Construction of bicyclic ring systems via a transannular SmI 2-mediated ketone-olefin cyclization strategy

Article abstract of DOI:10.1021/jo062292d

The development of novel methods and strategies for the formation of polycyclic ring structures is of utmost importance in organic synthesis. The present study describes the investigation of a transannular cyclization strategy for constructing bicyclic ri

Full text of DOI:10.1021/jo062292d

Construction of Bicyclic Ring Systems via a Transannular
SmI2-Mediated Ketone-Olefin Cyclization Strategy
Gary A. Molander,* Barbara Czako´, and Michael Rheam
Roy and Diana Vagelos Laboratories, Department of Chemistry, UniVersity of PennsylVania,
Philadelphia, PennsylVania 19104-6323
gmolandr@sas.upenn.edu
ReceiVed NoVember 6, 2006
The development of novel methods and strategies for the formation of polycyclic ring structures is of
utmost importance in organic synthesis. The present study describes the investigation of a transannular
cyclization strategy for constructing bicyclic ring systems. To test the viability of the approach, the SmI2-
mediated ketone-olefin coupling reaction, a method previously developed in this laboratory, was examined.
Investigation of the transannular cyclization of cyclooctene, cyclodecene, and cycloundecene derivatives
revealed that the process proceeds with high yield and diastereoselectivity, and in the case of larger
ring-sized compounds, with excellent regioselectivity. The regioselectivity of the annulation process could
be rationalized based on examining the low energy conformations of the keto alkene starting materials.
These results demonstrate the efficiency and the potential of the transannular cyclization tactic for the
creation of bicyclic ring systems.
Introduction
In addition to these strategies, a third possible approach is
the formation of bicycles via transannular cyclizations
(Figure 2).
A thorough examination of the literature reveals that besides
the transannular Diels-Alder reaction, this strategy has not been
systematically studied.18,19 Transannular transformations appear
in the chemical literature rather sporadically, mainly in con-
nection with method development as isolated examples of a
general, nontransannular process.20-32 A small number of
The development of efficient methods for constructing
polycyclic compounds has been a longstanding objective of
synthetic organic chemists. Traditionally, bicyclic ring systems
are created via two approaches: (1) annulation of a side chain
onto a preexisting ring1 and (2) cycloaddition reactions (such
as the Diels-Alder reaction, [3 + 2] cycloaddition, etc.)
(Figure 1).2-17
(1) Molander, G. A.; Etter, J. B. Tetrahedron Lett. 1984, 25, 3281-
3284.
(14) Fringuelli, F., Taticchi, A. The Diels-Alder Reaction: Selected
Practical Methods; Wiley: New York, 2002.
(15) Boger, D. L., Weinreb, S. M. Hetero Diels-Alder Methodology in
Organic Synthesis; Academic Press: Orlando, 1987.
(2) Varela, J. A.; Saa, C. Chem. ReV. 2003, 103, 3787-3801.
(3) Gothelf, K. V.; Jorgensen, K. A. Chem. Commun. 2000, 1449-1458.
(4) Brummond, K. M.; Kent, J. L. Tetrahedron 2000, 56, 3263-3283.
(5) Mascarenas, J. L. AdV. Cycloadd. 1999, 6, 1-54.
(16) Wollweber, H. Diels-Alder Reaction; Thieme: Stuttgart, 1972.
(17) Wassermann, A. Diels-Alder Reactions: Organic Background and
Physico-Chemical Aspects; Elsevier: New York, 1965.
(18) Marsault, E.; Toro, A.; Nowak, P.; Deslongchamps, P. Tetrahedron
2001, 57, 4243-4260.
(19) Deslongchamps, P. Aldrichim. Acta 1991, 24, 43-56.
(20) Dowbenko, R. J. Am. Chem. Soc. 1964, 86, 946-947.
(21) Dowbenko, R. Tetrahedron 1964, 20, 1843-1858.
(22) Fang, J. M.; Chen, M. Y.; Cheng, M. C.; Lee, G. H.; Wang, Y.;
Peng, S. M. J. Chem. Res., Synop. 1989, 272-273.
(6) Wender, P. A.; Love, J. A. AdV. Cycloadd. 1999, 5, 1-45.
(7) Gothelf, K. V.; Jorgensen, K. A. Chem. ReV. 1998, 98, 863-909.
(8) Fruehauf, H.-W. Chem. ReV. 1997, 97, 523-596.
(9) Sieburth, S. M.; Cunard, N. T. Tetrahedron 1996, 52, 6251-6282.
(10) Winkler, J. D. Chem. ReV. 1996, 96, 167-176.
(11) Lautens, M.; Klute, W.; Tam, W. Chem. ReV. 1996, 96, 49-92.
(12) Stanovnik, B. Tetrahedron 1991, 47, 2925-2945.
(13) Padwa, A.; Schoffstall, A. M. AdV. Cycloadd. 1990, 2, 1-89.
10.1021/jo062292d CCC: $37.00 © 2007 American Chemical Society
Published on Web 02/02/2007
J. Org. Chem. 2007, 72, 1755-1764
1755

Molander et al.
SCHEME 1
FIGURE 1. Traditional cyclization approaches.
reagent that is capable of promoting of a wide variety of
processes ranging from functional group interconversions to
carbon-carbon bond formations.41-54 One of the most interest-
ing and unique processes induced by SmI2 is the reductive
coupling of carbonyls with alkenes via ketyl radical anion
intermediates. The first example of this transformation was
reported by Fukuzawa et al. in 1986.55 They described the SmI2-
mediated coupling of acetophenone 1 with ethyl acrylate 2 in
THF in the presence of t-BuOH, affording the lactone product
3 in 70% yield. Later it was demonstrated by the same group
that the reaction can be performed in an intramolecular fashion,
producing the corresponding bicyclic lactones 5 in moderate to
good yields (Scheme 1).56
FIGURE 2. Transannular cyclization.
examples were also found in which transannular transformations
were utilized in natural product synthesis.33-40
Because of the scarcity of data regarding the transannular
ring formation tactic, we initiated a study that focused on
investigating the synthetic utility of this strategy. The importance
of the systematic investigation of the transannular ring formation
strategy is twofold: (1) Polycyclic compounds with immense
skeletal and functional group diversity are abundant in nature,
and the development of novel methods and strategies enabling
the synthesis of structures of increasing complexity is essential.
(2) Examination of the factors influencing the inherent regio-
and diastereoselectivity of transannular processes would con-
tribute to the general understanding of these transformations.
To test the viability of the strategy, the SmI2-mediated
ketone-olefin coupling reaction, a method that was previously
developed in this laboratory, was examined. Since its introduc-
tion to organic synthesis, SmI2 has proven to be an extraordinary
Shortly after the first report, Molander and co-workers
published an extensive study of SmI2-mediated intramolecular
ketone-olefin cyclizations in which the coupling of â-keto
esters and amides with unactivated olefins was described.57-61
(23) Fang, J. M.; Chen, M. Y. Tetrahedron Lett. 1987, 28, 2853-2856.
(24) Hodgson, D. M.; Lee, G. P. Tetrahedron: Asymmetry 1997, 8,
2303-2306.
(41) Namy, J. L.; Girard, P.; Kagan, H. B. NouV. J. Chim. 1977, 1, 5-7.
(42) Girard, P.; Namy, J. L.; Kagan, H. B. J. Am. Chem. Soc. 1980,
102, 2693-2698.
(25) Reingold, I. D.; Drake, J. Tetrahedron Lett. 1989, 30, 1921-1922.
(26) Engling, G.; Emrick, T.; Hellmann, J.; McElroy, E.; Brandt, M.;
Reingold, I. D. J. Org. Chem. 1994, 59, 1945.
(27) Dalgard, J. E.; Rychnovsky, S. D. Org. Lett. 2004, 6, 2713-2716.
(28) Mueller, P.; Riegert, D.; Bernardinelli, G. HelV. Chim. Acta 2004,
87, 227-239.
(43) Kagan, H. B. Tetrahedron 2003, 59, 10351-10372.
(44) Steel, P. G. J. Chem. Soc., Perkin Trans. 1 2001, 2727-2751.
(45) Krief, A.; Laval, A.-M. Chem. ReV. 1999, 99, 745-777.
(46) Nomura, R.; Endo, T. Chem.- Eur. J. 1998, 4, 1605-1610.
(47) Molander, G. A.; Harris, C. R. Tetrahedron 1998, 54, 3321-3354.
(48) Skrydstrup, T. Angew. Chem., Int. Ed. Engl. 1997, 36, 345-347.
(49) Molander, G. A.; Harris, C. R. Chem. ReV. 1996, 96, 307-338.
(50) Molander, G. A. Org. React. 1994, 46, 211-367.
(51) Curran, D. P.; Fevig, T. L.; Jasperse, C. P.; Totleben, M. J. Synlett
1992, 943-961.
(29) Chu, Y.; White, J. B.; Duclos, B. A. Tetrahedron Lett. 2001, 42,
3815-3817.
(30) Kropp, P. J.; Mason, J. D.; Smith, G. F. H. Can. J. Chem. 1985,
63, 1845-1849.
(31) Price, J. D.; Johnson, R. P. J. Am. Chem. Soc. 1985, 107, 2187-
2189.
(32) Yamamura, S.; Iguchi, M.; Niwa, M. J. Chem. Soc., Chem. Commun.
1971, 974-975.
(33) Curran, D. P.; Shen, W. Tetrahedron 1993, 49, 755-770.
(34) De Boeck, B.; Pattenden, G. Tetrahedron Lett. 1998, 39, 6975-
6978.
(35) Pattenden, G.; Teague, S. J. Tetrahedron 1987, 43, 5637-5652.
(36) Wender, P. A.; Correia, C. R. D. J. Am. Chem. Soc. 1987, 109,
2523-2525.
(37) Inoue, M.; Sato, T.; Hirama, M. J. Am. Chem. Soc. 2003, 125,
10772-10773.
(38) Collado, I. G.; Alonso, M. S.; Hernandez-Galan, R.; Madero, J. G.;
Massanet, G. M. Tetrahedron 1994, 50, 10531-10538.
(39) Matsuda, H.; Kageura, T.; Inoue, Y.; Morikawa, T.; Yoshikawa,
M. Tetrahedron 2000, 56, 7763-7777.
(40) Kitayama, T.; Yokoi, T.; Kawai, Y.; Hill, R. K.; Morita, M.;
Okamoto, T.; Yamamoto, Y.; Fokin, V. V.; Sharpless, K. B.; Sawada, S.
Tetrahedron 2003, 59, 4857-4866.
(52) Molander, G. A. Chem. ReV. 1992, 92, 29-68.
(53) Soderquist, J. A. Aldrichim. Acta 1991, 24, 15-23.
(54) Edmonds, D. J.; Johnston, D.; Procter, D. J. Chem. ReV. 2004, 104,
3371-3403.
(55) Fukuzawa, S.; Nakanishi, A.; Fujinami, T.; Sakai, S. J. Chem. Soc.,
Chem. Commun. 1986, 624-625.
(56) Fukuzawa, S.; Lida, M.; Nakanishi, A.; Fujinami, T.; Sakai, S.
J. Chem. Soc., Chem. Commun. 1987, 920-921.
(57) Molander, G. A.; Etter, J. B.; Zinke, P. W. J. Am. Chem. Soc. 1987,
109, 453-463.
(58) Molander, G. A.; Kenny, C. Tetrahedron Lett. 1987, 28, 4367-
4370.
(59) Molander, G. A.; McKie, J. A. J. Org. Chem. 1995, 60, 872-882.
(60) Molander, G. A.; McKie, J. A. J. Org. Chem. 1994, 59, 3186-
3192.
(61) Molander, G. A.; McKie, J. A. J. Org. Chem. 1992, 57, 3132-
3139.
1756 J. Org. Chem., Vol. 72, No. 5, 2007

Transannular SmI2-Mediated Ketone-Olefin Cyclization
SCHEME 2
SCHEME 3
via a Wittig reaction.33,67 To investigate the feasibility of the
transannular ketone-olefin cyclization of activated alkene
substrates, (5-oxo-cyclooctylidene)acetic acid methyl ester 12
was also prepared (Scheme 2).
This process was successfully utilized for the synthesis of
monocyclic and bicyclic ring systems in high yield and excellent
diastereoselectivity (eq 1).
The next objective was to synthesize larger ring-sized cyclic
keto alkene derivatives. An efficient synthesis of (E)-cyclodec-
5-enone 21 was achieved following the procedure developed
by Kato and co-workers (Scheme 3).69 According to this route,
2-chlorocyclohexanone 13 was reacted with vinylmagnesium
bromide at room temperature over 1 h, producing the corre-
sponding 2-chloro-1-vinylcyclohexanol 15. This product was
exposed to another 1.25 equiv of vinylmagnesium chloride in
the same pot at 50 °C and kept at this temperature overnight,
affording a separable 7:1 mixture of diastereomeric 1,2-
divinylcyclohexanols. According to the literature procedure,
(1R*,2S*)-1,2-divinylcyclohexanol 19 was warmed to 220 °C
to effect the oxy-Cope rearrangement, leading to (E)-cyclodec-
5-enone 21.70,71 However, under the above conditions, the
starting material was recovered intact from the reaction. Further
optimization revealed that the transformation can be realized
under anionic oxy-Cope conditions using KH and 18-crown-6
in THF at 80 °C.72 The synthesis of (E)-cycloundec-5-enone
22 was accomplished in a similar fashion. 2-Chlorocyclohep-
tanone 14 was exposed to 2.5 equiv of vinylmagnesium chloride
in two portions, affording (1R*,2S*)-1,2-divinylcycloheptanol
20 in 54% yield. Subsequent anionic oxy-Cope rearrangement
delivered the requisite (E)-cycloundec-5-enone 22 in 62% yield.
To examine the diastereoselectivity of the ketone-olefin
coupling, the synthesis of substituted 5-methylenecyclooctanones
and (E)-cyclodec-5-enones was targeted. 2-Methyl-5-methyl-
enecyclooctanone 23 was obtained along with 2,2-dimethyl-5-
methylenecyclooctanone (24) by the methylation of 5-methyl-
enecyclooctanone 9 using LHMDS and methyl iodide (eq 2).
In the same publication, the intramolecular cyclization of
alkynes and nitriles with â-keto esters was also described.
During the following two decades, the reductive coupling of
carbonyls promoted by SmI2 was extensively investigated, and
the substrate scope of the reaction was extended to unactivated
ketones59,60 and allenes.62 The ketone-olefin cyclization was
further exploited in sequential processes, leading to more densely
functionalized and highly complex carbocyclic and heterocyclic
products. Representative examples for sequenced reactions are
the tandem nucleophilic acyl substitution/ketone-olefin cou-
pling, radical cyclization/intermolecular nucleophilic addition,
and the ketone-olefin coupling/â-elimination sequence.63,64
Results and Discussion
Synthesis of Substrates. To test the viability of the transan-
nular cyclization strategy, the SmI2-mediated ketone-olefin
coupling reaction of cyclooctenone, cyclodecenone, and cy-
cloundecenone derivatives was studied, focusing on the ef-
ficiency, functional group tolerance, and diastereoselectivity of
the process. A key element to the success of this strategy was
the rapid construction of the medium-sized ring starting
materials.
A common precursor to several substrates was cyclooctane-
1,5-dione 8. The first substrate, 5-methylenecyclooctanone 9,
was easily prepared from cyclooctane-1,5-dione 8 via Wittig
reaction utilizing Ph3PdCH2, providing the product in excellent
yield.65-67 To examine the difference between the transannular
ketone-olefin cyclization of endocyclic and exocyclic alkenes,
the endocyclic variant of 9, (Z)-5-methylcyclooct-4-enone 10,
was prepared. This compound was synthesized from 5-meth-
ylenecyclooctanone 9 by exposing it to 10% Pd/C and H2 in
EtOAc at room temperature overnight.68 5-Ethylidenecyclooc-
tanone 11 was prepared starting from cyclooctane-1,5-dione 8
2-Phenyl-5-methylenecyclooctanone 25 was prepared from
5-methylenecyclooctanone 9 using the Buchwald-Hartwig
(62) Molander, G. A.; Cormier, E. P. J. Org. Chem. 2005, 70, 2622-
2626.
(63) Molander, G. A.; Harris, C. R. J. Am. Chem. Soc. 1996, 118, 4059-
(69) Kato, T.; Kondo, H.; Nishino, M.; Tanaka, M.; Hata, G.; Miyake,
4071.
A. Bull. Chem. Soc. Jpn. 1980, 53, 2958-2961.
(64) Molander, G. A.; Harris, C. R. J. Org. Chem. 1998, 63, 812-816.
(65) Baklan, V. F. Zh. Org. Khim. 1975, 11, 746-750.
(66) Bishop, R. Aust. J. Chem. 1984, 37, 319-325.
(67) Wittig, G.; Schollkopf, U. Chem. Ber. 1954, 97, 1318-1330.
(68) Molander, G. A.; Le Huerou, Y.; Brown, G. A. J. Org. Chem. 2001,
66, 4511-4516.
(70) Berson, J. A.; Jones, M., Jr. J. Am. Chem. Soc. 1964, 86, 5017-
5018.
(71) Berson, J. A.; Jones, M., Jr. J. Am. Chem. Soc. 1964, 86, 5019-
5020.
(72) Evans, D. A.; Golob, A. M. J. Am. Chem. Soc. 1975, 97, 4765-
4766.
J. Org. Chem, Vol. 72, No. 5, 2007 1757

Molander et al.
SCHEME 4
SCHEME 5
cyclization. The first reaction examined was the annulation of
the simplest substrate, 5-methylenecyclooctanone 9 (eq 5).
Surprisingly, under standard ketone-olefin coupling conditions,
according to which the THF solution of the substrate (c ) 0.03
M) and t-BuOH was added to a SmI2/HMPA solution (c ) 0.13
M) at room temperature over 15 min, the dimerized product 31
was formed exclusively.
ketone arylation procedure.73,74 To achieve this transformation,
various conditions were tested including changing the Pd source
[Pd2dba3, Pd(OAc)2], the base (NaOt-Bu, K3PO4), and the
solvent (THF, toluene) (eq 3). The best results were obtained
when dicyclohexyl(2′-methylbiphenyl-2-yl)phosphine was used
as a ligand and NaOt-Bu was used as base in THF at reflux,
affording the product in 61% based on recovered starting
material.
The structure of compound 31 was established by X-ray
crystallography. This outcome can be explained by the rapid
reduction of the ketone to the corresponding ketyl radical anion,
which results in the local depletion of the SmI2 concentration
(Scheme 5). The ketyl radical 32 undergoes an intramolecular
addition onto the alkene, producing methyl radical 33. Subse-
quent reduction of this radical to the corresponding organosa-
marium species 34 is disfavored because of the low SmI2
concentration (Path A). On the other hand, the high concentra-
tion of radical 33 creates ideal conditions for the dimerization,
leading to product 31 (Path B).
(E)-10-Methylcyclodec-5-enone 26 could be accessed from
1,2-divinylcyclohexanol 19 via an oxy-Cope rearrangement and
subsequent quenching of the resulting enolate with methyl iodide
(eq 4).75
To avoid dimerization, extensive optimization studies were
conducted. The obvious first experiment was to perform the
reaction under more dilute conditions, employing a 0.004 M
substrate concentration and increasing the addition time to 4 h.
Although under these conditions the monomer/dimer ratio
increased to 1.8:1, still a substantial amount of dimer formed
(entry 2, Table 1). Further reduction of the concentration of the
substrate to 0.002 M did not lead to significant improvement,
resulting in a 3.2:1 monomer/dimer ratio (entry 3, Table 1).78
Next, the effect of radical scavengers was examined. Unfor-
tunately, addition of 2,6-di-tert-butyl-4-methylphenol (BHT) did
not change the outcome.79 Performing the reaction under high
dilution conditions in the presence of BHT afforded high yields,
but as a 3.1:1 mixture of the monomer and dimer (entry 4, Table
The requisite 2- and 4-methyl-substituted cyclodec-5-enone
derivatives were synthesized by a general sequence according
to which 2-chlorocyclohexanone was reacted with the appropri-
ate Grignard reagent followed by oxy-Cope rearrangement as
depicted in Scheme 4.75-77
Optimization of the Transannular Cyclization. Having
prepared the requisite substrates, attention was turned to the
exploration of the transannular SmI2-mediated ketone-olefin
(73) Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald, S. L. J. Am. Chem.
Soc. 2000, 122, 1360-1370.
(74) Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1997, 119, 12382-
12383.
(75) Chu, Y.; White, J. B.; Duclos, B. A. Tetrahedron Lett. 2001, 42,
3815-3817.
(76) Holt, D. A. Tetrahedron Lett. 1981, 22, 2243-2245.
(77) Urabe, H.; Kuwajima, I. Tetrahedron Lett. 1983, 24, 4241-4244.
(78) Mandelt, K.; Fitjer, L. Synthesis 1998, 1523-1526.
(79) Mikuni, T.; Tatsuta, M.; Kamachi, M. J. Natl. Cancer Inst. 1987,
79, 281-283.
1758 J. Org. Chem., Vol. 72, No. 5, 2007

Transannular SmI2-Mediated Ketone-Olefin Cyclization
TABLE 1. Optimization of the Ketone-Olefin Coupling
SCHEME 6
substrate
entry concn (M)
addition
time
additive
35: 31 yield (%)
1
2
3
4
0.03
-
-
-
15 min 31 (70%)
0.004
0.002
0.002
4 h
4 h
4 h
1.8:1 (59%, 33%)
3.2:1 (75%, 23%)
3.1:1 (72%, 23%)
2,6-di-tert-butyl-4-
methylphenol
5
6
7
8
0.05
0.05
0.05
0.05
(EtO)2P(O)H (5 equiv) 20 min 2:1 (56%, 28%)
reaction proceeds through the sterically more hindered, kineti-
cally stable secondary radical, dimer formation is inhibited.
These examples demonstrated that the transannular SmI2-
mediated ketone-olefin coupling of substrates containing an
unactivated alkene occurs readily. As expected, activated alkenes
also undergo the transformation. The transannular cyclization
of methyl (5-oxo-cyclooctylidene)acetic acid methyl ester 12
proceeded with ease; however, the reaction did not stop after
the first transannular bond formation, but the resulting samarium
alkoxide 38 reacted further with the ester moiety, producing
the tricyclic lactone product 39 (Scheme 6).83,84
Ph2P(O)H (5 equiv)
PhSH (5 equiv)
20 min 5.3:1 (64%, 12%)
20 min 35 (80%)
PhSH (1.4 equiv)
20 min 35 (80%)
1). Carrying out the reaction in the presence of 5 equiv of diethyl
phosphonite under standard conditions, employing a substrate
concentration of 0.05 M and a 20 min addition time, furnished
a 2:1 mixture of the monomer and dimer (entry 5, Table 1).80
Utilizing diphenylphosphine oxide under the standard conditions
led to further improvement, providing a 5.3:1 ratio of the
monomer and dimer (entry 6, Table 1).81 Finally, thiophenol
was tested.82 Performing the reaction under standard conditions
in the presence of five equivalents of thiophenol led to the
exclusive formation of the monomeric product (entry 7,
Table 1). Gratifyingly, identical results were obtained when the
reaction was performed in the presence of 1.4 equiv of
thiophenol (entry 8, Table 1).
Exploring Substrate Scope. Next, the effect of changing the
position of the double bond from exocyclic to endocyclic was
examined. To this end, the transannular ketone-olefin coupling
of (Z)-5-methylcyclooct-4-enone 10 was performed (eq 6).
Under standard conditions, in the absence of a radical scavenger,
the reaction led to the clean formation of the expected bicyclic
alcohol 35.
Extension of the Method to Larger Ring-Sized Com-
pounds. Successful application of the transannular ketyl-olefin
cyclization to the synthesis of [3.3.0] bicyclic ring systems
prompted the investigation of the cyclization reaction of
compounds with a larger ring size. First, the transannular
cyclization of (E)-cyclodec-5-enone 21 was examined. Depend-
ing on the regio- and diastereoselectivity of the process, this
cyclization could lead to the formation of four different products.
Addition of the ketyl radical to the C-5 position of the double
bond could potentially produce the cis- or trans-bicyclo[5.3.0]-
decan-1-ol products, while annulation onto the C-6 position of
the alkene would result in the formation of the cis- or trans-
bicyclo[4.4.0]decan-1-ol products. Performing the reaction under
standard conditions, in the presence of the radical scavanger,
revealed that the transformation proceeds with high regio- and
diastereoselectivity, furnishing cis-bicyclo[5.3.0]decan-1-ol 40
in 62% yield (eq 8). In the absence of thiophenol, the formation
of a small amount of dimeric product could be observed. The
structure of the bicyclic product was established by comparison
to literature data.1,85
To determine whether dimerization occurs when the reaction
proceeds through an exocyclic secondary radical intermediate,
the annulation of 5-ethylidenecyclooctanone 11 was examined.
Performing the reaction under standard conditions furnished the
expected bicycle 37 as the single product, and no dimer could
be detected (eq 7).
The outcome of these experiments indicated that dimerization
occurs only in the case of substrates when the reaction proceeds
through the sterically accessible primary radical. When the
It is important to note that a synthesis of the same compound
employing an intramolecular Barbier strategy delivered the
product in a much lower 2:1 diastereoselectivity (eq 9).1,86 In
this instance, the transannular cyclization approach was clearly
superior to the traditional annulation strategy.
(80) Barton, D. H. R. J., D. O.; Jaszberenyi, J. C. Tetrahedron Lett. 1992,
33, 2311-2314.
(81) Barks, J. M. G., B. C.; Parsons, A. F.; Upeandran, B. Tetrahedron
Lett. 2001, 42, 3137-3140.
(82) Banwell, M. G. H., David, C. R.; McLeod, Malcolm, D. New J.
Chem. 2003, 27, 50-59.
(84) Tobe, Y.; Hayauchi, Y.; Odaira, Y. J. Org. Chem. 1981, 46, 5219-
5221.
(83) Kakiuchi, K.; Masaki, U.; Takeda, M.; Tadaki, T.; Kato, Y.;
Nagashima, T.; Tobe, Y.; Koike, H.; Ida, N.; Odaira, Y. Chem. Pharm.
Bull. 1987, 35, 617-631.
(85) Li, J.; Gallardo, T.; White, J. B. J. Org. Chem. 1990, 55, 5426-
5428.
(86) Molander, G. A.; Etter, J. B. J. Org. Chem. 1986, 51, 1778-1786.
J. Org. Chem, Vol. 72, No. 5, 2007 1759

Molander et al.
TABLE 2. Minimum Energy Conformations of
(E)-Cyclodec-5-enone 21
SCHEME 8
ol systems. However, the only detectable product that formed
in this reaction was cis-bicyclo[6.3.0]undecan-1-ol 44.87,88 The
structure of this compound was established based on X-ray
crystallography analysis.
When the reaction was carried out under identical conditions
but at -78 °C, the only product that formed was the reduced
alcohol 45 (eq 11). This result suggests that at low temperatures,
the reduction of the radical becomes faster than the annulation
process.
SCHEME 7
The high regio- and diastereoselectivity of the transannular
process can be rationalized based on the reaction mechanism
(Scheme 7). Examining the structure of the ketyl radical anion
intermediate 43 reveals that the LUMO orbital of the alkene is
lined up in a fashion that is perfect for the addition of the ketyl
radical to the C-5 position of the double bond. This alignment
also accounts for the cis diastereoselectivity of the process.
Addition of the radical to the C-6 position of the double bond
is less favored. This position is more distant to the ketyl radical,
and the orbital alignment is not ideal for the bond formation.
The conformation of the ketyl radical anion intermediate 43
was based on the minimum energy conformation of (E)-
cyclodec-5-enone 21 that was obtained from MMFF calculations
using the Spartan modeling program. Examining the five lowest
energy conformers of 21 demonstrates that transition structures
based on the conformers shown in entries 1, 2, and 4 would
favor the formation of cis-bicyclo[5.3.0]decan-1-ol 40
(Table 2).
To rationalize the high regio- and stereochemical outcome
of the transannular transformation, a similar analysis as de-
scribed above was used. In the ketyl radical anion intermediate
46, the alignment of the molecular orbitals is ideal for bond
formation between the ketyl radical and the C-5 position of the
alkene functionality. However, bond formation between the
radical and the C-6 position of the alkene appears to be
unfavorable (Scheme 8). This alignment also accounts for the
cis diastereoselectivity of the transformation.
The conformation of the ketyl radical anion intermediate was
based on the minimum energy conformation of (E)-cycloundec-
5-enone 22 (entry 1, Table 3). Examining the next four
conformers also predicts the formation of the cis-bicyclo[6.3.0]-
undecane ring system (entries 2-5, Table 3).
Examining the Diastereoselectivity. To investigate the
diastereoselectivity of the SmI2-mediated transannular ketone-
olefin coupling, the cyclization of substituted 5-methylenecy-
clooctanone and (E)-cyclodec-5-enone derivatives was exam-
Next, attention was turned to the transannular cyclization of
(E)-cycloundec-5-enone 22 (eq 10). Theoretically, this reaction
also could provide four different products: cis- or trans-bicyclo-
[6.3.0]undecan-1-ol and cis- or trans-bicyclo[5.4.0]undecan-1-
(90) Colclough, D.; White, J. B.; Smith, W. B.; Chu, Y. J. Org. Chem.
1993, 58, 6303-6313.
(91) Crandall, J. K.; Magaha, H. S. J. Org. Chem. 1982, 47, 5368-
5371.
(92) Hiyama, T.; Fujita, S.; Nozaki, H. Bull. Chem. Soc. Jpn. 1972, 45,
2797-2801.
(87) Crandall, J. K.; Magaha, H. S.; Henderson, M. A.; Widener, R. K.;
Tharp, G. A. J. Org. Chem. 1982, 47, 5372-5380.
(93) Shono, T.; Kise, N.; Fujimoto, T.; Tominaga, N.; Morita, H. J. Org.
Chem. 1992, 57, 7175-7187.
(88) Suginome, H.; Kondoh, T.; Gogonea, C.; Singh, V.; Goto, H.;
Osawa, E. J. Chem. Soc., Perkin Trans. 1 1995, 69-71.
(94) Stuedemann, T.; Ibrahim-Ouali, M.; Cahiez, G.; Knochel, P. Synlett
1998, 143-144.
(89) Bessiere, J. M.; Christol, H. Bull. Soc. Chim. Fr. 1969, 4063-4068.
1760 J. Org. Chem., Vol. 72, No. 5, 2007

Transannular SmI2-Mediated Ketone-Olefin Cyclization
TABLE 3. Minimum Energy Conformations of
(E)-Cycloundec-5-enone 22
SCHEME 9
ined. Performing the SmI2-mediated cyclization of 2-methyl-
5-methylenecyclooctanone 23 afforded a 4.7:1 mixture of
diastereomers (eq 12), the stereochemical assignment of which
was conducted by NOESY experiments (see Supporting Infor-
mation). This ratio was determined based on the H NMR
analysis of the reaction mixture.
case of the transannular cyclization of 5-methyl-2-methylenecy-
clooctanone 23.
1
Subsequently, the transannular cyclization of methyl substi-
tuted cyclodec-5-enone derivatives was investigated. Treatment
of (E)-10-methylcyclodec-5-enone 26 with SmI2 under standard
conditions led to the formation of a 3.5:1 mixture of diastere-
omers (eq 14).
The outcome of this transformation can be explained by
examining the ketyl radical anion intermediates leading to the
two diastereomeric products (Scheme 9). When the reaction
follows path A, the methyl group at the C-2 position is situated
in a seemingly favorable quasi-equatorial orientation. However,
further examination of intermediate 49 reveals that in this case,
an unfavorable gauche interaction develops between the methyl
group at the C-2 position and the samarium alkoxide, rendering
this pathway less favored. On the other hand, when the reaction
proceeds through transition structure 50, although the methyl
group is in a quasi-axial orientation, the unfavorable steric
interaction between the C-2 methyl and the samarium alkoxide
is avoided, thus rendering this pathway the major route.
When the methyl group was exchanged to the bulkier phenyl
substituent, the transannular cyclization proceeded with complete
diastereoselection furnishing bicycle 51 as a single product
(eq 13).
The stereochemical outcome of the transformation can be
rationalized based on conformational analysis of the ketyl radical
anion intermediate. The regioselectivity of the annulation as well
as the diastereoselectivity at the ring juncture can be well
explained by using the same analysis that was employed in the
case of the annulation of (E)-cyclodec-5-enone 21 (Scheme 10).
When the methyl group in the ketyl radical anion intermediate
in the minimum energy conformation of the cyclodec-5-enone
ring is situated in a quasi-equatorial orientation, there is an
unfavorable steric interaction between the samarium alkoxide
and the methyl group (Path A). On the other hand, when the
methyl group is positioned quasi-axially (Path B), this gauche
interaction is avoided, thus rendering this route the major
pathway of the transformation.
Transannular cyclization of (E)-4-methylcyclodec-5-enone 29
and (E)-2-methylcyclodec-5-enone 30 proceeded with compa-
rable yield and diastereoselectivity. Treatment of (E)-4-meth-
ylcyclodec-5-enone 29 with SmI2 under standard conditions
provided an 18:4:4:1 mixture of isomers in 60% yield, and the
reaction of (E)-2-methylcyclodec-5-enone 30 furnished a 2.6:1
separable mixture of diastereomers in 72% yield (Scheme 11).
The stereochemical outcome of the reaction can be explained
based on similar arguments to those that were presented in the
J. Org. Chem, Vol. 72, No. 5, 2007 1761

Molander et al.
SCHEME 10
underwent the transformation equally well. The strategy was
extended to larger ring-sized compounds. Subjecting (E)-
cyclodec-5-enone 21 to the reaction conditions proceeded with
very high regio- and diastereoselectivity, affording bicycle 40
as the major product. The cyclization of (E)-cycloundec-5-enone
22 also proved to be efficient, providing bicyclic compound 44
as the only product. The excellent regio- and diastereoselectivity
of these processes could be rationalized by examining the orbital
alignment of the ketyl radical anion intermediates that were
based on the lowest energy conformation of the keto alkene
starting materials. Investigation of the transannular cyclization
of 2-methyl- and 2-phenylcyclooctanone as well as the cycliza-
tion of substituted cyclodecenone derivatives revealed that the
annulation proceeds with high diastereoselectivity. The stereo-
chemical outcome of these processes was governed by the
substituents occupying the sterically more favorable quasi-axial
position in the transition state.
The above results demonstrate that the SmI2-mediated trans-
annular ketone-olefin coupling provides efficient access to
bicyclic alcohols. Extension of the transannular cyclization
strategy to other methods holds enormous potential as it can
become a novel disconnection for the creation of polycyclic
ring structures.
Experimental Section
Tetrahydrofuran (THF) was distilled prior to use from sodium/
benzophenone under nitrogen. Samarium metal (99.9%) was
purchased from Strem Chemical, Inc. and stored under nitrogen.
Diiodomethane was purified via distillation, stored over copper
beads and protected from light. HMPA was distilled from sodium.
Air-sensitive materials were handled using standard benchtop
techniques. For purification, standard flash chromatography methods
were employed using 32-63 µm silica gel purchased from Sorbent
Technologies.
SCHEME 11
General Procedure for the Transannular SmI2-Mediated
Ketyl-Olefin Cyclization: Preparation of SmI2 Solution in THF
and HMPA. A flame-dried round-bottom flask was charged with
Sm metal (135 mg, 0.9 mmol) (Strem) and THF (4.1 mL) under
Ar. This was followed by the addition of CH2I2 (216 mg, 0.81
mmol) in two portions over 30 min. The reaction mixture was stirred
at room temperature for 4 h. HMPA was added (1.3 g, 1.3 mL, 7.3
mmol), and the solution was stirred for 15 min at room temperature.
Method A. The substrate (0.18 mmol) was dissolved in THF
(3.6 mL), and t-BuOH (26 mg, 0.36 mmol) was added. This solution
was added dropwise to the SmI2/THF/HMPA solution (5.4 mL)
under Ar at room temperature over 15 min. The reaction was stirred
for 2-4 h. Upon consumption of the starting material, saturated
NaHCO3 solution (3 mL) was added and stirring was continued
for another 10 min. This was followed by the addition of Et2O.
The phases were separated, and the aqueous phase was extracted
with Et2O (3 × 5 mL). The combined organic phases were dried
(Na2SO4) and filtered, and the solvent was evaporated.
Method B. The substrate (0.18 mmol) was dissolved in THF
(3.6 mL) and t-BuOH (26 mg, 0.36 mmol), and PhSH (27 mg,
0.25 mmol) was added. This solution was added dropwise to the
SmI2/THF/HMPA solution (5.4 mL) under Ar at room temperature
over 15 min. The reaction was stirred for 2-4 h. Upon consumption
of the starting material, saturated NaHCO3 solution (3 mL) was
added and stirring was continued for another 10 min. This was
followed by the addition of Et2O. The phases were separated, and
the aqueous phase was extracted with Et2O (3 × 5 mL). The
combined organic phases were dried (Na2SO4) and filtered, and
the solvent was evaporated.
The stereochemical outcome of these transformations can be
rationalized based on a similar analysis to that employed in the
case of the transannular cyclization of (E)-10-methylcyclodec-
5-enone 26.
Conclusion
The goal of this study was to investigate the efficiency of
the transannular cyclization tactic for creating bicyclic ring
structures. To test the strategy, the SmI2-mediated ketone-olefin
cyclization was selected. The transannular cyclization of cy-
clooctanone derivatives revealed that this is a powerful approach
to construct bicyclo[3.3.0]octane ring systems. Although initially
the annulation of 5-methylenecyclooctanone 9 led to dimer
formation exclusively, this side reaction could be completely
avoided by employing thiophenol as a radical scavenger. (Z)-
5-Methylcyclooct-4-enone 10 also underwent the transformation
demonstrating that compounds containing an endocyclic double
bond were viable substrates in the annulation. Reaction of
5-ethylidenecyclooctanone 11 afforded the bicycle without the
need to employ a radical scavenger. Activated alkene 12
Preparation of the Dimer of 5-Methylbicyclo[3.3.0]octan-1-
ol 31. Prepared from 5-methylenecyclooctanone 9 (10 mg, 0.072
mmol) according to the general procedure described in Method A,
1762 J. Org. Chem., Vol. 72, No. 5, 2007

Transannular SmI2-Mediated Ketone-Olefin Cyclization
to afford the product after flash chromatography on Florisil, using
Et2O-pentane (10%) as eluent (7 mg, 70%). 1H NMR (500 MHz,
CDCl3): 1.87-1.82 (m, 4H), 1.72-1.67 (m, 4H), 1.64-1.58 (m,
8H), 1.57-1.56 (m, 2H), 1.48-1.43 (m, 8H), 1.29 (s, 4H). 13C
NMR: (125 MHz, CDCl3): δ 90.4, 53.2, 42.1, 38.3, 31.9, 22.7.
IR (film): 3325, 2947, 2860, 1458, 1445, 1395, 1309, 1289, 1230,
1139, 1106, 1080, 1035 cm-1. HRMS: calcd for C18H30O2 [M]+
261.2245, found 261.2233.
multiplets, 8H), 1.30-1.12 (series of multiplets, 5H). 13C NMR:
(125 MHz, CDCl3): δ 132.1, 130.8, 71.3, 36.0, 35.1, 34.1, 34.1,
26.7, 26.2, 24.7, 24.0. IR (film): 3341, 2927, 2845, 1457, 1438,
1348, 1233, 1164, 1065, 1034, 976 cm-1. HRMS: calcd for
C11H20O [M]+ 168.1514, found 168.1523.
Preparation of 2,5-Dimethylbicyclo[3.3.0]octan-1-ol 47. Pre-
pared from 2,5-dimethylcyclooctanone 23 (110 mg, 0.72 mmol)
according to the general procedure described in Method B, to afford
a 4.7:1 mixture of diastereomers after flash chromatography on
Preparation of 5-Methylbicyclo[3.3.0]octan-1-ol 35.78 Prepared
from 5-methylenecyclooctanone 9 (10 mg, 0.072 mmol) according
to the general procedure described in Method B, to afford the
product after flash chromatography on Florisil, using Et2O-pentane
(10%) as eluent (8 mg, 80%). 5-Methylbicyclo[3.3.0]octan-1-ol 35
was also prepared from (Z)-5-methylcyclooct-4-enone 10 (50 mg,
0.38 mmol) according to the general procedure described in Method
A, to afford the product after flash chromatography on Florisil,
using Et2O-pentane (10%) as eluent (37 mg, 70%). 1H NMR (500
MHz, CDCl3): 1.81-1.77 (m, 2H), 1.71-1.60 (m, 2H), 1.60-
1.57 (m, 2H), 1.53-1.45 (series of multiplets, 6H), 1.32 (s, 1H),
0.98 (s, 3H). 13C NMR: (125 MHz, CDCl3): δ 89.5, 50.2, 41.7,
41.0, 23.1, 22.4. IR (film): 3389, 2935, 2857, 1462, 1451, 1376,
1116, 993 cm-1. HRMS: calcd for C9H15 [M - OH]+ 123.1173,
found 123.1165.
Preparation of 5-Ethylbicyclo[3.3.0]octan-1-ol 37. Prepared
from methyl 5-ethylenecyclooctanone 11 (25 mg, 0.16 mmol)
according to the general procedure described in Method A, to afford
the product after flash chromatography on Florisil, using Et2O-
pentane (10%) as eluent (20 mg, 72%). 1H NMR (500 MHz,
CDCl3): 1.84-1.81 (m, 2H), 1.69-1.63 (m, 2H) 1.60-1.55 (series
of multiplets 4H), 1.45-1.41 (series of multiplets, 4H), 1.41 (s,
1H), 1.30 (q, J ) 7.3 Hz, 2H), 0.91 (t, J ) 7.3 Hz, 3H). 13C NMR:
(125 MHz, CDCl3): δ 90.2, 42.0, 39.5, 37.6, 28.4, 22.6, 9.9. IR
(film): 3422, 2935, 2857, 1689, 1460, 1451, 1376, 1309, 1295,
1258, 1233, 1127, 1076, 1032 cm-1. HRMS: calcd for C10H17 [M
- OH]+ 137.1330, found 137.1333.
1
Florisil, using Et2O-pentane (10%) as eluent (80 mg, 72%). H
NMR (500 MHz, CDCl3): 1.75 (m, 1H), 1.62 (m, 1H), 1.60 (m,
2H), 1.50 (m, 2H), 1.50-1.43 (series of multiplets, 4H), 1.16 (s,
1H), 1.10 (m, 1H), 0.98 (d, J ) 6.6 Hz, 3H), 0.98 (s, 3H). 13C
NMR: (125 MHz, CDCl3): δ 90.9, 50.2, 44.5, 42.2, 38.8, 36.2,
29.5, 23.8, 23.3, 13.6. IR (film): 3417, 2941, 2868, 1636, 1454,
1379, 1289, 1258, 1211, 1130, 1088, 1071, 1034, 1001, 984 cm-1
HRMS: calcd for C10H17 [M
137.1321.
.
-
OH]+ 137.1330, found
Preparation of 2-Phenyl-5-methylbicyclo[3.3.0]octan-1-ol 51.
Prepared from 2-phenyl-5-methylcyclooctanone 25 (50 mg, 0.234
mmol) according to the general procedure described in Method B,
to afford the product after flash chromatography on Florisil, using
Et2O-pentane (10%) as eluent (36 mg, 73%). 1H NMR (500 MHz,
CDCl3): 7.36-7.29 (series of multiplets, 4H), 7.24 (m, 1H), 3.04
(t J ) 9.6 Hz, 1H), 1.85-1.83 (series of multiplets, 2H), 1.74-
1.68 (series of multiplets, 2H), 1.61-1.49 (series of multiplets, 5H),
1.43 (s, 1H), 1.14 (m, 1H), 1.10 (s, 3H). 13C NMR: (125 MHz,
CDCl3):δ 141.1, 127.9, 127.8, 126.2, 91.2, 54.7, 50.6, 42.6, 38.7,
38.6, 25.6, 24.1, 23.4. IR (film): 3473, 3086, 3058, 3030, 2941,
2862, 1949, 1876, 1801, 1600, 1496, 1446, 1373, 1269, 1208, 1130,
1071, 1034, 1001 cm-1. HRMS: calcd for C15H20O [M]+ 216.1514,
found 216.1501.
Preparation of 2-Methylbicyclo[3.3.0]decan-1-ol 52. Prepared
from 10-methyl-(E)-cyclodec-5-one 26 (20 mg, 0.12 mmol) ac-
cording to the general procedure described in Method B, to afford
the product after flash chromatography on Florisil, using Et2O-
pentane (10%) as eluent (13 mg, 65%). 1H NMR (500 MHz,
CDCl3): 2.15-2.12 (m, 1H), 1.82-1.72 (series of multiplets, 3H),
1.71-1.58 (series of multiplets, 6H), 1.53-1.49 (m, 1H), 1.32-
1.26 (series of multiplets, 4H), 1.26-1.03 (series of multiplets, 2H),
0.96 (d, J ) 5.95 Hz, 3H). 13C NMR (125 MHz, CDCl3): 86.2,
53.5, 41.8, 41.4, 35.3, 34.0, 32.6, 30.6, 30.4, 23.7, 18.7. IR: 3550-
3050 (bs), 2918, 2857, 1451, 1376, 1320, 1261, 1205, 1090, 1020,
959, 925. HRMS: calcd for C11H20O [M+] 168.1514, found.
168.1515.
Preparation of Compound 39.83,84 Prepared from (5-oxo-
cyclooctylidene)acetic acid methyl ester 12 (44 mg, 0.22 mmol)
according to the general procedure described in Method A, to afford
the product after flash chromatography on Florisil, using Et2O-
pentane (10%) as eluent (29 mg, 80%). 1H NMR (500 MHz,
CDCl3): 2.57 (s, 2H), 2.01 (m, 2H), 1.75-1.68 (series of multiplets,
10H). 13C NMR: (125 MHz, CDCl3): δ 177.8, 104.7, 55.3, 43.9,
40.6, 38.7, 25.2. IR (film): 2946, 2857, 1767, 1462, 1451, 1412,
1323, 1297, 1253, 1211, 1180, 1146, 976 cm-1. HRMS: calcd for
C10H14O2 [M]+ 166.0993, found 166.0994.
Preparation of Bicyclo[3.3.0]decan-1-ol 40.1,85,87,89-94 Prepared
from (E)-cyclodec-5-one 21 (50 mg, 0.32 mmol) according to the
general procedure described in Method B, to afford the product
after flash chromatography on Florisil, using Et2O-pentane (10%)
as eluent (32 mg, 62%). Characterization data are in agreement
with the reported literature data.
Preparation of 8-Methylbicyclo[3.3.0]decan-1-ol 56. Prepared
from 4-methyl-(E)-cyclodec-5-one 29 (88 mg, 0.52 mmol) accord-
ing to the general procedure described in Method B, to afford an
18:4:4:1 mixture of isomeric products after flash chromatography
on Florisil, using Et2O-pentane (10%) as eluent (54 mg, 60%).
1H NMR (500 MHz, CDCl3): δ 1.01 (d, J ) 6.0 Hz, 3H), 1.13
(m, 1H), 1.24-1.32 (series of m, 4H), 1.33-1.50 (series of m, 3H),
1.51-1.72 (series of m, 6 H), 1.73-1.87 (series of m, 3H). 13C
NMR (125 MHz, CDCl3): δ 19.5, 23.6, 29.5, 31.5, 32.2, 33.0, 40.2,
43.2, 43.3, 61.4, 84.8. IR(film): 3378, 2857, 1451, 1376, 1345,
1323, 1289, 1275, 1211, 1158, 1121, 1104, 1012, 984, 962, 914
cm-1. HRMS: Calculated for C11H20O [M+] 168.1514 found
168.1506.
Preparation of 10-Methylbicyclo[3.3.0]decan-1-ol 57 and 58.
Prepared from 2-methyl-(E)-cyclodec-5-one 30 (88 mg, 0.52 mmol)
according to the general procedure described in Method B, to afford
a 2.6:1 mixture of isomeric products after flash chromatography
on Florisil, using Et2O-pentane (10%) as eluent (72 mg, 81%).
1H NMR (500 MHz, CDCl3): Major diastereomer: δ 0.89 (d, J )
5.95 Hz, 3H), 0.95-1.06 (series of m, 2H), 1.22 (m, 2H), 1.26-
1.43 (series of m, 3H), 1.50 (m, 1H), 1.54-1.64 (series of m, 4H),
1.75-1.83 (series of m, 3 H), 1.88 (m, 1 H), 1.96 (m, 1H). Minor
diastereomer: δ 0.88 (d, J ) 5.65 Hz, 3H), 1.20-1.38 (series of
m, 6H), 1.70-1.86 (series of m, 5 H), 1.87-1.91 (series of m,
Preparation of Bicyclo[3.3.0]undecan-1-ol 44. Prepared from
(E)-cycloundec-5-one 22 (60 mg, 0.36 mmol) according to the
general procedure described in Method B, to afford the product
after flash chromatography on Florosil, using Et2O-pentane (10%)
1
as eluent (37 mg, 61%). H NMR (500 MHz, CDCl3): 2.22 (m,
1H), 1.82-1.28 (series of multiplets, 18H), 1.15 (s, 1H). 13C
NMR: (125 MHz, CDCl3): δ 83.9, 49.6, 42.1, 36.6, 33.9, 33.4,
31.0, 25.7, 25.6, 23.6, 21.0. IR (film): 3375, 2919, 2853, 2708,
1463, 1443, 1369, 1323, 1287, 1229, 1202, 1170, 1117, 1069 cm-1
.
HRMS: calcd for C11H18 [M - H2O]+ 150.1408, found
150.1399.
Preparation of (E)-Cycloundec-5-ol 45. Prepared from (E)-
cycloundec-5-one 22 (60 mg, 0.36 mmol) according to the general
procedure described in Method B, with the exception of performing
the reaction at -78 °C, to afford the product after flash chroma-
tography on Florisil, using Et2O-pentane (20%) as eluent (39 mg,
1
63%). H NMR (500 MHz, CDCl3): 5.39 (m, 2H), 3.77 (m, 1H),
2.20 (m, 2H), 1.96 (m, 1H), 1.87 (m, 1H), 1.67-1.40 (series of
J. Org. Chem, Vol. 72, No. 5, 2007 1763

Molander et al.
4H), 1.92-2.02 (series of m, 2H). 13C NMR (125 MHz, CDCl3):
Major diastereomer: δ 12.0, 23.3, 30.2, 31.6, 32.2, 32.5, 35.0, 38.1,
45.1, 53.6, 84.0. Minor diastereomer: δ 15.6, 23.1, 29.8, 31.2, 31.9,
32.0, 34.6, 35.0, 48.3, 53.1, 85.7. IR(film): Major diastereomer:
3602, 3468, 2919, 2857, 2689, 2364, 1457, 1385, 1323, 1276, 1259,
1208, 1169, 1150, 1105, 1066, 1035, 999, 979, 929, 864, 822, 792
cm-1. Minor diastereomer: 3384, 2919, 2852, 2695, 2359, 1457,
1376, 1345, 1329, 1278, 1258, 1128, 1203, 1164, 1133, 1105, 1074,
[M+], found 168.1516. Minor diastereomer: Calculated for C11H18
[M+ - H2O] 150.1409, found 150.1403.
Acknowledgment. We acknowledge the National Institutes
of Health (GM35249) for the generous support of this work.
Supporting Information Available: Experimental details and
structural data for all new compounds not described within this text.
This material is available free of charge via the Internet at
http://pubs.acs.org.
1046, 1013, 976, 959, 929, 912, 867, 842, 822, 792, 738 cm-1
.
HRMS: Major diastereomer: Calculated for C11H20O 168.1514
JO062292D
1764 J. Org. Chem., Vol. 72, No. 5, 2007