Alkoxy radical cyclizations onto silyl enol ethers relative to alkene cyclization, hydrogen atom transfer, and fragmentation reactions

Article abstract of DOI:10.1021/jo200992m

This study examines the chemoselectivity of alkoxy radical cyclizations onto silyl enol ethers compared to competing cyclizations, 1,5-hydrogen atom transfers (1,5-HATs), and β-fragmentations. Cyclization onto silyl enol ethers in a S-exo mode is greatly preferred over cyclization onto a terminal alkene. The selectivity decreases when any alkyl substitution is present on the competing alkene radical acceptor. Alkoxy radical 5-exo cyclizations displayed excellent chemoselectivity over competing β-fragmentations. Alkoxy radical S-exo cyclizations onto silyl enol ether also outcompeted 1,5-HATs, even for activated benzylic hydrogen atoms. In tetrahydropyran synthesis, where 1,5-HAT has plagued alkoxy radical cyclization methodologies, 6-exo cyclizations were the dominant mode of reactivity. β-Fragmentation still remains a challenge for tetrahydropyran synthesis when an aryl group is present in the β position.

Full text of DOI:10.1021/jo200992m

ARTICLE
pubs.acs.org/joc
Alkoxy Radical Cyclizations onto Silyl Enol Ethers Relative to Alkene
Cyclization, Hydrogen Atom Transfer, and Fragmentation Reactions
Montserrat Rueda-Becerril, Joe C. T. Leung, Christine R. Dunbar, and Glenn M. Sammis*
Department of Chemistry, 2036 Main Mall, University of British Columbia, Vancouver, British Columbia V6T 1Z1, Canada
S Supporting Information
b
ABSTRACT:
This study examines the chemoselectivity of alkoxy radical cyclizations onto silyl enol ethers compared to competing cyclizations,
1,5-hydrogen atom transfers (1,5-HATs), and β-fragmentations. Cyclization onto silyl enol ethers in a 5-exo mode is greatly
preferred over cyclization onto a terminal alkene. The selectivity decreases when any alkyl substitution is present on the competing
alkene radical acceptor. Alkoxy radical 5-exo cyclizations displayed excellent chemoselectivity over competing β-fragmentations.
Alkoxy radical 5-exo cyclizations onto silyl enol ether also outcompeted 1,5-HATs, even for activated benzylic hydrogen atoms. In
tetrahydropyran synthesis, where 1,5-HAT has plagued alkoxy radical cyclization methodologies, 6-exo cyclizations were the
dominant mode of reactivity. β-Fragmentation still remains a challenge for tetrahydropyran synthesis when an aryl group is present
in the β position.
’ INTRODUCTION
Radical cyclizations are powerful methods for the construction
of complex molecular architectures.1 Alkyl radical cyclizations are
widely used both for the construction of building blocks and for
late-stage cascade annulations2 because much is known about the
rates of cyclization relative to competing radical reactions.3 In
contrast, alkoxy radical cyclizations are rarely utilized in synthesis
because it is often difficult to control the high reactivity of oxygen-
centered radicals.4 Alkoxy radicals primarily undergo three reac-
tions: cyclization (Figure 1, eq 1),5 1,5-hydrogen atom transfer
(1,5-HAT; eq2),6 and β-fragmentation (eq 3).7 Itischallengingto
Figure 1. Alkoxy radical reactions.
achieve cyclization chemoselectivity as all three are fast processes,
with rates measured to be between 108 and 109 sÀ1 at 80 °C.8À10
Despite the potential versatility of alkoxy radical cyclizations, their
seemingly uncontrollable nature has limited their use in natural
product synthesis.11
The challenges of achieving high chemoselectivity in alkoxy
radical cyclizations are particularly evident in literature case studies
investigating the syntheses of tetrahydropyrans.12 An alkoxy radical
can undergo the desired 6-exo cyclization or a 1,5-HAT of the
allylic hydrogen atom (Figure 2). When there is no substitution
Figure 2. Competing reactions in alkoxy radical cyclizations to form
tetrahydropyrans.
through incorporation of aryl or alkyl groups (eq 6).12c,d These
on the alkene (R = H), the alkoxy radical chemoselectively
undergoes a 1,5-HAT and no cyclization is observed.13 Even
studies constitute an important advance in tetrahydropyran
when an R,β-enoate, a good radical acceptor, was incorporated,
low yields of tetrahydropyran were reported (Scheme 1, eq 4).12b
Cyclization has been promoted through the use of gem-dialkyl
Received: May 17, 2011
Published: August 05, 2011
effects12a (eq 5) or increasing the substitution of the alkene
r
2011 American Chemical Society
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Scheme 1. Alkoxy Radical Cyclizations To Form
Tetrahydropyrans
Figure 3. Cyclization competition substrates.
cyclizations. The relative rate of β-fragmentation compared to
cyclization was explored in type D substrates. The final substrate,
type E, was used to explore the relative rate of alkoxy radical 6-exo
cyclization versus both competing 1,5-HAT and β-fragmentation.
The synthetic routes to the competition substrates outlined in
Figure 3 intercepted common intermediate 9 (Scheme 2). De-
pending on the substrate class, alcohol 9 was prepared using
standard methods that include either Grignard reagent-mediated
epoxide opening or addition of a Grignard reagent to an aldehyde.
The final four steps in the synthesis for each of the competi-
tion substrates were similar. Mitsunobu installation of the
N-alkoxyphthalimide15 followed by silyl deprotection16 afforded
primary alcohol 11. A subsequent Ley oxidation17 followed by
formation of a Z-enriched silyl enol ether afforded the desired
cyclization substrate (12). Alternatively, the E-enriched silyl enol
ether could be synthesized using (TBS)Cl and DBU.
formation using alkoxy radicals. Unfortunately, radical 1,5-HAT is
still the dominant mode of reactivity during attempted 6-exo
cyclization processes.
We recently reported the first use of silyl enol ethers as
acceptors for alkoxy radical cyclizations.14 Silyl enol ethers are
excellent acceptors for alkoxy radicals in 5-exo cyclizations, pro-
viding substituted tetrahydrofurans in good to excellent yields
and diastereoselectivities. More importantly, silyl enol ethers
enable the syntheses of tetrahydropyrans with high chemoselec-
tivity (eq 7). While products resulting from an alkoxy radical
1,5-HAT are still observed, the 6-exo cyclization is the dominant
mode of reactivity. Cyclizations onto silyl enol ethers have the
additional benefit of providing versatile silyl ethers that enable
postcyclization functionalization.
The high chemoselectivity for 6-exo cyclization onto silyl enol
ethers compared to a competing 1,5-HAT clearly indicates the
synthetic potential of this methodology in complex molecular
settings. However, little is known about the chemoselectivity of
5- and 6-exo cyclizations onto heteroatom-substituted alkenes
compared to other alkoxy radical reactions (Figure 1). An
extensive knowledge of this relative chemoselectivity is vital for
alkoxy radical cyclizations to be more predictable and thus more
commonly utilized in natural product synthesis. This study
examines the reactivity of alkoxy radical cyclizations onto silyl
enol ethers relative to competing alkene cyclization, 1,5-HAT,
and β-fragmentation utilizing a series of competition substrates.
The information obtained from these competition substrates
details the scope and potential utility of these cyclizations in a
complex molecular target.
Competition between Alkoxy Radical Cyclization onto a
Silyl Enol Ether and Cyclization onto a Substituted Alkene
(Type A Substrates). Investigations began with competition
studies between alkoxy radical cyclizations onto silyl enol ethers
and cyclizations onto simple alkenes (Figure 4). Achieving
chemoselectivity between two competing alkoxy radical cycliza-
tions was anticipated to be challenging because these cyclizations
are irreversible and very fast, with rates on the order of 109 sÀ1 8
.
Once generated, alkoxy radical A will either cyclize onto the
alkene to provide tetrahydrofuran 13 or cyclize onto the silyl enol
ether to afford tetrahydrofuran 14. The resulting radical is too far
from the remaining π-radical acceptor to cyclize again, so the
only pathway left is a simple hydrogen transfer to provide the
corresponding tetrahydrofurans 15 and 16. Since alkoxy radical
cyclizations are not reversible,8c,12d the relative rates of cycliza-
tion between the two radical acceptors can be determined from
the ratio of the two tetrahydrofuran products (15 and 16).
Part 1. Validation of the Competition Substrate Strategy. For
these intramolecular competition experiments to be self-consis-
tent and generalizable, the electronics of the acceptor needs to be
the overriding factor that governs cyclization chemoselectivity. In
an effort to validate this competition substrate strategy, we began
our investigations with an alkoxy radical cyclization competition
between a terminal alkene and a trans-disubstituted alkene
(Scheme 3, 17) because the individual rates of a secondary alkoxy
’ RESULTS AND DISCUSSION
Substrate Design and Synthesis. Five different types of
competition substrates were used to probe the relative reactivity
of cyclization onto a silyl enol ether versus competing alkene
cyclization (Figure 3, type A), 1,5-HAT (types B and C),
β-fragmentation (type D), or multiple pathways (type E). Types
B and C substrates were used to explore the relative reactivity
of cyclization compared to 1,5-HAT in both 6-exo and 5-exo
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Scheme 2. Synthetic Route for the Preparation of the Competition Substrates
Figure 4. Intramolecular cyclization competition studies.
Scheme 3. Comparison of Competing Cyclization Substrate with Literature Cyclization Rates
radical cyclization onto a terminal alkene (eq 9) and a sec-
ondary alkoxy radical cyclization onto a disubstituted alkene (eq
10) have been reported by Hartung and Gallou.8c If the increased
sterics of the competition substrate do not significantly affect the
rate of cyclization, then the relative ratios of the two tetrahydrofurans
(18 and 19) should match the ratios of the known cyclization rates.
Cyclization of 17 provided tetrahydrofurans 18 and 19 (Scheme 3,
eq 8) in an 83:17 ratio,18 which matches well with the known
rates (Scheme 3, eqs 9 and 10).19,20 As the competition compares
an averaged rate of cyclization onto either alkene, this compar-
ison is rigorous if both cyclization acceptors, the terminal alkene
and the trans-disubstituted alkene, provide the same diastereo-
meric ratio (dr). Cyclization studies confirm that alkoxy radical
cyclization onto each acceptor occurs with the same diastereo-
selectivity.8c For type A competition substrates, it is assumed that
siloxy substitution does not significantly alter cyclization diastereo-
selectivity. Previous rate studies validate this assumption as
substitution on the alkene acceptor does not modify cyclization
dr21 and increases in temperature merely degrade the dr toward
nonselectivity.8c
Part 2. Cyclization of Type A Substrates:22 With successful
validation of the experimental method, we next examined a series
of competition substrates between silyl enol ethers and substi-
tuted alkenes (type A substrates). Cyclization of competition
substrate 24, which features the competition of an alkoxy radical
cyclization between a trans-disubstituted alkene and a silyl enol
ether (Scheme 4, eq 11), provides a 67:33 ratio of cyclization
products 26 and 25. In addition to providing useful cyclization
comparisons, the data from substrates 24 and 17 (Scheme 3,
eq 8) can be used to further examine the predictability and self-
consistency of these cyclization experiments. Given that compe-
tition between a terminal alkene and a trans-disubstituted alkene
favored cyclization onto the latter in a ratio of 83:17 (Scheme 3,
17, eq 8) and that competition of a trans-disubstituted alkene and
a silyl enol ether favored cyclization onto the silyl enol ether in a
ratio of 67:33 (Scheme 4, eq 11), competition between a silyl
enol ether and a terminal alkene (Scheme 4, substrate 27) should
favor the silyl enol ether in a ratio of 91:9. However, in a previous
cyclization competition experiment between a terminal alkene
and a silyl enol ether, the only product isolated was believed to be
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Scheme 4. Cyclization of Alkoxy Radicals onto Silyl Enol Ethers vs Cyclization onto Substituted Alkenes
Figure 5. Competing cyclization versus 1,5-HAT substrates.
the silyl enol ether cyclized product (29) and small amounts of
uncyclized competition substrate 27.14 Re-examination of 29
indicated minute amounts of tetrahydrofuran 28 that were
masked by the uncyclized product. As it is possible that more
substantial amounts of alkene cyclized product 28 were present
but decomposed upon isolation, cyclization of substrate 27 was
repeated in deuterated benzene and the crude reaction mixture
was analyzed prior to any workup.23 1H NMR analysis indicated
that the cyclization reaction still strongly favors cyclization onto
the silyl enol ether in an 89:11 ratio (eq 12).24
We next examined the cyclization competition between a
trialkyl-substituted alkene and a silyl enol ether (eq 13, 30).
Despite observed increases in the relative rates between 6-exo
cyclization and 1,5-HAT between silyl enol ethers and trialkyl-
substituted alkenes (Scheme 1, eqs 6 and 7), there was no
noteworthy difference in the ratios of 5-exo cyclization between
the two radical acceptors (Scheme 4, eq 13). Changing the silyl
enol ether geometry from Z-enriched (eq 13 30a) to E-enriched
(eq 14, 30b) did not have a significant effect on the ratio of
tetrahydrofurans 31 and 32. One possible explanation for why
the two acceptors provided identical relative cyclization rates in
5-exo cyclizations despite an increase in the electron density of
the acceptor is there is an upper threshold to which these
competition substrates can measure differences. The cyclization
rates of all these alkoxy radicals are extremely fast, so subtle
differences in cyclization rate may be impossible to observe using
these competition substrates. However, notable differences were
observed in tetrahydropyran synthesis (Scheme 1, eqs 6 and 7).
This may be due to slower rates of 6-exo cyclization, so the
differences in electron density are manifested to a greater degree.
Competition between Alkoxy Radical Cyclization onto a
Silyl Enol Ether and 1,5-HAT (Type B and C Competition
Substrates). Two substrate designs were used to probe compet-
ing alkoxy radical cyclizations onto silyl enol ethers and 1,5-
HATs (Figure 5). The first substrate design (type B) compares
the relative rate of a 6-exo cyclization onto a silyl enol ether
compared to a 1,5-HAT of an allylic hydrogen atom. The
substrate design facilitates testing differences in reactivity be-
tween primary and secondary alkoxy radicals (type B, R1 = H,
alkyl). The second substrate design (type C) is analogous to the
substrates used to probe competing cyclizations and can be used
to examine the rates of 5-exo cyclizations relative to a 1,5-HAT.
Achieving high cyclization chemoselectivity compared to a
competing 1,5-HAT has far-reaching consequences, particularly
in the context of challenging tetrahydropyran syntheses. We have
previously shown that primary alkoxy radicals preferentially
cyclize onto silyl enol ethers in an 89:11 ratio over products
resulting from a 1,5-HAT (Scheme 1, eq 7).13 Primary alkoxy
radical precursor 7 was first re-examined using our new, and more
accurate, analysis methods.20 The 90:10 ratio of tetrahydrofuran
8 to linear alcohol 37 (Scheme 5, eq 15) closely matched our
previously reported ratio.
We next examined how substitution along the backbone would
affect the relative rate of 6-exo cyclization. Secondary alkoxy
radical precursor 38 (Scheme 5, eq 16) was subjected to the
same radical cyclization conditions. The secondary alkoxy radical
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Scheme 5. Competition of an Alkoxy Radical 6-exo Cyclization onto Silyl Enol Ethers vs 1,5-HAT
Scheme 6. Competition of an Alkoxy Radical 5-exo Cyclization onto Silyl Enol Ethers vs 1,5-HAT
1
favored tetrahydropyran formation over 1,5-HAT, albeit in a
slightly decreased ratio of 86:14.25 Cyclization of alkoxy radical
precursor 41,26 possessing a phenyl substitution on the silyl enol
ether, provided an 83:17 ratio of tetrahydropyran 42 to linear
alcohol 43. While the phenyl group provided an increase in the
relative rate of 1,5-HAT compared to cyclization, the tetrahy-
dropyran is still the primary product observed.
The next series of substrates examined competitions between
alkoxy radical 5-exo cyclizations and 1,5-HAT (Figure 5, type C).
We have previously demonstrated that the alkoxy radical gener-
ated from substrate 44 does not undergo a 1,5-HAT of the
terminal carbonÀhydrogen bond and cyclizes exclusively to
provide tetrahydrofuran 45 (Scheme 6, eq 18).14 We next
examined cyclizations relative to weaker carbonÀhydrogen
bonds (eqs 19 and 20). Competition substrate 47 explored the
competition between 5-exo cyclization and 1,5-HAT from a
secondary hydrogen. Similar to competition substrate 44, the
reaction displayed excellent cyclization chemoselectivity27 and
the 1,5-HAT product (49) could not be detected by H NMR
spectroscopic analysis.
With perfect chemoselectivity for all substrates attempted thus
far, we next examined a more challenging competition, substrate
50, which compares alkoxy radical cyclization and 1,5-HAT of a
benzylic hydrogen. A benzylic hydrogen was selected in this
competition as they are particularly susceptible to radical abstrac-
tion. Gratifyingly, competition substrate 50 exclusively cyclized
to provide tetrahydrofuran 51.28 It is clear from these studies that
1,5-HAT pathways do not compete with 5-exo cyclizations onto
silyl enol ethers.
Competition between Alkoxy Radical Cyclization onto a
Silyl Enol Ether and β-Fragmentation (Type D Competi-
tion Substrate). The next class of competing reactions we ex-
amined were competitions between alkoxy radical cyclization and
β-fragmentation reactions (Figure 6, type D). Alkoxy radicals can
be induced to efficiently undergo β-fragmentation in a strained
cyclic system or through the positioning of a radical-stabilizing
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group β to the alkoxy radical. Alkoxy radical cyclization sub-
strates with substitution at C2 (Figure 6, R = alkyl, phenyl) can be
used to examine the competition between alkoxy radical cycliza-
tion and β-fragmentation.
’ CONCLUSION
Despite the high reactivity inherent in an oxygen-centered
radical, these studies indicate that the cyclization of an alkoxy
radical onto a silyl enol ether generally outcompetes common
radical pathways, such as cyclizations onto alkenes, 1,5-HATs,
and β-fragmentations (Table 1). These results are noteworthy
given the high rates of all the competing radical processes. The
greatest degree of chemoselectivity, and thus reaction control,
was observed in competitions between 5-exo cyclization and
1,5-HAT, where cyclization was the only product observed in all
substrates attempted (Table 1, type C competition substrate).
Even in tetrahydropyran synthesis, where 1,5-HAT has plagued
alkoxy radical cyclization methodologies, 6-exo cyclizations were
the dominant mode of reactivity (Table 1, competition substrate
B). Cyclization onto silyl enol ethers in a 5-exo mode is greatly
preferred over cyclization onto a terminal alkene (Table 1, type A
competition substrate). The selectivity decreases when alkyl
substitution is present on the competing alkene radical acceptor.
Alkoxy radical 5-exo cyclization also outcompeted β-fragmenta-
tion, even when radical-stabilizing groups were introduced β to
the oxygen-centered radical (Table 1, type D competition sub-
strate). β-Fragmentation still remains a challenge for tetrahy-
dropyran synthesis when an aryl group is present in the β position.
However, cyclization still occurs in appreciable conversion
(Table 1, type E competition substrate). We believe the demon-
strated high chemoselectivity exhibited by silyl enol ethers as
radical acceptors expands the scope of alkoxy radical cyclizations
and makes these reactions suitable candidates for complex total
synthesis.
In our previous study investigating the cyclization of alkoxy
radicals onto silyl enol ethers, two of the substrates had the
potential for β-fragmentation relative to cyclization onto a
silyl enol ether.14 Simple alkyl substitution β to the alkoxy
radical (Scheme 7, eq 21) does not induce fragmentation, and
only cyclized product was detected.29 However, the presence
of a good radical-stabilizing group, such as a phenyl substituent
β to the alkoxy radical, facilitates β-fragmentation. The reaction
of radical precursor 57 produced both cyclization product 5830
and fragmentation product 59 in a ratio of 84:16, favoring
cyclization.
Cyclization versus β-Fragmentation and 1,5-HAT (Type E
Competition Substrate). The last substrate to conclude our
study was the combined triple competition of cyclization onto a
silyl enol ether, 1,5-HAT, and β-fragmentation (Scheme 8, type
E). Competition substrate 6022 contains the elements for all
three possible radical pathways and might mimic the level of
complexity found in late-stage total synthesis. Treatment of
phthalimide 60 with the standard radical reaction conditions
produced a mixture of products. 1H NMR spectroscopic analysis
of the reaction mixture indicated a 41% conversion to 6-exo
cyclization product 61.31 We were unable to cleanly identify the
other reaction products, but on the basis of literature
precedent12d and the products obtained from competition sub-
strates 7 (Scheme 1) and 57 (Scheme 7), the remainder of the
mass balance likely consists of both fragmentation product 62
and 1,5-HAT product 63.
’ EXPERIMENTAL SECTION
General Methods. All reactions were performed under a nitrogen
atmosphere in flame-dried glassware. Tetrahydrofuran, diethyl ether,
and dichloromethane were purified by a solvent purification system. All
other solvents were used without further purification. Silica gel used in
column chromatography was stirred with triethylamine prior to packing.
Figure 6. Competing cyclization versus β-fragmentation.
Scheme 7. 5-exo Cyclization of Alkoxy Radicals onto Silyl Enol Ethers vs Fragmentation
Scheme 8. Competition among 6-exo Cyclization into a Silyl Enol Ether, 1,5-HAT, and β-Fragmentation
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Table 1. Summary of Competition Experiments
All chemicals were purchased from commercial sources and used as
received.
129.2, 123.58, 123.53, 88.0, 77.5, 77.2, 76.8, 63.2, 62.7, 33.0, 32.8, 32.2, 26.1,
25.8, 23.90, 23.80, 20.9, 17.9, À5.1. IR (CDCl3): 2916.55, 2879.55, 1789.55,
1732.98, 1374.89, 1187.59, 976.36, 877.88, 702.05 cmÀ1. HRMS-ESI(m/z):
[M + Na]+ calcd for C25H39NO4NaSi 468.2546, found 468.2537.
2-((7-((tert-Butyldimethylsilyl)oxy)heptan-2-yl)oxy)isoindoline-1,3-
dione (10e). 1H NMR (300 MHz, CDCl3): δ 7.82 (dd, J = 5.5, 3.1 Hz,
2H), 7.73 (dd, J = 5.5, 3.1 Hz, 2H), 4.36 (d, J = 6.2 Hz, 1H), 3.60 (t, J =
6.4 Hz, 2H), 1.86À1.36 (m, 8H), 1.32 (d, J = 6.2 Hz, 3H), 0.87 (s, 9H),
0.03 (s, 6H). 13C NMR (75 MHz, CDCl3): δ 164.5, 134.5, 129.1, 123.5,
84.6, 63.3, 35.0, 32.9, 26.10, 25.96, 25.2, 18.9, 18.5, À5.1. IR (CDCl3):
2931.29, 2857.32, 1790.49, 1737.02, 1467.69, 1375.30, 1255.03,
1097.58, 976.12, 835.84, 701.73 cmÀ1. HRMSÀEI (m/z): [M]+ calcd
for C21H23NO4NaSi 414.2077, found 414.2087.
General Mitsunobu Reaction Procedure. To a 0.1 M solution of
alcohol 9 (1.0 equiv) in dry THF at 0 °C were added N-hydroxyphthalimide
(1.5 equiv) and triphenylphosphine (1.5 equiv), each in one portion.
The resulting solution was stirred for 10 min, and then diisopropyl
azodicarboxylate (1.8 equiv) was added slowly over 30 min. The
resulting red solution was stirred for 18 h at ambient temperature.
The reaction mixture was diluted with Et2O and washed with saturated
NaHCO3(aq) until the aqueous layer was colorless. The combined
organics were washed with brine, dried over Na2SO4, and filtered, and
the solvent was removed by rotary evaporation. Flash chromatography
purification (95:5 hexanes/AcOEt) yielded the N-alkoxyphthalimide 10.32
(E)-2-((1-((Triethylsilyl)oxy)dec-8-en-5-yl)oxy)isoindoline-1,3-dione
(10a). 1H NMR (400 MHz, CDCl3): δ 7.82 (dd, J = 5.3, 3.1 Hz, 2H),
7.73 (dd, J = 5.3, 3.2 Hz, 2H), 5.50À5.38 (m, 2H), 4.23 (q, J = 6.0 Hz,
1H), 3.61 (d, J = 5.7 Hz, 2H), 2.20 (ddt, J = 37.6, 14.8, 7.6 Hz, 2H),
1.75À1.67 (m, 4H), 1.62 (d, J = 5.6 Hz, 3H), 1.55 (t, J = 6.3 Hz, 4H),
0.94 (t, J = 7.9 Hz, 9H), 0.58 (q, J = 7.9 Hz, 6H). 13C NMR (101 MHz,
CDCl3): δ 164.5, 134.5, 130.6, 125.7, 123.5, 87.9, 62.8, 33.0, 32.53,
32.41, 28.2, 22.6, 21.4, 18.1, 6.9, 4.6. IR (CDCl3): 2951.57, 2875.16,
179.86, 1737.19, 1731.47, 1700.06, 975.80, 701.44 cmÀ1. HRMS-ESI
(m/z): [M + Na]+ calcd for C24H37NO4NaSi 454.2390, found 454.2397.
2-((1-((tert-Butyldimethylsilyl)oxy)-9-methyldec-8-en-5-yl)oxy)-
isoindoline-1,3-dione (10c). 1H NMR (CDCl3, 300 MHz) δ 7.81À7.91
(m, 2H), 7.70À7.81 (m, 2H), 5.14 (t, 1H, J = 7.1 Hz), 4.19À4.34 (m, 2H),
3.55À3.74 (m, 2H), 2.10À2.33 (m, 2H), 1.47À1.82 (m, 14H), 0.91
(s, 9H), 0.07 (s, 6H). 13C NMR (101 MHz, CDCl3): δ 164.6, 134.6,
2-((1-((tert-Butyldimethylsilyl)oxy)nonan-5-yl)oxy)isoindoline-1,3-
dione (10g). Polar impurities were removed using a silica plug, and the
semicrude mixture was used without further purification.
2-((8-((tert-Butyldimethylsilyl)oxy)-1-phenyloctan-4-yl)oxy)isoindoline-
1,3-dione (10h). Polar impurities were removed using a silica plug, and
the semicrude mixture was used without further purification.
General Deprotection Procedure. To a 0.1 M solution of
N-alkoxyphthalimide 10 in MeOH was added camphorsulfonic acid
(0.1 equiv) in one portion. The resulting solution was stirred at ambient
temperature for 1.5 h. The solvent was removed by rotary evaporation,
and the resulting oil was purified by flash chromatography (gradient 4:1
to 7:3 hexanes/AcOEt) to yield alcohol 11.32
(E)-2-((1-Hydroxydec-8-en-5-yl)oxy)isoindoline-1,3-dione (11a). This
compound was not isolated, and the semicrude mixture was used without
further purification.
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2-((1-Hydroxy-9-methyldec-8-en-5-yl)oxy)isoindoline-1,3-dione (11c).
1H NMR (400 MHz, CDCl3): δ 7.82 (dt, J = 5.9, 3.1 Hz, 2H), 7.75 (dt, J =
5.9, 3.1 Hz, 2H), 5.11 (ddd, J = 7.1, 5.8, 1.3 Hz, 1H), 4.25 (dd, J = 7.1, 4.1
Hz, 1H), 3.68 (t, J = 6.0 Hz, 2H), 2.18 (t, J = 7.6 Hz, 2H), 1.72À1.62 (m,
16H). 13C NMR (101 MHz, CDCl3): δ 164.6, 134.5, 132.3, 129.2, 123.75,
123.57, 88.0, 77.5, 77.1, 76.8, 62.7, 32.8, 32.2, 25.8, 23.9, 20.9, 17.9. IR
(CDCl3): 2936.72, 1789.29, 1782.94, 1374.85, 1187.71, 1123.03, 1081.48,
1015.08, 976.59, 877.99, 702.07 cmÀ1. HRMS-ESI (m/z): [M + Na]+ calcd
for C19H25NO4NaSi 354.1681, found 354.1674.
837.97, 701.73 cmÀ1. HRMS-ESI (m/z): [M + Na]+ calcd for
C24H35NO4NaSi 452.2233, found 452.2225.
2-((1-((tert-Butyldimethylsilyl)oxy)-9-methyldeca-1,8-dien-5-yl)oxy)-
isoindoline-1,3-dione (30a). 1H NMR (CDCl3, 400 MHz): δ 7.80À7.88
(m, 2H), 7.68À7.79 (m, 2H), 6.33 (d, 0.2H, J = 11.8 Hz, trans), 6.18
(d, 0.8H, J = 5.7 Hz, cis), 5.13 (t, 1H, J = 7.0), 4.49 (q, 1H, J = 7.0 Hz),
4.19À4.34 (m, 1H), 2.14À2.37 (m, 4H), 1.70À1.84 (m, 4H), 1.68
(s, 3H), 0.91 (s, 9H), 0.11 (s, 5H). 13C NMR (101 MHz, CDCl3):
δ 164.5, 139.2, 134.4, 129.3, 123.5, 109.9, 109.5, 88.0, 35.2, 32.67, 32.54,
25.87, 25.79, 23.8, 19.6, À5.2. IR (neat): 2928.66, 2856.76, 1790.68,
1735.35, 1655.08, 1467.2, 13, 1362.84, 1255.55, 1187.55, 1120.57, 976.79,
837.76, 701.62 cmÀ1. HRMS-ESI (m/z): [M + Na]+ calcd for C25H37-
NO4NaSi 466.2390, found 466.2393.
2-((7-Hydroxyheptan-2-yl)oxy)isoindoline-1,3-dione (11e). 1H NMR
(300 MHz, CDCl3): δ 7.83 (dd, J = 5.5, 3.1 Hz, 2H), 7.74 (dd, J = 5.5, 3.1
Hz, 2H), 4.38 (sextet, J = 6.0 Hz, 1H), 3.67 (d, J = 3.7 Hz, 2H), 1.87À1.40
(m, 9H), 1.33 (d, J = 6.3 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 164.5,
134.6, 129.1, 123.6, 84.4, 62.9, 35.0, 32.7, 25.7, 25.0, 19.1. IR (CDCl3):
3390.48, 2936.41, 2861.78, 1789.09, 1731.80, 1466.93, 1377.34, 1187.83,
1123.92, 1081.99, 1016.02, 976l45, 878.51, 702.07 cmÀ1. HRMS-EI
(m/z): [M]+ calcd for C15H19NO4 277.13141, found 277.13115.
2-((1-Hydroxynonan-5-yl)oxy)isoindoline-1,3-dione (11g). 1H NMR
(400 MHz, CDCl3): δ 7.83 (dd, J = 5.4, 3.1 Hz, 2H), 7.74 (dd, J = 5.4,
3.1 Hz, 2H), 4.23 (t, J = 5.5 Hz, 1H), 3.68 (s, 2H), 1.70À1.35 (m, 14H),
0.91 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 164.6,
134.6, 129.2, 123.6, 88.3, 62.7, 32.8, 32.27, 32.17, 27.3, 22.9, 20.9, 14.2. IR
(neat): 3408.94, 2937.80, 2868.87, 1789.81, 1728.20, 1467.82, 1374.75,
2-((1-((tert-Butyldimethylsilyl)oxy)-9-methyldeca-1,8-dien-5-yl)oxy)-
isoindoline-1,3-dione(30b).33. 1H NMR(400 MHz, CDCl3):δ 7.83 (dd,
J = 5.4, 3.1 Hz, 2H), 7.74 (dd, J = 5.6, 2.9 Hz, 2H), 6.32 (d, J = 11.8 Hz,
0.67H, trans), 6.17 (d, J = 5.8 Hz, 0.33H, cis), 5.12À5.10 (m, 1H), 4.99
(dt, J = 11.9, 7.5 Hz, 1H), 4.48 (dd, J = 13.2, 7.0 Hz, 1H), 4.27À4.20
(m, 1H), 2.23À2.14 (m, 4H), 1.75À1.62 (m, 9H), 0.90 (d, J = 3.8 Hz,
9H), 0.11 (s, 6H). 13C NMR (101 MHz, CDCl3): δ 164.5, 139.2, 134.4,
129.3, 123.5, 109.9, 109.5, 88.0, 35.2, 32.67, 32.54, 25.87, 25.79, 23.8, 19.6,
À5.2. IR (neat): 2928.66, 2856.76, 1790.68, 1735.35, 1655.08, 1467.2, 13,
1362.84, 1255.55, 1187.55, 1120.57, 976.79, 837.76, 701.62 cmÀ1
.
HRMS-ESI (m/z): [M + Na]+ calcd for C25H37NO4NaSi 466.2390,
found 466.2393.
1187.73, 1122.80, 1081.81, 1015.84, 976.65, 878.71, 701.56 cmÀ1
.
HRMS-ESI (m/z): [M + Na]+ calcd for C17H23NO4NaSi 328.1525,
found 328.1532.
(Z)-2-((7-((tert-Butyldimethylsilyl)oxy)hept-6-en-2-yl)oxy)isoindoline-
1,3-dione (38). 1H NMR (300 MHz, CDCl3): δ 7.30 (dd, J = 5.4, 3.1 Hz,
2H), 6.79 (dd, J = 5.4, 3.1 Hz, 2H), 6.35 (d, J = 11.9 Hz), 6.20 (d, J = 5.9
Hz, 1H), 5.16 (dt, J = 11.8, 7.5 Hz), 4.57À4.50 (m, 1H), 4.40À4.31 (m,
1H), 2.35À2.28 (m, 2H), 1.89À1.61 (m, 5H), 1.23 (d, J = 6.2 Hz, 3H),
0.94 (s, 9H), 0.05 (s, 6H). 13C NMR (101 MHz, CDCl3): δ 164.5, 139.0,
134.5, 129.2, 123.5, 110.1, 84.6, 34.6, 25.8, 25.5, 23.6, 19.0, 18.3, À5.2. IR
(CDCl3): 2928.97, 2856.45, 1790.07, 1732.63, 1652.70, 1465.77, 1373.58,
2-((8-Hydroxy-1-phenyloctan-4-yl)oxy)isoindoline-1,3-dione (11h).
1H NMR (400 MHz, CDCl3): δ 7.89 (dd, J = 5.4, 3.1 Hz, 2H), 7.80
(dd, J = 5.5, 3.1 Hz, 2H), 7.33À7.21 (m, 5H), 4.32 (t, J = 5.6 Hz, 1H), 3.71
(t, J = 5.9 Hz, 2H), 2.79À2.66 (m, 2H), 1.97À1.59 (m, 11H). 13C NMR
(101 MHz, CDCl3): δ 164.6, 142.3, 134.6, 129.1, 128.58, 128.42, 125.9,
123.6, 88.0, 62.7, 35.9, 32.7, 32.16, 32.05, 26.9, 20.9. IR (neat): 3415.94,
2939.82, 2862.88, 1788.78, 1726.18, 1466.82, 1454.83, 1373.71, 1187.65,
1123.75, 1081.71, 975.53, 877.60, 699.31. HRMS-ESI (m/z): [M + Na]+
calcd for C22H25NO4Na 390.1681, found 390.1685.
1255.34, 1186.97, 1080.26, 974.80, 877.57, 836.03, 700.50 cmÀ1
.
HRMS-TOF ES+ (m/z): [M]+ calcd for C21H32NO4Si 390.2101, found
390.2091.
General Ley Oxidation17 Followed by an Enolization Pro-
cedure. To a 0.1 M solution of alcohol 11 (1 equiv) in dichloromethane
at 0 °C were added 4 Å molecularsieves followed byN-methylmorpholine
N-oxide (2.0 equiv). The reaction was then stirred for 15 min. Tetra-
propylammonium perruthenate (5 mol %) was added in one portion. The
resulting black suspension was stirred for 1 h at 0 °C and 1 h at ambient
temperature and then filtered through a bed of silica. The filtrate was
washed with Et2O. The organics were combined, and the solvent was
removed via rotary evaporation to yield the desired aldehyde. The crude
material was used without further purification. To a 0.1 M solution of
aldehyde 11 in dry dichloromethane at 0 °C was added diisopropylethy-
lamine (2.0 equiv) in one portion, and the resulting solution was stirred at
0 °C for 15 min. tert-Butyldimethylsilyl trifluoromethanesulfonate was
then added in one portion and the resulting solution stirred at 0 °C for
30 min and then at ambient temperature for 1.5 h. The reaction mixture
was quenched with saturated NaHCO3(aq) and extracted with dichlor-
omethane. The combined organics were washed with brine, dried over
Na2SO4, and filtered, and the solvent was removed by rotary evaporation.
Purification using flash chromatography (95:5 hexanes/AcOEt) provided
silyl enol ether 12.32
2-(((8E)-1-((tert-Butyldimethylsilyl)oxy)deca-1,8-dien-5-yl)oxy)-
isoindoline-1,3-dione (24). 1H NMR (400 MHz, CDCl3): δ 7.88À7.79
(m, 2H), 7.79À7.70 (m, 2H), 6.33 (d, J = 11.9 Hz, 1H (0.16 trans)), 6.18
(d, J = 5.8 Hz, 1H (0.84 cis)), 5.57À5.35 (m, 2H), 4.51À4.46 (m, 1H),
4.31À4.23 (m, 1H), 2.38À2.13 (m, 4H), 1.86À1.70 (m, 5H), 1.64 (d,
J = 5.1 Hz, 3H), 0.91 (s, 9H), 0.12 (s, 6H). 13C NMR (101 MHz,
CDCl3): δ 18.07, 19.54, 21.49, 25.79, 28.14, 32.44, 32.50, 48.49, 87.75,
123.53, 125.56, 129.29, 130.71, 134.46, 139.21, 164.49, À5.2. IR
(CDCl3): 2928.27, 2855.68, 1736.68, 1255.87, 1119.82, 976.41,
(Z)-2-(6-(tert-Butyldimethylsilyloxy)-6-phenylhex-5-enyloxy)isoindo-
line-1,3-dione (41). This cyclization precursor was not accessed through
the general procedure. See the Supporting Information for more synthetic
details. 1H NMR (400 MHz, CDCl3): δ 7.81À7.87 (m, 2H), 7.72À7.77
(m, 2H), 7.20À7.45 (m, 5H), 5.11 (t, J = 7.04 Hz, 1H), 4.24 (t, J = 6.65
Hz, 2H), 2.28 (q, J = 7.44 Hz, 2H), 1.86 (quintet, J = 6.65 Hz, 2H),
1.54À1.70 (m, 3H), 0.98 (s, 7H), 0.91 (s, 2H), 0.03 (s, 1H), À0.05
(s, 5H). 13C NMR (100 MHz, CDCl3): δ 164.7, 150.8, 140.7, 135.4,
130.0, 129.4, 128.9, 128.8, 126.9, 124.5, 112.2, 79.5, 28.9, 26.9, 26.7,
À3.0, À3.5. IR (neat): 2954, 2930, 2887, 2857, 1790, 1732, 1650,
1468 cmÀ1. HRMS-ESI (m/z): [M + Na]+ calcd for C26H33NO4SiNa
474.2077, found 474.2073.
2-((1-((tert-Butyldimethylsilyl)oxy)non-1-en-5-yl)oxy)isoindoline-
1,3-dione (47). 1H NMR (400 MHz, CDCl3): δ 7.82 (dd, J = 5.5, 3.1 Hz,
2H), 7.74 (dt, J = 5.8, 3.1 Hz, 2H), 6.32 (d, J = 11.9 Hz, 0.11), 6.16 (d, J =
5.8 Hz, 0.89 H), 4.98 (dt, J = 11.9, 7.5 Hz), 4.48 (q, J = 6.6 Hz, 1H), 4.25
(quintet, J = 6.0 Hz, 1H), 2.29À2.18 (m, 2H), 1.78À1.68 (m, 4H),
1.57À1.32 (m, 5H), 0.89 (s, 9H), 0.10 (d, J = 1.5 Hz, 6H). 13C NMR
(101 MHz, CDCl3): δ 164.5, 139.2, 134.4, 129.3, 123.5, 109.5, 88.2,
32.5, 32.1, 27.1, 25.8, 22.9, 19.6, 18.4, 14.2, À5.2. IR (neat): 3032.97,
2955.78, 2930.77, 2858.83, 1790.82, 1731.19, 1655.75, 1467.76, 1362.74,
1254.63, 1187.65, 1121.59, 1101.65, 1082.59, 975.49, 877.58, 835.32,
779.42, 699.25 cmÀ1. HRMS-ESI (m/z): [M + Na]+ calcd for C23H35-
NO4NaSi 440.2233, found 440.2240.
2-((8-((tert-Butyldimethylsilyl)oxy)-1-phenyloct-7-en-4-yl)oxy)-
isoindoline-1,3-dione (50). 1H NMR (400 MHz, CDCl3): δ 7.30 (dd,
J = 5.4, 3.1 Hz, 2H), 7.19À7.05 (m, 21H), 6.79 (dd, J = 5.4, 3.1 Hz, 2H),
6.51 (d, J = 11.9 Hz, 0.1 H), 6.16 (d, J = 5.8 Hz, 0.9 H), 5.19 (dt, J = 11.9,
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ARTICLE
7.5 Hz), 4.60 (q, J = 6.6 Hz, 1H), 4.40 (quintet, J = 5.8 Hz, 1H),
2.70À2.45 (m, 4H), 2.09À1.72 (m, 6H), 0.92 (s, 9H), 0.03 (s, 5H).
13C NMR (101 MHz, CDCl3): δ 164.1, 142.6, 139.2, 133.6, 129.5,
128.8, 128.5, 122.9, 109.9, 100.1, 87.8, 36.1, 32.9, 32.3, 26.9, 25.7, 20.0,
18.4, À5.4. IR (neat): 3028.94, 2950.83, 2929.81, 2857.85, 1790.82,
1730.20, 1654.75, 1467.79, 1362.75, 1254.65, 1187.66, 1119.56, 1081.60,
975.50, 877.59, 835.35, 779.45, 747.60, 697.19 cmÀ1. HRMS-ESI (m/z):
[M + Na]+ calcd for C28H37NO4NaSi 502.2390, found 502.2379.
(Z)-2-(6-(tert-Butyldimethylsilyloxy)-2-phenylhex-5-enyloxy)isoindoline-
1,3-dione (60). This cyclization precursor was not accessed through the
general procedure. See the Supporting Information for more synthetic
details. 1H NMR (300 MHz, CDCl3): δ 7.67À7.83 (m, 4H), 7.14À7.33
(m, 5H), 6.18 (d, J = 5.71 Hz, 1H), 4.38À4.54 (m, 2H), 4.24À4.38 (m,
1H), 3.09À3.26 (m, 1H), 1.94À2.16 (m, 4H), 1.58À1.84 (m, 1H), 0.93
(s, 5H), 0.87 (s, 9H), 0.11 (s, 3H), 0.09 (s, 6H). 13C NMR (75 MHz,
CDCl3): δ 163.5, 141.3, 139.1, 134.5, 129.0, 128.6, 128.1, 126.8, 123.5,
109.9, 82.0, 60.6, 44.6, 32.9, 25.9, 25.8, 21.4, 21.2, 18.4, 18.2, 14.4, À3.4,
À5.2. IR (neat): 3030, 2954, 2930, 2886, 2857, 1790, 1732, 1656,
1469 cmÀ1. HRMS-ESI (m/z): [M + Na]+ calcd for C26H33NO4SiNa
474.2077, found 474.2080.
spectrometer (20 scans, 4 s overall pulse sequence). See the Supporting
Information for analysis of the cyclization products.
’ ASSOCIATED CONTENT
S
Supporting Information. Complete experimental proce-
b
dures and characterization data. This material is available free of
charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: gsammis@chem.ubc.ca.
’ ACKNOWLEDGMENT
This work was supported by the University of British Columbia,
the Natural Sciences and Engineering Research Council of
Canada (NSERC), a doctoral fellowship from Consejo Nacional
de Ciencia y Tecnología (CONACyT) to M.R.-B., and a doctoral
fellowship from NSERC to J.C.T.L. We also thank Dr. J. Traer for
assistance with spectroscopic analysis.
Synthesis of (E)-2-(Deca-1,8-dien-5-yloxy)isoindoline-1,3-
dione (17). To magnesium turnings (0.48 g, 20 mmol, 4.0 equiv) and a
small iodine crystal was added dropwise a solution of crotyl chloride
(0.98 mL, 10 mmol, 2.0 equiv) in THF (10 mL), maintaining a
gentle reflux. The resulting suspension was heated to reflux for 1 h.
THF (10 mL) was then added, and the reaction was removed from the
heat source for 5 min. To a separate flask containing copper(I) iodide
(95 mg, 0.5 mmol, 0.1 equiv) and 1,2-epoxy-5-hexene (0.56 mL, 5 mmol,
1.0 equiv) was added THF (5 mL), and the resulting solution was cooled
to 0 °C. To the suspension was added the Grignard solution over 15 min.
The reaction was stirred for 18 h and allowed to warm to ambient
temperature. The reaction was quenched with saturated NH4Cl(aq)
(10 mL) and poured into Et2O (100 mL). The organics were washed
with water (25 mL), 1.0 M HCl(aq) (2 Â 25 mL), and brine (25 mL),
dried over Na2SO4, and filtered. Removal of the solvent by rotary
evaporation provided the crude alcohol as a yellow oil. To this oil were
added N-hydroxypthalimide (1.2 g, 7.5 mmol, 1.5 equiv), triphenylpho-
sphine (1.96 g, 7.5 mmol, 1.5 equiv), and THF (50 mL). The solution
was cooled to 0 °C, and diisopropyl azodicarboxylate (1.8 mL, 9.0 mmol,
1.8 equiv) was added dropwise over 20 min. The reaction was stirred
for 18 h and allowed to warm to ambient temperature. The reaction was
quenched with saturated NaHCO3(aq) (50 mL) and poured into
Et2O (100 mL). The organics were washed with saturated NaHCO3(aq)
(2 Â 50 mL) and brine (25 mL), dried over Na2SO4, and filtered. Rotary
evaporation and flash chromatography purification (3:1 hexanes/Et2O)
yielded 315 mg (21%) of N-alkoxypthalimide 17 as a clear colorless
oil. 1H NMR (400 MHz, C6D6): δ 7.28 (dd, J = 3.0, 5.2 Hz, 2H), 6.78
(dd, J = 3.0, 5.2 Hz, 2H), 5.74À5.91 (m, J = 6.7, 6.7, 10.1, 17.0 Hz,
1H), 5.38À5.57 (m, 2H), 5.13 (d, J = 17.1 Hz, 1H), 5.00 (d, J = 10.1 Hz,
1H), 4.29 (quin, J = 5.6 Hz, 1H), 2.33À2.52 (m, 2H), 2.11À2.33
(m, 2H), 1.73À1.87 (m, 2H), 1.68 (qd, J = 5.2, 9.7 Hz, 2H), 1.54À1.63
(m, 3H). 13C NMR (101 MHz, C6D6): δ 164.5, 138.8, 134.1,
131.4, 129.8, 126.0, 123.4, 115.5, 87.8, 87.6, 33.2, 33.1, 32.5, 29.9,
29.8, 28.7, 23.1, 18.5. IR (CHCl3): 2922.74, 2854.08, 1772.00,
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1730.23, 1700.30, 1638.83, 1652.87, 1187.69, 976.12, 701,18 cmÀ1
.
HRMS-ESI (m/z): [M + Na]+ calcd for C18H21NO3Na: 322.1419,
found 322.1409.
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(15) (a) Kim, S.; Lee, T. A.; Song, Y. Synlett 1998, 471–472.
(b) Mitsunobu, O. Synthesis 1981, 1–28.
(16) For 10a a triethylsilyl ether was utilized. See the Supporting
Information for details.
(17) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639–666.
(18) Ratio obtained from the average of two runs. All cyclizations
reported in this paper went to complete conversion, and no other
products were observed other than those reported. NMR yields of the
products closely matched yields based solely on reported product ratios.
See the Supporting Information for details.
(19) On the basis of the reported rate constants from Hartung and
Gallou,8c the predicted ratio of products is 84:16 at 30 °C. We observed
an 83:17 ratio of products at 80 °C. Because these reactions are very fast,
it is possible that a difference in 50 K does not significantly influence the
relative cyclization rates.
(20) All of the cyclization experiments utilized Bu3SnH. While
(Me3Si)3SiH also provided cyclized products, the reactions frequently
did not go to completion. No other metal hydride reagents were
examined.
(21) When a large steric substituent, such as a 2,6-disubstituted
phenyl group, is adjacent to the alkoxy radical, substitution on the alkene
moderately affects the diastereomeric ratio. Substrates from this com-
petition study do not possess steric bulk of that magnitude; see: Hartung,
J; Hiller, M.; Schmidt, P. Liebigs Ann. 1996, 1425–1436.
(22) The cyclization diastereoselectivity was not determined for
substrates 26, 29, and 32. However, substrates with identical substitu-
tion patterns and comparable sterics (48 and 51) cyclized in a 67:33 ratio
of trans to cis isomers.
(23) For a full description of this new analysis method, see the
Supporting Information.
(24) The silyl enol ether started as an 18:82 mixture of E/Z isomers.
This ratio did not change after cyclization was complete, suggesting that
there was no preference for cyclization of either geometric isomer.
(25) The tetrahydropyran was formed in a 53:47 ratio of cis/trans
isomers.
(26) Synthesis of substrates 41 and 60 did not follow the general
route outlined in Scheme 2. See the Supporting Information for details.
(27) The tetrahydrofuran was formed in a 67:33 ratio of trans/cis
isomers.
(28) The tetrahydrofuran was formed in a 67:33 ratio of trans/cis
isomers.
(29) The tetrahydrofuran was formed in a 58:42 ratio of cis/trans
isomers.
(30) The tetrahydrofuran was formed in a 72:28 ratio of cis/trans
isomers.
(31) The tetrahydropyran was formed in a 69:31 ratio of trans/cis
isomers.
(32) The syntheses of compounds 7, 10b, 10d, 10f, 10i, 11b, 11d, 11f,
11i, 27, 44, and 57 can be found in the Supporting Information of ref 13.
(33) Different enolization conditions were used for the synthesis of
30b. See the Supporting Information for details.
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dx.doi.org/10.1021/jo200992m |J. Org. Chem. 2011, 76, 7720–7729