates containing an allylic initiator
having a single carbon substituent at the allyl terminus
failed to undergo the desired rearrangement.
The major side products formed in these allyl cation-
initiated annulations are bicyclic ethers 35, which pre-
sumably arise from capture of the allyl cation by the silyl
ether (or possibly the free tertiary alcohol formed by prior
cleavage of the silyl ether). Attempts to minimize the
formation of 35 by protecting the tertiary alcohol as a
diisopropylethylsilyl ether failed to improve the yields.25
Use of other anhydrides or Lewis acids to initiate the
reactions did not lead to increased yields; moreover,
addition of the hindered base, 2,6-di-tert-butyl-4-meth-
ylpyridine (DTBMP), led to slower reaction rates with
no improvement in yields.
SCHEME 4a
a
Key: (a) 2-propenylMgBr, CeCl3; (b) n-BuLi, TES-OTf; (c)
OsO4, NMO; (d) Pb(OAc)4, NaHCO3; (e) 2-bromo-3-methyl-2-
butene, s-BuLi; (f) Tf2O, -78 °C.
Previous studies of the scope and limitations of the
oxonium ion-initiated ring expanding cyclopentane an-
nulations showed that substrates such as 36 that contain
an unbranched vinyl substituent such as 1-propenyl fail
to undergo ring-enlarging cyclopentane annulation to
deliver octahydroazulen-4-ones having a hydrogen sub-
stituent at the angular position and a carbon side chain
at C3.2,26
To potentially arrive at products of this type by a two-
step sequence, reactions of substrates 37 containing a
1-(thiophenyl)alkenyl substituent were examined.27 As
shown in Scheme 3, both Z-37 and E-37 were trans-
formed in the presence of triflic anhydride and DTBMP
to octahydroazulen-4-one 38 (44-50%) with >20:1 dias-
tereoselectivity. It was essential in these cases to add the
substrate to a solution of triflic anhydride and DTBMP
at 0 °C; reactions carried out in the absence of the
hindered base DTBMP provided complex mixtures of
products. This procedure also minimized formation of a
1
side product provisionally assigned, on the basis of H
NMR, IR, and MS data, as R-hydroxy decalone 39.28
To illustrate the feasibility of synthesizing enantioen-
riched cycloalkanones in this way, cyclohexyl precursor
(+)-23b was prepared as shown in Scheme 4. Addition
of 2-propenylmagnesium bromide to (-)-2-allylcyclohex-
anone29 provided alcohol 41 with >20:1 diastereoselec-
tivity; this product was judged to be 80% ee by chiral
HPLC analysis. In a three-step sequence, alcohol 41 was
converted to aldehyde (-)-19b in 58% overall yield by
silylation of the free alcohol using n-BuLi/TES-OTf,30
followed by OsO4-catalyzed dihydroxylation of the ter-
minal olefin and cleavage of the resulting diol with lead
tetraacetate. Addition of 2-lithio-3-methyl-2-butene31 to
(-)-19b provided (+)-23b in 78% yield. Reaction of this
(22) It is extremely important that the triflic acid formed under the
reaction conditions be neutralized at -78 °C by the addition of aqueous
NaHCO3 prior to warming. Failure to quench the reactions at low
temperature led to double-bond isomerization.
(23) The stereochemistry of all products was assigned by NOE
studies. See the Supporting Information for details.
(24) Analogous precursors containing an alkyne rather than an
alkene reacted to give complex mixtures of products; only low yields
(<30%) of products of ring-enlarging cyclopentene annulation were
obtained.
(25) It was not possible to prepare substrates containing silyl ethers
larger than diisopropylethylsilyl.
(26) For a notable exception using a thionium ion initiator, see ref
8.
(28) The side product had a molecular weight of 264 and showed
IR stretches at 3549 and 1702 cm-1. The alkenyl methyl groups and
the ethyl substituent were clearly visible in the 1H NMR, as were
signals at 3.05, 2.59, and 1.83 that are consistent with the presence of
an allylic hydrogen, a hydrogen adjacent to a ketone, and a hydrogen
at a ring fusion.
(29) This material was prepared according to the literature proce-
dure and was estimated to be 80% ee by optical rotation; see: Meyers,
A. I.; Williams, D. R.; Erickson, G. W.; White, S.; Druelinger, M. J .
Am Chem. Soc. 1981, 103, 3081-3087.
(30) Other methods to install a TES ether failed; epimerization of
the C1 stereocenter occurred if the TES-OTf-mediated silylation
reactions were warmed above -40 °C.
(27) The stereochemistry of E- and Z-37 was assigned by analogy
to the other substrates.
6424 J . Org. Chem., Vol. 67, No. 18, 2002

Cationic Olefin Cyclization-Pinacol Reactions
SCHEME 5
intermediate with triflic anhydride gave rise to (-)-32b
in 83% yield and 80% ee, confirming that ring-enlarging
cyclopentane annulation occurred without detectable loss
of enantiomeric purity.
The low stereoselection observed in the conversion of
21b to 31b (see eq 1) makes this variant of the allyl
cation-initiated cyclization-pinacol rearrangement se-
quence impractical for the preparation of products con-
taining an unbranched alkenyl side. To address this
problem, we reasoned that such products might be
produced from cyclization substrates bearing a trialkyl-
silyl group at C3 of the allylic alcohol side chain. We
expected such precursors to react with high diastereo-
selectivity to deliver products that upon protodesilylation
would have an unbranched alkenyl side chain. Accord-
ingly, cis-1-[2-isopropenyl-2-(triethylsiloxy)cyclohexyl]-4-
methyl-3-(trimethylsilyl)pent-3-en-2-ol (26b) was pre-
pared and cyclized by reaction with triflic anhydride at
-78 °C in dichloromethane (eq 2). To our delight,
hydroazulenone 31b was formed with >20:1 stereoselec-
tivity and 80% yield (eq 2), protodesilylation having
occurred under the reaction conditions. Monitoring the
reaction by GC-MS confirmed that the hydroazulenone
having a 2-methyl-1-trimethylsilyl-1-propenyl side chain
was generated initially and then more slowly underwent
protodesilylation.32 In a similar fashion, substrates 25b
and 27a were, respectively, transformed to 42b and 43a
(eq 2). Again in these cases, diastereoselection was
excellent (>20:1); however, yields were modest (54% in
each case). Unfortunately, substrates that contained a
trimethylsilyl group at C3 and a single alkyl substituent
at C4 of the allylic alcohol side chain provided low yields
of the desired products.
Ghosez and co-workers have extensively developed the
synthesis of cyclobutanones by the reaction of keten-
iminium ions with alkenes.33 Keteniminium ions are
typically generated from tertiary amides by reaction with
triflic anhydride and a hindered pyridine base and react
with alkenes to provide iminium salts, which when
hydrolyzed under biphasic conditions yield cyclobutanone
products. In incisive mechanistic investigations, Ghosez
showed that these formal cycloadditions are not con-
certed, but instead proceed in a stepwise manner by way
of cationic intermediates.34 In our projected application
(eq 3), geometric constraints should result in the initially
generated bicyclic cation 44 undergoing pinacolic ring
expansion rather than intramolecular reaction with the
enamine functionality to generate a product containing
a high energy bicyclo[2.2.0]hexane unit.
This new annulation sequence was initially examined
with cis-1-pyrrolidin-1-yl-2-[2-triethylsiloxy-2-isoprope-
nylcyclohexyl]ethanone (16b) (Scheme 5). Reaction of this
unsaturated siloxy amide with triflic anhydride and
DTBMP at -20 °C, followed by heating overnight at 65
°C in 1,2-dichloroethane generated iminium salt 45b.
This intermediate was characterized by diagnostic 13C
NMR signals at δ 213.3 and 192.7 ppm and IR stretches
at 1702 and 1620 cm-1. Hydrolysis of the crude iminium
salt with aqueous KHCO3/Et2O provided cis-3a-methyl-
octahydroazulene-2,4-dione (46b) in 72% yield. Stereo-
selection in generating the cis isomer was >20:1 as
1
judged by comparison of the H and 13C NMR spectra of
Keten im in iu m Ion -In itia ted Cycliza tion -P in a col
Rea r r a n gem en ts. To further expand the scope of ring-
enlarging cyclopentane annulations, we briefly examined
the use of keteniminium ions to initiate ring-enlarging
cyclopentane annulations. Our expectation was that upon
aqueous workup these reactions would deliver directly
dione products having a carbonyl group in the newly
formed cyclopentane ring (eq 3). The cyclopentanone
carbonyl could then serve as a locus for further function-
alization of the five-membered ring.
the product to those previously reported for 46b.2
As summarized in Table 2, a number of related
unsaturated siloxy amides were converted to the bicyclo-
[n.3.0]alkanediones. Although diastereoselection was
generally >20:1 favoring formation of the cis isomer,
yields varied widely (27-80%).35 This reaction is not as
general as the allyl cation-initiated cyclizations discussed
(31) Pasynkiewicz, S.; Pietrzykowski, A.; Buchowicz, W.; Poptawska,
M. J . Organomet. Chem. 1993, 463, 235-238.
(32) Mixtures of silylated and desilylated products were isolated
from incomplete reactions.
(33) (a) Falmagne, J .-B.; Escudero, J .; Taleb-Sahraoui, S.; Ghosez,
L. Angew. Chem., Int. Ed. Engl. 1981, 20, 879-880. (b) Ghosez, L.;
Marko, I.; Hesbain-Frisque, A.-M. Tetrahedron Lett. 1986, 27, 5211-
5214. (c) Schmidt, C.; Falmagne, J . B.; Escudero, J .; Vanlierde, H.;
Ghosez, L. Org. Synth. 1990, 69, 199-204. (d) For a review, see:
Snider, B. B. Chem. Rev. 1988, 88, 793-811.
(34) Saimoto, H.; Houge, C.; Hesbain-Frisque, A.-M.; Mockel, A.;
Ghosez, L. Tetrahedron Lett. 1983, 24, 2251-2254.
(35) The stereochemistry of 46a ,b and 47b,c was assigned by
comparing the 1H and 13C NMR spectra of these products to the
previously published data. The stereochemistry of 46c and 48b was
assigned by analogy to the related compounds 47c and 46b.
J . Org. Chem, Vol. 67, No. 18, 2002 6425

Overman and Wolfe
TABLE 2. Ta n d em Keten im in iu m Ion -Olefin
Cycliza tion /P in a col Rea r r a n gem en ts
more limited than that of related annulations initiated
by R-heterocarbenium ions.2-8 Ring-enlarging cyclopen-
tane annulations that directly introduce an alkenyl side
chain in the newly formed cyclopentane ring can be
accomplished by the reaction of cis-1-[2-alkenyl-2-(tri-
ethylsiloxy)cycloalkyl]but-3-en-2-ol derivatives with triflic
anhydride at -78 °C. As summarized in Table 1, cis-
bicyclo[n.3.0]alkanones and related tricyclic products
incorporating a tetrasubstituted alkene side chain on the
more-hindered concave face are formed in yields ranging
from 54 to 90% and with diastereoselectivities typically
in excess of 20:1. Introduction of a trimethylsilyl group
at C3 of the allylic alcohol side chain of the cyclization
precursor allows cis-bicyclo[n.3.0]alkanones having a
2-methyl-2-propenyl side chain to be prepared with high
stereocontrol, but in slightly lower yields (54-80%). In
contrast, reaction of 21b, which bears a hydrogen rather
than a methyl or trimethylsilyl group at C3 of the allyl
alcohol side chain, produced hydroazulenone 31b with
low diastereoselectivity (1.5:1).
Bicyclo[n.3.0]alkanones having carbon side chains at
both C2 and C3 can be synthesized by rearrangement of
substrates having a phenylthio substituent at the inter-
nal alkene carbon; excellent diastereoselectivities (>20:
1) are observed, although yields are modest (44-50%).
Only products in which the C1 substituent is oriented
on the convex face of the cis-fused bicyclic product are
accessible, because both vinyl sulfide stereoisomers pro-
vide the same product.
Whereas the present study focused solely on ring-
enlarging cyclopentane annulations of five- to seven-
membered ring precursors, this new ring-enlarging cy-
clopentane annulation is expected to be applicable to
cyclic precursors of various ring sizes.2 Moreover, as no
loss of enantiopurity was observed during allyl cation-
initiated cyclization-pinacol rearrangement reaction of
enantioenriched precursor (+)-23b, this chemistry should
be useful for enantioselective synthesis of polycarbocyclic
products whenever the starting 2-substituted alkanone
is readily available in high enantiopurity.
Ring-enlarging cyclopentane annulations that directly
introduce carbonyl functionality in the newly formed
cyclopentane ring were developed also. In this case,
keteniminium ions generated from the reaction of cis-(2-
siloxy-2-alkenylcycloalkyl)pyrrolidin-1-ylethanones with
triflic anhydride and DTBMP at -20 to +65 °C initiate
the cyclization rearrangement cascade. After hydrolysis
of the crude keto iminium ion product with aqueous
KHCO3, cis-bicyclo[n.3.0]cycloalkane-2,4-diones are formed
in low to moderate yields (see Table 2). The cis stereo-
isomer was produced in these reactions with high selec-
tivity (>20:1), except for reactions of substrates bearing
a 2-vinyl substituent, where epimerization of the bicyclo-
[n.3.0]cycloalkane-2,4-dione product is possible. The scope
of the keteniminium ion-initiated ring-enlarging cyclo-
pentanone annulation is more limited than related an-
nulations initiated by R-heterocarbenium ions2-8 or allyl
cations.
previously. For example, cyclopentyl amide 15a and
cycloheptyl amide 17a bearing vinyl substituents (see
Scheme 1) provided <10% yield of the desired product,
whereas cyclohexyl amide 16a was transformed in 60%
yield to trans-octahydroazulene-2,4-dione (46a ). Analysis
of crude reaction mixtures by 1H NMR indicated that the
intermediate iminium salts were generated in >80%
yields in the reactions of the propenyl substrates 15b,
16b, and 17b and 50-60% yield from cyclopentenyl
substrates 15c and 16c.36 Attempts to modify the hy-
drolysis conditions to improve the yields of the dicarbonyl
products were unsuccessful. For example, hydrolysis of
the intermediate iminium salts using mixtures of ether,
acetone or methanol and aqueous NaOH, Na2CO3, NaH-
CO3, or pH 7 phosphate buffer failed to improve the
yields. In the absence of the pyridine base, no reaction
37
was observed.
Discu ssion
Syn th etic Scop e. The scope of the two new ring-
expanding cyclopentane annulations reported herein is
Mech a n ism a n d Ster eoch em istr y. Our analysis of
the mechanism of allyl cation-initiated cyclization-
pinacol reactions, which parallels that postulated for
related transformations initiated by oxonium ions, is
shown in Figure 2.1,2 Initial reaction of the allylic alcohol
substrate with triflic anhydride affords an allyl cation,12
(36) NMR yields were judged using 4-iodotoluene as an internal
standard.
(37) Analogous substrates containing
a C1 alkyne substituent
provided only trace amounts of related enedione products.
6426 J . Org. Chem., Vol. 67, No. 18, 2002

Cationic Olefin Cyclization-Pinacol Reactions
F IGURE 2. Key: the TMS group is cleaved from the initially formed product under the reaction conditions to provide a product
having R ) H.
F IGURE 3.
which can react with the tethered alkene by either of two
favored chair-topography pathways: 50 f 51 or 53 f
54. The transition structure of the latter pathway suffers
from unfavorable 1,3-diaxial interactions between the
terminal carbons of the original allyl unit and the C2 and
C2’ substituents; these destabilizing steric interactions
are avoided in the 50 f 51 pathway. This analysis nicely
rationalizes the observation that stereoselection is typi-
cally >20:1 when the internal carbon of the allyl cation
is substituted, but much less when this substituent is
hydrogen.
Stereoisomeric vinyl sulfides Z-37 and E-37 both
provided diastereomer 38, which suggests that the vinyl
sulfide stereoisomers interconvert more rapidly than they
react (Figure 3). The preference for forming 38 likely
arises from preferential reaction of the Z vinylsulfide
stereoisomer by chair cyclization topography 56 in which
the ethyl group adopts a favorable quasiequatorial orien-
tation. The related chair transition structure for cycliza-
tion of the E stereoisomer that evolves from 57 would be
destabilized by developing syn-pentane interactions be-
tween the ethyl substituent and both the siloxy group
and the methyl substituent at C3′′ of the original allyl
cation side chain.
ently pinacol rearrangement of 58 is sufficiently slow that
competitive trapping of the thionium ion with adventi-
tious water (or the triflate anion) occurs to provide a
thiohemiacetal (or R-trifluoroacetoxy sulfide) intermedi-
ate that evolves to the decalone product.
The keteniminium ion-initiated ring-expanding cyclo-
pentanone annulation is believed to proceed by the
sequence outlined in Figure 5. Thus, reaction of the
pyrrolidine amide with triflic anhydride in the presence
of DTBMP leads initially to the formation of a O-
trifluoromethansulfonylated amide 60,39 which is depro-
tonated to provide keteniminium ion 61 (Figure 4).33 The
intermediacy of a keteniminium ion is supported by the
requirement for an added pyridine base; direct cyclization
of the O-acylated amide would not be consistent with the
observation that no reaction was observed in the absence
of DTBMP. Cyclization of the keteniminium ion through
a chairlike conformer then provides carbenium ion 62,
which undergoes pinacol rearrangement to afford enam-
ine 63. This intermediate is protonated under the reac-
tion conditions by the pyridinium triflate salt to give
iminium salt 64,40 which is hydrolyzed upon treatment
with aqueous base to yield the observed diketone prod-
The R-hydroxydecalone side product 39 observed in
reactions of the vinyl sulfide substrates E-37 and Z-37
presumably arises from the high stability38 of the pro-
posed thionium ion intermediate 58 (Figure 4). Appar-
(38) Hevesi, L. Bull Chem. Soc. Fr. 1990, 127, 697-703.
(39) Charette, A. B.; Chua, P. Tetrahedron Lett. 1998, 39, 245-248.
(40) Paukstelis, J . V. In Enamines: Synthesis, Structure, and
Reactivity; Cook, A. G., Ed; Marcel Dekker: New York, 1969; pp 169-
209.
J . Org. Chem, Vol. 67, No. 18, 2002 6427

Overman and Wolfe
F IGURE 4.
F IGURE 5.
appropriate allylic alcohol (1.0 equiv) in dichloromethane (0.1
M) was cooled to -78 °C, and trifluoromethanesulfonic anhy-
dride (1.3 equiv) was added dropwise. The mixture was stirred
at -78 °C until the starting material had been completely
consumed as judged by TLC analysis (∼3 h). The reaction then
was quenched at -78 °C with aqueous NaHCO3 (equal volume
to solvent) and allowed to warm to rt. The resulting mixture
was extracted with ether (3 × 30 mL), and the combined
organic extracts were dried over sodium sulfate, filtered, and
concentrated. The crude product was purified by flash chro-
matography on silica gel using ethyl acetate/hexanes (1% f
2%) as the eluant.
ucts. In the case of intermediates 64 having R ) H,
epimerization of the C3a stereocenter likely occurs under
the reaction conditions to afford a mixture of products
favoring the more stable trans diastereomer.41
Con clu sion s
Two new variants of ring-enlarging cyclopentane an-
nulations were developed. In one, an allyl cation, gener-
ated by reaction of an allylic alcohol with triflic anhy-
dride, initiates a cyclization-pinacol cascade that expands
the starting ring and fuses in cis fashion a cyclopentane
ring bearing a 2-alkenyl side chain. Yields of this
sequence are generally good and diastereoselection is
high (typically >20:1). In the second more limited variant,
a keteniminium ion, formed by the reaction of a pyrro-
lidine amide with triflic anhydride and a hindered base,
initiates the cyclization-pinacol rearrangement se-
quence.
(2S,3a R,7a R)-2-(1,2-Dim et h ylp r op en yl)-3a -m et h yloc-
ta h yd r oa zu len -4-on e (32b). Reaction of 0.22 mmol of 23b
following the general procedure afforded 46 mg (90%) of the
title compound as a colorless oil. This material was judged to
1
be a 16:1 mixture of diastereomers by H NMR analysis (the
crude reaction mixture was found to be a 10:1 mixture of
diastereomers): 1H NMR (400 MHz, CDCl3) δ 3.20-3.13 (m,
1 H), 2.70 (td, J ) 2.8, 8.5 Hz, 1 H), 2.41-2.36 (m, 1 H), 2.04-
1.98 (m, 2 H), 1.89-1.78 (m, 3 H), 1.68 (d, J ) 1.2 Hz, 3 H),
1.64-1.59 (m, 4 H), 1.55 (s, 3 H), 1.54-1.40 (m, 2 H), 1.30-
1.20 (m, 6 H); 13C NMR (125 MHz, CDCl3) δ 216.2, 128.1, 124.7,
58.4, 47.4, 40.2, 39.1, 38.10, 38.06, 35.2, 21.1, 19.9, 13.3; IR
(film) 1698 cm-1. Anal. Calcd for C16H26O: C, 81.99; H, 11.18.
Found: C, 82.05; H, 11.29.
Exp er im en ta l Section 42
Gen er a l P r oced u r e for Allyl Ca tion -In itia ted Cycliza -
tion -P in a col Rea r r a n gem en t Rea ction s. A solution of the
Gen er a l P r oced u r e for Ta n d em Keten im in iu m Ion
Olefin Cycliza tion -P in a col Rea r r a n gem en ts. A solution
of the appropriate amide substrate (1.0 equiv), 2,6-di-tert-butyl-
4-methylpyridine (1.25 equiv), and 1,2-dichloroethane (0.1 M)
was cooled to -20 °C, and trifluoromethanesulfonic anhydride
(1.25 equiv) was added dropwise. The mixture was allowed to
slowly warm to rt and then was heated to 65 °C for 18 h. The
(41) The NMR yield of iminium salt 44a (judged against 4-iodo-
toluene as an internal standard) was 74%. Approximately 15% of the
material contained side products retaining a terminal vinyl group. The
remainder of the material was not identified. As a result of the
complexity of the crude 1H NMR spectra, we were unable to ascertain
the epimeric purity of iminium salt 44a .
(42) General experimental details have been described.6
6428 J . Org. Chem., Vol. 67, No. 18, 2002

Cationic Olefin Cyclization-Pinacol Reactions
reaction mixture was cooled to rt and concentrated; the
resulting residue was dissolved in aqueous KHCO3 (3 mL) and
ether (3 mL) and stirred vigorously at rt for 5 h. This mixture
was extracted with ether (3 × 20 mL), and the combined
organic extracts were dried over sodium sulfate, filtered and
concentrated. The crude product was purified by flash chro-
matography on silica gel using ethyl acetate/hexanes (10% f
20%) as the eluant.
stricted support from Merck, Pfizer, and Roche Bio-
sciences is gratefully acknowledged as is NIH postdoc-
toral fellowship (GM 20140) support of J .P.W. NMR and
mass spectra were determined at UC Irvine using
instruments acquired with the assistance of NSF and
NIH shared instrumentation grants.
(3aR,5aR)-3a-(Meth yl)octah ydr oazu len e-2,4-dion e (46b).
Reaction of 0.26 mmol of 16b following the general procedure
afforded 29 mg (61%) of the title compound as a colorless oil.
This material was judged to be a >20:1 mixture of diastere-
omers by NMR analysis. Data for this compound have been
reported previously.2
Su p p or tin g In for m a tion Ava ila ble: Complete experi-
mental details and characterization data for compounds 9-48,
tables of NOE data, and copies of 1H and 13C NMR spectra of
all new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
Ack n ow led gm en t. We thank the NIH (NS-12389)
for financial support of this research. Additional unre-
J O025927R
J . Org. Chem, Vol. 67, No. 18, 2002 6429