Zeolite-mediated cyclization of an epoxide-containing polyene

Article abstract of DOI:10.1021/jo960745g

The utility of zeolites as promoters for the cyclization of an epoxide-containing polyene has been investigated. Reaction of polyene 1 with oven-dried 4 ? molecular sieves (type A zeolite) proceeds efficiently to generate bicyclic alcohol 2 in a 90% isola

Full text of DOI:10.1021/jo960745g

9534
J . Org. Chem. 1996, 61, 9534-9537
Zeolite-Med ia ted Cycliza tion of a n Ep oxid e-Con ta in in g P olyen e†
Stephanie E. Sen,* Yan zhi Zhang, and Steven L. Roach
Department of Chemistry, Indiana University-Purdue University at Indianapolis (IUPUI),
402 North Blackford Street, Indianapolis, Indiana 46202
Received April 22, 1996 (Revised Manuscript Received October 16, 1996X)
The utility of zeolites as promoters for the cyclization of an epoxide-containing polyene has been
investigated. Reaction of polyene 1 with oven-dried 4 Å molecular sieves (type A zeolite) proceeds
efficiently to generate bicyclic alcohol 2 in a 90% isolated yield. The reaction is sensitive to a variety
of factors, including solvent type, water content, and zeolite acidity. Reactivity is apparently due
to the zeolite lattice, since alumina and silica either are unreactive or generate a complex mixture
of epoxide ring-opened products. Compared to the aluminum-based Lewis acid Me2AlCl, the zeolite-
promoted cyclization of 1 was a more facile reaction, providing excellent product recovery after
filtration. These results indicate that zeolites represent a new class of promoters in biomimetic
polyene cyclizations.
Sch em e 1
In tr od u ction
Biomimetic polyene cyclization represents an impor-
tant method for the preparation of polycycles with
controlled stereochemistry. While substantial progress
has been made with the introduction of acetal and allylic
alcohol functionalities as initiating groups in these cy-
clization reactions,1 few successful applications of the
epoxide functionality, the normal initiator for many
naturally-occurring cyclases, have been demonstrated.2
Unfortunately, known methodology for the cyclization of
epoxide-containing polyenes using aluminum- and tita-
nium-based Lewis acids3 can result in low yields and the
production of both partially cyclized and rearranged
byproducts. Because of the importance of epoxides in
biological cyclizations4 and their synthetic utility in
generating lanostane-type A ring systems, the develop-
ment of new promoters for the biomimetic cyclization of
epoxide-containing polyenes continues to be an active
area of research.
The utility of zeolites as selective adsorbents and as
cracking catalysts in the petroleum industry has been
known for many years.5,6 However, zeolites have also
been examined as catalysts for other synthetic transfor-
mations.7 Examples of zeolite-promoted reactions include
Friedel-Crafts alkylation and acylation,8,9 aldol conden-
sations,10 photochemical and acid-catalyzed cycliza-
tions,11,12 and ring-opening reactions.13 Modification of
the zeolite either by the introduction of reactive metal
centers or by reagent “doping” has expanded the range
of reactions now available with this porous material.14
Because of the known properties of zeolites as super-
acids and as cavity-selective catalysts, we became inter-
ested in determining the utility of these materials in
generating polycycles by polyene cyclization methodology.
Herein, we report our initial results involving the zeolite-
induced bicyclization of polyene 1, which possesses an
epoxide initiator and a silicon (propargylic silane) ter-
minator (Scheme 1). Cyclizations of this polyene using
(i-PrO)TiCl3 and Me2AlCl were also examined so that a
comparison between traditional Lewis acid promoters
and zeolite methodology could be made. Reaction of
polyene 1 with oven-dried 4 Å molecular sieves in
refluxing CHCl3 for 40 min results in conversion of
starting material to bicyclic product 2. As described
below, the reaction requires the proper balance between
solvent type, water content, and zeolite acidity.
Resu lts a n d Discu ssion
† This paper is dedicated to the memory of William S. J ohnson.
X Abstract published in Advance ACS Abstracts, November 15, 1996.
(1) J ohnson, W. S. Tetrahedron 1991, 47, xi.
(2) (a) Taylor, S. K. Org. Prep. Proc. Int. 1992, 24, 245. (b) Corey,
E. J .; Lee, J . J . Am. Chem. Soc. 1993, 115, 8873. (c) Corey, E. J .; Lin,
S. J . Am. Chem. Soc. 1996, 118, 8765.
(3) (a) Fish, P. V.; J ohnson, W. S. J . Org. Chem. 1994, 59, 2324. (b)
Mori, K.; Aki, S.; Kido, M. Liebigs Ann. Chem. 1994, 319. (c) Corey, E.
J .; Sodeoka, M. Tetrahedron Lett. 1991, 32, 7005. (d) Yee, N. K. N.;
Coates, R. M. J . Org. Chem. 1992, 57, 4598. (e) Aziz M.; Rouessac, F.
Tetrahedron 1988, 44, 101. (f) Armstrong, R. J .; Weiler, L. Can. J .
Chem. 1983, 61, 214.
Polyene 1 was synthesized in seven steps (37% overall
yield) from 3-chloropropionaldehyde diethyl acetal using
the procedures developed by J ohnson and co-workers for
the construction of larger polyene skeletons (Scheme 2).15
The final step of the reaction sequence, formation of the
(10) (a) Xu, T.; Munson, E. J .; Haw, J . F. J . Am. Chem. Soc. 1994,
116, 1962. (b) Climent, M. J .; Corma, A.; Iborra, S.; Primo, J . J . Catal.
1995, 151, 60.
(4) Abe, I.; Rohmer, M.; Prestwich G. D. Chem. Rev. 1993, 93, 2189.
(5) Ho¨lderich, W.; Hesse, M.; Na¨umann, F. Angew. Chem., Int. Ed.
Engl. 1988, 27, 226.
(11) Ramamurthy, V.; Sanderson, D. R. Tetrahedron Lett. 1992, 33,
2757.
(12) (a) Sreekumar, R.; Narayana Murthy, Y. V. S.; Narayana Pillai,
C. J . Chem. Soc., Chem. Commun. 1992, 1624. (b) Stamm, T.;
Kouwenhoven, H. W.; Seebach, D.; Prins, R. J . Catal. 1995, 155, 268.
(13) (a) Takeuchi, H.; Kitajima, K.; Yamamoto, Y.; Mizuno, K. J .
Chem. Soc., Perkin Trans. 2 1993, 199. (b) Onaka, M.; Sugita, K.;
Izumi, Y. J . Org. Chem. 1989, 54, 1116.
(14) (a) Martin-Luengo, M. A.; Yates, M. J . Mater. Sci. 1995, 30,
4483. (b) Kumar, P.; Kumar, R.; Pandey, B. SynLett 1995, 289. (c)
Sheldon, R. A. J . Mol. Catal. 1996, 107, 75.
(6) For a recent article on regioselective hydrocarbon isomerization,
see: Martens, J . A.; Souverijns, W.; Verrelst, W.; Parton, R.; Froment,
G. F.; J acobs, P. A. Angew. Chem., Int. Ed. Engl. 1995, 34, 2528.
(7) Dartt, C. B.; Davis, M. E. Catal. Today 1994, 19, 151.
(8) (a) Sugi, Y.; Toba, M. Catal. Today 1994, 19, 187. (b) Gunnewegh,
E. A.; Hoefnagel, A. J .; van Bekkum, H. J . Mol. Catal. 1995, 100, 87.
(9) (a) Chiche, B.; Finiels, A.; Gauthier, C.; Geneste, P. J . Org. Chem.
1986, 51, 2128. (b) Singh, A. P.; Bhattacharya, D.; Sharma, S. J . Mol.
Catal. 1995, 102, 139. (c) Gunnewegh, E. A.; Gopie, S. S.; van Bekkum,
H. J . Mol. Catal. 1996, 106, 151.
(15) J ohnson, W. S.; Yarnell, T. M.; Myers, R. F.; Morton, D. R.;
Boots, S. G. J . Org. Chem. 1980, 45, 1254.
S0022-3263(96)00745-1 CCC: $12.00 © 1996 American Chemical Society

Zeolite-Mediated Polyene Cyclization
J . Org. Chem., Vol. 61, No. 26, 1996 9535
Sch em e 2. Syn th esis of P olyen e 1a
Ta ble 1. Effect of Differ en t Solven ts on th e Cycliza tion
of P olyen e 1a
reaction conditions
recovered materials (%)b
solvent
temp (°C)
time
bicycles 2 (4)
polyene 1
toluene
toluene
benzene
CH3CN
THF
25
110
80
82
66
68
76
40
61
2 days
5 h
5 h
0
92c
0d
43 (6)
65
6
0e
4 h
79f
100
0g
4.5 h
4.5 h
3.5 h
3.5 h
40 min
0
hexane
CCl4
60 (18)
64 (5)
100 (0)
100 (0)
18h
0
CH2Cl2
i
CHCl3
0
a
Reaction conditions: 2 mg of polyene 1 and 30 mg of oven-
a
dried, crushed 4 Å molecular sieves in 5 mL of solvent, at reflux.
Conditions: (a) Li acetylide‚EDA, DMSO (79%); (b) n-BuLi,
b
GC yield of isolated reaction mixture. c Byproduct composition:
then Me3SiCH2I (99%); (c) PPTS, acetone/H2O (quantitative);
(d) CH2dC(CH3)MgBr, THF (85%); (e) CH3C(OEt)3, propionic
acid (74%); (f) DIBALH, THF, -94 °C (97%); (g) (CH3)2CHSPh2BF4,
t-BuLi, THF, -78 °C (78%).
d
5% 5 and 3% 6. Byproduct composition: 9% 7, 16% 5, 6% 6,
remainder (<4% each) unidentified. e Byproduct composition: 19%
6, remainder (<5% each) unidentified. f Byproduct composition:
h
15% 5. g Remaining material (<5% each) unidentified. Byproduct
i
composition: 7% 7, 6% 5. Distilled from K2CO3 prior to use.
gem-dimethyl epoxide from aldehyde 3, was troublesome
due to the instability of diphenylsulfonium isopropylide.
Reactions with the sulfur ylide required the rigorous
exclusion of both air and moisture and, because of its
thermal instability were typically conducted between -78
and -60 °C. Under these conditions, epoxide 1 was
formed in 75-80% isolated yield. Diphenylsulfonium
isopropylide was generated from diphenylisopropylsul-
fonium tetrafluoroborate, prepared by the method of J ulia
and co-workers, involving triflic acid-induced addition of
phenyl sulfide to 2-propanol, followed by anion exchange
with tetrafluoroboric acid.16 Although the alternative
condensation of phenyl sulfide with 2-iodopropane in the
presence of silver tetrafluoroborate17 provided higher
reaction yields (45-55% compared to 10-25%), the
resulting salt contained unidentified contaminants that
led to difficulties in epoxide isolation.
Ta ble 2. Effect of Wa ter Con ten t on th e Cycliza tion
of P olyen e 1a
recovered materials (%)b
bicycles
bicyclic
zeolite type
2 (4)
ketone 5 ether 7 polyene 1
110 °C dried zeolite 70
0
6
9
0
3
4
30
45
5c
unactivated zeolite
36 (10)
500 °C dried zeolite 23 (32)
a
Reaction conditions: 3.5 mg of polyene 1 and 70 mg of crushed
b
4 Å molecular sieves in 4 mL of CHCl3 at reflux for 30 min. GC
yield of isolated reaction mixture. c Remaining material (<4%
each) unidentified.
To determine optimal conditions for the cyclization of
polyene 1, small-scale reactions (2-5 mg) were per-
formed. Several potential factors responsible for zeolite
reactivity were explored, and the results of these experi-
ments are summarized below.
Solven t Effects. Results from the cyclization of 1
with 4 Å molecular sieves (type A zeolite, Na form) using
several different solvents are presented in Table 1. The
cyclization of polyene 1 occurred in a variety of nonpolar
and halogenated solvents but was significantly inhibited
when coordinating solvents were used. Although tem-
perature had an important effect on reaction rate (toluene
at rt versus reflux), the use of lower-boiling halogenated
solvents increased both the rate and the selectivity of the
reaction. Thus, cyclization of polyene 1 using toluene as
solvent (at reflux) occurred within 5 h to provide 2 and a
mixture of epoxide ring-opened and partially cyclized
materials, while reaction of 1 in refluxing CHCl3 required
only 40 min for complete consumption of starting mate-
rial to yield bicycle 2 as the sole reaction product. The
inhibitory effects of both THF and CH3CN suggest that
these solvents compete with the reactant for coordinating
sites on the zeolite,18 thus impeding cyclization chemistry.
Wa ter Con ten t. A qualitative examination of differ-
ing amounts of water present within the zeolite was
undertaken to determine its effect on the cyclization of
epoxide-containing polyene 1. A sample of 4 Å molecular
F igu r e 1. Byproducts identified in the reaction of 1 with 4 Å
molecular sieves under nonoptimal cyclization conditions.
sieves was separated into three portions and subjected
to different activation methods (unactivated, dried at 110
°C overnight, and dried at 500 °C for 5 h). The results
of these experiments (Table 2) indicate that small
amounts of water are essential in order for efficient
cyclization to proceed. In addition to slowing down the
reaction rate, too much water resulted in an increase in
byproduct formation. Compared to either oven-dried or
untreated zeolites, those that were activated at 500 °C
not only were significantly less effective promoters of the
bicyclization of 1 but also yielded proportionatly higher
quantities of O-silylated bicycle 4 (Figure 1).
(16) Badet, B.; J ulia, M. Tetrahedron Lett. 1979, 13, 1101.
(17) (a) The Chemistry of the Sulfonium Group; Stirling, C. J . M.,
Patai, S., Eds.; J ohn Wiley & Sons: New York, 1981. (b) Corey, E. J .;
J autelat, M.; Oppolzer, W. Tetrahedron Lett. 1967, 24, 2325.
(18) Corma, A.; Esteve, P.; Mart´ınez, A. J . Catal. 1996, 161, 11.
Zeolite Equ iva len ts. The amount of accessible zeo-
lite surface present was found to be related to the
cyclization rate of polyene 1 (Table 3). Thus, the reaction

9536 J . Org. Chem., Vol. 61, No. 26, 1996
Sen et al.
Ta ble 3. Effect of Zeolite Qu a n tity on th e Cycliza tion of
P olyen e 1a
Ta ble 4. Rea ctivity of Silica , Alu m in a , a n d
Ca tion -Exch a n ged Zeolites
zeolite equivalents
(by weight)
reaction
timeb
reaction conditionsa
recovered material (%)b
solvent
cyclization
promoter
10
20
30
15
20
30
toluene
toluene
toluene
8 hc
5 h
3.5 h
2.5 h
1.5 h
40 min
time (h) bicycles 2 (4) polyene 1 byproducts
nonec
SiO2
Al2O3
LiAd
NaAd
KAd
30
1
0.5
1
1
100
100
100
d
CHCl3
CHCl3
CHCl3
d
100
83 (2)
d
15e
61f
15g
a
1
0.5
39 (0)
12 (2)
Reaction conditions: 3 mg of polyene 1 in 4 mL of solvent at
CsAd
71
b
reflux. Time required for complete consumption of starting
material. c 2% starting material remaining. Distilled from K2CO3
d
a
Reaction conditions: (a) SiO2 reactions, 2.5 mg of polyene 1
and 50 mg of SiO2 in 4 mL of reluxing CHCl3; (b) AlO2 reactions,
3 mg of polyene 1 and 90 mg of AlO2 in 4 mL of refluxing CHCl3;
(c) zeolite reactions, 3.5 mg of polyene 1 and 70 mg of cation-
exchanged zeolite in 4 mL of refluxing CHCl3. b GC yield of isolated
prior to use.
was faster when crushed versus pellet zeolite was used,
and the rate increased with increasing zeolite content and
stirring rate. These results are expected for heteroge-
neous reactions that require adsorption onto a solid
surface. Although the reaction proceeds smoothly within
2.5 h when using 15 equiv (by weight) of crushed 4 Å
molecular sieves, the reaction time can conveniently be
modulated by the presence of more or less zeolite,
resulting in no change in the yield of product formed.
reaction mixture. c Reaction performed in toluene. Prepared by
d
soaking Na-form zeolite A in 1 M solution of the appropriate
chloride salt, followed by filtration, washing the solid with
deionized water, and drying at 110 °C overnight. e The sole
byproduct for this reaction was bicyclic ether 7. f Byproduct
composition: 24% 5, 13% 6, 10% 7, remainder (<5% each)
unidentified. g Byproduct composition: 5% 5, 3% 6, 2% 7, remain-
der unidentified.
Byp r od u ct Ch a r a cter iza tion . The structures of the
reaction byproducts were determined by combining sev-
eral crude reaction mixtures from nonoptimized reactions
and isolating the compounds by flash chromatography.
ously reported procedures20 and then reacted with poly-
ene 1. The results from these studies are summarized
in Table 4.
Reaction of polyene 1 with either silica or neutral
alumina resulted in no reaction when conditions identical
to the zeolite-promoted cyclization were used. However,
the use of acidic alumina (data not shown) resulted in
the formation of 28% bicyclic products, along with 18%
byproducts (1 h reflux in toluene), suggesting that acidity
may play an important role in the observed reactivity.21
Since the relative acidity within the zeolite cavity is, in
part, a function of the type of neutralizing cation, the acid
strength of a particular zeolite can be modified by simple
cation exchange. For zeolite type X, the relative acidity
trend has been determined to be HX (proton-exchanged
zeolite X) > LiX > NaX > KX > CsX.22 Cyclization of 1
using ion-exchanged zeolite A showed a direct correlation
with this acidity trend. Thus, lithium-exchanged zeolite
A was the most effective promoter, while the activity of
CsA was greatly diminished. For reactions involving K-
and Cs-exchanged zeolite A, a much higher proportion
of unwanted byproducts was formed, including a signifi-
cant amount of ketone 5 (Figure 1).
1
The fractions thus obtained were then analyzed by H
NMR and cross-correlated with the corresponding GC
retention times. Results indicated that the major byprod-
ucts were typically TMS ether 4, epoxide ring-opened
products 5 and 6, and bridging bicyclic ether 7 (Figure
1). Although compounds 5 and 7, which result from
premature termination of the cyclization process, are
commonly seen in the cyclization of related epoxide-
containing polyenes using titanium- and aluminum-based
Lewis acids,3 alcohol 6 is not, suggesting that there are
subtle differences in the acidity between zeolites and
these conventional cyclization promoters. In addition,
significant amounts of byproducts were formed in toluene
and when improperly dried zeolites were used. Surpris-
ingly, little if any cis-fused bicycle 8 and monocyclic
alcohols 9 were formed under any of the zeolite-promoted
reactions so far examined.
Effect of Differ en t Ca ta lysts a n d Acid Str en gth .
The effectiveness of 4 Å molecular sieves in promoting
the bicyclization of polyene 1 can be ascribed to the acidic
property of zeolites. For every aluminum center that is
present in an aluminosilicate zeolite, a cation (metal
cation or proton) is required for charge neutralization.
From both structural and theoretical studies, it is now
established that zeolite activity is a result of increased
acidity due to the Al-O-Si linkages.19 Proposed cata-
lytic mechanisms all involve the initial formation of a
Lewis acid-Lewis base complex by coordination of the
substrate to either a proton or a metal cation at the Al-
O-Si cluster.
Experiments were performed to determine whether the
observed reactivity is the result of characteristics unique
to zeolites. First, to establish the prerequisite for the
aluminosilicate structure, the cyclization of polyene 1 was
attempted using either silica gel or neutral alumina.
Second, to test the effect of zeolite acidity on cyclization
efficiency, type A zeolite (Na form) was ion-exchanged
with lithium, potassium, and cesium according to previ-
To compare the efficiency of zeolite-mediated reactions
with conventional biomimetic polyene cyclization promot-
ers, reactions of 1 with (i-PrO)TiCl3 and with Me2AlCl
were performed. Using the mixed titanium reagent,
conversion of 1 into bicycle 2 proceeded smoothly,23 while
reaction of 1 with the aluminum-based Lewis acid
resulted in recovery of starting material and of partially
cyclized products (including compounds 7 and 9) and
ketone 5 (data not shown).24
Desilyla tion . NMR studies were performed to deter-
mine the mode of desilylation upon cyclization of polyene
1. Reaction of epoxide 1 with 4 Å molecular sieves in
(20) Onaka, M.; Kawai, M.; Izumi, Y. Bull. Chem. Soc. J pn. 1986,
59, 1761.
(21) Shi, B.; Davis, B. H. J . Catal. 1995, 157, 359.
(22) Murray, D. K.; Chang, J .-W.; Haw, J . F. J . Am. Chem. Soc.
1993, 115, 4732.
(23) The Ti(i-OPr)Cl3-promoted cyclization of 1 was performed using
the procedure described in ref 3a. Reaction of 1 (9 mg, 0.03 mmol) with
10 equiv of Ti(i-OPr)Cl3 in CH2Cl2 at -78 °C gave 2 (5 mg, 76%).
(24) The Me2AlCl-promoted cyclization of 1 was performed using
the procedure reported ref 3c.
(19) Ozin, G. A. Adv. Mater. 1994, 6, 71.

Zeolite-Mediated Polyene Cyclization
J . Org. Chem., Vol. 61, No. 26, 1996 9537
h and then quenched by the addition of saturated aqueous
NH4Cl (2 mL). After warming to rt, the two layers were
separated, and the aqueous layer was extracted with ether (3
× 5 mL). The combined organic layers were washed (brine),
dried (MgSO4), and concetrated in vacuo to give a light yellow
oil. Flash chromatography using a hexane to 5% EtOAc/
CDCl3, followed by NMR analysis of the filtrate, indicated
a 2:1 ratio of bicycle 2 to hexamethyldisiloxane. This
result, in addition to the nearly quantitative mass
recovery of cyclic products, indicates that loss of the TMS
group from the polyene is mediated by trace amounts of
water retained in the zeolite lattice, as opposed to
silylation of the zeolite surface. In situations where there
is insufficient water available to mediate desilylation, the
hydroxyl moiety of the bicycle participates in the termi-
nation step to provide bicycle 4.
hexane gradient gave 1 as a colorless oil (206 mg, 74%): tR
)
9.40 min; IR (neat) 2952, 2917, 2217, 1652, 1248 cm-1; 1H NMR
(CDCl3) δ 5.22 (br s, 1 H), 2.69 (t, 1 H, J ) 6 Hz), 2.15 (br m,
6 H), 1.61 (br m, 5 H), 1.39 (s, 2 H), 1.28 (s, 3 H), 1.24 (s, 3 H),
0.07 (s, 9 H); 13C NMR δ 135.0, 123.9, 78.6, 76.6, 64.1, 58.2,
36.3, 28.1, 27.4, 24.8, 19.4, 18.7, 16.1, 6.9, -2.2. Anal. Calcd
for C17H30OSi: C, 73.31; H, 10.86. Found: C, 73.03; H, 10.74.
Con clu sion
P r ep a r a tive-Sca le Cycliza tion P r oced u r e. To a sus-
pension of oven-dried (110 °C, overnight), crushed 4 Å molec-
ular sieves (3.3 g, 30-fold excess by weight compared to 1) in
CHCl3 (100 mL) at rt was added a solution of 1 (111 mg, 0.4
mmole) in 5 mL of CHCl3. The mixture was stirred under
argon and heated to reflux for 2 h. The flask was then cooled
to rt, the suspension was filtered through a fritted glass funnel,
and the recovered zeolite was rinsed consecutively with ether
and methanol (3 × 10 mL each). The combined filtrate was
dried over MgSO4, filtered, and concentrated in vacuo. The
resulting oil was purified by flash chromatography using 5%
EtOAc/hexane as eluent to provide bicycles 2 and 4 (61 and
18 mg, respectively, 90% yield), along with ketone 5 (3.8 mg)
and bicyclic ether 7 (5.5 mg). Bicycle 2: tR ) 7.32 min; IR
The studies described above indicate that molecular
sieves hold promise as a new class of promoters in the
cyclization of epoxide-containing polyenes. The zeolite-
induced cyclization of epoxypolyene 1 proceeds cleanly,
yielding bicycle 2 in excellent yield when halogenated
solvents are used. Reactivity results from the zeolite
structure and is enhanced with the use of acidic alumi-
nosilicates. Compared to traditional Lewis acid cycliza-
tions, the zeolite-mediated reaction is more convenient,
requiring only filtration for product recovery. Work is
currently under way to expand the scope of this reaction
to higher-order polyene cyclizations and to larger-pore
zeolites for use in stereoselective ring-forming reactions.
(neat) 3459, 2966, 1955, 1700, 1036, 852 cm-1 1H NMR
;
(CDCl3) δ 4.68 (m, 2 H), 3.32 (dd, 1 H, J ) 11 Hz, 5 Hz), 2.59
(m, 1 H), 2.41 (m, 1 H), 1.8-1.2 (br m, 7 H), 1.02 (s, 3 H), 0.99
(s, 3 H), 0.86 (s, 3 H); 13C NMR (CDCl3) δ 200.0, 112.8, 79.8,
56.9, 44.2, 38.6, 34.8, 28.8, 28.5, 27.2, 21.1, 20.5, 15.2. Anal.
Calcd for C14H22O: C, 81.49; H 10.75. Found: C, 81.20; H,
10.43.
Exp er im en ta l Section
Gen er a l Meth od s. Unless otherwise stated, all chemicals
and solvents were obtained from commercial sources and were
used without further purification. Molecular sieves (4 Å, both
powder and pellet forms) were purchased from Aldrich Chemi-
cal Co. THF was distilled from sodium benzophenone ketyl,
CHCl3 was distilled from K2CO3, and benzene and toluene
were distilled from CaH2. 1H and 13C NMR spectra were
recorded on a GE QE-300 spectrometer at 300 and 75 MHz,
respectively. Flash chromatography was performed using
silica gel 60 (230-400 mesh, EM Science). Gas chromatog-
raphy (GC) was performed on a Hewlett-Packard Model 5890
gas chromatograph equipped with a flame ionization detector,
using a DB5-HT 30 m capillary column (J & W Scientific) and
the following temperature gradient: 150 °C for 1 min, 10 °C/
min to 325 °C for 5 min. Elemental analyses were performed
by Desert Analytics Laboratory, Tucson, AZ.
Isop r op yld ip h en ylsu lfon iu m Tetr a flu or obor a te. To a
solution of phenyl sulfide (10.3 g, 55 mmol) in 2-propanol (50
mL, 12 equiv) was added trifluoromethanesulfonic acid (30 mL,
6 equiv) dropwise at 0 °C. The reaction mixture was allowed
to warm to rt over 0.5 h and then heated to 45 °C for 3 days.
After cooling the dark brown reaction mixture, water and
ether were added (50 mL each), and the resulting two layers
were separated. The lower aqueous layer was extracted with
ether (3 × 50 mL), and the combined organic extracts were
washed (brine), dried (MgSO4), and concentrated in vacuo. The
resulting light brown oil was dissolved in ethanol (50 mL) and
treated with fluoroboric acid (48% solution, 24 mL, 3.3 equiv).
After the mixture was stirred for 1 h at rt, the reaction was
quenched by the addition of water (20 mL) and CH2Cl2 (150
mL). The aqueous layer was extracted with CH2Cl2 (4 × 20
mL), and the combined organic layers were washed (brine),
dried (MgSO4), and concentrated in vacuo to give a light brown
semisolid, which was triturated with petroleum ether (3 × 15
mL). The crude product was recrystallized from CH3OH/ether
(1:1) to provide the sulfonium salt as a fine white powder (2.2
g, 13%): mp 116.5-118.4 °C (lit.16 mp 123 °C).
Byp r od u ct Ch a r a cter iza tion . Bicycle 4: tR ) 8.05 min;
IR (neat) 2956, 1963, 1253, 1098, 1057, 845 cm-1 1H NMR
;
(CDCl3) δ 4.67 (m, 2 H), 3.27 (dd, 1 H, J ) 11.1, 4.4 Hz), 2.58
(m, 1 H), 2.41 (m, 1 H), 1.78-1.22 (m, 7 H), 1.01 (s, 3 H), 0.88
(s, 3 H), 0.82 (s, 3 H), 0.10 (s, 9 H); 13C NMR (CDCl3) δ 199.9,
113.1, 80.3, 56.9, 44.1, 38.9, 34.8, 29.1, 28.9, 27.2, 21.1, 20.5,
15.6, 0.4.
(6E)-2,6-Dim eth yl-12-(tr im eth ylsilyl)-6-d od ecen -10-yn -
3-on e (5): tR ) 9.75 min; IR (neat) 2961, 1716, 1253, 862 cm-1
;
1H NMR (CDCl3) δ 5.18 (m, 1 H), 2.63 (septet, 1 H, J ) 6.6
Hz), 2.54 (t, 2 H, J ) 8.1 Hz), 2.23 (t, 2 H, J ) 8.1 Hz), 2.15
(br s, 4 H), 1.61 (s, 3 H), 1.41 (s, 2 H), 1.08 (d, 6 H, J ) 6.6
Hz), 0.08 (s, 9 H); 13C NMR (CDCl3) δ 214.5, 134.9, 123.6, 78.6,
77.5, 40.8, 39.0, 33.4, 28.0, 19.3, 18.2, 16.2, 6.9, -2.1.
(6E)-2,6-Dim eth yl-12-(tr im eth ylsilyl)-1,6-d od eca n d ien -
10-yn -3-ol (6): tR ) 10.04 min; IR (neat) 3378, 2960, 2224,
1
1656, 1250, 1056, 844 cm-1; H NMR (CDCl3) δ 5.23 (br m, 1
H), 4.94 (s, 1 H), 4.84 (s, 1 H), 4.05 (dd, 1 H, J ) 6.3, 6.3 Hz),
2.16 (br s, 4 H), 2.03 (m, 2 H), 1.73 (s, 2 H), 1.62 (s, 3 H), 1.57
(s, 3 H), 1.41 (s, 2 H), 0.08 (s, 9 H); 13C NMR (CDCl3) δ 147.5,
135.7, 123.7, 111.0, 78.6, 77.4, 75.6, 35.7, 33.1, 28.1, 19.4, 17.6,
16.1, 6.9, -2.1.
1,3,3-Tr im e t h yl-2-[5-(t r im e t h ylsilyl)-3-p e n t yn yl]-7-
oxa bicyclo[2.2.1]h ep ta n e (7): tR ) 8.94 min; IR (neat) 2963,
1
2132, 1247, 1006 cm-1; H NMR (CDCl3) δ 3.72 (d, 1 H, J )
5.2 Hz), 2.24-2.05 (m, 3 H), 1.92 (m, 1 H), 1.80-1.47 (m, 5
H), 1.43 (br s, 2 H), 1.32 (s, 3 H), 1.06 (s, 3 H), 0.99 (s, 3 H),
0.09 (s, 9 H); 13C NMR (CDCl3) δ 86.6, 86.1, 77.8, 77.2, 54.1,
45.2, 38.9, 27.6, 26.0, 25.7, 23.4, 19.0, 18.8, 6.9, -2.1.
(6E)-2,3-Ep oxy-2,6-d im eth yl-12-(tr im eth ylsilyl)-6-d od e-
cen -10-yn e (1). To a suspension of isopropyldiphenylsulfo-
nium tetrafluoroborate (948 mg, 3 mmol) in THF (12 mL) was
added dropwise at -78 °C tert-butyllithium (1.7 M solution in
hexanes, 2.6 mmol). After the resulting yellow reaction
mixture was stirred for 30-40 min, a solution of aldehyde 315
(236 mg, 1 mmol) in THF (2 mL) was added. The light yellow
reaction mixture was stirred between -78 and -60 °C for 1.5
Ack n ow led gm en t. This work was supported by the
American Heart Association, Indiana Affiliate, Inc.
S.L.R. is the recipient of an American Heart Association
predoctoral fellowship.
J O960745G