Strategies to control alkoxy radical-initiated relay cyclizations for the synthesis of oxygenated tetrahydrofuran motifs

Article abstract of DOI:10.1021/jo502499a

Radical relay cyclizations initiated by alkoxy radicals are a powerful tool for the rapid construction of substituted tetrahydrofurans. The scope of these relay cyclizations has been dramatically increased with the development of two strategies that utilize an oxygen atom in the substrate to accelerate the desired hydrogen atom transfer (HAT) over competing pathways. This has enabled a chemoselective 1,6-HAT over a competing 1,5-HAT. Furthermore, this allows for a chemoselective 1,5-HAT over competing direct cyclizations and β-fragmentations. Oxygen atom incorporation leads to a general increase in cyclization diastereoselectivity over carbon analogues. This chemoselective relay cyclization strategy was utilized in the improved synthesis of the tetrahydrofuran fragment in (-)-amphidinolide K. (Chemical Equation Presented).

Full text of DOI:10.1021/jo502499a

Article
pubs.acs.org/joc
Strategies to Control Alkoxy Radical-Initiated Relay Cyclizations for
the Synthesis of Oxygenated Tetrahydrofuran Motifs
Hai Zhu, Joe C. T. Leung, and Glenn M. Sammis*
Department of Chemistry, 2036 Main Mall, University of British Columbia, Vancouver, British Columbia V6T 1Z1, Canada
S
* Supporting Information
ABSTRACT: Radical relay cyclizations initiated by alkoxy radicals
are a powerful tool for the rapid construction of substituted
tetrahydrofurans. The scope of these relay cyclizations has been
dramatically increased with the development of two strategies that
utilize an oxygen atom in the substrate to accelerate the desired
hydrogen atom transfer (HAT) over competing pathways. This has
enabled a chemoselective 1,6-HAT over a competing 1,5-HAT.
Furthermore, this allows for a chemoselective 1,5-HAT over
competing direct cyclizations and β-fragmentations. Oxygen atom
incorporation leads to a general increase in cyclization diastereoselectivity over carbon analogues. This chemoselective relay
cyclization strategy was utilized in the improved synthesis of the tetrahydrofuran fragment in (−)-amphidinolide K.
further synthetic manipulation. Overall, this enables the rapid
conversion of simple starting compounds to the key tetrahy-
drofuran motif.
INTRODUCTION
■
Over the past few decades, tetrahydrofuran (THF)-containing
macrolides, such as (−)-amphidinolide K (1)1−4 and man-
delalide A (2),5,6 have emerged as an important class of bioactive
macrolides (Figure 1).7 As they are often isolated in only small
We have previously developed a radical relay cyclization
methodology8 in which N-alkoxyphthalimides were utilized as
alkoxy radical precursors.14 While this methodology focused on
the formation of carbocycles, we reported that three substrates
could be used for the formation of tetrahydrofurans (Scheme 1).
Simple tetrahydrofuran 7 (eq 1) was formed in high yield and
diastereoselectivity. Furthermore, the cyclization afforded a
2,4,5-trisubstituted tetrahydrofuran (9) favoring the all cis
stereoisomer with high selectivity (eq 2). We also demonstrated
that the relay methodology could be used to form the
tetrahydrofuran motif in (−)-amphidinolide K (1) in only five
steps from commercially available starting materials (eq 3).
The most significant limitation of our initial methodology was
that the 1,5-HAT necessitates a three-carbon chain between the
alcohol and the ring (Figure 3, 13). This oxygenation pattern is
ideal for the synthesis of tetrahydrofuran motifs like those found
in (−)-amphidinolide K; however, application of this method-
ology to other THF-containing macrolides, such as mandelalide
A, would require further redox steps to access the required
oxygenation pattern. This significantly limits the applicability and
utility of our initial methodology for future applications to the
synthesis of most of the THF-containing macrolides.
Figure 1. Representative tetrahydrofuran-containing, bioactive polyke-
tide macrolides.
amounts, the ability to synthetically access these important
natural products is critical for structural elucidation, stereo-
chemical confirmation, and additional medicinal testing. The
synthesis of these polyketides has received considerable
attention, and construction of the THF ring is often a key
component of the overall strategy.7
Our strategy8 to synthesize the THF rings in these important
macrolides is to utilize radical relay (or translocation) cyclization
cascades9−11 initiated by alkoxy radicals (Figure 2).12,13 The first
step of these cascade reactions involves the generation of a highly
reactive alkoxy radical species (3) that can undergo a 1,5-
hydrogen atom transfer (1,5-HAT) of an unactivated or an
activated carbon−hydrogen bond to form carbon radical 4. Once
the radical has been “relayed” across the substrate, a radical
cyclization cascade takes place to form the key tetrahydrofuran
(5). This approach has two key advantages over previously
developed methods: no prefunctionalization is required at C-5
(3), and initiating with an alkoxy radical leaves an alcohol for
One possible method to increase the substrate scope is to
utilize the oxygen of the ether to bias the chemoselectivity of the
initial hydrogen atom transfer to favor the 1,6-HAT over the
standard 1,5-HAT (Figure 4, Type A). This substrate class has
the advantage of allowing direct access to a homologated
oxygenation pattern of the THF-containing product (15). It is
Received: October 30, 2014
© XXXX American Chemical Society
A
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Figure 2. Radical relay cascade.
alkene,24,25 can be faster than the desired 1,5-HAT.26,27 While
the oxygen of the ether should accelerate the desired 1,5-HAT
compared to the direct cyclization, it should also accelerate other
undesired reactions, such as a β-fragmentation.
Scheme 1. Previously Demonstrated Alkoxy Radical-Initiated
Relay Cyclizations for the Synthesis of THF Rings
In addition, it is essential to have a better understanding of the
factors that are involved in cyclization diastereoselectivity for
these reactions to be generally useful for the synthesis of the THF
rings found in bioactive macrolides. In our initial studies, the
three tetrahydrofurans (7, 9, and 11, Scheme 1) were synthesized
in notably higher diastereoselectivities compared to the carbon
analogues. However, more substrates need to be examined to
determine the influence of oxygen on cyclization diastereose-
lectivity.
In this paper, we present new investigations into radical relay
cyclizations initiated by alkoxy radicals. We first examined the
cyclization diastereoselectivities when forming THF and THP
rings. We then detail studies into the development of new relay
cyclizations using substrates of Types A and B (Figure 4) that use
the ether oxygen atom to direct the initial hydrogen atom
transfer. Finally, we compared our new methodology to a
previously reported synthesis of the THF ring of (−)-amphidi-
nolide K.
RESULTS AND DISCUSSION
■
Figure 3. Substrate scope limitations in the original relay cyclization
methodology.
Relay Cyclization Diastereoselectivity Study. In our
initial communication,8 the diastereoselectivity for cyclization of
the simplest straight-chain substrate (6, Scheme 1) was
significantly higher compared to the carbon analogue (90:10 vs
75:25).28 As this was the only direct comparison, additional
studies are necessary to determine if this is a general trend. We
focused our studies on the oxa-analogues of previously studied
relay cyclization substrates.8 Synthetic routes to the cyclization
precursors are outlined in Scheme 2.
We started our investigation by examining the effect secondary
N-alkoxyphthalimides have on reaction diastereoselectivity
(Table 1, entries 1, 2). In our previous study, cyclization of
19b provided the corresponding cyclopentane derivative in an
80:20 ratio of cis- to trans-isomers (entry 2).8 Similar to what was
previously observed, cyclization of the oxygen-containing
analogue (19a) afforded tetrahydrofuran derivative 30a with
notably higher diastereoselectivity (entry 1).
Figure 4. This work: strategies to improve the substrate scope of the
radical relay cyclization.
We next examined 1,5-HATs, followed by cyclizations onto
1,2-disubstituted alkenes (Table 1, entries 3−7). Cyclization of
phenyl-substituted alkene substrate 19c afforded the correspond-
ing tetrahydrofuran 30c in an 83:17 mixture of cis- to trans-
isomers (entry 3). This is an improvement over the carbon
analogue in our previous study, which afforded the correspond-
ing cyclopentane in a 75:25 ratio favoring the cis-isomer. A direct
comparison of these two results may not directly reflect the
influence of oxygen incorporation as the E/Z ratio between the
two starting materials is notably different (80:20 for 19c
compared to 65:35 for the carbon analogue). To address this
concern, we examined the cyclization of 19d, which is more
enriched in the E isomer. The cyclization to 30d occurred in
comparable diastereoselectivity (entry 4, 77:23 ratio of cis- to
trans-isomers) to what was previously reported, which indicates
well-known that an oxygen atom will stabilize an adjacent
radical15−20 and will lead to an increase in reaction rate. This has
been utilized to control hydrogen abstraction by alkoxy
radicals,21 and to increase the rates of 1,6-HATs over competing
1,5-HATs in cyclic systems.10b,22,23 For this strategy to be
successfully employed in these linear substrates, the relative rate
of the desired hydrogen abstraction pathway must increase by
several orders of magnitude to compete with other very fast
processes, such as 5-exo cyclizations.
Branched substrates (Figure 4, Type B) would significantly
increase the versatility of alkoxy radical-initiated relay cycliza-
tions if they could be utilized as viable cyclization precursors.
However, these substrates present a formidable challenge as the
rate of side reactions, such as the direct 5-exo cyclization onto an
B
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Scheme 2. Synthetic Routes for the Synthesis of Substrates 1929
that the increase in selectivity for the oxa-analogue was not the
result of the difference in starting olefin geometry.
The general increase in cyclization diastereoselectivity
between the carbo- and the oxacycles may be explained based
on the calculations of the Beckwith and Houk groups for radical
5-exo cyclizations.30 According to calculations, the two lowest
energy transition states for 5-exo radical cyclizations should be
the two chairlike transition states depicted in Figure 5.31
Transition state 34, leading to cis-cyclization product 35 should
be lower in energy than transition state 32 as orienting R1 in the
pseudoequatorial position minimizes 1,3-diaxial-type interac-
tions. When an oxygen atom is incorporated in the ring, the bond
lengths in both chairlike transition states (36 and 38) are
shortened. This decreased bond length should not significantly
affect transition state 38, but should increase the 1,3-diaxial
interactions in 36. This greater steric interaction between R1 and
the pseudoaxial protons results in a greater relative energy
difference between 36 and 38 and, thus, should provide higher
cis-selectivities. Consistent with our study, secondary N-
alkoxyphthalimides should have minimal impact on cyclization
diastereoselectivity. A similar rationale can be used to explain the
selectivities for the 6-endo cyclizations (Table 1, entries 8, 9).
While this model rationalizes the trend in cyclization
diastereoselectivities for the majority of oxygen-containing
relay substrates, it appears to be limited when cyclizing onto
electron-rich olefins (Table 1, entries 5−7).
Cyclizations onto silyl enol ethers provide an additional handle
for further synthetic manipulation. Under our standard relay
cyclization conditions, silyl enol ether substrate 19e cyclized to
afford tetrahydrofuran 30e as a 66:34 mixture of cis- to trans-
isomers (entry 5). Cyclization of both E- and Z-enriched carbon
analogues 19f afforded the corresponding cyclopentane
derivatives (30f) in similar diastereoselectivities (entries 6, 7).
This again suggests that the starting alkene geometry is not the
determining factor for the difference in observed cyclization
diastereoselectivities between the carbon and oxa-analogues.
With encouraging improvements in selectivities for five-
membered ring formation, we next examined the formation of
THP rings. In our initial investigations, 6-exo cyclizations formed
the corresponding cyclohexane or tetrahydropyran (THP) ring
in moderate to poor yields with low cyclization diastereose-
lectivities. We, therefore, focused on comparing the selectivity of
6-endo cyclizations. As previously reported,8 cyclization of the
gem-disubstituted alkene 19h afforded the corresponding
cyclohexane (31h) in a moderate 65:35 ratio of trans- to cis-
isomers (entry 9), while the oxygen-containing analogue,
precursor 19g, cyclized to form 31g in good yield almost
exclusively as the trans-isomer (entry 8).
C
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a b c d e f
, , , , ,
Table 1. Relay Cyclization Diastereoselectivity Study
a
b
c
Reactions were carried out on a >0.25 mmol scale. The relative stereochemistry was determined by NOE experiments. Isolated yields of the
d
e
1
mixture of diastereomers after flash chromatography. The diastereomeric ratio was determined by H NMR spectroscopy. The isolated yield
corresponds to a two-step cyclization/silylation procedure. Experimental details for this reaction can be found in ref 8.
f
preferential 1,6-HAT10b,22,23,32,33 forming radical intermediate
1,6-HAT RELAY CYCLIZATIONS
■
47, which would then cyclize to form tetrahydrofuran 48 (Path
With a general understanding of the influence of oxygen
B). Using the previously optimized relay cyclization conditions,8
incorporation on cyclization diastereoselectivity, we next focused
precursor 42 cyclized to tetrahydrofuran 48 in 66% isolated yield
on accessing different oxygenation patterns in the THF motifs.
We began by investigating homologated substrates that would
as an 80:20 ratio of isomers (Scheme 4).34
To further examine preferential 1,6-HATs over competing 1,5-
allow for a longer tether between the alcohol and the THF ring
HATs, we examined cyclization of oxygen-transposed substrate
(Figure 4, Type A). To accomplish this, the oxygen of the ether
43 (Scheme 5). If the reaction proceeds exclusively through a
1,6-HAT pathway, then the resulting radical is too close to the
olefin to cyclize efficiently and will simply quench with tributyltin
hydride to form a linear alcohol (Path A). However, if the
generated alkoxy radical undergoes a 1,5-HAT, then the resulting
5-exo cyclization is significantly faster than hydrogen quenching,
and a cyclized product should be observed (Path B). Treatment
must direct an initial 1,6-HAT over a competing 1,5-HAT.
Investigations began with the preparation of cyclization test
substrates 42 and 43 (Scheme 3).
Alkoxy radical 44 (Figure 6) may first undergo a 1,5-hydrogen
atom transfer, followed by a 6-exo cyclization, to form
tetrahydropyran derivative 46 (Path A). Alternatively, the
oxygen of the ether should be sufficient to bias the system to a
D
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Branched Relay Cyclization Substrates. We next
examined whether we could significantly alter the oxygenation
pattern of the THF-containing motif by initiating the relay
cyclization from a branched position (Figure 7, 53). This is a
Figure 5. Chairlike transition states for the 5-exo cyclization step of the
radical relay process.
Scheme 3. Synthesis of Substrates 42 and 43
Figure 7. Competing radical pathways.
challenging substrate as there are two radical pathways that may
interfere with the desired 1,5-HAT: direct 5-exo cyclization with
the alkene24,25 and β-fragmentation.11a,g,36 The rate of the direct
alkene cyclization is very fast, on the order of 108 s−1,25 and
should compete with the desired 1,5-HAT. In substrates where
there is no oxygen adjacent to the site of hydrogen abstraction
(such as 61, Scheme 6),37 the 5-exo cyclization pathway
Scheme 6. Competition between 5-exo Cyclization and 1,5-
HAT
Figure 6. Competition between 1,5-HAT and 1,6-HAT.
Scheme 4. Relay Cyclization Starting with a 1,6-HAT
dominates. The second competing pathway available for 53
(Figure 7) is a β-fragmentation, which should also be accelerated
by the presence of an oxygen atom in the substrate.
Not only are the branched relay cyclization substrates
interesting for testing chemoselectivity but also they are
synthetically useful building blocks. These substrates have the
advantage of being synthesized in only 3−4 synthetic steps
(Schemes 7 and 8) from readily available enantioenriched
of 43 under the standard radical relay cyclization conditions
affords exclusively the linear alcohol (41), confirming that, under
these reaction conditions, the 1,6-HAT of a C−H bond α to an
oxygen is indeed over 2 orders of magnitude faster than a 1,5-
HAT of a secondary alkyl C−H, and this strategy is effective for
synthesizing tetrahydrofurans with hydroxybutyl substituents.35
Scheme 5. Competition between 1,6-HAT and 1,5-HAT
E
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Scheme 7. Synthesis of Branched Substrate Intermediate
Scheme 8. Incorporation of an N-Hydroxyphthalimide into the Branched Substrate
a b c d e
, , , ,
Table 2. Temperature Effects on Radical Relay Cyclizations
a
b
Determined by 1H NMR anlaysis. The direct cyclization product can undergo several subsequent radical reactions. The reported yield represents
c
all subsequent products resulting from an initial direct cyclization. See the Supporting Information for details. This number refers to the
temperature of the oil bath, not the internal reaction temperature. The number in brackets indicates the isolated yield after flash column
chromatography. The relay cyclization products are volatile, so the substrates were protected first as tert-butyldiphenylsilyl ethers prior to isolation.
d
e
The number in brackets indicates the isolated yield after this two-step procedure.
epoxides or through allylation reactions (Scheme 7). The N-
hydroxyphthalimide can be incorporated in the penultimate step
through either an SN2 displacement or a Mitsunobu reaction38
(Scheme 8). This synthetic route is highly modular with respect
to both the incorporation of the radical acceptor and the ether.
Furthermore, the stereocenter can be used to direct the overall
cyclization, providing enantioenriched cyclization product 55.
F
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We first investigated a cyclization of substrates that are biased
toward the desired 1,5-HAT through the use of phenyl
substitution α to the proton to be abstracted (Table 2, entries
1, 2). The presence of a heteroatom and a group capable of
resonance stabilization should provide additional capto-dative
stabilization17a to allow a 1,5-HAT to compete with the direct
cyclization and fragmentation pathways. Indeed, cyclization of
53a provided exclusive formation of the radical relay product in
74% isolated yield as a 53:45:2 mixture of diastereomers,39 with
no direct cyclization or β-fragmentation products observed
(entry 1). Cyclization of alkyne-containing precursor 53b (entry
2) afforded radical relay product in 88% NMR yield (70%
isolated yield as a >95:5 mixture of diastereomers favoring the all-
cis-stereoisomer) along with 12% NMR yield of the product
resulting from direct cyclization onto the alkyne.
Scheme 9. Synthesis of the Tetrahydrofuran Fragment within
(−)-Amphidinolide K Using a Type B (Figure 4) Relay
Substrate
We next examined substrates containing only ether oxygen
stabilization with no additional substitution α to the proton to be
abstracted (53c,d). Cyclization of 53c under the radical relay
conditions provided radical relay cyclization product 55c as the
minor product (entry 3, Table 2) compared to direct cyclization
(44%) and β-fragmentation (31%). As each of the different
radical reactions should have markedly different reaction profiles
to changes in temperature, we decreased the temperature to 70
°C (entry 4). The yield of radical relay cyclization product 55c
did not change. Decreasing the temperature to 60 °C only
slightly improved the relative rate of radical relay cyclization
compared to direct cyclization and β-fragmentation, providing
cyclization product 55c in 27% yield (entry 5).40 A similar
temperature effect was observed when the acceptor was changed
to an alkyne (entries 6, 7).
The final substrates examined contained alkyl substitution α to
the oxygen (R = CH3, 53e,f). At 90 °C, cyclized product 55e was
the major compound observed, but it was only formed in 41%
NMR yield (entry 8, Table 2). Decreasing the temperature to 70
°C led to a decrease in direct cyclization product, with a
concomitant small change in the amount of β-fragmentation
(entry 9). At 60 °C, the reaction proceeded to the radical relay
cyclization product in usable isolated yields with approximately a
93:7 isomeric mixture favoring the all cis-diastereoisomer (entry
10). Cyclization onto an alkyne acceptor provided a similar trend
in regioselectivity (entries 11, 12). At 60 °C, the reaction afforded
cyclized product 55f in 61% yield as an 85:15 mixture of cis- and
trans-isomers (entry 12).
Application to the Synthesis of the Tetrahydrofuran
Fragment of (−)-Amphidinolide K. We have previously
demonstrated that the tetrahydrofuran fragment of (−)-amphi-
dinolide K can be rapidly synthesized using our alkoxy radical-
initiated methodology.8 We chose this same fragment to test our
new branched relay cyclizations because it provides a good point
of comparison to evaluate the efficiency of our new trans-
formation. Furthermore, the branched relay cyclization products
provide direct access to the opposite alcohol protection pattern
of (−)-amphidinolide K THF fragment 11 (Scheme 1), which
avoids two additional protection and deprotection steps.
The synthesis began with the opening of commercially
available enantioenriched epoxide 71 with a lithiated alkyne to
provide alcohol 72 in excellent yield (Scheme 9). A subsequent
etherification, followed by silyl deprotection and N-alkoxy-
phthalimide installation using a Mitsunobu reaction, afforded
cyclization precursor 75. Under the cyclization conditions at 60
°C, the desired tetrahydrofuran (76) was isolated in 60% yield as
a >95:5 mixture of cis- to trans-isomers.41 The isolated yield
closely matches the yield reported for the cyclization of similarly
substituted cyclization precursor 53f (Table 2, entry 12). Overall,
the desired tetrahydrofuran fragment was synthesized in only five
steps from commercially available material. It is noteworthy that
the yield is comparable to the original cyclization despite the
potential competing pathways available to cyclization precursor
75.
CONCLUSION
■
We have developed two methods that utilize the ether oxygen
atom to direct the initial hydrogen atom transfer. In our first
approach using homologated linear substrates, a 1,6-HAT was
favored over a competing 1,5-HAT. In our second approach,
branched substrates displayed preferential 1,5-HAT over the
usually dominant 5-exo cyclization pathway. We have utilized this
new cyclization approach in an alternative synthesis of the
tetrahydrofuran moiety in (−)-amphidinolide K. We have also
successfully demonstrated that oxygen atom incorporation
generally leads to higher diastereoselectivities compared to
carbon analogues. Overall, the high cyclization diastereoselectiv-
ities, coupled with the chemoselectivity of the hydrogen atom
transfer, significantly increase the potential substrate scope of
radical relay cyclizations and demonstrate that these relay
cyclizations are effective for the rapid synthesis of functionalized
tetrahydrofurans.
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. Thin-layer
chromatography (TLC) was performed on UV254 precoated TLC plates.
Chromatographic separations were effected over silica gel (230−400
mesh). Basefied silica gel has been stirred with triethylamine prior to
packing. All chemicals were purchased from commercial sources and
used as received. Chemical shifts are reported in parts per million (ppm)
and are referenced to the centerline of deuterochloroform (7.27 ppm 1H
NMR; 77.0 ppm 13C NMR) or deuterobenzene (7.16 ppm H NMR;
1
128.4 ppm 13C NMR). High-resolution mass spectra (HRMS) were
measured by TOF.
Synthesis of Substrates 19. 2-((5-(But-3-en-1-yloxy)pentan-2-
yl)oxy)isoindoline-1,3-dione (19a). To a stirring solution of NaH (60%
dispersion in mineral oil, 589 mg, 14.7 mmol) in anhydrous DMF (25
mL) was added 3-buten-1-ol (0.65 mL, 554 mg, 7.38 mmol). The
solution was stirred for 10 min at ambient temperature, after which a
solution of 4-((tert-butyldimethylsilyl)oxy)pentyl-4-methylbenzene-
sulfonate42 (2.5 g, 6.70 mmol) in anhydrous DMF (2.0 mL) was
added. The solution was then heated to 75 °C and stirred for 2 h, and
allowed to cool to ambient temperature. The reaction was quenched via
the slow addition of H2O (40 mL), followed by saturated NaHCO3 (10
G
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mL). The reaction was extracted with Et2O (3 × 50 mL), and the
combined organic layers were washed with H2O (20 mL) and brine (20
mL), dried over Na2SO4, and concentrated by rotary evaporation to
yield crude ((5-(but-3-en-1-yloxy)pentan-2-yl)oxy)(tert-butyl)-
dimethylsilane as a colorless oil. The crude oil was dissolved in THF
(20 mL), and tetrabutylammonium fluoride (1.0 M in THF, 4.55 mL,
4.55 mmol) was added. The solution was then stirred for 12 h at ambient
temperature. The reaction was quenched with H2O (20 mL) and
extracted with Et2O (3 × 20 mL). The combined organic layers were
washed with H2O (20 mL) and brine (20 mL), dried over Na2SO4, and
concentrated by rotary evaporation. The product was semipurified using
flash column chromatography (3:1 hexanes/EtOAc) to yield 5-(but-3-
en-1-yloxy)pentan-2-ol as a colorless oil. To a solution of this alcohol
(210 mg, 1.32 mmol) in THF (13 mL) were sequentially added
triphenylphosphine (521 mg, 1.99 mmol) and N-hydroxyphthalimide
(324 mg, 1.99 mmol). The solution was stirred until all solids were
dissolved, at which point diisopropylazodicarboxylate (0.47 mL, 483 mg,
2.38 mmol) was added via syringe pump (rate = 0.8 mL/h). The
resulting yellow solution was stirred for 12 h at ambient temperature,
and was then quenched with H2O (10 mL). The aqueous layer was
extracted with EtOAc (3 × 20 mL), and the combined organic layers
were washed with NaHCO3 (3 × 20 mL) and brine (20 mL). The
organic layer was dried over Na2SO4, concentrated using rotary
evaporation, and purified by flash column chromatography (3:1
hexanes/Et2O) to provide N-alkoxyphthalimide 19a as a colorless oil
(321 mg, 16% over 3 steps). IR (neat): 2930, 2847, 1795, 1734, 1373,
1117, 878, 695 cm−1; 1H NMR (400 MHz, CDCl3): δ = 7.87−7.81 (m, 2
H), 7.79−7.72 (m, 2 H), 5.82 (tdd, J = 6.8, 10.3, 17.0 Hz, 1 H), 5.09 (dd,
J = 1.4, 17.4 Hz, 1 H), 5.02 (d, J = 10.6 Hz, 1 H), 4.46−4.37 (m, 1 H),
3.54−3.45 (m, 4 H), 2.33 (q, J = 6.6 Hz, 2 H), 1.89−1.64 (m, 4 H), 1.36
(d, J = 6.5 Hz, 3 H); 13C NMR (100 MHz, CDCl3): δ = 164.3, 135.3,
134.4, 129.0, 123.4, 116.2, 84.1, 70.4, 70.0, 34.1, 31.5, 25.4, 18.8; HRMS-
ESI (m/z): calcd. for C17H22NO4 [M + H]+: 304.1549, found 304.1547.
Synthesis of 19c. 4-((4-Phenylbut-3-en-1-yl)oxy)butan-1-ol (21).
To a stirring suspension of sodium hydride (60 wt % dispersion in
mineral oil, 281 mg, 7.04 mmol) in anhydrous DMF (19 mL) was added
2043 (870 mg, 5.87 mmol). The solution was stirred for 1 h, after which a
solution of 4-((tert-butyldimethylsilyl)oxy)butyl tosylate22 (1.04 g, 2.89
mmol) in DMF (2.0 mL) was added. The solution was then heated to 50
°C and stirred overnight, and then allowed to cool to ambient
temperature. The reaction was quenched via the slow addition of H2O
(10 mL), followed by saturated NaHCO3 (10 mL). The reaction was
extracted with Et2O (3 × 20 mL), and the combined organic layers were
dried over Na2SO4, concentrated by rotary evaporation, and purified
using flash column chromatography (50:1 hexanes/Et2O) to yield tert-
butyldimethyl(4-((4-phenylbut-3-en-1-yl)oxy)butoxy)silane as a color-
less oil (615 mg, 35%). This compound was carried forward without
further purification. To a stirring solution of the silyl ether (270 mg, 0.80
mmol) in THF (3 mL) was added tetrabutylammonium fluoride (1.0 M
in THF, 2.4 mL, 2.4 mmol), and the solution was stirred overnight at
ambient temperature. The reaction was quenched with H2O (5 mL) and
extracted with Et2O (3 × 10 mL). The combined organic layers were
washed with H2O (10 mL) and brine (10 mL), dried over Na2SO4, and
concentrated by rotary evaporation. The product was purified using
flash column chromatography (4:1 then 1:1 hexanes/EtOAc) to yield
alcohol 21 as a colorless oil (130 mg, 80%, E:Z = 80:20). IR (neat):
3391, 2921, 2865, 1726, 1452, 1265, 1113, 800, 704 cm−1; 1HNMR (400
MHz, CDCl3): δ = 7.40−7.28 (m, 4 H), 7.26−7.18 (m, 1 H), 6.53 (d, J =
11.6 Hz, 0.2 H, Z alkene), 6.47 (d, J = 15.8 Hz, 0.78 H), 6.23 (td, J = 7.0,
15.8 Hz, 0.8 H), 5.71 (td, J = 7.2, 11.6 Hz, 0.2 H, Z alkene), 3.66−3.60
(m, 2 H), 3.59−3.53 (m, 2 H), 3.53−3.44 (m, 2 H), 2.85 (br. s., 1 H),
2.64 (dq, J = 1.5, 6.9 Hz, 0.43 H, Z alkene), 2.51 (q, J = 6.7 Hz, 1.6 H),
1.76−1.59 (m, 4 H); 13C NMR (100 MHz, CDCl3): δ = 137.3, 137.1 (Z
alkene), 131.5, 130.4 (Z alkene), 128.5 (Z alkene), 128.3 (Z alkene),
128.2, 127.9 (Z alkene), 126.8, 126.6, 126.5 (Z alkene), 125.8, 70.7, 70.6
(Z alkene), 70.2, 62.1, 33.2, 29.7, 29.7 (Z alkene), 28.9 (Z alkene), 26.3,
26.3 (Z alkene); HRMS-ESI (m/z): calcd. for C14H21O2 [M + H]+:
221.1542, found 221.1539.
were sequentially added triphenylphosphine (233 mg, 0.89 mmol) and
N-hydroxyphthalimide (145 mg, 0.89 mmol). The solution was stirred
until the solids were dissolved, at which point diisopropylazodi-
carboxylate (0.22 mL, 222 mg, 1.1 mmol) was added via syringe pump
(rate = 0.8 mL/h). The resulting yellow solution was stirred overnight at
ambient temperature, and was then quenched with H2O (10 mL). The
aqueous layer was extracted with EtOAc (3 × 20 mL), and the combined
organic layers were washed with NaHCO3 (3 × 20 mL) and brine (20
mL) and were dried over Na2SO4. The organics were concentrated using
rotary evaporation and purified by flash column chromatography (4:1
hexanes/EtOAc) to provide N-alkoxyphthalimide 19c as a colorless oil
(200 mg, 92%, E:Z = 80:20). IR (neat): 2921, 2865, 1791, 1730, 1478,
1
1378, 1265, 1178, 1108, 969, 878, 700 cm−1; H NMR (400 MHz,
CDCl3): δ = 7.87−7.80 (m, 2 H), 7.78−7.71 (m, 2 H), 7.37−7.28 (m, 4
H), 7.22−7.15 (m, 1 H), 6.53−6.41 (m, 1 H), 6.24 (td, J = 7.0, 15.8 Hz,
0.78 H), 5.70 (td, J = 7.2, 11.8 Hz, 0.16 H, Z alkene), 4.29−4.20 (m, 2 H),
3.60−3.48 (m, 4 H), 2.62 (dq, J = 1.5, 6.8 Hz, 0.4 H, Z alkene), 2.50 (dq, J
= 0.9, 6.7 Hz, 1.6 H), 1.95−1.77 (m, 4 H); 13C NMR (100 MHz,
CDCl3): δ = 163.7 (Z alkene), 163.5, 137.5, 137.3 (Z alkene), 134.3,
134.2 (Z alkene), 131.4, 130.3 (Z alkene), 128.8, 128.7 (Z alkene), 128.6
(Z alkene), 128.3, 128.0 (Z alkene), 127.0, 126.9, 126.5 (Z alkene), 125.9,
123.3, 123.3 (Z alkene), 108.7 (Z alkene), 78.1, 70.2 (Z alkene), 70.2,
70.1, 70.1 (Z alkene), 69.0 (Z alkene), 33.4, 30.7 (Z alkene), 29.1 (Z
alkene), 25.7, 25.0, 22.4 (Z alkene); HRMS-ESI (m/z): calcd. for
C22H24NO4 [M + H]+: 366.1705, found 366.1702.
2-(9-Phenylnon-8-enyloxy)-2H-isoindoline-1,3-dione (19d). To a
solution of alcohol 2222 (640 mg, 2.93 mmol) in THF (50 mL) were
sequentially added triphenylphosphine (1.15 g, 4.4 mmol) and then N-
hydroxyphthalimide (1.06 g, 4.4 mmol). The solution was stirred until
all solids were dissolved, at which point diisopropylazodicarboxylate
(1.06 g, 5.27 mmol) was added via syringe pump (rate = 0.8 mL/h). The
resulting yellow solution was allowed to stir overnight at ambient
temperature. The reaction was quenched with H2O (25 mL) and
extracted with Et2O (3 × 25 mL). The combined organic extracts were
dried over Na2SO4, concentrated using rotary evaporation, and then
purified by flash column chromatography (4:1 hexanes/EtOAc) to yield
the title compound as a white solid (851 mg, 80%, E:Z = 73:27). The
compound obtained matched literature characterization data.22 1H
NMR (400 MHz, CDCl3): δ = 7.81−7.74 (m, 2 H), 7.71−7.64 (m, 2 H),
7.31−7.18 (m, 4 H), 7.17−7.08 (m, 1 H), 6.39−6.27 (m, 1 H), 6.16 (td,
J = 6.8, 15.7 Hz, 0.73 H), 5.60 (td, J = 7.3, 11.8 Hz, 0.27 H), 4.14 (q, J =
6.8 Hz, 2 H), 2.27 (dq, J = 1.5, 7.3 Hz, 0.56 H), 2.15 (q, J = 6.8 Hz, 1.45
H), 1.80−1.66 (m, 2 H), 1.51−1.23 (m, 8 H).
Synthesis of 19e. 4-(4-((tert-Butyldimethylsilyl)oxy)butoxy)-
butan-1-ol (24). To a stirring solution of alkene 2322 (800 mg, 3.09
mmol) in dry THF (12 mL) at 0 °C was added borane (1.0 M in THF,
5.80 mL, 5.80 mmol) dropwise, and the solution was stirred 2 h at 0 °C
and then allowed to warm to ambient temperature and stirred overnight.
The reaction was cooled to 0 °C, and H2O (5 mL) was added dropwise,
followed by addition of 3 N NaOH (15 mL) and H2O2 (15 mL). The ice
bath was removed, and the resulting mixture was stirred for an additional
30 min and extracted with CH2Cl2 (3 × 20 mL). The organic layers were
dried over Na2SO4, and concentrated by rotary evaporation. The
product was purified using flash column chromatography (4:1 hexanes/
EtOAc) to yield alcohol 24 as a colorless oil (757 mg, 88%). IR (neat):
3382, 2939, 2847, 1469, 1356, 1252, 1078, 839, 773, 665 cm−1; 1H NMR
(400 MHz, CDCl3): δ = 3.60 (t, J = 6.2 Hz, 4 H), 3.47−3.39 (m, 4 H),
2.81 (br. s, 1 H), 1.72−1.48 (m, 8 H), 0.86 (s, 9 H), 0.02 (s, 6 H); 13C
NMR (100 MHz, CDCl3): δ = 70.8, 70.7, 62.8, 62.5, 30.2, 29.4, 26.8,
26.0, 25.9, 18.2, −5.4; HRMS-ESI (m/z): calcd. for C14H33O3Si [M +
H]+: 277.2199, found 277.2206.
4-(4-((tert-Butyldimethylsilyl)oxy)butoxy)butyl 4-Methylbenzene-
sulfonate (25). To a stirring solution of 24 (645 mg, 2.33 mmol) in
CH2Cl2(20 mL) at 0 °C were sequentially added para-toluenesulfonyl
chloride (533 mg, 2.80 mmol) and triethylamine (0.65 mL, 4.66 mmol)
and 4-(dimethylamino)pyridine (28 mg, 0.23 mmol). The resulting
solution was stirred overnight. The solvent was evaporated, and the
residue was diluted with Et2O (50 mL). The resulting mixture was
washed with aqueous saturated NaHCO3 (10 mL) and brine (10 mL)
and dried over Na2SO4. The organic layer was filtered and concentrated
2-(4-((4-Phenylbut-3-en-1-yl)oxy)butoxy)isoindoline-1,3-dione
(19c). To a solution of alcohol 21 (130 mg, 0.59 mmol) in THF (20 mL)
H
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by rotary evaporation. The product was purified by flash column
chromatography (20:1 hexanes/EtOAc) to yield the title compound
(25) as a colorless oil (613 mg, 61%). IR (neat): 2923, 2854, 1264, 1215,
1191, cm−1; 1H NMR (400 MHz, CDCl3): δ = 7.79 (d, J = 8.2 Hz, 2 H),
7.35 (d, J = 7.9 Hz, 2 H), 4.06 (t, J = 6.5 Hz, 2 H), 3.61 (t, J = 6.1 Hz, 2
H), 3.36 (q, J = 6.1 Hz, 4 H), 2.45 (s, 3 H), 1.80−1.69 (m, 2 H), 1.61−
1.49 (m, 6 H), 0.89 (s, 9 H), 0.05 (s, 6 H); 13C NMR (100 MHz,
CDCl3): δ = 144.6, 133.2, 129.8, 127.9, 70.8, 70.4, 69.7, 62.9, 29.5, 26.1,
25.9, 25.9, 25.7, 21.6, 18.3, −5.3; HRMS-ESI (m/z): calcd. for
C21H39O5SSi [M + H]+: 431.2287, found 431.2283.
4-(4-Hydroxybutoxy)butyl-4-methylbenzenesulfonate (26). To a
stirred solution of 25 (570 mg, 1.33 mmol) in THF (10 mL) was added
tetrabutylammonium fluoride (1.0 M in THF, 2.66 mL, 2.66 mmol).
The resulting solution was stirred for 5 h before being diluted with
aqueous NH4Cl (20 mL). The aqueous layer was extracted with Et2O (3
× 20 mL). The combined organic layers were dried over Na2SO4 and
concentrated using rotary evaporation, and purified by column
chromatography (3:2 hexanes/EtOAc) to yield the title compound
(26) as a colorless oil (400 mg, 95%). IR (neat): 3411, 1215, 1191, 815
cm−1; 1H NMR (400 MHz, CDCl3): δ = 7.79 (d, J = 8.2 Hz, 2 H), 7.35
(d, J = 7.9 Hz, 2 H), 4.06 (t, J = 6.3 Hz, 2 H), 3.66−3.61 (m, 2 H), 3.42
(q, J = 5.9 Hz, 4 H), 2.46 (s, 3 H), 2.36 (br. s., 1 H), 1.80−1.50 (m, 8 H);
13C NMR (100 MHz, CDCl3): δ =144.7, 129.8, 127.9, 126.4, 70.9, 70.3,
18.8, −4.8, −5.0; HRMS-ESI (m/z): calcd. for C22H34NO5Si [M + H]+:
420.2206, found 420.2195.
(Z)-2-((9-((tert-Butyldimethylsilyl)oxy)non-8-en-1-yl)oxy)isoin-
doline-1,3-dione (19f, Table 1, entry 7). To a solution of aldehyde 2722
(800 mg, 2.56 mmol) and CH2Cl2 (14 mL) at 0 °C was added N,N-
diisopropylethylamine (662 mg, 5.12 mmol). To this solution was added
tert-butyldimethyltrifluoromethanesulfonate (1.01g, 3.84 mmol) drop-
wise over 5 min, and the yellow solution was allowed to warm to room
temperature and stirred overnight. The reaction was quenched by
addition of aqueous NaHCO3 (10 mL), and extracted with CH2Cl2 (2 ×
10 mL). The organic layers were washed with brine (10 mL), dried over
Na2SO4, concentrated using rotary evaporation, and semipurified by
column chromatography (10:1 hexanes/EtOAc) to yield a colorless oil,
which was used immediately. To a solution of (Z)-9-((tert-butyl-
dimethylsilyl)oxy)non-8-en-1-yl 4-methylbenzenesulfonate in DMF (5
mL) were added N-hydroxyphthalimide (248 mg, 1.51 mmol), and
diisopropylethylamine (0.35 mL, 2.02 mmol). The solution was heated
to 90 °C and stirred for 5 h. The reaction mixture was cooled to room
temperature and quenched with H2O (20 mL), and extracted with Et2O
(3 × 20 mL). The combined organics were washed with H2O (20 mL)
and brine (20 mL), dried over Na2SO4, concentrated by rotary
evaporation, and purified by flash column chromatography (3:1 hexane/
EtOAc) to yield N-alkoxyphthalimide 19f as a colorless oil (270 mg,
33% over 2 steps, E:Z > 5:95). IR (neat): 2942, 2866, 1791, 1736,1654,
1466, 1398,1369, 1258, 1187, 1127, 1092 cm−1; 1H NMR (400 MHz,
CDCl3): δ = 7.90−7.81 (m, 2 H), 7.79−7.71 (m, 2 H), 6.17 (td, J = 1.5,
5.8 Hz, 1 H), 4.44 (dt, J = 5.8, 7.2 Hz, 1 H), 4.20 (t, J = 6.8 Hz, 2 H), 2.08
(dq, J = 1.4, 7.2 Hz, 2 H), 1.85−1.74 (m, 2 H), 1.54−1.42 (m, 2 H),
1.41−1.29 (m, 6 H), 0.93 (s, 9 H), 0.12 (s, 6 H); 13C NMR (100 MHz,
CDCl3): δ = 163.7, 138.4, 134.4, 129.0, 123.5, 110.7, 78.7, 29.6, 29.2,
29.1, 28.1, 25.6, 25.5, 23.5, 18.3, −5.4; HRMS-ESI (m/z): calcd. for
C23H35NNaO4Si [M + Na]+: 440.2233, found 440.2230.
70.0, 62.8, 30.1, 26.8, 25.8, 25.6, 21.6; HRMS-ESI (m/z): calcd. for
C15H25O5S [M + H]+: 317.1423, found 317.1421.
2-(4-((4-((tert-Butyldimethylsilyl)oxy)but-3-en-1-yl)oxy)butoxy)-
isoindoline-1,3-dione (19e). To a solution of oxalyl chloride (95 mg,
0.75 mmol) in dry CH2Cl2 (4 mL) at −78 °C was added dimethyl
sulfoxide (118 mg, 1.51 mmol) dropwise over 1 min. The solution was
stirred at −78 °C for 30 min, and then 26 (200 mg, 0.63 mmol) in
CH2Cl2 (1 mL) was added dropwise over 1 min. The resulting solution
was stirred for 90 min at −78 °C. Triethylamine (0.44 mL, 319 mg, 3.16
mmol) was then added, and the solution was allowed to warm to
ambient temperature and stirred for 12 h. The reaction was poured into
H2O (10 mL) and extracted with CH2Cl2 (3 × 20 mL). The combined
organic layers were washed with brine (30 mL), dried over Na2SO4, and
concentrated using rotary evaporation to give a crude aldehyde, which
was used for the next step without further purification. To a solution of
crude aldehyde in CH2Cl2 (6 mL) at 0 °C was added N,N-
diisopropylethylamine (168 mg, 1.26 mmol). To this solution was
added tert-butyldimethyltrifluoromethanesulfonate (249 mg, 4.2 mmol)
dropwise over 5 min, and the yellow solution was allowed to stir
overnight at 0 °C. The reaction was quenched by addition of aqueous
NaHCO3 (10 mL) and extracted with CH2Cl2 (2 × 10 mL). The organic
layers were washed with brine (10 mL), dried over Na2SO4,
concentrated using rotary evaporation, and semipurified by column
chromatography (3:2 hexanes/EtOAc) to yield a colorless oil, which was
used immediately. To a stirred solution of 4-((4-((tert-butyldimethyl-
silyl)oxy)but-3-en-1-yl)oxy)butyl 4-methylbenzenesulfonate (220 mg,
0.6 mmol), N-hydroxyphthlamide (147 mg, 0.9 mmol) in DMF (3 mL)
was added diisopropylethylamine (155 mg, 1.2 mmol). The resulting
mixture then was heated to 90 °C and stirred for 2 h. The solution was
cooled to room temperature and quenched with H2O (10 mL), and
extracted with Et2O (3 × 10 mL). The combined organic layers were
washed with H2O (10 mL), aqueous NaHCO3 (10 mL), and brine (10
mL) and dried over Na2SO4. The organic layer was filtered,
concentrated by rotary evaporation, then purified by flash column
chromatography (4:1 hexanes/EtOAc) to yield the title compound
(19f) as a colorless oil (150 mg, 58% over 3 steps, E:Z = 44:56). IR
(neat): 2925, 1995, 1737, 1261,1216, 1192 cm−1; 1H NMR (400 MHz,
C6D6): δ = 7.30 (dd, J = 3.1, 5.1 Hz, 2 H), 6.84−6.76 (m, 2 H), 6.34 (d, J
= 12.3 Hz, 0.44 H, E alkene), 6.22 (d, J = 6.1 Hz, 0.55 H), 5.20 (td, J = 7.6,
11.9 Hz, 0.42 H, E alkene), 4.65 (q, J = 6.8 Hz, 0.56 H), 4.09−4.01 (m, 2
H), 3.39 (t, J = 7.0 Hz, 1.13 H, E alkene), 3.31 (t, J = 5.8 Hz, 1.19 H),
3.29−3.22 (m, 2 H), 2.59 (dq, J = 1.2, 7.0 Hz, 1.13 H), 2.17 (q, J = 7.1
Hz, 0.91 H, E alkene), 1.82−1.66 (m, 4 H), 0.95 (s, 4 H, E alkene), 0.93
(s, 5 H), 0.08 (s, 2.7 H, E alkene), 0.03 (s, 3.3 H);13C NMR (100 MHz,
C6D6): δ = 163.7, 142.2, 140.2, 134.1, 134.0, 129.9, 123.3, 108.6, 107.7,
78.7, 78.6, 72.0, 71.2, 70.6, 70.6, 28.9, 26.7, 26.2, 26.1, 25.9, 25.9, 25.6,
Synthesis of 19g. 4-((3-Phenylbut-3-en-1-yl)oxy)butan-1-ol (29).
To a dry round-bottom flask was added sodium hydride (60% wt.
dispersion in mineral oil, 450 mg, 6.41 mmol), and the dispersion was
washed with hexanes (3 × 5 mL). To the resulting solid was added
anhydrous DMF (22 mL), and the suspension was cooled to 0 °C. 2844
(1.0 g, 6.75 mmol) was added dropwise over 5 min and stirred until the
evolution of gas had ceased. A solution of 4-((tert-butyldimethylsilyl)-
oxy)butyl tosylate (3.97 g, 11.07 mmol) in anhydrous DMF (2 mL) was
added dropwise over 5 min. The resulting solution was heated to 75 °C,
and stirred overnight. The solution was then allowed to cool to ambient
temperature. The reaction was quenched with the dropwise addition of
H2O (5 mL) and extracted with Et2O (4 × 20 mL). The combined
organic layers were washed with aqueous NaHCO3 (25 mL), H2O (25
mL), and brine (25 mL) and dried over Na2SO4, and concentrated by
rotary evaporation. The crude compound was semipurified by flash
column chromatography (20:1 hexanes/Et2O) to yield tert-butyl-
dimethyl(4-((3-phenylbut-3-en-1-yl)oxy)butoxy)silane as a colorless
oil. To a stirring solution of the silyl ether (870 mg, 2.6 mmol) in THF
(5 mL) was added tetrabutylammonium fluoride (1.0 M in THF, 7.8
mL, 7.8 mmol), and the solution was stirred overnight at ambient
temperature. The reaction was quenched with H2O (5 mL) and
extracted with Et2O (3 × 15 mL). The combined organic layers were
washed with H2O (10 mL) and brine (10 mL), dried over Na2SO4, and
concentrated by rotary evaporation. The product was purified using
flash column chromatography (gradient 4:1 to 1:1 hexanes/EtOAc) to
yield alcohol 29 as a colorless oil (510 mg, 39%). IR (neat): 3395, 2939,
1
2860, 1721, 1682, 1447, 1108, 1056, 700 cm−1; HNMR (400 MHz,
CDCl3): δ = 7.39−7.32 (m, 2 H), 7.30−7.24 (m, 2 H), 7.23−7.18 (m, 1
H), 5.29 (d, J = 1.4 Hz, 1 H), 5.07 (q, J = 1.1 Hz, 1 H), 3.55 (t, J = 5.8 Hz,
2 H), 3.49 (t, J = 7.2 Hz, 2 H), 3.40−3.35 (m, 2 H), 2.75 (dt, J = 1.0, 7.0
Hz, 2 H), 2.71 (br. s., 1 H), 1.64−1.51 (m, 4 H); 13C NMR (100 MHz,
CDCl3): δ = 145.0, 140.7, 128.2, 127.3, 125.9, 113.8, 70.8, 69.5, 62.4,
35.4, 30.0, 26.5; HRMS-ESI (m/z): calcd. for C14H20O2Na [M + Na]+:
243.1361, found 243.1365.
2-(4-((3-Phenylbut-3-en-1-yl)oxy)butoxy)isoindoline-1,3-dione
(19g). To a solution of alcohol 29 (350 mg, 1.59 mmol) in regular THF
(60 mL) were sequentially added triphenylphosphine (624 mg, 2.38
mmol) and N-hydroxyphthalimide (388 mg, 2.38 mmol). The solution
I
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was stirred until the solids were dissolved, at which point diisopropyl-
azodicarboxylate (0.56 mL, 578 mg, 2.86 mmol) was added via syringe
pump (0.8 mL/h). The resulting yellow solution was stirred overnight at
ambient temperature, and was then quenched with H2O (10 mL). The
aqueous layer was extracted with EtOAc (3 × 30 mL), and the combined
organic layers were washed with aqueous NaHCO3 (3 × 25 mL), H2O
(25 mL), and brine (25 mL) and were dried over Na2SO4. The organic
layers were concentrated using rotary evaporation and semipurified by
flash column chromatography (4:1 hexanes/EtOAc) to provide the title
compound (19g) as a colorless oil contaminated with diisopropyl 1,2-
hydrazinedicarboxylate45 (520 mg, 89%, 92% purity). which was
immediately subjected to general cyclization procedure A (see details
below). 1H NMR (400 MHz, CDCl3): δ = 7.35 (d, J = 7.3 Hz, 2 H), 7.29
(dd, J = 3.0, 5.2 Hz, 2 H), 7.25−7.03 (m, 3 H), 6.79 (dd, J = 3.0, 5.2 Hz, 2
H), 5.32 (s, 1 H), 5.07 (s, 1 H), 4.04 (t, J = 6.2 Hz, 2 H), 3.39 (t, J = 7.0
Hz, 2 H), 3.19 (t, J = 5.9 Hz, 2 H), 2.73 (t, J = 6.9 Hz, 2 H), 1.76−1.59
(m, 4 H).
General Cyclization Procedures. Procedure A. To a 0.02 M
solution of cyclization precursor (1 equiv) in degassed benzene at reflux
was added a 0.2 M solution of tributyltin hydride (1.2 equiv) and AIBN
(0.15 equiv) in degassed benzene by syringe pump (0.4 mL/h). The
reaction was then stirred for an additional 1 h at reflux.
Procedure B. To a 0.02 M solution of cyclization precursor (1 equiv)
in degassed d6-benzene at 70 °C was added a 0.2 M solution of
tributyltin hydride (1.8 equiv) and AIBN (0.15 equiv) in degassed d6-
benzene by syringe pump (0.3 mL/h). The reaction was then stirred for
an additional 1 h at 70 °C.
procedure A. Purification with the general procedure and finally by flash
column chromatography (4:1 hexanes/EtOAc) afforded 30c as a
colorless oil (50 mg, 75%, cis:trans = 83:17). IR (neat): 3381, 2934,
2869, 1608, 1500, 1460, 1386, 1352, 1256, 1065, 1021, 800, 752, 704
cm−1; 1H NMR (400 MHz, CDCl3): δ = 7.34−7.27 (m, 2 H), 7.24−7.15
(m, 3 H), 4.02−3.89 (m, 1.72 H), 3.87−3.81 (m, 0.28 H), 3.80−3.59
(m, 2.75 H), 3.55 (dt, J = 2.0, 8.2 Hz, 0.15 H), 2.85 (dd, J = 3.9, 12.8 Hz,
0.85 H), 2.78 (dd, J = 5.8, 13.7 Hz, 0.18 H), 2.72−2.36 (m, 2.9 H), 2.13−
1.94 (m, 0.34 H), 1.94−1.82 (m, 0.96 H), 1.80−1.52 (m, 4.67 H), 1.50−
1.42 (m, 0.11 H); 13C NMR (100 MHz, CDCl3): δ = 140.8, 128.8,
128.7, 128.4, 126.1, 126.0, 84.1, 81.5, 66.7, 66.2, 62.9, 62.8, 46.2, 43.1,
39.0, 34.6, 32.5, 31.6, 30.5, 30.4, 29.9, 27.8; HRMS-ESI (m/z): calcd. for
C14H20O2Na [M + Na]+:243.1361, found 243.1363.
(3-(2-Benzylcyclopentyl)propoxy)(tert-butyl)dimethylsilane (30d).
N-Alkoxyphthalimide 19d (230 mg, 0.63 mmol) was subjected to
general cyclization procedure A. To the crude mixture in CH2Cl2 (20
mL) were sequentially added triethylamine (202 mg, 2.0 mmol) and
then tert-butyldimethylsilyl chloride (218 mg, 0.94 mmol), and the
mixture was stirred overnight. The solvent was evaporated, and the
residue was dissolved in Et2O (20 mL). The organic layer was washed
with aq. NaHCO3 (10 mL) and brine (10 mL) and dried over Na2SO4,
and concentrated using rotary evaporation. The crude product was
purified using flash column chromatography (20:1 hexanes/EtOAc) to
afford 30d as a colorless oil (160 mg, 55%, two steps, cis:trans = 77:23).
The compound obtained matched literature characterization data.8 1H
NMR (400 MHz, CDCl3):δ = 7.27 (s, 2 H), 7.22−7.13 (m, 3 H), 3.65 (t,
J = 6.4 Hz, 1.52 H), 3.60 (t, J = 5.9 Hz, 0.46 H), 2.86 (dd, J = 4.4, 13.2 Hz,
0.23 H), 2.76 (dd, J = 4.6, 13.1 Hz, 0.76 H), 2.39 (dd, J = 9.1, 13.4 Hz,
0.23 H), 2.29 (dd, J = 10.4, 13.4 Hz, 0.77 H), 2.23−2.13 (m, 0.76 H),
1.95−1.83 (m, 1 H), 1.81−1.46 (m, 7 H), 1.45−1.06 (m, 3 H), 0.93 (s,
6.2 H), 0.93 (s, 2.8 H), 0.09 (s, 4.2 H), 0.08 (s, 1.8 H).
Procedure C. To a 0.02 M solution of cyclization precursor (1 equiv)
in degassed d6-benzene at 60 °C was added a 0.2 M solution of
tributyltin hydride (1.8 equiv) and AIBN (0.15 equiv) in degassed d6-
benzene by syringe pump (0.4 mL/h). The reaction was then stirred for
an additional 1 h at 60 °C.
3-(3-(((tert-Butyldimethylsilyl)oxy)methyl)tetrahydrofuran-2-yl)-
propan-1-ol (30e). N-Alkoxyphthalimide 19e (23 mg, 0.05 mmol) was
subjected to general cyclization procedure A. Purification with the
general procedure and finally by flash column chromatography (3:1
hexanes/EtOAc) afforded 30e as a solution in hexanes (8.3 mg, 60%, 3.4
M, cis:trans = 66:33). IR (neat): 3375, 2527, 2855, 1259, 1215, 1192,
749 cm−1; 1H NMR (400 MHz, CDCl3); δ = 3.79−3.43 (m, 5.76 H),
3.41−3.31 (m, 1.36 H), 2.18−2.09 (m, 0.65 H), 2.07 (t, J = 6.0 Hz, 0.34
H), 1.96 (t, J = 5.6 Hz, 0.65 H), 1.87−1.34 (m, 6.86 H), 0.96 (s, 6 H),
0.95 (s, 3 H), 0.03 (s, 4 H), 0.01 (s, 2 H); 13C NMR (100 MHz, CDCl3):
δ = 82.6, 81.3, 67.2, 66.5, 65.2, 63.2, 63.2, 62.9, 47.5, 44.7, 33.1, 31.7,
31.0, 29.9, 29.4, 28.0, 26.4, 18.8, 18.8, −5.0, −5.0; HRMS-ESI (m/z):
calcd. for C14H30NaO3Si [M + Na]+: 297.1862, found 297.1859.
33-(2-(((tert-Butyldimethylsilyl)oxy)methyl)cyclopentyl)propan-1-
ol (30f, Table 1, entry 6). N-Alkoxyphthalimide 19f (150 mg, 0.35
mmol) was subjected to general cyclization procedure A. Purification
with the general procedure and finally by flash column chromatography
(4:1 hexanes/EtOAc) afforded 30f as a colorless oil (62 mg, 62%,
cis:trans = 70:30). IR (neat): 3381, 2934, 2869, 1608, 1500, 1460, 1386,
General Purification Procedures. The resulting solution was
allowed to cool to ambient temperature, concentrated by evaporation,
and semipurified by flash column chromatography to afford a mixture of
cyclized products and linear alcohol as a colorless oil. The product
mixture was then dissolved in CH2Cl2 (0.3 M) and cooled to 0 °C. meta-
Chloroperbenzoic acid (3 equiv) was added in one portion. The
resulting mixture was allowed to warm to ambient temperature and
stirred overnight. The reaction was quenched with 2.0 M aq. Na2S2O3
(10 mL), washed with saturated aqueous Na2CO3 (3 × 5 mL) and H2O
(5 mL), dried over Na2SO4, and concentrated by rotary evaporation.
The cyclized products were purified by flash column chromatography.
The relative stereochemistry of the cyclized products was determined
using NOE experiments, and the major diastereomer is shown.
Characterization for compounds 30b, 30d, 30f, and 31h have been
previously reported.8
Methyl((4-((2S,3S)-3-methyltetrahydrofuran-2-yl)butan-2-yl)-
oxy)diphenylsilane (30a). N-Alkoxyphthalimide 19a (285 mg, 0.93
mmol) was subjected to general cyclization procedure A. To the crude
mixture in CH2Cl2 (20 mL) were sequentially added triethylamine (303
mg, 3.0 mmol) and then methyldiphenylsilyl chloride (349 mg, 1.50
mmol), and the mixture was stirred overnight. The solvent was
evaporated, and the residue was dissolved in Et2O (20 mL). The organic
layer was washed with aq. NaHCO3 (20 mL) and brine (20 mL) and
dried over Na2SO4, and concentrated using rotary evaporation. The
crude product was purified using flash column chromatography (10:1
hexanes/EtOAc) to afford 30a as a colorless oil (180 mg, 55%, two steps,
cis:trans = 91:9). IR (neat): 2960, 2869, 1430, 1369, 1256, 1121, 1069,
1004, 800, 739, 700 cm−1; 1H NMR (400 MHz, CDCl3): δ = 7.70−7.58
(m, 4 H), 7.48−7.35 (m, 6 H), 4.11−3.86 (m, 1.92 H), 3.84−3.77 (m,
0.18 H), 3.77−3.61 (m, 1.82 H), 3.32−3.18 (m, 0.07 H), 2.28−2.00 (m,
1.92 H), 1.84−1.33 (m, 4.79 H), 1.20 (d, J = 5.8 Hz, 3 H), 1.01 (d, J = 6.8
Hz, 0.25 H), 0.94−0.83 (m, 2.72 H), 0.69 (d, J = 1.7 Hz, 3 H); 13C NMR
(100 MHz, CDCl3): δ = 136.8, 136.8, 134.4, 134.4, 129.6, 127.7, 81.9,
81.4, 69.7, 69.1, 65.9, 65.9, 36.7, 36.2, 35.2, 35.2, 33.8, 33.8, 27.0, 26.1,
23.8, 23.5, 14.2, 14.1, −2.3; HRMS-ESI (m/z): calcd. for C22H31SiO2
[M + H]+:355.2093, found 355.2102.
1
1352, 1256, 1065, 1021, 800, 752, 704 cm−1; H NMR (400 MHz,
CDCl3): δ = 3.68−3.57 (m, 2.73 H), 3.54 (dd, J = 5.8, 9.9 Hz, 0.34 H),
3.51−3.41 (m, 1 H), 2.13−2.00 (m, 0.75 H), 1.95−1.42 (m, 9.69 H),
1.41−1.13 (m, 3 H), 0.89 (s, 9 H), 0.04 (s, 6 H); 13C NMR (100 MHz,
CDCl3): δ = 66.6, 63.4, 63.3, 63.3, 47.9, 44.3, 41.9, 41.6, 32.8, 32.1, 31.8,
31.7, 31.0, 29.3, 28.1, 25.9, 25.9, 25.8, 24.4, 22.9, 18.3, 18.3, −5.3, −5.4;
HRMS-ESI (m/z): calcd. for C15H32O2NaSi [M + Na]+: 295.2069,
found 295.2067.
33-(2-(((tert-Butyldimethylsilyl)oxy)methyl)cyclopentyl)propan-1-
ol (30f, Table 1, entry 7). N-Alkoxyphthalimide 19f (150 mg, 0.35
mmol) was subjected to the general cyclization procedure A.
Purification with the general procedure and finally by flash column
chromatography (4:1 hexanes/EtOAc) afforded 30f as a colorless oil
(62 mg, 62%, cis:trans = 75:25).
3-(4-Phenyltetrahydro-2H-pyran-2-yl)propan-1-ol (31g). N-
Alkoxyphthalimide 19g (212 mg, 0.58 mmol) was subjected to general
cyclization procedure A. Purification with the general procedure and
finally by flash column chromatography (1:1 hexanes/EtOAc) afforded
31g as a colorless oil (126 mg, 65%, cis:trans > 5:95). IR (neat): 3373,
2943, 2852, 1734, 1452, 1373, 1265, 1073, 921, 800, 760,717 cm−1; 1H
3-(3-Benzyltetrahydrofuran-2-yl)propan-1-ol (30c). N-Alkoxyph-
thalimide 19c (111 mg, 0.30 mmol) was subjected to general cyclization
J
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The Journal of Organic Chemistry
Article
NMR (400 MHz, CDCl3): δ = 7.37−7.30 (m, 2 H), 7.25−7.20 (m, 3 H),
4.15 (td, J = 3.2, 11.3 Hz, 1 H), 3.73−3.56 (m, 3 H), 3.50−3.43 (m, 1 H),
2.85−2.75 (m, 1 H), 2.50 (t, J = 5.8 Hz, 1 H), 1.86−1.46 (m, 10 H); 13C
NMR (100 MHz, CDCl3): δ = 145.6, 128.5, 126.7, 126.3, 77.9, 68.2,
62.9, 41.7, 39.5, 33.5, 33.3, 29.3; HRMS-ESI (m/z): calcd. for
C14H20O2Na [M + Na]+: 243.1361, found 243.1357.
chromatography (5:1 hexanes/EtOAc) to provide N-alkoxyphthalimide
43 as a colorless oil (400 mg, 64%). IR (neat): 2943, 2860, 1791, 1730,
1465, 1365, 1191, 1126, 1078, 986, 873, 704 cm−1; 1H NMR (400 MHz,
CDCl3): δ = 7.84−7.78 (m, 2 H), 7.76−7.70 (m, 2 H), 5.97−5.83 (m, 1
H), 5.24 (qd, J = 1.7, 17.1 Hz, 1 H), 5.17−5.10 (m, 1 H), 4.19 (t, J = 6.7
Hz, 2 H), 3.94 (td, J = 1.5, 5.5 Hz, 2 H), 3.44 (t, J = 6.3 Hz, 2 H), 1.86−
1.75 (m, 2 H), 1.70−1.60 (m, 2 H), 1.60−1.50 (m, 2 H); 13C NMR (100
MHz, CDCl3): δ = 163.5, 134.9, 134.3, 128.9, 123.4, 116.6, 78.3, 71.7,
70.0, 29.3, 27.9, 22.2; HRMS-ESI (m/z): calcd. for C16H20NO4 [M +
H]+: 290.1392, found 290.1397.
4-(3-Methyltetrahydrofuran-2-yl)butan-1-ol (48). N-Alkoxy-
phthalimide 42 (100 mg, 0.30 mmol) was subjected to general
cyclization procedure A. Purification with the general procedure and
finally by flash column chromatography (1:1 hexanes/EtOAc) afforded
48 (major isomer) as a colorless oil (31 mg, 66%, ratio 80:20). IR (neat):
3385, 2934, 2870, 1709, 1458, 1375, 1055 cm−1; 1H NMR (400 MHz,
CDCl3): δ = 3.95−3.87 (m, 1 H), 3.77−3.70 (m, 2 H), 3.67 (t, J = 6.4
Hz, 2 H), 2.30−2.17 (m, 1 H), 2.15−2.01 (m, 1 H), 1.68−1.37 (m, 8 H),
0.91 (d, J = 7.0 Hz, 3 H); 13C NMR (100 MHz, CDCl3): δ = 81.6, 65.9,
62.7, 35.3, 33.9, 32.8, 30.1, 22.9, 14.2; HRMS-ESI (m/z): calcd. for
C9H19O2 [M + H]+:159.1385, found 159.1382.
General Procedures for Synthesis of 53. To a 0.1 M solution of
sodium hydride (60% dispersion in mineral oil, 2 equiv) in dry THF at 0
°C was added a 5 M solution of 1-((tert-butyldimethylsilyl)oxy)pent-4-
en-2-ol (66a, P = TBS),48 1-((tert-butyldiphenylsilyl)oxy)pent-4-en-2-
ol (66a, P = TBDPS),42 or 66b in THF dropwise over 10 min. The
solution was stirred for an additional 30 min at 0 °C. Alkyl iodide or aryl
iodide (2 equiv) was added dropwise over 5 min, and the solution was
warmed to ambient temperature and stirred overnight. The reaction was
quenched with H2O, and the aqueous layer was extracted with EtOAc.
The combined organic layers were washed with brine, dried over
Na2SO4, and concentrated by rotary evaporation to provide ether as a
colorless oil. To a stirred 0.1 M solution of ether in THF at 0 °C was
added tetrabutylammonium fluoride (1.5 equiv). The mixture was
allowed to warm to ambient temperature and stirred overnight. The
reaction was quenched with saturated aq. NH4Cl (10 mL) and extracted
with Et2O (3 × 20 mL). The combined organic extracts were dried over
Na2SO4 and concentrated using rotary evaporation. Purification by flash
column chromatography (3:1 hexanes/EtOAc) afforded an alcohol,
which was used immediately. To 0.03 M solution of the alcohol in THF
were sequentially added triphenylphosphine (1.5 equiv) and N-
hydroxyphthalimide (1.5 equiv). The solution was stirred until the
solids had dissolved, at which point diisopropylazodicarboxylate (2
equiv) was added dropwise via syringe pump (rate = 0.8 mL/h). The
resulting yellow solution was stirred overnight at ambient temperature
and then quenched with H2O (20 mL). The aqueous layer was extracted
with EtOAc (3 × 30 mL), and the combined organic layers were washed
with NaHCO3 (3 × 30 mL) and brine (30 mL) and were dried over
Na2SO4. The organics were concentrated using rotary evaporation and
purified by flash column chromatography to provide the N-
alkoxyphthalimide.
4-(But-3-enyloxy)butan-1-ol (40). To a stirring solution of sodium
hydride (60% dispersion in mineral oil, 220 mg, 5.50 mmol) in
anhydrous DMF (10 mL) was added 3-buten-1-ol (0.32 mL, 272 mg,
3.78 mmol). The solution was stirred for 1 h, after which a solution of 5-
((tert-butyldimethylsilyl)oxy)pentyl 4-methylbenzenesulfonate46 (1.03
g, 2.89 mmol) in anhydrous DMF (1.0 mL) was added. The solution was
then heated to 75 °C and stirred for 1 h, and allowed to cool to ambient
temperature. The reaction was quenched via the slow addition of H2O
(10 mL), followed by saturated aq. NaHCO3 (10 mL). The reaction was
extracted with Et2O (3 × 20 mL), and the combined organic layers were
dried over Na2SO4, concentrated by rotary evaporation, and semi-
purified using flash column chromatography (50:1 hexanes/Et2O) to
yield ((5-(but-3-en-1-yloxy)pentyl)oxy)(tert-butyl)dimethylsilane as a
colorless oil, which was used without further purification. To a stirring
solution of ((5-(but-3-en-1-yloxy)pentyl)oxy)(tert-butyl)dimethyl-
silane (400 mg, 1.46 mmol) in THF (7 mL) was added tetrabutyl-
ammonium fluoride (1.0 M in THF, 4.4 mL, 4.4 mmol), and the solution
was stirred 12 h at ambient temperature. The reaction was quenched
with H2O (10 mL) and extracted with Et2O (3 × 10 mL). The combined
organic layers were washed with H2O (10 mL) and brine (10 mL), dried
over Na2SO4, and concentrated by rotary evaporation. The product was
purified using flash column chromatography (1:1 hexanes/EtOAc) to
yield the title compound as a colorless oil (196 mg, 43% over 2 steps). IR
(neat): 3369, 2930, 2857, 1730, 1639, 1117, 1059, 904, 791 cm−1;
1HNMR (400 MHz, CDCl3): δ = 5.80 (tdd, J = 6.7, 10.4, 17.2 Hz, 1 H),
5.07 (qd, J = 1.7, 17.2 Hz, 1 H), 5.03−4.99 (m, 1 H), 3.60 (t, J = 6.5 Hz, 2
H), 3.48−3.38 (m, 4 H), 2.31 (tq, J = 1.4, 6.8 Hz, 2 H), 2.07 (s, 1 H),
1.63−1.51 (m, 4 H), 1.45−1.35 (m, 2 H); 13C NMR (100 MHz,
CDCl3): δ = 135.4, 116.4, 70.9, 70.3, 62.8, 34.3, 32.6, 29.5, 22.6. HRMS-
ESI (m/z): calcd. for C9H19O2 [M + H]+: 159.1385, found 159.1382.
Synthesis of 2-((5-(But-3-en-1-yloxy)pentyl)oxy)isoindoline-1,3-
dione (42). To a solution of alcohol 40 (130 mg, 0.82 mmol) in THF
(20 mL) were sequentially added triphenylphosphine (322 mg, 1.23
mmol) and then N-hydroxyphthalimide (200 mg, 1.23 mmol). The
solution was stirred until all solids were dissolved, at which point
diisopropylazodicarboxylate (0.29 mL, 297 mg, 1.47 mmol) was added
via syringe pump (rate = 0.8 mL/h). The resulting yellow solution was
stirred for 12 h at ambient temperature, and was then quenched with
H2O (10 mL). The aqueous layer was extracted with EtOAc (3 × 20
mL), and the combined organic layers were washed with aq. NaHCO3(3
× 20 mL) and brine (20 mL) and were dried over Na2SO4. The organics
were concentrated using rotary evaporation and purified by flash column
chromatography (4:1 hexanes/EtOAc) to provide N-alkoxyphthalimide
42 as a colorless oil (186 mg, 69%). IR (neat): 2943, 2856, 1795, 1726,
1
1473, 1378, 1191, 1117, 982, 886, 704 cm−1; H NMR (400 MHz,
CDCl3): δ = 7.83 (dd, J = 3.0, 5.2 Hz, 2 H), 7.74 (dd, J = 3.0, 5.5 Hz, 2
H), 5.82 (tdd, J = 6.7, 10.3, 17.1 Hz, 1 H), 5.08 (dd, J = 1.5, 17.1 Hz, 1
H), 5.03 (d, J = 10.1 Hz, 1 H), 4.21 (t, J = 6.7 Hz, 2 H), 3.51−3.42 (m, 4
H), 2.33 (q, J = 6.7 Hz, 2 H), 1.82 (quin, J = 7.1 Hz, 2 H), 1.72−1.51 (m,
4 H); 13C NMR (100 MHz, CDCl3): δ = 163.6, 135.3, 134.4, 128.9,
123.4, 116.2, 78.4, 70.6, 70.1, 34.2, 29.3, 27.9, 22.24; HRMS-ESI (m/z):
calcd. for C17H22NO4 [M + H]+: 304.1549, found 304.1544.
Synthesis of 2-((5-(Allyloxy)pentyl)oxy)isoindoline-1,3-dione (43).
To a solution of 4147 (310 mg, 2.15 mmol) in THF (20 mL) were
sequentially added triphenylphosphine (844 mg, 3.22 mmol) and then
N-hydroxyphthalimide (525 mg, 3.22 mmol). The solution was stirred
until all solids were dissolved, at which point diisopropylazo-
dicarboxylate (0.76 mL, 782 mg, 3.86 mmol) was added via syringe
pump (rate = 0.8 mL/h). The resulting yellow solution was stirred for 12
h at ambient temperature, and was then quenched with H2O (10 mL).
The aqueous layer was extracted with EtOAc (3 × 20 mL), and the
combined organic layers were washed with NaHCO3 (3 × 20 mL) and
brine (20 mL) and were dried over aq. Na2SO4. The organics were
concentrated using rotary evaporation and purified by flash column
2-((2-(Benzyloxy)pent-4-en-1-yl)oxy)isoindoline-1,3-dione (53a).
Colorless oil (21% over 3 steps). IR (neat):3069, 2926, 2860, 1786,
1730, 1473, 1373, 1186, 1130, 1026, 991, 917, 878, 704 cm−1; 1H NMR
(400 MHz, CDCl3): δ = 7.85−7.78 (m, 2 H), 7.77−7.70 (m, 2 H),
7.38−7.32 (m, 2 H), 7.31−7.20 (m, 3 H), 5.89 (tdd, J = 7.1, 9.9, 17.1 Hz,
1 H), 5.18 (dd, J = 1.2, 17.2 Hz, 1 H), 5.12 (d, J = 9.9 Hz, 1 H), 4.74 (d, J
= 11.6 Hz, 1 H), 4.68 (d, J = 11.6 Hz, 1 H), 4.35−4.24 (m, 2 H), 3.99−
3.89 (m, 1 H), 2.57−2.41 (m, 2 H); 13C NMR (100 MHz, CDCl3): δ =
163.3, 138.3, 134.4, 133.6, 128.9, 128.2, 127.8, 127.5, 123.5, 118.0, 79.8,
76.5, 71.9, 35.9; HRMS-ESI (m/z): calcd. for C20H20NO4 [M + H]+:
338.1392, found 338.1385.
2-((2-(Benzyloxy)pent-4-yn-1-yl)oxy)isoindoline-1,3-dione (53b).
Colorless oil (35% over 3 steps). IR (neat): 3286, 2956, 1786, 1726,
1465, 1373, 1265, 1186, 1104, 1030, 878, 804, 700 cm−1; 1H NMR (400
MHz, C6D6): δ = 7.28 (d, J = 7.3 Hz, 2 H), 7.24 (dd, J = 3.0, 5.2 Hz, 2 H),
7.09 (t, J = 7.2 Hz, 2 H), 7.05−7.00 (m, 1 H), 6.77 (dd, J = 3.2, 5.3 Hz, 2
H), 4.51 (d, J = 11.6 Hz, 1 H), 4.45 (d, J = 11.6 Hz, 1 H), 4.38−4.24 (m,
2 H), 3.84 (quin, J = 5.4 Hz, 1 H), 2.50−2.34 (m, 2 H), 1.70 (t, J = 2.6
Hz, 1 H); 13C NMR (100 MHz, CDCl3): δ = 163.4, 139.1, 134.0, 129.7,
K
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The Journal of Organic Chemistry
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128.7, 128.2, 127.9, 123.4, 80.5, 79.6, 76.4, 72.4, 71.3, 21.8; HRMS-ESI
(m/z): calcd. for C20H17NaNO4 [M + Na]+: 358.1055, found 358.1066.
2-((2-Methoxypent-4-en-1-yl)oxy)isoindoline-1,3-dione (53c).
Colorless oil (13% over 3 steps). IR (neat): 2930, 1786, 1730, 1473,
128.1, 127.3, 107.6, 83.9, 78.8, 64.4, 34.5; HRMS-ESI (m/z): calcd. for
C12H15O2 [M + H]+: 191.1072, found 191.1074.
tert-Butyl((4-methyltetrahydrofuran-2-ol)methoxydiphenylsilane
(55c). N-Alkoxyphthalimide 53c (88 mg, 0.33 mmol) was subjected to
general cyclization procedure A. To the crude mixture were sequentially
added imidazole (45 mg, 0.66 mmol) and then tert-butyldiphenylsilyl
chloride (137 mg, 0.50 mmol), and the mixture was stirred overnight.
The solvent was evaporated, and the residue was dissolved in Et2O (50
mL). The organic layers were washed with brine (20 mL) and dried over
Na2SO4, and concentrated using rotary evaporation. The crude product
was purified using flash column chromatography (4:1 hexanes/EtOAc)
to afford 55c as a colorless oil (28 mg, 20%, two steps, cis:trans > 95:5).
1
1382, 1186, 1134, 1082, 986, 873, 717 cm−1; H NMR (400 MHz,
C6D6): δ = 7.29 (dd, J = 3.0, 5.2 Hz, 2 H), 6.80 (dd, J = 3.0, 5.5 Hz, 2 H),
5.78 (tdd, J = 7.0, 10.1, 17.2 Hz, 1 H), 5.06 (dd, J = 1.7, 17.5 Hz, 1 H),
5.00 (dd, J = 0.9, 10.1 Hz, 1 H), 4.22−4.14 (m, 1 H), 4.12−4.03 (m, 1
H), 3.59−3.48 (m, 1 H), 3.26 (s, 3 H), 2.30−2.22 (m, 2 H)); 13C NMR
(100 MHz, CDCl3): δ = 163.3, 134.4, 133.4, 128.9, 123.5, 118.0, 79.3,
78.2, 57.5, 35.2; HRMS-ESI (m/z): calcd. for C15H15NaN2O [M +
Na]+: 262.1082, found 262.1087.
1
IR (neat): 2969, 2921, 2856, 1739, 1478, 1434, 1117, 708 cm−1; H
2-((2-Methoxypent-4-yn-1-yl)oxy)isoindoline-1,3-dione (53d).
Colorless oil (60%). IR (neat): 2982, 2926, 1791, 1734, 1473, 1382,
NMR (300 MHz, C6D6): δ = 7.91−7.80 (m, 4 H), 7.27−7.20 (m, 6 H),
4.11−4.00 (m, 1 H), 3.86−3.66 (m, 3 H), 3.29 (t, J = 8.2 Hz, 1 H), 2.07−
1.90 (m, 1 H), 1.82−1.70 (m, 1 H), 1.27−1.13 (m, 10 H), 0.79 (d, J = 6.6
Hz, 3 H); 13C NMR (100 MHz, C6D6/CDCl3 ∼2/1): δ = 136.4, 134.4,
130.2, 128.3, 80.8, 77.7, 75.5, 67.3, 37.2, 35.0, 27.5, 19.9, 17.5; HRMS-
ESI (m/z): calcd. for C22H30NaSiO2 [M + Na]+: 377.1913, found
377.1911.
tert-Butyl((4-methylenetetrahydrofuran-2-yl)methoxy)diphenyl-
silane (55d). N-Alkoxyphthalimide 53d (160 mg, 0.61 mmol) was
subjected to general cyclization procedure A. To the crude mixture were
sequentially added imidazole (81 mg, 1.2 mmol), and then tert-
butyldiphenylsilyl chloride (202 mg, 0.74 mmol), and the mixture was
stirred overnight. The solvent was evaporated, and the residue was
dissolved in Et2O (50 mL). The organic layer was washed with brine (20
mL) and dried over Na2SO4, and concentrated using rotary evaporation.
The crude product was purified using flash column chromatography
(25:1 hexanes/EtOAc) to afford 55d as a colorless oil (60 mg, 25%, two
steps). IR (neat): 2982, 2926, 1791, 1734, 1473, 1382, 1269, 1182, 1108,
1030, 991,882, 708 cm−1; 1H NMR (400 MHz, C6D6): δ = 7.84−7.77
(m, 4 H), 7.23 (t, J = 2.9 Hz, 6 H), 4.83 (quin, J = 2.2 Hz, 1 H), 4.70 (t, J
= 2.1 Hz, 1 H), 4.36−4.28 (m, 1 H), 4.21−4.14 (m, 1 H), 4.10−4.03 (m,
1 H), 3.71 (dd, J = 2.6, 4.7 Hz, 2 H), 2.37−2.31 (m, 2 H), 1.17 (s, 9 H);
13C NMR (100 MHz, CDCl3): δ = 147.9, 135.6, 133.6, 129.6, 127.6,
1
1269, 1182, 1108, 1030, 991, 882, 708 cm−1; H NMR (400 MHz,
C6D6): δ = 7.27 (dd, J = 3.0, 5.5 Hz, 2 H), 6.78 (dd, J = 3.0, 5.5 Hz, 2 H),
4.27 (d, J = 5.5 Hz, 2 H), 3.58 (quin, J = 5.5 Hz, 1 H), 3.15 (s, 3 H),
2.35−2.32 (m, 2 H), 1.68 (t, J = 2.7 Hz, 1 H); 13C NMR (100 MHz,
C6D6/CDCl3 ∼ 2/1): δ = 163.8, 134.8, 129.5, 123.9, 80.2, 79.3, 77.7,
71.2, 58.1, 21.2; HRMS-ESI (m/z): calcd. for C14H14NO4 [M + H]+:
260.0923, found 260.0925.
2-((2-(Ethoxy)pent-4-en-1-yl)oxy)isoindoline-1,3-dione (53e). Col-
orless oil (35% over 3 steps). IR (neat): 2978, 2891, 1795, 1734, 1473,
1373, 1256, 1195, 1108, 1026, 878, 791, 704 cm−1; 1H NMR (400 MHz,
CDCl3): δ = 7.88 (dd, J = 3.0, 5.2 Hz, 2 H), 7.79 (dd, J = 3.2, 5.3 Hz, 2
H), 5.90 (tdd, J = 7.0, 10.1, 17.2 Hz, 1 H), 5.19 (d, J = 17.1 Hz, 1 H), 5.14
(d, J = 10.1 Hz, 1 H), 4.32−4.20 (m, 2 H), 3.86−3.78 (m, 1 H), 3.75−
3.60 (m, 2 H), 2.49−2.36 (m, 2 H), 1.19 (t, J = 7.0 Hz, 3 H); 13C NMR
(100 MHz, C6D6): δ = 163.5, 134.7, 134.1, 129.8, 123.4, 118.0, 80.3,
77.4, 65.6, 36.6, 16.0; HRMS-ESI (m/z): calcd. for C15H18NO4 [M +
H]+: 276.1234, found 276.1236.
2-((2-Ethoxypent-4-yn-1-yl)oxy)isoindoline-1,3-dione (53f). Col-
orless oil (35%). IR (neat): 2982, 2926, 1791, 1734, 1473, 1382, 1269,
1182, 1108, 1030, 991, 882, 708 cm−1; 1H NMR (400 MHz, CDCl3):δ =
7.90−7.82 (m, 2 H), 7.81−7.70 (m, 2 H), 4.44−4.28 (m, 2 H), 3.94−
3.84 (m, 1 H), 3.75−3.58 (m, 2 H), 2.61 (dd, J = 2.7, 6.0 Hz, 2 H), 2.02
(t, J = 2.6 Hz, 1 H), 1.15 (t, J = 7.0 Hz, 3 H); 13C NMR (100 MHz,
CDCl3): δ =163.3, 134.5, 128.9, 123.5, 79.9, 78.9, 75.7, 70.5, 65.5, 21.1,
15.3; HRMS-ESI (m/z): calcd. forC15H15NaNO4 [M + Na]+: 296.0899,
found 296.0897
Synthesis of 55a−g. (4-Methyl-5-phenyltetrahydrofuran-2-yl)-
methanol (55a). N-Alkoxyphthalimide 53a (62 mg, 0.18 mmol) was
subjected to general cyclization procedure A. Purification with the
general procedure and finally by flash column chromatography (4:1
hexanes/EtOAc) afforded 55a as a colorless oil (42 mg, 74%, ratio
53:45:2). IR (neat): 3404, 2917, 2865, 1713, 1456, 1273, 1069, 1021,
704 cm−1; 1H NMR (400 MHz, CDCl3): δ = 7.31−7.15 (m, 5 H), 5.01
(d, J = 5.5 Hz, 0.02 H), 4.95 (d, J = 7.0 Hz, 0.44 H), 4.43−4.36 (m, 0.02
H), 4.36−4.29 (m, 0.09 H), 4.26 (d, J = 8.5 Hz, 0.5 H), 4.22−4.14 (m,
0.39 H), 4.12−4.03 (m, 0.4 H), 3.84−3.75 (m, 0.42 H), 3.73−3.63 (m, 1
H), 3.62−3.54 (m, 0.42 H), 3.51 (td, J = 6.0, 11.7 Hz, 0.14 H), 2.55 (spt,
J = 7.2 Hz, 0.45 H), 2.21−1.89 (m, 2.45 H), 1.77−1.66 (m, 0.51 H),
1.55−1.45 (m, 0.09 H), 1.45−1.33 (m, 0.47 H), 0.95 (d, J = 6.1 Hz, 1.6
H), 0.56 (d, J = 7.0 Hz, 0.12 H), 0.54−0.49 (m, 1.33 H); 13C NMR (100
MHz, CDCl3): δ = 140.7, 140.1, 128.4, 128.4, 127.9, 127.8, 127.1, 126.5,
126.4, 126.3, 88.7, 87.7, 83.9, 79.6, 79.1, 78.3, 65.8, 65.3, 65.2, 43.8, 42.0,
37.6, 36.8, 36.2, 35.4, 16.6, 16.2, 15.3; HRMS-ESI (m/z): calcd. for
C12H16NaO2 [M + Na]+: 215.1048, found 215.1046.
104.2, 79.8, 71.3, 66.0, 34.9, 26.8, 19.2; HRMS-ESI (m/z): calcd. for
C22H28NaSiO2 [M + Na]+:375.1756, found 375.1753.
tert-Butyl((4,5-dimethyltetrahydrofuran-2-yl)methoxy)diphenyl-
silane (55e). N-Alkoxyphthalimide 53e (250 mg, 0.91 mmol) was
subjected to general cyclization procedure C. To the crude mixture were
sequentially added imidazole (116 mg, 1.7 mmol) and then tert-
butyldiphenylsilyl chloride (370 mg, 1.36 mmol), and the mixture was
stirred overnight. The solvent was evaporated, and the residue was
dissolved in Et2O (50 mL). The organic layer was washed with brine (20
mL), dried over Na2SO4, and concentrated using rotary evaporation.
The crude product was purified using flash column chromatography
(30:1 hexanes/Et2O) to afford 55e (major isomer) as a colorless oil (200
mg, 62%, two steps, ratio 93:7 mixture of isomers). IR (neat): 2965,
2921, 2843, 1469, 1426, 1378, 1265, 1113, 830, 795, 739, 704 cm−1; 1H
NMR (400 MHz, C6D6): δ = 7.90−7.81 (m, 4 H), 7.26−7.21 (m, 6 H),
4.04−3.95 (m, 1 H), 3.92 (quin, J = 6.5 Hz, 1 H), 3.81−3.73 (m, 2 H),
2.01−1.89 (m, 1 H), 1.78 (td, J = 7.2, 12.3 Hz, 1 H), 1.28 (td, J = 8.0, 12.4
Hz, 1 H), 1.20 (s, 9 H), 1.03 (d, J = 6.4 Hz, 3 H), 0.73 (d, J = 7.0 Hz, 3
H); 13C NMR (100 MHz, CDCl3): δ = 135.7, 135.7, 133.8, 133.7, 129.5,
127.6, 78.8, 77.6, 67.0, 36.2, 35.9, 26.8, 19.2, 16.8, 14.9; HRMS-ESI (m/
z): calcd. for C23H32NaSiO2 [M + Na]+:391.2069, found 391.2064.
tert-Butyl((5-methyl-4-methylenetetrahydrofuran-2-yl)methoxy)-
diphenylsilane (55f). N-Alkoxyphthalimide 53f (100 mg, 0.36 mmol)
was subjected to general cyclization procedure A. To the crude mixture
were sequentially added imidazole (49 mg, 0.73 mmol) and then tert-
butyldiphenylsilyl chloride (120 mg, 0.44 mmol), and the mixture was
stirred overnight. The solvent was evaporated, and the residue was
dissolved in Et2O (30 mL). The organic layer was washed with brine (20
mL) and dried over Na2SO4, and concentrated using rotary evaporation.
The crude product was purified using flash column chromatography
(25:1 hexanes/EtOAc) to afford 55f as a colorless oil (60 mg, 25%, two
steps, cis:trans = 85:15). IR (neat): 2982, 2926, 1791, 1734, 1473, 1382,
(4-Methylene-5-phenyltetrahydrofuran-2-yl)methanol (55b). N-
Alkoxyphthalimide 53b (70 mg, 0.21 mmol) was subjected to general
cyclization procedure A. Solvent was evaporated and the mixture was
purified by flash column chromatography (4:1 hexanes/EtOAc) to
afford 55b as a colorless oil (28 mg, 70%, cis:trans > 95:5). IR (neat):
3391, 2921, 1717, 1447, 1260, 1095, 1026, 800,700 cm−1; 1H NMR (400
MHz, C6D6): δ = 7.33−7.27 (m, J = 6.8 Hz, 2 H), 7.21−7.00 (m, 3 H),
5.11 (s, 1 H), 4.82 (q, J = 2.2 Hz, 1 H), 4.60 (q, J = 2.0 Hz, 1 H), 3.92−
3.82 (m, 1 H), 3.59 (ddd, J = 3.1, 6.4, 11.7 Hz, 1 H), 3.41 (td, J = 5.9, 11.4
Hz, 1 H), 2.45−2.33 (m, 1 H), 2.21 (dd, J = 6.4, 15.6 Hz, 1 H), 1.56 (t, J
= 6.5 Hz, 1 H); 13C NMR (100 MHz, CDCl3): δ = 151.3, 141.0, 128.5,
1
1269, 1182, 1108, 1030, 991,882, 708 cm−1; H NMR (400 MHz,
C6D6):δ = 7.87−7.78 (m, 4 H), 7.25−7.20 (m, 6 H), 4.85−4.79 (m, 1
L
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H), 4.69 (q, J = 2.1 Hz, 1 H), 4.56−4.47 (m, 0.17 H), 4.32 (s, 0.80 H),
4.16 (s, 0.17 H), 3.98 (tdd, J = 4.5, 6.7, 8.7 Hz, 0.82 H), 3.80−3.72 (m,
1.67 H), 3.68 (dd, J = 3.5, 4.7 Hz, 0.31 H), 2.47−2.35 (m, 1.82 H), 2.35−
2.31 (m, 0.17 H), 1.27 (d, J = 6.4 Hz, 2.55 H), 1.23 (d, J = 6.4 Hz, 0.89
H), 1.18 (s, 7.4 H), 1.17 (s, 2.1 H); 13C NMR (100 MHz, CDCl3): δ =
152.7, 135.7, 135.6, 135.6, 133.7, 133.6, 129.6, 129.6, 127.6, 127.6, 104.2,
104.1, 78.1, 77.2, 77.2, 66.1, 66.1, 35.4, 34.8, 26.8, 20.8, 20.5, 19.3;
HRMS-ESI (m/z): calcd. forC15H30NaO2Si [M + Na]+: 293.1913,
found 293.1913.
−5.41, −5.44; HRMS-ESI (m/z): calcd. for C17H37Si2O2 [M + H]+:
329.2332, found 329.2327.
2-(Benzyloxy)pent-4-en-1-yl-4-methylbenzenesulfonate (69a). To
a stirring solution of 2-(benzyloxy)pent-4-en-1-ol50 (170 mg, 0.88
mmol) in dry CH2Cl2 (5 mL) were sequentially added para-
toluenesulfonyl chloride (202 mg, 1.06 mmol) and then triethylamine
(0.24 mL, 1.76 mmol). The resulting solution was stirred overnight.
H2O (5 mL) was added, and the reaction mixture was stirred for another
10 min. The organic layer was washed with aqueous saturated aq.
NaHCO3 (5 mL), H2O (5 mL), and brine (5 mL) and dried over
Na2SO4. The organic layer was filtered and concentrated by rotary
evaporation. The product was purified by flash column chromatography
(10:1 hexanes/EtOAc) to yield the title compound (69a) as a colorless
oil (254 mg, 83%). IR (neat): 2926, 1726, 1595, 1447, 1356, 1173, 1091,
978, 913, 813 cm−1; 1H NMR (400 MHz, CDCl3): δ = 7.75 (d, J = 7.9
Hz, 2H), 7.31−7.22 (m, 7H), 5.75−5.65 (m, 1H), 5.05 (d, J = 5.8 Hz,
1H), 5.01 (s, 1H), 4.50 (s, 2 H), 4.07−3.97 (m, 2 H), 3.65 (quin, J = 5.5
Hz,1H), 2.41 (s, 3 H), 2.27 (t, J = 6.5 Hz,2H); 13C NMR (100 MHz,
CDCl3): δ = 144.8, 137.9, 133.0, 132.9, 129.8, 128.3, 127.9, 127.7, 127.7,
118.2, 75.9, 72.0, 70.9, 35.6, 21.6; HRMS-ESI (m/z): calcd. for
C19H22NaSO4 [M + Na]+: 369.1137, found 369.1131.
Synthesis of (R)-1-((tert-Butyldiphenylsilyl)oxy)-5-(triethylsilyl)-
pent-4-yn-2-ol (72). To a solution of triethylsilylacetylene (3.45 g,
24.1 mmol) in dry THF (70 mL) at −78 °C was added a solution of
butyllithium (1.6 M in hexane, 15 mL, 24.1 mmol) dropwise over 10
min. The solution was stirred for an additional 10 min at −78 °C. Boron
trifluoride diethyl etherate (3.0 mL, 3.43 g, 24.1 mmol) was added
dropwise over 5 min, and the solution was stirred for an additional 20
min. A solution of epoxide 7151 (5.0 g, 16.1 mmol) in anhydrous THF
(30 mL) was then added dropwise over 10 min. The resulting mixture
was stirred for 2 h at −78 °C. The reaction was quenched with saturated
aqueous NH4Cl (25 mL) and extracted with EtOAc (3 × 25 mL). The
combined organic extracts were washed with brine (25 mL), dried over
Na2SO4, concentrated by rotary evaporation, and purified by flash
chromatography (20:1 hexanes/EtOAc) to afford alcohol 72 (with trace
amounts of EtOAc) as a colorless oil (6.47 g, 88%). [α]2D1 − 10.5 (c 1.56,
CHCl3); IR (neat): 3447, 3069, 3043, 2956, 2926, 2869, 2173, 1469,
1421, 1260, 1113, 1004, 821, 739, 695, 621 cm−1; 1H NMR (400 MHz,
CDCl3): δ = 7.68 (d, J = 7.5 Hz, 4 H), 7.50−7.35 (m, 6 H), 3.90 (sxt, J =
5.6 Hz, 1 H), 3.81 (dd, J = 4.4, 10.2 Hz, 1 H), 3.72 (dd, J = 6.1, 9.9 Hz, 1
H), 2.62−2.48 (m, 3 H), 1.09 (s, 9 H), 0.95 (t, J = 7.9 Hz, 9 H), 0.55 (q, J
= 7.7 Hz, 6 H); 13C NMR (100 MHz, CDCl3): δ = 135.5, 135.5, 133.1,
133.1, 129.8, 127.8, 103.5, 84.4, 70.3, 66.4, 26.8, 24.7, 19.3, 7.4, 4.4;
HRMS-ESI (m/z): calcd. for C27H40NaSi2O2 [M + Na]+: 475.2465,
found 475.2470.
Synthesis of (R)-2-(4-(Trityloxy)butoxy)pent-4-yn-1-ol (74). To a
suspension of sodium hydride (60 wt % dispersion in mineral oil, 247
mg, 6.18 mmol) in anhydrous DMF (12 mL) was added 72 (1.87 g, 4.12
mmol) in anhydrous DMF (2 mL). This solution was stirred for 1 h at
ambient temperature. 4-(Trityloxy)butyl-4-methylbenzenesulfonate52
(2.06 g, 4.12 mmol) in anhydrous DMF (10 mL) was added dropwise in
60 min. The resulting solution was stirred overnight. The reaction was
quenched with H2O (25 mL), and the aqueous layer was extracted with
Et2O (3 × 30 mL). The combined organic extracts were washed with
brine (15 mL), dried over Na2SO4, and concentrated by rotary
evaporation. The crude product was used in the next step without
further purification. To a solution of the resulting mixture in anhydrous
THF (20 mL) was added tetrabutylammonium fluoride (1.0 M in THF,
6.8 mL, 6.8 mmol), and the reaction was stirred for 12 h. The reaction
was quenched with saturated aqueous NH4Cl (10 mL) and extracted
with Et2O (3 × 20 mL). The combined organic extracts were washed
with brine (20 mL), dried over Na2SO4, and concentrated using rotary
evaporation. Purification by flash column chromatography (5:1
hexanes/EtOAc) afforded alcohol 74 as a clear oil (440 mg, 48% over
2 steps). [α]2D1 − 4.5 (c 1.23, CHCl3); IR (neat): 3430, 3295, 3086, 3052,
3021, 2921, 2860, 1491,1443, 1213, 1073, 752, 708, 634 cm−1; 1H NMR
(400 MHz, C6D6): δ = 7.56 (d, J = 7.5 Hz, 6 H), 7.14 (t, J = 7.9 Hz, 6 H),
7.08−7.00 (m, 3 H), 3.63−3.45 (m, 2 H), 3.27−3.17 (m, 2 H), 3.16−
3.03 (m, 3 H), 2.18 (dd, J = 2.7, 6.5 Hz, 2 H), 1.70 (t, J = 2.7 Hz, 1 H),
1.68−1.46 (m, 5 H); 13C NMR (100 MHz, C6D6): δ = 145.4, 129.5,
3-Vinyl Hexanol (60). To a solution of methyl 3-vinylhexanoate49
(174 mg, 1.1 mmol, 1 equiv) in Et2O (11 mL) cooled to 0 °C (ice/water
bath) was added lithium aluminum hydride (64 mg, 1.7 mmol, 1.5
equiv) in small portions over 30 s. The gray suspension was stirred for 30
min, and then quenched with the slow addition of Na2SO4 decahydrate
(1 g) over 3 min (violent bubbling observed during quenching). The
suspension was filtered through a plug of MgSO4, and the solids were
washed with Et2O (5 × 40 mL). The combined organic extracts were
concentrated by rotary evaporation to yield 100 mg (70%) of alcohol 60
as a colorless oil. IR (neat): 3331, 3076, 2958, 2930, 1640, 1466, 1458,
1
1419, 1379, 1046, 995, 912 cm−1; H NMR (400 MHz, C6D6): δ =
5.49−5.32 (m, 1H), 4.94 (s, 1H), 4.93−4.88 (m, 1H), 3.47−3.33 (m,
2H), 2.12−1.96 (m, 1H), 1.51−1.40 (m, 1H), 1.36−1.07 (m, 5H), 0.86
(t, J = 7.0 Hz, 3H), 0.64 (bs, 1H); 13C NMR (100 MHz, C6D6): δ =
143.6, 115.0, 61.2, 41.3, 38.6, 38.0, 20.9, 14.6; HRMS-ESI (m/z): [M +
H]+ calcd for C8H17O: 129.1279, found: 129.1277.
Synthesis of 2-(3-Vinylhexyloxy)isoindoline-1,3-dione (61). To 3-
vinyl hexanol 60 (98 mg, 0.77 mmol, 1.0 equiv) were added N-
hydroxyphthalimide (189 mg, 1.16 mmol, 1.5 equiv), triphenyl-
phosphine (301 mg, 1.16 mmol, 1.5 equiv), and THF (7.7 mL). The
solution was cooled to 0 °C (ice/water bath), and diisopropylazodi-
carboxylate (280 mL, 1.4 mmol, 1.8 equiv) was added dropwise over 10
min. The colorless solution turned to an orange-red solution during
addition. The reaction was stirred for 18 h and allowed to warm to
ambient temperature. The light-yellow solution was poured into Et2O
(75 mL), and washed with 50% saturated aq. NaHCO3 (2 × 25 mL) and
brine (25 mL). The yellow organic extract was dried over Na2SO4,
filtrated, and concentrated by rotary evaporation to provide a yellow oil.
Purification by flash chromatography (7:2 hexanes:Et2O), followed by
crystallization from cold pentanes (−10 °C), yielded two crops of N-
alkoxyphthalimide 61 (156 mg combined, 74%) as fluffy white needles.
mp 44−45.5 °C; IR (CHCl3): 3683, 3621, 1790, 1732, 1468, 1188, 878,
703 cm−1; 1H NMR (400 MHz, C6D6): δ = 7.30 (dd, J = 5.4, 3.0 Hz,
2H), 6.80 (dd, J = 5.4, 3.0 Hz, 2H), 5.41−5.26 (m, 1H), 5.10 (dd, J =
17.1, 1.8 Hz, 1H), 4.99 (dd, J = 10.3, 1.8 Hz, 1H), 4.29−3.90 (m, 2H),
2.41−2.13 (m, 1 H), 1.88−1.74 (m, 1H), 1.55−1.40 (m, 1H), 1.38−1.06
(m, 4H), 0.85 (t, J = 7.0 Hz, 1H); 13C NMR (100 MHz, C6D6): δ =
163.7, 142.5, 134.1, 129.8, 123.4, 116.0, 77.1, 40.9, 37.8, 33.9, 20.9, 14.6;
HRMS-ESI (m/z): [M + Na]+ calcd for C16H19NO3Na: 296.1263,
found: 296.1265.
1-((tert-Butyldimethylsilyl)oxy)-5-(triethylsilyl)pent-4-yn-2-ol
(66b). To a solution of triethylsilylacetylene (1.11 g, 7.95 mmol) in dry
THF (20 mL) at −78 °C was added a solution of butyllithium (1.6 M in
hexanes, 5.0 mL, 7.95 mmol) dropwise over 10 min. The solution was
stirred for an additional 30 min at −78 °C. Boron trifluoride diethyl
etherate (1.0 mL, 1.13 g, 7.95 mmol) was added dropwise over 5 min,
and the solution was stirred for another 20 min. A solution of tert-
butyldimethyl(oxiran-2-ylmethoxy)silane (1.0 g, 5.3 mmol) in anhy-
drous THF (2.6 mL) was then added dropwise over 5 min. The resulting
mixture was stirred for 1 h. The reaction was quenched with saturated
aq. NH4Cl (25 mL) and extracted with EtOAc (3 × 25 mL). The
combined organic extracts were washed with brine (25 mL), dried over
Na2SO4, concentrated by rotary evaporation, and purified by flash
chromatography (20:1 hexanes/EtOAc) to afford 1-((tert-butyl-
dimethylsilyl)oxy-5-(triethylsilyl)pent-4-yn-2-ol as a colorless oil (1.44
g, 83%). IR (neat): 3421, 2956, 2873, 2169, 1460, 1265, 1121, 1017,
852, 817, 773, 717 cm−1; 1H NMR (400 MHz, CDCl3): δ = 3.74−3.63
(m, 2H), 3.64−3.68 (m, 1H), 2.43−2.56 (m, 3H), 0.99 (t, J = 8.0 Hz, 9
H), 0.92 (s, 9 H), 0.59 (q, J = 8.0 Hz, 6 H), 0.09 (s, 6H); 13C NMR (100
MHz, CDCl3): δ = 103.7, 84.3, 70.2, 65.4, 25.8, 24.5, 18.3, 7.45, 4.43,
M
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128.4, 127.5, 87.2, 81.3, 79.0, 70.8, 69.9, 64.1, 63.9, 27.5, 27.4, 21.1;
HRMS-ESI (m/z): calcd. for C28H30NaO3 [M + Na]+: 437.2093, found
437.2102.
(3) For a synthesis of (−)-amphidinolide K, see: Ko, H. M.; Lee, C. W.;
Kwon, H. K.; Chung, H. S.; Choi, S. Y.; Chung, Y. K.; Lee, E. Angew.
Chem., Int. Ed. 2009, 48, 2364−2366.
(R)-2-((2-(4-(Trityloxy)butyoxy)pent-4-yn-1-yl)oxy)isoindoline-
1,3-dione (75). To the alcohol 74 (100 mg, 0.24 mmol) in dry THF (2
mL) were sequentially added triphenylphosphine (90 mg, 0.34 mmol)
and N-hydroxyphthalimide (55 mg, 0.34 mmol). The solution was
stirred until the solids were dissolved, at which point diisopropylazo-
dicarboxylate (83 mg, 0.41 mmol) was added dropwise via syringe pump
(0.8 mL/h). The resulting yellow solution was stirred overnight at
ambient temperature, and was then quenched with H2O (2 mL). The
aqueous layer was extracted with EtOAc (3 × 10 mL), and the combined
organic extracts were washed with aq. NaHCO3 (3 × 10 mL) and brine
(10 mL) and were dried over Na2SO4. The organics were concentrated
using rotary evaporation and purified by flash column chromatography
(5:1 hexanes/EtOAc) to provide N-alkoxyphthalimide 75 as a colorless
oil (107 mg, 80%). [α]2D1 − 6.5 (c 2.56, CHCl3); IR (neat): 3282, 2947,
2865, 1800, 1730, 1443, 1373, 1186, 1078, 1078, 1008, 878, 704 cm−1;
1H NMR (400 MHz, CDCl3): δ = 7.85−7.79 (m, 2 H), 7.73−7.69 (m, 2
H), 7.45−7.39 (m, 6 H), 7.32−7.27 (m, 5 H), 7.25−7.19 (m, 3 H),
4.39−4.26 (m, 2 H), 3.86−3.78 (m, 1 H), 3.60−3.51 (m, 2 H), 3.01 (t, J
= 5.6 Hz, 2 H), 2.61−2.54 (m, 2 H), 1.99 (t, J = 2.7 Hz, 1 H), 1.61 (d, J =
5.8 Hz, 4 H); 13C NMR (100 MHz, CDCl3): δ = 163.3, 144.4, 134.4,
128.9, 128.7, 127.7, 126.8, 123.5, 86.2, 79.9, 78.7, 75.8, 70.5, 69.9, 63.1,
26.7, 26.5, 21.0; HRMS-ESI (m/z): calcd. for C36H33NaNO5 [M +
Na]+: 582.2256, found 582.2249.
((2R,5R)-4-Methylene-5-(3-trityloxy)propyl)tetrahydrofuran-2-yl)-
methanol (76). N-Alkoxyphthalimide 75 (170 mg, 0.30 mmol) was
subjected to general cyclization procedure C. Solvent was evaporated,
and the mixture was purified by flash column chromatography (3:2
hexanes/Et2O) afforded 76 as a colorless oil (78 mg, 60%, cis:trans >
95:5). [α]2D1 + 8.65 (c 10.5, CHCl3); IR (neat): 3413, 2965, 2917, 2847,
1737, 1447, 1265, 1073 cm−1; 1H NMR (400 MHz, C6D6): δ = 7.60−
7.56 (m, 6 H), 7.12 (t, J = 7.5 Hz, 6 H), 7.06−7.00 (m, 3 H), 4.78 (q, J =
2.0 Hz, 1 H), 4.67 (q, J = 2.3 Hz, 1 H), 4.20−4.15 (m, 1 H), 3.74−3.67
(m, 1 H), 3.55−3.48 (m, 1 H), 3.34−3.26 (m, 1 H), 3.21 (t, J = 6.4 Hz, 2
H), 2.28−2.18 (m, 1 H), 2.09 (dd, J = 6.1, 15.8 Hz, 1 H), 1.96−1.84 (m,
1 H), 1.82−1.66 (m, 2 H), 1.62−1.44 (m, 2 H); 13C NMR (100 MHz,
C6D6): δ = 152.3, 145.4, 129.5, 128.3, 127.5, 104.9, 87.3, 81.4, 78.9, 64.8,
64.3, 35.1, 32.7, 26.9; HRMS-ESI (m/z): calcd. for C28H30NaO3 [M +
Na]+: 437.2093, found 437.2102.
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ASSOCIATED CONTENT
■
S
* Supporting Information
Complete characterization analysis and 1H and 13C spectral data
is included in the Supporting Information. This material is
available free of charge via the Internet at http://pubs.acs.org.
(12) For a review on the reactivity of alkoxy radicals, see: Hartung, J.;
Gottwald, T.; Spehar, K. Synthesis 2002, 1469−1498.
(13) For other examples of the use of alkoxy radicals to initiate relay
̌
̌
cyclizations, see: (a) Cekovic, Z.; Ilijev, D. Tetrahedron Lett. 1988, 29,
́
AUTHOR INFORMATION
Corresponding Author
*E-mail: gsammis@chem.ubc.ca (G.M.S.).
1441−1444. (b) Rawal, V. H.; Newton, R. C.; Krishnamurthy, V. J. Org.
Chem. 1990, 55, 5181−5183.
■
(14) (a) Kim, S.; Lee, T. A.; Song, Y. Synlett 1998, 471−472.
(b) Okada, K.; Okamoto, K.; Oda, M. J. Am. Chem. Soc. 1998, 110,
8736−8738. (c) Barton, D. H. R.; Blundell, P.; Jaszberenyl, J. C.
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21, 249−258.
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W. J. Am. Chem. Soc. 1988, 110, 5900−5902. (b) Curran, D. P.; Shen, W.
J. Am. Chem. Soc. 1993, 115, 6051−6059.
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(19) For a representative study examining the bond strength of C−H
bonds α to oxygen, see: Cruickshank, F. R.; Benson, S. W. J. Am. Chem.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the University of British Columbia,
the Natural Sciences and Engineering Research Council of
Canada (NSERC), and a doctoral fellowship from NSERC to
J.C.T.L. We also thank Prof. Ciufolini for helpful discussions. We
would also like to thank C. Chatalova Sazepin and M. Rueda
Becerril for assistance with manuscript preparation.
REFERENCES
■
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N
DOI: 10.1021/jo502499a
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The Journal of Organic Chemistry
Article
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O
DOI: 10.1021/jo502499a
J. Org. Chem. XXXX, XXX, XXX−XXX