Regioselective and stereoselective cyclizations of cyclohexadienones tethered to active methylene groups

Article abstract of DOI:10.1039/c1ob06125a

The cyclization of 2,5-cyclohexadienones tethered to activated methylene groups was studied. The substitution around the cyclohexadienone ring serves to regioselectively direct these cyclizations based primarily on electronic effects. In the case of brominated substrates, these reactions proceed to give highly unusual electron-deficient tricyclic cyclopropanes. By using a Cinchona alkaloid-based phase-transfer catalyst, prochiral cyclohexadienones can be desymmetrized with moderate stereoselectivity.

Full text of DOI:10.1039/c1ob06125a

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PAPER
Regioselective and stereoselective cyclizations of cyclohexadienones tethered
to active methylene groups†
Rodolfo Tello-Aburto, Kyle A. Kalstabakken, Kelly A. Volp and Andrew M. Harned*
Received 8th July 2011, Accepted 9th August 2011
DOI: 10.1039/c1ob06125a
The cyclization of 2,5-cyclohexadienones tethered to activated methylene groups was studied. The
substitution around the cyclohexadienone ring serves to regioselectively direct these cyclizations based
primarily on electronic effects. In the case of brominated substrates, these reactions proceed to give
highly unusual electron-deficient tricyclic cyclopropanes. By using a Cinchona alkaloid-based
phase-transfer catalyst, prochiral cyclohexadienones can be desymmetrized with moderate
stereoselectivity.
to be demonstrated for oxidations that occur at the para-position
(i.e., for the synthesis of 2,5-cyclohexadienones).
Our group has recently reported a Pd-catalyzed cyclization
Introduction
Cyclohexadienones are highly useful synthetic intermediates:1
of alkyne-tethered cyclohexadienones.10 During this work, we
found that the cyclization of chiral, albeit racemic, substrates
proceeds with predictable regioselectivity. We concluded that
this regioselectivity was primarily due to steric effects and that
the vinyl Pd intermediate generated during the reaction would
preferentially bind to the less hindered C–C double bond. We
questioned whether this same regioselectivity would be observed
if the cyclization was changed such that an anionic intermediate
was employed. Additionally, we were interested in the extension
of this cyclization to include the desymmetrization of prochiral
substrates by using a chiral phase-transfer catalyst (PTC). The
desymmetrized products would allow access to bicyclic lactones
that are found in natural products such as sorbicillactone A11
and 5-bromoochrephilone12 (Fig. 1). Herein we report our ef-
forts aimed at studying the reaction scope and regioselectivity
of intramolecular cyclizations of cyclohexadienones tethered to
their ease of preparation from phenols and their versatile reactivity
make them attractive intermediates for natural product synthesis2
and drug discovery efforts.3 Despite the progress that has been
made investigating the reactivity of this class of compounds, there
are still several areas that need further development. For instance,
the influence of various substituents on the regioselectivity of
conjugate additions into the dienone moiety has not been the
subject of systematic work. While examples of regioselective
conjugate additions do exist,4 the underlying factors responsible
for selectivity are often unclear. Gaining additional insight into
this matter will undoubtedly prove useful for synthetic planning.
Another area that has seen only limited work is the enantiose-
lective desymmetrization5 of prochiral cyclohexadienones.6 Such
reactions are attractive for several reasons. The desymmetrization
event will not only set the configuration of the fully substituted
carbon atom, but under most circumstances will also result in
the concomitant installation of a second contiguous stereocenter
(and possibly more). Additionally, the symmetry-breaking event
will leave behind an enone moiety that can be engaged in
further synthetic manipulations.7 Lastly, the desymmetrization of
2,5-cyclohexadienones could serve as a solution to the problems
associated with the direct enantioselective dearomatization of
phenols. While progress has been made in carrying out enantiose-
lective oxidations at the ortho-position,8,9 these methods have yet
Department of Chemistry, University of Minnesota, 207 Pleasant St SE,
Minneapolis, MN, USA, 55455. E-mail: harned@umn.edu; Fax: +1 (612)
626-7541; Tel: +1 (612) 625-1036
† Electronic supplementary information (ESI) available: optimization of
desymmetrization reaction, synthesis and characterization data for all
compounds, copies of 1H and 13C NMR spectra, chiral HPLC traces
for enantioenriched products, and crystallographic data for 12r. CCDC
reference numbers 837018. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c1ob06125a
Fig. 1 Desymmetrization of EWG-tethered cyclohexadienones and po-
tential synthetic targets.
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Table 1 Preparation of substratesa
Entry
Quinol
R1
H
R2
H
R3
R4
H
Method (yield)
Ester
EWG
Method (yield)
1
2
3
4
2
3
4a
5
CO2allyl
CO2Bn
CO2t-Bu
B (66%)
B (63%)
B (43%)
C (96%)
14
1a
Me
—
5
6
C (57%)b
15
6
7
8
9
10
11
1b
1c
1d
1e
1f
H
H
H
H
H
H
H
H
H
H
H
H
Ph
i-Pr
CH2CO2Me
CH2C(CH3)3
CH2CH2OTBS
H
H
H
H
H
H
—
4b
4c
4d
4e
4f
CO2t-Bu
CO2t-Bu
CO2t-Bu
CO2t-Bu
CO2t-Bu
CO2t-Bu
B (36%)
B (56%)
B (38%)
C (>99%)
C (74%)
C (50%)
A16 (73%)
A17 (40%)
A (31%)
18
—
1g
A (37%)
4g
12
13
14
15
16
17
18
19
20
21
22
23
1h
1i
Me
SiMe3
Me
Me
H
SiMe3
H
H
Me
Br
H
H
OMe
H
Me
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
i-Pr
Me
SiMe3
H
H
H
A14 (78%)
Ac (67%)
A (80%)
A (74%)
A (48%)
Ac (51%)
A (76%)
A (74%)
A (51%)
4h
4i
CO2t-Bu
CO2t-Bu
CO2t-Bu
CO2t-Bu
CO2t-Bu
CO2t-Bu
CO2t-Bu
CO2t-Bu
CO2t-Bu
CO2t-Bu
CO2t-Bu
CO2t-Bu
C (>99%)
C (86%)
C (98%)
C (95%)
C (73%)
C (82%)
B (69%)
C (96%)
C (55%)
C (>99%)
C (95%)
C (81%)
1j
4j
1k
1l
4k
4l
1m
1n
1o
1p
1q
1r
1s
H
4m
4n
4o
4p
4q
4r
4s
H
Br
Br
Br
Br
Br
Br
Me
OMe
H
H
H
19
—
A (78%)
A (74%)
Br
Br
24
1t
Br
H
CH2CH2OTBS
Br
Ac (42%)
4t
CO2t-Bu
C (96%)
a Method A: PhI(OAc)2, CH3CN, H2O. Method B: HO2CCH2EWG, TFAA, then 1, DME. Method C: DCC, DMAP, 1, CH2Cl2. All yields are following
purification using silica gel chromatography. See experimental section for more details. b After oxidation of the corresponding sulfide. c Acetone–H2O
used as solvent.
activated methylene groups and our initial efforts aimed at the
desymmetrization of cyclohexadienones with a chiral PTC.
(entries 1, 2, 3) as well as other electron-withdrawing groups such
as amides (entry 4) and sulfones (entry 5).
Cyclization of symmetric substrates
Results and discussion
Despite the base sensitivity that cyclohexadienones generally
exhibit,1a the cyclization of the para-substituted‡ dienones 2, 3,
4a–4g, 5, and 6 proceeded well with Cs2CO3 in CH3CN (Scheme
1). Even in cases where steric problems might arise (e.g., 4c, 4e, and
4g), cyclization occurred efficiently. Substrate 4d is also notable, as
the potential problem of tertiary carboxylate elimination was not
observed. In all cases, the bicyclic lactone product was isolated as
a single diastereomer. The cis-fused ring system was confirmed by
NOE experiments on 7 and 9h (see the ESI for details†), while the
configuration of the stereocenter bearing the electron-withdrawing
group was assigned through coupling constant analysis. At this
Substrate synthesis
All substrates used for our studies were prepared in two steps from
the corresponding phenols; PhI(OAc)2 oxidation was followed by
coupling of the resulting quinols to malonic acid monoesters
or other activated methylene compounds. This was initially
accomplished with a trifluoroacetic anhydride-mediated coupling
of the tertiary alcohol with the malonic acid monoester;13 however,
the use of DCC was later found to be more convenient and
cost effective, particularly on larger scales. These reactions are
applicable to a wide range of substrates (Table 1), including those
with sterically demanding R3 substituents (entries 7, 9, 11, 22,
23). Malonates with orthogonal protecting groups are tolerated
‡ For substitution patterns around the cyclohexadienones, we utilize
nomenclature from the corresponding phenols.
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Scheme 1 Cyclization of symmetric substrates.
Scheme 2 Regioselective cyclizations.
time, it is not clear if a second diastereomer also forms during
the reaction and then epimerizes under the reaction or isolation
conditions.
ortho-Disubstituted cyclohexadienones also underwent cycliza-
tion successfully. In the case of 4h, the product 9h contains four
contiguous stereocenters and was formed as a single diastereomer.
Although disilane 4i did cyclize successfully, the product contained
only one trimethylsilyl group. This is not surprising as a-silyl
ketones are known to undergo facile protodesilylation.20
synthesis of sorbicillactone A21) in high yield. This result can
most simply be explained by electronic effects, as one olefin of
the cyclohexadienone can be considered to be a vinylogous ester
and, consequently, less electrophilic.
The methylated substrates 4k and 4l cyclized with very good
regioselectivity, but also raised questions as to whether this effect
is electronic or steric in nature. Compound 4k, with the methyl
group a to the ketone, cyclized with a regioselectivity of 9 : 1.
This is in agreement with an observation made by Giomi and co-
workers concerning the addition of diethyl malonate to an ortho-
methyl-substituted dienone.22 Higher regioselectivity (12 : 1) was
observed in the cyclization of 4l to 9l, where the methyl group
is in the b position. This dependence could easily be attributed
to steric effects; however, an electronic argument involving the
weakly electron-donating nature of methyl substituents should
not be discounted.
Regioselective cyclizations
We were interested in examining the influence of various sub-
stituents on the regioselectivity of these anionic reactions (Scheme
2). The cyclization of meta-methoxy substrate 4j was completely
regioselective and afforded 9j (an intermediate used in our
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Scheme 3 Cyclization of brominated substrates.
Scheme 4 Cyclization of 4p.
Finally, we chose to investigate vinyl silane 4m. Considering a
purely steric model, the increased bulk of the trimethylsilyl group
in 4m as compared to the methyl group in 4k should increase
selectivity. Similarly, the lower group electronegativity of SiMe3
(2.06)23 relative to CH3 (~2.3)24 would also be expected to give rise
to higher regioselectivity. However, the cyclization of 4m actually
afforded product 9a as the major product (6.6 : 1 ratio of 9a and
9i). In this case, compound 9a is the product of conjugate addition
onto the silicon-bearing olefin, followed by protodesilylation.
This reversal in selectivity can be attributed to silicon’s ability to
stabilize an adjacent negative charge,25 while the aforementioned
electronegativity difference likely explains why complete selectivity
is not observed.
complete regioselectivity. We did not observe any products arising
from addition into the less substituted double bond in 4n. Sim-
ilarly, substrate 4o cyclized to give cyclopropane 12o exclusively.
This cyclopropanation could also be extended to the symmetric
dibromides 4q–4t.
Interestingly, while the cyclization of 4p proceeded well, it was
noticeably slower than the reaction of 4n and 4o. If the reaction
of 4p was terminated early, bromide 9p could be isolated as a
single diastereomer (Scheme 4). The configuration of the bromine-
bearing stereocenter in 9p does not allow for backside attack by the
malonate. By resubjecting bromide 9p to the reaction conditions
(or allowing 4p to react overnight), the complete reaction can be
realized. Presumably, this occurs by epimerization of the relevant
stereocenter. The slow epimerization of 9p might be related to
the pKa difference between the a-bromoenones (e.g., 7n) formed
during the reactions in Scheme 3 and the a-bromovinylogous ester
contained in 9p.
Cyclization of brominated substrates
If the regioselectivity observed during the cyclizations described in
the previous section was indeed strongly influenced by electronic
effects, then it stands to reason that the presence of an electron-
withdrawing group on the cyclohexadienone should reverse the
observed regioselectivity. In other words, an anionic nucleophile
should preferentially attack the olefin bearing the electron-
withdrawing group. We found bromine to be particularly attractive
in that it is easily installed, usually has a positive impact in terms
of chemical yield on the oxidative dearomatization step, and serves
as a useful handle for further synthetic transformations.
When the bromine-containing substrate 4n was subjected to
our cyclization conditions, the tricyclic cyclopropane 12n was
obtained (Scheme 3). While this was an unexpected outcome,
there have been numerous examples in the literature of similar
cyclopropanations.26,27 Importantly, the conjugate addition re-
quired to initiate the cyclopropanation pathway occurred with
Cyclizations with Cinchona alkaloid catalysts
Recognizing that the symmetric dienones discussed above contain
enantiotopic olefins, we hypothesized that a chiral phase-transfer
catalyst might be able to desymmetrize these prochiral compounds.
Asymmetric phase-transfer catalysis has proven to be a valuable
tool for constructing enantioenriched products.28 However, to the
best of our knowledge, there have been no examples of enantios-
elective phase-transfer catalyzed desymmetrizations.29 While we
were confident that the desired cyclization would occur on only
one face of the dienone, we expected the discrimination of the two
enantiotopic olefins based solely on non-bonding interactions to
be a significant challenge.
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Scheme 5 Desymmetrization via phase-transfer catalysis.
We were attracted to the Cinchona alkaloid-based phase-
transfer catalysts owing to their ready availability and ease of
modification. Our efforts toward optimization included variations
of the electronic and steric properties of the catalyst; modifications
of the base, temperature, and solvent; and a brief survey of the
malonate ester (substrates 2–4a). The best reaction conditions
were determined to be those shown in Scheme 5.† Importantly,
when using catalyst B, the pseudo-enantiomer of catalyst A, the
opposite enantiomer ent-3c was obtained with similar levels of
enantioinduction.
We were concerned that the background reaction might be a
competing process, which would lead to the diminished selectivity
relative to other asymmetric phase-transfer reactions. Importantly,
under otherwise identical conditions (1 equiv. Cs2CO3, CH2Cl2,
0
◦C, 4 h), no conversion of 4a to 9a was observed. We also
thought that the reaction might be reversible, again leading to
lower selectivity. When isolated 9a of 71 : 29 er was treated with
catalyst A and Cs2CO3 over an extended reaction time (0 C →
Fig. 2 Asymmetric cyclization products.
◦
r.t., 12 h), the product was isolated with 67 : 33 er. In a separate
experiment, substrate 4a was cyclized in the absence of catalyst
(1 equiv. Cs2CO3) to give racemic 9a. Catalyst A was then added
and the reaction continued for another 12 h. In this case, only
racemic product was isolated. While these experiments do not
conclusively rule out the possibility of a reversible reaction, such a
process does not seem to be important with rapid reaction times.
Interestingly, we observed increased enantioselectivity on sub-
strates bearing more sterically demanding substituents at the para
position of the cyclohexadienone ring (compounds 9b to 9g),
and speculated that substituents in the ortho positions of the
cyclohexadienone might offer similar steric benefits. In practice,
desymmetrization of the dibromo compounds 4q–4t produced
enantioenriched cyclopropanes 12q–12t (Fig. 2) with enantioselec-
tivity that was improved relative to their desbromo counterparts,
with the exception of 12s, which showed reduced enantioselectivity
after the extended reaction time needed for complete conversion.
Additionally, the absolute configuration of 12r was determined by
X-ray diffraction analysis.† Curiously, substrates 4h and 4i were
poor substrates for these desymmetrization reactions, affording 9h
and 9i with 69 : 31 and 65 : 35 er, respectively. These two reactions
were noticeably slower than the others and required 36 h and 4
days, respectively, to reach complete conversion. At this point, it
is not clear if the decreased enantioselectivity is due to catalyst
decomposition over the prolonged reaction times or to poor
interaction with the catalyst.
We also speculated that we might not be achieving optimal se-
lectivity due to the fact that the malonate substrates are capable of
forming two different reactive intermediates (i.e., the enolate could
form on the carbonyl of either ester). These two intermediates
might have different interactions with the catalyst and therefore
lead to different levels of enantioinduction. In an attempt to
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address this, we performed the cyclization on substrates containing
electron-withdrawing groups other than esters (compounds 5
and 6). By introducing additional electronic differentiation, using
amides or sulfones, we had hoped to favor the formation of only
one reactive intermediate that could proceed to the cyclization
event. Unfortunately, a decreased level of enantioselectivity was
actually observed and products 10 and 11 (Fig. 3) were both
obtained with a modest 68 : 32 er.
Scheme 7 Elaboration of 9a to b-ketolactone 16. Reagents and condi-
tions: (a) NaH, AcCl, THF, 0 ◦C to r.t.; (b) TFA, 0 ◦C to r.t., 46% over
two steps (not optimized).
NaH, followed by reaction with acetyl chloride, produced 15,
which upon acidic hydrolysis underwent rapid decarboxylation
to give b-ketoester 16.
Conclusions
In conclusion, we have shown that intramolecular conjugate
additions of cyclohexadienones can proceed regioselectively. The
selectivity of these cyclizations appears to be governed largely by
electronic factors, although steric effects likely play a role in some
cases. This is in contrast to our previously reported Pd-catalyzed
cyclizations, which were controlled mainly by steric factors. To-
gether, these observations will be important for synthetic planning
and may prove to be a useful tool for elucidating the mechanisms
of future reactions.
Fig. 3 Asymmetric cyclization products containing varied EWGs.
To further interrogate this problem, we were also interested
in testing cyclohexadienone-tethered b-ketoesters, which would
also be useful in the pursuit of natural products such as
5-bromoochrephilone. However, we were unable to obtain these
compounds due to the facile decarboxylation of acetoacetic acid
and its derivatives, as well as the propensity of the desired sub-
strates to undergo rearomatization via Carroll rearrangement.30
We have also shown that chiral phase-transfer catalysts can
be used to desymmetrize prochiral cyclohexadienones. The fact
that the Cinchona alkaloid catalysts are capable of differentiating
the two enantiotopic olefins solely on the basis of non-bonding
interactions is remarkable. Efforts are underway to improve the
selectivity of this reaction and the results will be reported in due
course.
Further transformations of products
We have already begun to explore the utility of these bicyclic
lactones as synthetic intermediates. The electron-deficient tricyclic
cyclopropanes appear to be unknown in the literature and may
prove to be valuable synthetic scaffolds as well.31 For example,
heating cyclopropane 12o with toluenethiol in toluene produced
the sulfide 13 as a ~2 : 1 mixture of epimers (Scheme 6). Alterna-
tively, the cyclopropane ring of 12r can be reductively cleaved32
with SmI2 to form 14. Notably, the bromoenone moiety was left
intact. Enone 14 is interesting in that it is formally the product of
an enantioselective dearomatization/conjugate addition sequence.
However, the occurrence of such a hypothetical conjugate addition
does not seem probable as the cyclization would actually occur on
the olefin bearing the bromine (cf., Scheme 3).
Experimental
Materials and methods
Unless otherwise stated, reactions were performed in flame- or
oven-dried glassware under an argon or nitrogen atmosphere
using anhydrous solvents. Acetonitrile and CH2Cl2 were dried
by passage through an activated alumina column under argon.
˚
Powdered 4 A molecular sieves were activated by heating under
◦
vacuum and kept at 90 C until use. Thin-layer chromatography
(TLC) was performed using plates precoated with silica gel XHL
w/UV254 (250 mm) or alumina W/UV and visualized by UV
light or KMnO4, phosphomolybdic acid, or anisaldehyde stains,
followed by heating. Silica gel (particle size 32–63 mm) was used
for flash chromatography. 1H and 13C NMR spectra are reported
1
relative to the residual solvent peak (d 7.26 and d 77.2 for H
and 13C, respectively). Data for 1H NMR spectra are reported as
follows: chemical shift (d (ppm)) (multiplicity, coupling constant
(Hz), integration). Spectra are described using the following
abbreviations: s = singlet, d = doublet, t = triplet, q = quartet,
hept = heptet, m = multiplet. IR samples were prepared on NaCl
plates either neat or by evaporation from CHCl3 or CH2Cl2.
Scheme 6 Elaboration of cyclopropane products 12o and 12r. Reagents
and conditions: (a) 12o, toluenethiol, toluene, 115 ◦C, 37% (from 4o); (b)
12r, 2.1 equiv. SmI2, THF, 0 ◦C, 39% yield (yields not optimized).
General method 1: cyclization using Cs2CO3 in MeCN
In a final one-pot sequence, we have been able to address the
problems associated with forming cyclization substrates contain-
ing b-ketoesters (Scheme 7). Deprotonation of malonate 9a with
A solution of the appropriate substrate (1 equiv.) in MeCN
(0.05 M in substrate) was treated with solid Cs2CO3 (2.5 equiv.).
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The reaction mixture was stirred until consumption of the
starting material (usually within 30 min for sterically unhindered
substrates), and then concentrated and purified directly by flash-
column chromatography.
(RTfirst = 20.4 min, RTsecond = 23.7 min). Also, using general method
1, racemic 8 was obtained in 91% yield. IR (thin film) 3059, 3032,
2910, 1778, 1731, 1679, 1378, 1291, 1158, 1090, 987 cm-1; 1H NMR
(300 MHz, CDCl3) d 7.39–7.36 (m, 5 H), 6.68 (dd, J = 10.4, 2.0 Hz,
1 H), 6.08 (d, J = 10.4 Hz, 1 H) 5.28 (d, J = 12.3 Hz, 1 H), 5.22
(d, J = 12.3 Hz, 1 H), 3.52 (d, J = 12.5 Hz, 1 H), 3.39–3.32 (m, 1
H), 2.74 (dd, J = 17.8, 5.3 Hz, 1 H), 2.63 (dd, J = 17.9, 2.3 Hz, 1
H), 1.73 (s, 3 H); 13C NMR (75 MHz, CDCl3, DEPT) d C 194.1
(C), 168.6 (C), 166.3 (C), 146.7 (CH), 134.8 (C), 129.5 (CH), 128.9
(CH ¥ 2), 128.8 (CH), 128.4 (CH ¥ 2), 80.6 (C), 68.3 (CH2), 51.5
(CH), 44.7 (CH), 35.9 (CH2), 23.9 (CH3); HRMS (ESI+) 323.0890
calcd for C17H16O5Na, found 323.0889.
General method 2: asymmetric cyclization using phase-transfer
catalysis
˚
A mixture of the cyclohexadienone substrate (1 equiv.), 4 A
molecular sieves (100% w/w), and catalyst A (10 mol%) was
suspended in trifluorotoluene (0.05 M in substrate) and cooled
to 0 ◦C. Cs2CO3 (1 equiv.) was added and the mixture was stirred
until consumption of the starting material. In cases where no
conversion was observed after ~4 h, the reaction mixture was
allowed to gradually reach r.t. and stirred until consumption of
the starting material. The solvent was then removed in vacuo and
the products purified directly by flash-column chromatography.
(3S,3aR,7aR)-tert-Butyl-7a-methyl-2,5-dioxo-2,3,3a,4,5,7a-
hexahydrobenzofuran-3-carboxylate (9a)
Using general method 2, 4a cyclized in 2 h to give 9a in 79%
yield after flash-column chromatography (5 : 1 hexanes–EtOAc).
Chiral-phase HPLC analysis (Chiralcel OJ, 8% isopropanol in
(3S,3aR,7aR)-Allyl-7a-methyl-2,5-dioxo-2,3,3a,4,5,7a-
hexahydrobenzofuran-3-carboxylate (7)
hexanes, 1 mL min-1, l = 225 nm) showed 75 : 25 er (RTmajor
=
20.4 min, RTminor = 23.7 min). Using general method 1, racemic 9a
was obtained in 80% yield. IR (thin film) 2983, 2929, 1786, 1728,
1686, 1371, 1295, 1150, 1148, 1089, 983 cm-1; 1H NMR (300 MHz,
CDCl3) d 6.67 (dd, J = 10.3, 1.6 Hz, 1 H), 6.08 (d, J = 10.3 Hz, 1
H), 3.35 (d, J = 12.3 Hz, 1 H), 3.32–3.29 (m, 1 H), 2.74 (dd, J =
17.8, 4.8 Hz, 1 H), 2.63 (d, J = 17.8 Hz, 1 H), 1.71 (s, 3 H), 1.49 (s,
9H); 13C NMR (75 MHz, CDCl3, DEPT) d 194.5 (C), 169.2 (C),
165.3 (C), 147.0 (CH), 129.4 (CH), 83.8 (C), 80.3 (C), 52.4 (CH),
44.5 (CH); 36.0 (CH2), 28.1 (CH3 ¥ 3), 24.0 (CH3); HRMS (ESI+)
289.1046 calcd for C14H18O5Na, found 289.1056.
Using a modification of general method 2, in which CH2Cl2
was used as solvent, CsOH·H2O was used as a base, and the
reaction temperature was -78 ◦C, 2 cyclized to give 7 in 75%
yield after flash-column chromatography (3 : 1 hexanes–EtOAc).
Chiral-phase HPLC analysis (Chiralcel OD, 3% ethanol in hex-
anes, 1.5 mL min-1, l = 225 nm) showed 65 : 35 er (RTmajor = 22.3
min, RTminor = 23.5 min). When crude 2 ◦(obtained using general
method B) was allowed to stand at -15 C overnight, racemic 7
was obtained in 88% yield after chromatographic purification. IR
(thin film) 2983, 2929, 1785, 1737, 1685, 1381, 1294, 1164, 1093,
998, 781 cm-1; 1H NMR (300 MHz, CDCl3) d 6.68 (dd, J = 10.3,
2.0 Hz, 1 H), 6.09 (d, J = 10.3 Hz, 1 H), 5.90 (dddd, J = 16.2,
10.5, 5.8, 5.8 Hz, 1 H), 5.38 (dq, J = 17.2, 1.4 Hz, 1 H), 5.28 (dd,
J = 10.4, 1.1 Hz, 1 H), 4.77–4.62 (m, 2 H), 3.49 (d, J = 12.5 Hz, 1
H), 3.38–3.31 (m, 1 H), 2.75 (dd, J = 17.8, 5.3 Hz, 1 H), 2.64 (dd,
J = 17.8, 1.6 Hz, 1 H), 1.72 (s, 3H); 13C NMR (75 MHz, CDCl3,
DEPT) d 194.2 (C), 168.7 (C), 166.1 (C), 146.7 (CH), 131.0 (CH),
129.5 (CH), 119.6 (CH2), 80.6 (C), 67.1 (CH2), 51.5 (CH), 44.7
(CH), 35.9 (CH2), 23.9 (CH3); HRMS (ESI+) 273.0733 calcd for
C13H14O5Na, found 273.0729; the NOE correlation used to assign
the relative stereochemistry of 7 is shown in Fig. 4.
(3S,3aR,7aR)-7a-Methyl-3-(morpholine-4-carbonyl)-3a,4-
dihydrobenzofuran-2,5(3H,7aH)-dione (10)
Using general method 2, 5 cyclized to give 10 in 87% yield af-
ter flash-column chromatography (2 : 1 hexanes–EtOAc). Chiral-
phase HPLC analysis (Chiralcel OD, 10% ethanol in hexanes, 1 mL
min-1, l = 225 nm) showed 68 : 32 er (RTminor = 23.2 min, RTmajor
=
42.5 min). Using general method 1, racemic 10 was obtained in
92% yield. IR (thin film) 2971, 2859, 1773, 1681, 1645, 1441, 1297,
1
1242, 1113, 1094, 975 cm-1; H NMR (300 MHz, CDCl3) d 6.68
(dd, J = 10.3, 2.0 Hz, 1 H), 6.06 (d, J = 10.3, 1.0 Hz, 1 H), 4.00 (dt,
J = 13.4, 3.0 Hz, 1 H), 3.82–3.57 (m, 6 H), 3.58 (d, J = 11.9 Hz,
1 H), 3.39–3.26 (m, 2 H), 2.72 (dd, J = 17.8, 5.5 Hz, 1 H), 2.54
(ddd, J = 17.9, 2.0, 1.1 Hz, 1 H), 1.72 (s, 3 H); 13C NMR (75
MHz, CDCl3, DEPT) d 195.2 (C), 169.9 (C), 162.4 (C), 147.1
(CH), 129.7 (CH), 80.9 (C), 66.9 (CH2), 66.6 (CH2), 48.5 (CH),
46.6 (CH2), 43.7 (CH), 43.2 (CH2), 36.2 (CH2), 23.9 (CH3); HRMS
(ESI+) 302.0999 calcd for C14H17NO5Na, found 302.1016.
Fig. 4 NOE correlation for 7.
(3aS,7aR)-7a-Methyl-3-tosyl-3a,4-dihydrobenzofuran-
2,5(3H,7aH)-dione (11)
(3S,3aR,7aR)-Benzyl-7a-methyl-2,5-dioxo-2,3,3a,4,5,7a-
hexahydrobenzofuran-3-carboxylate (8)
Using general method 2, 6 cyclized to give 11 in 90% yield
after flash column chromatography (1 : 1 hexanes–EtOAc). Chiral-
phase HPLC analysis (Chiralcel OD, 10% ethanol in hexanes, 1 mL
Using a modification of general method 2, in which CH2Cl2 was
used as solvent and the reaction was started at -78 ◦C and
gradually allowed to warm to r.t., 4b cyclized to give 8 in 99%
yield after flash-column chromatography (3 : 1 hexanes–EtOAc).
Chiral-phase HPLC analysis (Chiralcel OD-H, 8% ethanol in
hexanes, 1 mL min-1, l = 225 nm) showed ~racemic material
min-1, l = 225 nm) showed 68 : 32 er (RTminor = 27.9 min, RTmajor
=
32.0 min). Using general method 1, racemic 11 was obtained in
70% yield. IR (thin film) 2923, 1783, 1687, 1595, 1318, 1245,
1149, 1085, 965, 813 cm-1; 1H NMR (300 MHz, CDCl3) d 7.85 (d,
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J = 8.4 Hz, 2 H), 7.39 (d, J = 8.1 Hz, 2 H), 6.61 (dd, J = 10.4,
1.8 Hz, 1 H), 6.06 (dd, J = 10.4, 0.9 Hz, 1 H), 3.94 (d, J = 11.6 Hz,
1 H), 3.55 (ddt, J = 11.6, 5.8, 2.0 Hz, 1 H), 3.18 (ddd, J = 17.9,
1.8, 1.1 Hz, 1 H), 2.82 (dd, J = 17.9, 5.8 Hz, 1 H), 2.46 (s, 3
H), 1.75 (s, 3 H); 13C NMR (75 MHz, CDCl3, DEPT) d 193.9
(C), 165.6 (C), 146.5 (CH), 146.4 (C), 134.0 (C), 130.0 (CH ¥ 2),
129.9 (CH ¥ 2), 129.8 (CH), 80.1 (C), 67.1 (CH), 42.7 (CH), 36.7
(CH2), 23.9 (CH3), 22.0 (CH3); HRMS (ESI+) 343.0611 calcd for
C16H16O5SNa, found 343.0604.
(300 MHz, CDCl3) d 6.82 (dd, J = 10.4, 2.0 Hz, 1 H), 6.17 (d,
J = 10.4 Hz, 1 H), 3.74 (s, 3 H), 3.58–3.68 (m, 1 H), 3.35(d, J =
12.2 Hz, 1 H), 3.05 (d, J = 15.5 Hz, 1 H), 2.99 (d, J = 15.5 Hz, 1
H), 2.84 (dd, J = 18.0, 5.8 Hz, 1 H), 2.62 (d, J = 17.0 Hz, 1 H), 1.50
(s, 9 H); 13C NMR (75 MHz, CDCl3, DEPT) d 194.5 (C), 168.6
(C), 168.3 (C), 165.0 (C), 144.5 (CH), 130.7 (CH), 84.1 (C), 79.2
(C), 52.6 (CH3), 52.4 (CH), 42.7 (CH), 42.3 (CH2) 36.1(CH2), 28.1
(CH3 ¥ 3); HRMS (ESI+) 347.1101 calcd for C16H20O7Na, found
347.1111.
(3S,3aR,7aR)-tert-Butyl-2,5-dioxo-7a-phenyl-2,3,3a,4,5,7a-
(3S,3aR,7aR)-tert-Butyl-7a-neopentyl-2,5-dioxo-2,3,3a,4,5,7a-
hexahydrobenzofuran-3-carboxylate (9b)
hexahydrobenzofuran-3-carboxylate (9e)
Using general method 2, 4b cyclized in 3 h to give 9b in 72%
yield after flash-column chromatography (5 : 1 hexanes–EtOAc).
Chiral-phase HPLC analysis (Chiralcel OD-H, 10% isopropanol
Using general method 2, 4e cyclized in 2.5 h to give 9e in 52%
yield after flash-column chromatography (9 : 1 → 5 : 1 hexanes–
EtOAc). Chiral-phase HPLC analysis (Chiralcel OJ, 5% ethanol
in hexanes, 1 mL min-1, l = 225 nm) showed 80 : 20 er (RTmajor = 8.8
min, RTminor = 9.8 min). Using general method 1, racemic 9e was
obtained in 58% yield. IR (thin film) 2957, 1783, 1731, 1687, 1369,
in hexanes, 1 mL min-1, l = 225 nm) showed 78 : 22 er (RTminor
=
9.6 min, RTmajor = 10.3 min). Using general method 1, racemic 9b
was obtained in 95% yield. IR (thin film) 2976, 2930, 1786, 1727,
1688, 1370, 1293, 1144, 989, 767, 700 cm-1; 1H NMR (300 MHz,
CDCl3) d 7.47–7.44 (m, 5 H), 6.81 (dd, J = 10.3 Hz, 1 H), 6.37 (d,
J = 10.3 Hz, 1 H), 3.47–3.45 (m, 2 H), 2.78–2.71 (m, 1 H), 2.61
(d, J = 17.7 Hz, 1 H), 1.50 (s, 9 H). Note: An additional singlet
observed at 1.58 ppm was ascribed to residual water. 13C NMR
(75 MHz, CDCl3, DEPT) d 194.8 (C), 169.4 (C), 165.3 (C), 144.8
(CH), 137.3 (C), 130.9 (CH), 129.5 (CH), 129.4 (CH ¥ 2), 125.2
(CH ¥ 2), 84.0 (C), 83.2 (C), 52.9 (CH), 46.9 (CH), 35.6 (CH2),
28.1 (CH3 ¥ 3); HRMS (ESI+) 351.1203 calcd for C19H20O5Na,
found 351.1217.
1
1295, 1260, 1141, 983, 941 cm-1; H NMR (300 MHz, CDCl3) d
6.89 (d, J = 10.5 Hz, 1 H), 6.06 (d, J = 10.5 Hz, 1 H), 3.29 (s, 2 H),
2.74 (ddd, J = 17.9, 3.7, 1.4 Hz, 1 H), 2.61 (d, J = 18.2 Hz, 1 H),
2.04 (d, J = 15.2 Hz, 1 H), 1.93 (d, J = 15.2 Hz, 1 H), 1.49 (s, 9 H),
1.09 (s, 9 H); 13C NMR (75 MHz, CDCl3, DEPT) d 194.6 (C), 169.7
(C), 165.6 (C), 146.9 (CH), 128.7 (CH), 83.8 (C), 83.0 (C), 51.36
(CH), 51.30 (CH2), 45.7 (CH), 35.7(CH2), 31.5 (C), 31.4 (CH3 ¥
3), 28.0 (CH3 ¥ 3); HRMS (ESI+) 345.1672 calcd for C18H26O5Na,
found 345.1677.
tert-Butyl-7a-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2,5-dioxo-
(3S,3aR,7aR)-tert-Butyl-7a-isopropyl-2,5-dioxo-2,3,3a,4,5,7a-
2,3,3a,4,5,7a-hexahydrobenzofuran-3-carboxylate (9f)
hexahydrobenzofuran-3-carboxylate (9c)
Using general method 2, 4f cyclized in 22 h to give 9f in 89%
yield after flash-column chromatography (5 : 1 hexanes/EtOAc).
Chiral-phase HPLC analysis (Chiralcel OD-H, 2% isopropanol in
hexanes, 1 mL min-1, l = 225 nm) showed 75 : 25 er (RTmajor = 11.8
min, RTminor = 12.9 min). Using general method 1, racemic 9f was
obtained in 50% yield. IR (thin film) 2952, 2931, 2857, 1789, 1732,
Using general method 2, 4c cyclized in 3 h to give 9c in 77%
yield after flash-column chromatography (3 : 1 hexanes–EtOAc).
Chiral-phase HPLC analysis (Chiralcel OD-H, 10% isopropanol
in hexanes, 1 mL min-1, l = 225 nm) showed 80 : 20 er (RTminor
=
7.7 min, RTmajor = 8.2 min). Using general method 1, racemic 9c
was obtained in 96% yield. IR (thin film) 2976, 2937, 2884, 1784,
1730, 1688, 1470, 1369, 1294, 1149, 980 cm-1; 1H NMR (300 MHz,
CDCl3) d 6.70 (dd, J = 10.5, 1.9 Hz, 1 H), 6.21 (d, J = 10.5 Hz, 1
H), 3.43 (dddd, J = 12.0, 5.5, 1.9, 1.9 Hz, 1 H), 3.33 (d, J = 12.1 Hz,
1 H), 2.72 (dd, J = 18.3, 5.7, Hz, 1 H), 2.58 (d, J = 17.2 Hz, 1 H),
2.25 (hept. J = 6.9 Hz, 1 H), 1.49 (s, 9 H), 1.11 (d, J = 6.9 Hz),
3 H); 13C NMR (75 MHz, CDCl3, DEPT) d 194.9 (C), 169.3 (C),
165.6 (C), 145.6 (CH), 131.1 (CH), 84.7 (C), 83.8 (C), 53.6 (CH),
40.1 (CH), 37.4 (CH2), 36.1 (CH), 28.1 (CH3 ¥ 3), 17.7 (CH3),
16.8 (CH3); HRMS (ESI+) 317.1359 calcd for C16H22O5Na, found
317.1375.
1
1689, 1147, 1087, 838, 779 cm-1; H NMR (300 MHz, CDCl3) d
6.71 (dd, J = 10.4, 1.8 Hz, 1 H), 6.10 (d, J = 10.4 Hz), 3.91–3.79
(m, 2 H), 3.55 (dddd, J = 12.6, 5.6, 2.0, 2.0 Hz, 1 H), 3.34 (d, J =
12.4 Hz), 2.87 (dd, J = 17.9, 5.6 Hz, 1 H), 2.60 (d, J = 17.9 Hz,
1 H), 2.23 (ddd, J = 14.8, 7.1, 4.6 Hz, 1 H), 2.13 (ddd, J = 14.8,
6.1, 4.4 Hz, 1 H), 1.49 (s, 9 H), 0.88 (s, 9H), 0.07 (s, 6 H); 13C
NMR (75 MHz, CDCl3, DEPT) d 195.1 (C), 169.5 (C), 165.4 (C),
146.7 (CH), 129.6 (CH), 83.6 (C), 82.0 (C), 57.9 (CH2), 52.4 (CH),
43.0 (CH), 40.4 (CH2), 36.1 (CH2), 28.1 (CH3 ¥ 3), 25.9 (CH3 ¥
3), 18.2 (C), -5.4 (CH3 ¥ 2); HRMS (ESI+) 433.2028 calcd for
C21H34O6SiNa, found 433.1996.
(3S,3aR)-tert-Butyl-7a-(2-methoxy-2-oxoethyl)-2,5-dioxo-
(3S,3aR,7aR)-tert-Butyl-7a-(2-methylpent-4-en-2-yl)-2,5-dioxo-
2,3,3a,4,5,7a-hexahydrobenzofuran-3-carboxylate (9d)
2,3,3a,4,5,7a-hexahydrobenzofuran-3-carboxylate (9g)
Using general method 2, 4d cyclized in 3 h to give 9d in 44%
yield after flash-column chromatography (3 : 1 hexanes–EtOAc).
Chiral-phase HPLC analysis (Chiralcel OD-H, 10% isopropanol
Using general method 2, 4g cyclized in 19 h to give 9g in 88%
yield after flash-column chromatography (5 : 1 hexanes–EtOAc).
Chiral-phase HPLC analysis (Chiralcel OJ, 3% isopropanol in
hexanes, 1 mL min-1, l = 225 nm) showed 87 : 13 er. (RTmajor = 16.1
min, RTminor = 19.5 min). Using general method 1, racemic 9g was
obtained in 61% yield. IR (thin film) 2977, 2934, 1784, 1730, 1689,
in hexanes, 1 mL min-1, l = 225 nm) showed 77 : 23 er (RTmajor
=
21.9 min, RTminor = 27.4 min). Using general method 1, racemic 9d
was obtained in 53% yield. IR (thin film) 2979, 2926, 2884, 1783,
1
1
1724, 1679, 1431, 1364, 1298, 1253, 1131, 979 cm-1; H NMR
1369, 1291, 1146, 982, 784 cm-1; H NMR (300 MHz, CDCl3) d
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6.83 (dd, J = 10.7, 2.0 Hz, 1 H), 6.24 (d, J = 10.6 Hz, 1 H), 5.81
(dddd, J = 17.4, 10.2, 7.3, 7.3 Hz, 1 H), 5.13 (d, J = 10.2, Hz, 1 H)
5.08 (d, J = 17.6 Hz, 1 H), 3.66 (dddd, J = 11.8, 6.1, 1.8, 1.8 Hz,
1 H), 3.31 (d, J = 11.9 Hz, 1 H), 2.75 (dd, J = 18.6, 6.1 Hz, 1 H),
2.57 (d, J = 18.1 Hz, 1 H), 2.32–2.18 (m, 2 H), 1.50 (s, 9 H), 1.10
(s, 3 H), 1.09 (s, 3 H); 13C NMR (75 MHz, CDCl3, DEPT) d 194.7
(C), 169.2 (C), 165.7 (C), 145.0 (CH), 133.3
(CH), 131.4 (CH), 119.2 (CH2), 86.5 (C), 83.9 (C), 54.0 (CH),
41.7 (C), 41.5 (CH2), 38.4 (CH), 37.9 (CH2), 28.1 (CH3 ¥ 3), 22.0
(CH3), 21.8 (CH3); HRMS (ESI+) 357.1672 calcd for C19H26O5Na,
found 357.1662.
3), 24.1 (CH3), -1.5 (CH3 ¥ 3); HRMS (ESI+) 361.1442 calcd for
C17H26O5SiNa, found 361.1437.
tert-Butyl-7-methoxy-6,7a-dimethyl-2,5-dioxo-2,3,3a,4,5,7a-
hexahydrobenzofuran-3-carboxylate (9j)
Using a modification of general method 1, in which 1.1 equiv. of
Cs2CO3 was used, 4j cyclized to give 9j as a single regioisomer
in 95% yield after flash-column chromatography (3 : 1 hexanes–
EtOAc). IR (neat) 2978, 2928, 1784, 1732, 648, 1610, 1369, 1311,
1
1150 cm-1; H NMR (300 MHz, CDCl3) d 3.95 (s, 3 H), 3.35 (d,
J = 12.4 Hz, 1 H), 3.21 (ddd, J = 12.4, 4.9, 2.9 Hz, 1 H), 2.73–2.59
(m, 2 H), 1.79 (s, 3 H), 1.77 (s, 3 H), 1.48 (s, 9 H); 13C NMR (75
MHz, CDCl3, DEPT) d 195.1 (C), 169.4 (C), 166.4 (C), 165.4 (C),
121.2 (C), 83.8 (C), 82.6 (C), 61.4 (CH3), 52.0 (CH), 44.1 (CH),
35.7 (CH2), 28.0 (CH3 ¥ 3), 22.9 (CH3), 9.2 (CH3); HRMS (ESI+)
333.1309 calcd for C16H22O6Na, found 333.1308.
(3S,3aR,4R,7aS)-tert-Butyl-4,6,7a- trimethyl-2,5-dioxo-
2,3,3a,4,5,7a-hexahydrobenzofuran-3-carboxylate (9h)
Using general method 2, 4h cyclized in 36 h to give 9h in 67%
yield (isolated as a 12 : 1 mixture of diastereomers, measured
by 1H NMR) after flash-column chromatography (9 : 1→5 : 1
hexanes–EtOAc). Chiral-phase HPLC analysis (Chiralcel AS,
8% isopropanol in hexanes, 1 mL min-1, l = 225 nm) showed
69 : 31 er. RTminor = 5.0 min (major diastereomer); 5.9 min (minor
diastereomer) RTmajor = 6.4 min (both diastereomers of the major
enantiomer). Using general method 1, racemic 9h was obtained
in 74% yield. IR (thin film) 2991, 2987, 1785, 1736, 1690, 1451,
1371, 1283, 1148, 1078 cm-1; 1H NMR (300 MHz, CDCl3, data for
major diastereomer) d 6.34 (dq, J = 1.6, 1.4 Hz, 1 H), 3.32 (ddd,
J = 12.1, 5.0, 2.0 Hz, 1 H), 3.15 (d, J = 12.1 Hz, 1 H), 2.79 (qd, J =
6.9, 5.0 Hz, 1 H), 1.79 (d, J = 1.5 Hz, 1 H), 1.69 (s, 3 H), 1.46 (s, 9
H), 1.11 (d, J = 6.9 Hz, 3 H); 13C NMR (75 MHz, CDCl3, DEPT,
data for major diastereomer) d 197.9 (C), 170.3 (C), 166.7 (C),
141.2 (CH), 136.2 (C), 83.3 (C), 81.8 (C), 51.5 (CH), 51.4 (CH),
40.4 (CH), 27.8 (CH3 ¥ 3), 24.1 (CH3), 15.9 (CH3), 12.9 (CH3);
HRMS (ESI+) 317.1359 calcd for C16H22O5Na, found 317.1370;
the NOE correlation used to assign the relative stereochemistry of
9h is shown in Fig. 5.
(3aR,7aS)-tert-Butyl-6,7a-dimethyl-2,5-dioxo-2,3,3a,4,5,7a-
hexahydrobenzofuran-3-carboxylate (9k)
Using general method 1, 4k gave 9k and its regioisomer as a 9 : 1
inseparable mixture in 74% combined yield after flash-column
chromatography (9 : 1 → 5 : 1 hexanes–EtOAc). IR (thin film)
2981, 2932, 1785, 1730, 1684, 1369, 1297, 1151, 1078, 983, 916, 840
cm-1; 1H NMR (300 MHz, CDCl3, data for major regioisomer) d
6.42 (s, 1 H), 3.31 (d, J = 12.3 Hz, 1 H), 3.27–3.20 (m, 1 H), 2.71
(dd, J = 17.7, 4.6 Hz, 1 H), 2.63 (dd, J = 17.6, 2.2 Hz, 1 H), 1.80 (d,
J = 1.2 Hz, 3 H), 1.67 (s, 3 H), 1.48 (s, 9 H). Signals at d 6.58 (dd,
J = 10.3, 2.0 Hz) and d 6.04 (d, J = 10.3 Hz) were ascribed to the
minor regioisomer. 13C NMR (75 MHz, CDCl3, DEPT, data for
major regioisomer) d 195.0 (C), 169.6 (C), 169.5 (C), 142.3 (CH),
136.4 (C), 83.6 (C), 81.1 (C), 52.6 (CH), 44.7 (CH), 36.2 (CH2),
28.0 (CH3 ¥ 3), 24.2 (CH3), 15.8 (CH3); HRMS (ESI+) 303.1203
calcd for C15H20O5Na, found 303.1213.
tert-Butyl-7,7a-dimethyl-2,5-dioxo-2,3,3a,4,5,7a-hexahydro-
benzofuran-3-carboxylate (9l)
Using general method 1, 4l gave 9l and its regioisomer as a 12 : 1
inseparable mixture in 73% combined yield (3 : 1 hexanes–EtOAc).
IR (neat) 2986, 2921, 1783, 1732, 1660, 1369, 1304, 1145, 1084
cm-1; 1H NMR (300 MHz, CDCl3) d 5.94 (dq, J = 1.2, 1.2 Hz, 1
H), 3.36 (d, J = 12.7 Hz, 1 H), 3.27 (ddd, J = 12.7, 5.2, 2.1 Hz,
1 H), 2.71 (dd, J = 18.0, 5.3 Hz, 1 H), 2.59 (ddd, J = 18.0, 2.1,
0.9 Hz, 1 H), 2.02 (d, J = 1.4 Hz, 3 H), 1.72 (s, 3 H), 1.48 (s, 9
H); 13C NMR (75 MHz, CDCl3, DEPT) d 194.2 (C), 169.4 (C),
165.5 (C), 157.9 (C), 127.9 (CH), 83.7 (C), 82.4 (C), 51.9 (CH),
45.4 (CH), 35.7 (CH2), 28.0 (CH3 ¥ 3), 23.0 (CH3), 18.5 (CH3);
HRMS (ESI+) 303.1203 calcd for C15H20O5Na, found 303.1204.
Fig. 5 NOE correlation for 9h.
(3S,3aR,7aS)-tert-Butyl-7a-methyl-2,5-dioxo-6-(trimethylsilyl)-
2,3,3a,4,5,7a-hexahydrobenzofuran-3-carboxylate. (9i)
Using general method 2, 4i cyclized in 4 d to give 9i in 61% yield af-
ter flash-column chromatography (19 : 1 → 9 : 1 hexanes–EtOAc).
Chiral-phase HPLC analysis (Chiralcel OD-H, 8% isopropanol in
hexanes, 1 mL min-1, l = 225 nm) showed 65 : 35 er. (RTminor
4.7 min, RTmajor = 5.1 min). Using general method 1, racemic 9i
was obtained in 49% yield. IR (thin film) 2984, 2927, 1779, 1730,
1655, 1340, 1297, 1248, 1145, 1096, 978, cm-1; 1H NMR (300 MHz,
CDCl3) d 6.71 (d, J = 1.2 Hz, 1 H), 3.26–3.25 (m, 2 H), 2.71 (ddd,
J = 17.4, 3.9, 1.5 Hz, 1 H), 2.56 (dd, J = 17.5, 1.8 Hz, 1 H), 1.68
(s, 3 H), 1.49 (s, 9 H), 0.15 (s, 9 H); 13C NMR (75 MHz, CDCl3,
DEPT) d 197.9 (C), 169.6 (C), 165.4 (C), 153.4 (CH), 142.8 (C),
83.8 (C), 80.6 (C), 52.5 (CH), 44.4 (CH), 36.7 (CH2), 28.1 (CH3 ¥
=
Cyclization of 4m
Using general method 1, 4m cyclized to give 9a (70% yield) and
9i (8% yield) after flash-column chromatography (3 : 1 hexanes–
EtOAc). Both products were identified by comparison of their
spectroscopic data with that previously obtained.
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tert-Butyl-5a-methyl-2,3-dioxo-2,2a,2a1,2b,3,5a-hexahydro-
cyclopropa[cd]benzofuran-2a-carboxylate (12n)
(C), 44.8 (C), 42.3 (CH), 35.4 (CH), 28.0 (CH3 ¥ 3), 25.9 (CH3);
HRMS (ESI+) 342.0097 calcd for C14H15BrO5, found 341.9251.
Using a modification of general method 2, in which 1.0 equiv.
of Cs2CO3 was used and the concentration was 0.1 M in
substrate, 4n cyclized to give 12n in 45% yield after flash-column
chromatography (2 : 1 hexanes–EtOAc). IR (thin film) 2979, 2932,
(2a1R,5aS)-tert-Butyl-4-bromo-5a-isopropyl-2,3-dioxo-2,2a,2a1,
2b,3,5a-hexahydrocyclopropa[cd]benzofuran-2a-carboxylate (12r)
Using general method 2, 4r cyclized in 3.5 h to give 12r in 81%
yield after flash-column chromatography (5 : 1 hexanes–EtOAc).
Chiral-phase HPLC analysis (Chiralcel OD-H, 10% isopropanol
in hexanes, 1 mL min-1, l = 225 nm) showed 91 : 9 er. (RTmajor = 8.3
min, RTminor = 11.9 min). Using general method 1, racemic 12r was
obtained in 49% yield. IR (thin film) 3060, 2977, 1788, 1693, 1608,
1465, 1324, 1153, 1080, 955 cm-1; 1H NMR (300 MHz, CDCl3) d
7.33 (s, 1 H), 3.20 (d, J = 7.9 Hz, 1 H), 3.17 (d, J = 7.7 Hz, 1 H),
2.27 (qq, J = 6.8, 6.8 Hz, 1 H), 1.50 (s, 9 H), 1.10 (d, J = 6.9 Hz, 3
H), 1.09 (d, J = 6.8 Hz, 3 H); 13C NMR (75 MHz, CDCl3, DEPT)
d 182.0 (C), 165.4 (C), 163.0 (C), 147.8 (CH), 129.3 (C), 84.7 (C),
81.7 (C), 44.6 (C), 38.5 (CH), 34.6 (CH), 34.3 (CH), 28.0 (CH3
¥ 3), 16.1 (CH3), 15.6 (CH3); HRMS (ESI+) 370.0410 calcd for
C16H19BrO5, found 370.0141.
1
2856, 1784, 1726, 1685, 1370, 1315, 1137 cm -1; H NMR (300
MHz, CDCl3) d 6.87 (d, J = 9.8 Hz, 1 H), 6.18 (d, J = 9.8 Hz, 1
H), 3.18 (d, J = 7.5 Hz, 1 H), 3.02 (d, J = 7.5 Hz, 1 H), 1.80 (s,
3 H), 1.50 (s, 9 H); 13C NMR (75 MHz, CDCl3, DEPT) d 188.0
(C), 165.7 (C), 163.6 (C), 149.2 (CH), 131.6 (CH), 84.5 (C), 74.2
(C), 44.3 (C), 42.2 (CH), 35.6 (CH), 28.0 (CH3 ¥ 3), 25.6 (CH3);
HRMS (ESI+) 287.0890 calcd for C14H16O5Na, found 287.0880.
(2a1R,5aS)-tert-Butyl-5,5a-dimethyl-2,3-dioxo-2,2a,2a1,2b,3,5a-
hexahydrocyclopropa[cd]benzofuran-2a-carboxylate (12o)
Using general method 1, 4o cyclized to give 12o in >99% crude
yield. Attempts to further purify crude 12o by chromatography
resulted in decomposition. IR (thin film) 2980, 2934, 1782, 1724,
1671, 1370, 1314, 1251, 1161, 1032, 919, cm-1; 1H NMR (300 MHz,
CDCl3) d 6.03 (app. t, J = 1.3 Hz, 3 H), 3.13 (d, J = 7.5 Hz, 1 H),
3.01 (dd, J = 7.5, 1.2 Hz, 1 H), 2.06 (d, J = 1.5 Hz, 3 H), 1.77 (s, 3
H), 1.51 (s, 9 H); 13C NMR (75 MHz, CDCl3, DEPT) d 187.9 (C),
165.8 (C), 163.7 (C), 159.2 (C), 129.1 (CH), 84.4 (C), 76.5 (C), 44.0
(C), 42.9 (CH), 36.1 (CH), 28.0 (CH3 ¥ 3), 23.3 (CH3), 20.2 (CH3);
HRMS (ESI+) 301.1046 calcd for C15H18O5Na, found 301.1052.
(2a1R,5aS)-tert-Butyl-4-bromo-5a-(2-methylpent-4-en-2-yl)-2,3-
dioxo-2,2a,2a1,2b,3,5a-hexahydrocyclopropa[cd]benzofuran-2a-
carboxylate (12s)
Using general method 2, 4s cyclized in 6.5 d to give 12s in 63%
yield after flash-column chromatography (9 : 1 hexanes–EtOAc).
Chiral-phase HPLC analysis (Chiralcel OD, 10% isopropanol in
hexanes, 1 mL min-1, l = 225 nm) showed 72 : 23 er. (RTmajor = 6.4
min, RTminor = 10.0 min). Using general method 1, racemic 12s was
obtained in 42% yield. IR (thin film) 2976, 1786, 1728, 1694, 1314,
tert-Butyl-5-methoxy-4,5a-dimethyl-2,3-dioxo-2,2a,2a1,2b,3,5a-
hexahydrocyclopropa[cd]benzofuran-2a-carboxylate (12p)
1
1261, 1150, 1092, 990, 837 cm-1; H NMR (300 MHz, CDCl3) d
7.54 (s, 1 H), 5.83 (ddt, J = 17.4, 10.1, 7.4 Hz, 1 H), 5.17 (dd, J =
10.1, 1.0 Hz, 1 H), 5.12 (dd, J = 17.4, 1.5 Hz, 1 H), 3.31 (d, J =
7.7 Hz, 1 H), 3.16 (d, J = 7.7 Hz, 1 H), 2.22 (d, J = 7.4 Hz, 2 H), 1.51
(s, 9 H), 1.11j (s, 3 H), 1.09 (s, 3 H); 13C NMR (75 MHz, CDCl3,
DEPT) d 181.9 (C), 165.4 (C), 163.0 (C), 146.3 (CH), 132.8 (CH),
129.6 (C), 119.5 (CH2), 84.8 (C), 83.7 (C), 44.7 (C), 40.7 (CH2),
39.2 (C), 39.1 (CH), 34.3 (CH), 28.0 (CH3 ¥ 3), 21.0 (CH3), 20.6
(CH3); HRMS (ESI+) 433.0621 calcd for C19H23O5BrNa, found
433.0556.
Using a modification of general method 1, in which 1.1 equiv. of
Cs2CO3 was used, 4p cyclized to give 12p as a single regioisomer
in 65% yield after flash column chromatography (3 : 1 hexanes–
EtOAc). IR (neat) 2980, 2936, 1784, 1723, 1661, 1607, 1370, 1316,
1164, 1034 cm-1; 1H NMR (300 MHz, CDCl3) d 3.90 (s, 3 H), 3.08
(d, J = 7.7 Hz, 1 H), 3.02 (d, J = 7.7 Hz, 1 H), 1.86 (s, 3 H), 1.71
(s, 3 H), 1.49 (s, 9 H); 13C NMR (75 MHz, CDCl3, DEPT) d 189.3
(C), 170.4 (C), 166.0 (C), 163.4 (C), 120.5 (C), 84.2 (C), 78.3 (C),
61.6 (CH3), 43.8 (C), 41.6 (CH), 35.4 (CH), 28.0 (CH3 ¥ 3), 22.1
(CH3), 9.8 (CH3); HRMS (ESI+) 331.1152 calcd for C16H20O6Na,
found 331.1158.
tert-Butyl-4-bromo-5a-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2,3-
dioxo-2,2a,2a1,2b,3,5a-hexahydrocyclopropa[cd]benzofuran-2a-
carboxylate (12t)
(2a1R,5aS)-tert-Butyl 4-bromo-5a-methyl-2,3-dioxo-2,2a,2a1,
2b,3,5a-hexahydrocyclopropa[cd]benzofuran-2a-carboxylate (12q)
Using general method 2, 4t cyclized in 22 h to give 12t in 35%
yield after flash-column chromatography (9 : 1 hexanes–EtOAc).
Chiral-phase HPLC analysis (Chiralcel OD, 10% isopropanol in
hexanes, 1 mL min-1, l = 225 nm) showed 79 : 21 er. (RTmajor = 6.4
min, RTminor = 10.0 min). Using general method 1, racemic 12t was
obtained in 24% yield. IR (thin film) 2952, 2930, 2857, 1792, 1726,
1694, 1152, 837 cm-1; 1H NMR (500 MHz, CDCl3) d 7.55 (s, 1 H),
3.98–3.89 (m, 2 H), 3.59 (d, 7.5 Hz), 3.18 (d, 7.5 Hz), 2.33–2.18
(m, 2 H), 1.51 (s, 9 H), 0.90 (s, 9 H), 0.084 (s, 3 H), 0.078 (s, 3 H);
13C NMR (75 MHz, CDCl3, DEPT) d 181.8 (C), 165.2 (C), 163.0
(C), 149.2 (CH), 127.9 (C), 84.7 (C), 78.3 (C), 57.9 (CH2), 44.4
(C), 41.4 (CH), 40.2 (CH2), 35.4 (CH), 28.0 (CH3 ¥ 3), 26.0 (CH3
¥ 3), 18.3 (C), -5.4 (CH3 ¥ 2); HRMS (ESI+) 509.0965 calcd for
C21H31BrO6SiNa, found 509.0965.
Using general method 2, 4q cyclized in 5.5 h to give 12q in 56%
yield after flash-column chromatography (4 : 1 hexanes–EtOAc).
Chiral-phase HPLC analysis (Chiralcel OD-H, 10% isopropanol
in hexanes, 1 mL min-1, l = 225 nm) showed 83 : 17 er (RTmajor
=
13.1 min, RTminor = 16.6 min). Using a modification of general
method 1, in which CH2Cl2 was used as solvent and 10 mol%
tetrabutylammonium iodide was added, racemic 12q was obtained
in 85%. IR (thin film) 3055, 2980, 2929, 1786, 1723, 1692, 1602,
1454, 1326, 1154, 1036, 917 cm-1; 1H NMR (300 MHz, CDCl3) d
7.28 (s, 1 H), 3.25 (d, J = 7.5 Hz, 1 H), 3.18 (d, J = 7.5 Hz, 1 H) 1.81
(s, 3 H), 1.51 (s, 9 H); 13C NMR (75 MHz, CDCl3, DEPT) d 181.6
(C), 165.0 (C), 163.0 (C), 149.3 (CH), 128.5 (C), 84.9 (C), 76.3
7858 | Org. Biomol. Chem., 2011, 9, 7849–7859
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Acknowledgements
Financial support was provided by the University of Minnesota
and by the National Science Foundation through a Graduate
Research Fellowship to K.A.V. We thank Ms. Diane M. Johnson
(U of MN) for X-ray analysis.
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The Royal Society of Chemistry 2011
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