Total Synthesis of Clavilactones

Article abstract of DOI:10.1021/acs.joc.7b03268

Clavilactones A, B, and D are epidermal growth factor receptor tyrosine kinase inhibitors that were isolated from cultures of the fungus Clitocybe clavipes. Here, we report full details of the total synthesis of these clavilactones. A key feature of our s

Full text of DOI:10.1021/acs.joc.7b03268

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Article
Total Synthesis of Clavilactones
Ken-ichi Takao, Kento Mori, Kenya Kasuga, Ryuki Nanamiya, Ayumi Namba, Yuuki Fukushima,
Ryuichi Nemoto, Takuma Mogi, Hiroyuki Yasui, Akihiro Ogura, Keisuke Yoshida, and Kin-ichi Tadano
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b03268 • Publication Date (Web): 31 Jan 2018
Downloaded from http://pubs.acs.org on January 31, 2018
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Total Synthesis of Clavilactones
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Kenꢀichi Takao,* Kento Mori, Kenya Kasuga, Ryuki Nanamiya, Ayumi Namba, Yuuki Fukushima,
Ryuichi Nemoto, Takuma Mogi, Hiroyuki Yasui, Akihiro Ogura, Keisuke Yoshida,† and
Kinꢀichi Tadano‡
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Department of Applied Chemistry, Keio University, Hiyoshi, Kohoku-ku, Yokohama 223-8522,
Japan
takao@applc.keio.ac.jp
Abstract
Clavilactones A, B, and D are epidermal growth factor receptor tyrosine kinase inhibitors that
were isolated from cultures of the fungus Clitocybe clavipes. Here we report full details of the total
synthesis of these clavilactones.
A
key feature of our synthetic approach is
a
ringꢀopening/ringꢀclosing metathesis strategy, which allows the concise transformation of a
cyclobutenecarboxylate into a γꢀbutenolide. Coupled with enantioselective Ti/BINOLꢀcatalyzed
alkynylation of a multiꢀsubstituted benzaldehyde and ringꢀclosing metathesis of a diene bearing
silylene acetal to construct the 10ꢀmembered carbocycle, this strategy enabled the total synthesis of
the natural enantiomers (+)ꢀclavilactone A and (–)ꢀclavilactone B. In addition, the correct structure
of clavilactone D was determined by the synthesis of two newly proposed structures. This research
resulted in the asymmetric synthesis of the revised (+)ꢀclavilactone D.
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Introduction
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Mushrooms have frequently been important sources of bioactive natural products.1 Clitocybe
clavipes is a nonꢀtoxigenic fungus whose fruiting body is an edible mushroom named Agaricus
clavipes. In 1994, as a result of screening for novel metabolites from this fungus, Arnone and
coꢀworkers discovered three new compounds, designated clavilactones A (1), B (2), and C (3)
(Figure 1), that showed antibacterial and antifungal activities.2 The structures of these compounds
are characterized by a conformationally rigid 10ꢀmembered carbocycle and an α,βꢀepoxyꢀγꢀlactone.
Further investigations of the metabolites of Clitocybe clavipes by Merlini and coꢀworkers resulted
in the isolation of the related compounds clavilactones D and E (5).3 The structure of clavilactone D
was originally assigned as 4, which is similar to 2 except for substitution with a hydroxy group on
the quinone ring. In addition, clavilactones A, B, and D were identified as inhibitors of epidermal
growth factor receptor tyrosine kinase (IC50: 26, 27, and 5.5 ꢀM for 1, 2, and clavilactone D,
respectively).4
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Figure 1. Structures of clavilactones
The structural and biological characteristics of the clavilactones captured the attention of
synthetic chemists and several innovative synthetic strategies have been reported. In 2006, Barrett
and coꢀworkers succeeded in the first total synthesis of entꢀclavilactone B (the enantiomer of 2)
using convergent threeꢀcomponent benzyne coupling (Figure 2, eq. 1).5 This synthesis established
the absolute configuration of natural clavilactone. Around the same time, we initiated a project for
the synthesis of clavilactones and reported an unprecedented ringꢀopening/ringꢀclosing metathesis
(ROM/RCM) of a cyclobutenecarboxylate for access to a γꢀbutenolide.6 This approach resulted in
the total synthesis of the natural enantiomers 1 and 2 in 2013 (Figure 2, eq. 2).7 Subsequently, the Li
group achieved the synthesis of (±)ꢀ1, (±)ꢀ2, and (±)ꢀ4 through ironꢀcatalyzed carbonylation–
peroxidation of a 1,5ꢀdiene (Figure 2, eq. 3),8 and the Yoshimitsu group developed a new synthetic
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route to (±)ꢀ2 via a radical cyclization–fragmentation strategy (Figure 2, eq. 4).9 Recently, we
demonstrated the correct structure of clavilactone D to be 6 by synthesis of (±)ꢀ610 and we finally
achieved an asymmetric synthesis of natural enantiomer 6. Herein, we describe in full the evolution
of our synthetic strategy toward clavilactones.
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Figure 2. Synthetic strategies for clavilactones
Results and Discussion
Total Synthesis of Clavilactones A and B. We have been involved in applying sequential
metathesis to natural product syntheses.11,12 The focus of the present study is a ROM/RCM, also
called ringꢀrearrangement metathesis.13 A representative example of ROM/RCM is shown in
Scheme 1A. In this process, the formation of new carbocycles or heterocycles is accompanied by
the ringꢀopening of strained carbocyclic alkenes through olefin metathesis. We thought of using a
cyclobutenecarboxylate as a substrate for ROM/RCM. A survey of the literature provided limited
precedent for metathesis using a cyclobutenecarboxylate compound due to their instability and very
high reactivity;14 however, the proposed method seemed particularly attractive because the
γꢀbutenolide skeleton can be concisely formed in a single step. Our retrosynthetic analysis of
(+)ꢀclavilactone A (1) is depicted in Scheme 1B. We envisioned that the natural product could arise
from diene 7 via RCM. Formation of the carbon–carbon double bond using a RCM would assemble
the 10ꢀmembered carbocycle of the target molecule. The diene 7 was considered to be accessible
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from γꢀbutenolide 8, which would be constructed by ROM/RCM of cyclobutenecarboxylate 9.
Although potentially challenging, the success of this step would facilitate installation of the
α,γꢀdisubstituted γꢀbutenolide skeleton. In turn, cyclobutenecarboxylate 9 would ultimately be
derived from allylic alcohol 10 and known cyclobutenecarboxylic acid (11)15 by condensation.
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Scheme 1. Retrosynthetic analysis of (+)ꢀclavilactone A (1)
Investigations commenced by developing
a
method for the preparation of
cyclobutenecarboxylate, a substrate for ROM/RCM for constructing the γꢀbutenolide skeleton. The
preliminary study was conducted on the racemic form and we found success using an anhydride
method. Bromination of 2,5ꢀdihydroxybenzaldehyde (12) afforded known bromide 13,16 which was
dimethylated to 1417 (Scheme 2). Addition of Grignard reagent to 14 provided allylic alcohol (±)ꢀ10.
To prepare the acylating reagent, mixed anhydride 15 was prepared from cyclobutenecarboxylic
acid (11) and pivaloyl chloride. Then, the alkoxide derived from (±)ꢀ10 was reacted with 15 to
afford cyclobutenecarboxylate (±)ꢀ9 in 71% yield. The pivaloyl ester was also obtained as a minor
product (25%), but we next turned to ROM/RCM without further optimization of the acylation step
in the preliminary study.
Scheme 2. Synthesis of cyclobutenecarboxylate (±)ꢀ9
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We explored ROM/RCM of (±)ꢀ9 by using three kinds of catalysts: the firstꢀgeneration Grubbs
catalyst, the secondꢀgeneration Grubbs catalyst, and the firstꢀgeneration Hoveyda–Grubbs catalyst
(Scheme 3). The reactions using 5 mol % of each catalyst produced the desired γꢀbutenolide (±)ꢀ8
(Table 1, entries 1ꢀ3), and the firstꢀgeneration Grubbs catalyst showed the highest mass balance
(entry 1). However, the yield of (±)ꢀ8 was only 28% because the dimerized product (±)ꢀ16 was
easily formed and a significant amount of unreacted (±)ꢀ9 remained. The presence of much more
catalyst (15 mol %) resulted in a lower yield of (±)ꢀ8 and a higher yield of (±)ꢀ16, although the
conversion rate was improved (Table 1, entry 4). A plausible mechanism for the ROM/RCM of
(±)ꢀ9 is shown in Scheme 4. Initially, the exoꢀolefin in substrate (±)ꢀ9 reacts with Grubbs catalyst to
form ruthenium carbene complex I. Next, an intramolecular [2+2] cycloaddition constructs a
metallacyclobutane intermediate II, which cycloeliminates to produce a new complex III. In these
transformations, the strained cyclobutene ring is opened and the γꢀbutenolide skeleton is newly
formed. The catalytic cycle is completed by reaction between complex III and a second molecule of
substrate (±)ꢀ9 to provide γꢀbutenolide (±)ꢀ8 and complex I. However, due to the high reactivity of
the terminal olefin, the dimerization of (±)ꢀ8 by metathesis easily occurs, decreasing the yield of
(±)ꢀ8. Fortunately, we found a solution to this problem. The dimer (±)ꢀ16 was converted into the
desired product (±)ꢀ8 in good yield by metathesis with ethylene using the secondꢀgeneration Grubbs
catalyst (Scheme 3). Although the overall yield was modest, the ROM/RCM strategy provided the
first example of the conversion of a cyclobutenecarboxylate into a γꢀbutenolide. Therefore, we
completed the preliminary study and turned to devising an asymmetric and practical synthetic
strategy.
Scheme 3. ROM/RCM of cyclobutenecarboxylate (±)ꢀ9
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Table 1. Studies for ROM/RCM of cyclobutenecarboxylate (±)ꢀ9
entry catalyst
(±)ꢀ8 (%)
(±)ꢀ16 (%)
recovered
(±)ꢀ9 (%)
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1st Grubbs cat. (5 mol %)
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2nd Grubbs cat. (5 mol %)
1st Hoveyda–Grubbs cat.
(5 mol %)
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1st Grubbs cat. (15 mol %)
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Scheme 4. Plausible mechanism for ROM/RCM of (±)ꢀ9
The focus of the next stage was to prepare optically active allylic alcohol 10. This goal was
achieved using an enantioselective alkynylation developed by the You group18 (Scheme 5). The
chiral catalyst, generated from (S)ꢀBINOL, Nꢀmethylimidazole, and Ti(OiꢀPr)4, effectively
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catalyzed the enantioselective alkynylation of aldehyde 14 in the presence of Et2Zn to provide the
alkynylated product 17 in good yield and with good enantioselectivity (77% yield, 85% ee). When a
solution of 17 in acetone/hexane (1:20) was left to stand, the racemate preferentially crystallized out
and the filtrate was concentrated to provide almost enantiomerically pure 17. The trimethylsilyl
group was removed from 17 and the resulting alkyne 18 was subjected to Lindlar hydrogenation to
afford allylic alcohol 10. The absolute configuration of 10 was determined using a modification of
Mosher’s method on 19.19
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Scheme 5. Asymmetric synthesis of allylic alcohol 10
With allylic alcohol 10 available in an optically active form, we focused on the preparation of
γꢀbutenolide 8 on a practical scale. During the preliminary study, cyclobutenecarboxylate (±)ꢀ9 was
synthesized using mixed anhydride 15 (see Scheme 2). However, we encountered a problem when
we attempted this approach on a large scale: a considerable amount of the undesired byꢀproduct
pivaloyl ester was formed (~35%). Following reexamination of the reaction conditions, we found
that the acylation of 10 with anhydride 20, prepared from 11 with triphosgene and Et3N,20
uneventfully provided 9 in 85% yield (Scheme 6). To improve the overall yield of γꢀbutenolide 8,
the ROM/RCM reaction of 9, followed by ethenolysis of the resulting dimer 16, was performed in a
oneꢀpot operation. In addition, benzoquinone 21 was added to prevent isomerization of the terminal
olefin in 8.21 These efforts increased the yield of the product 8 to 81%.
Scheme 6. Synthesis of γꢀbutenolide 8
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Having prepared γꢀbutenolide 8 successfully, we sought to construct the 10ꢀmembered
carbocycle. To this end, formation of an epoxy ring and introduction of a 2ꢀmethylꢀ2ꢀpropenyl
group into 8 were required to prepare the substrate 7 for RCM (see Scheme 1). Although extensive
reaction conditions were examined, all attempts to form α,βꢀepoxyꢀγꢀlactone 22 from 8 proved
fruitless (Scheme 7).22 Therefore, γꢀbutenolide 8 was temporarily reduced with DIBALH to diol 23.
Due to its instability, diol 23 was immediately protected as silylene acetal 24.23 Attempts to protect
diol 23 as the isopropylidene acetal and cyclic carbonate failed. By using 24 as a substrate, we
examined a variety of conditions for chemoꢀ and stereoselective epoxidation (Table 2). The reaction
using mꢀCPBA at 0 °C produced the desired epoxide 25 in 51% yield and diepoxide 26 in 33%
yield (entry 1). Perfect stereoselectivity was observed, but the chemoselectivity was modest. At low
temperature (–20 °C), the yield of 25 was decreased to 37% (entry 2). Addition of NaHCO3 was
essentially ineffective (entry 3). When dimethyldioxirane (DMDO) was used, the terminal olefin
preferentially underwent epoxidation to give 27 as the major product (entries 4 and 5). Thus, entry 1
was determined to provide a preferable result compared to the other entries.
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Scheme 7. Synthesis of the 10ꢀmembered carbocycle 30
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Table 2. Studies for the epoxidation of 24
entry conditions
25 (%)
26 (%)
27 (%) recovered
24 (%)
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mꢀCPBA, CH2Cl2, 0 °C to rt
mꢀCPBA, CH2Cl2, –20 °C
mꢀCPBA, NaHCO3, CH2Cl2, 0 °C to rt
DMDO, acetone, –78 °C to rt
DMDO, acetone, –20 °C
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–
–
–
–
–
15
–
30
21
45
63
–
We incorporated a 2ꢀmethylꢀ2ꢀpropenyl group through Stille coupling of 25 and allylstannane
2824. In the presence of CuCl, the reaction provided diene 29 in 66% yield,25 whereas in the absence
of CuCl, the yield of 29 was only 38%. With diene 29 in hand, we examined RCM for constructing
the 10ꢀmembered carbocycle. The reaction proceeded slowly but gave the cyclized product 30 in
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83% yield. The stereochemistry and conformation of 30 were confirmed to be similar to the natural
4
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product 1 by H NMR analysis, including NOE experiments. Consequently, the geometrical
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selectivity of the RCM was perfect and allowed formation of the desired 30 as a single Zꢀisomer.
The end game of the synthesis is shown in Scheme 8. Treatment of 30 with TBAF removed the
silylene acetal to furnish diol 31, which was subjected to TPAP oxidation.26 The γꢀlactone was
reconstructed through chemoselective oxidation of the primary alcohol to produce 32, the dimethyl
ether of 1.2 Oxidation of 32 with CAN provided (–)ꢀclavilactone B (2).5 Finally, the quinone in 2
was reduced with NaBH4 to furnish (+)ꢀclavilactone A (1).2 Spectroscopic analysis of the synthetic
materials and comparisons to the reported properties of the corresponding natural samples validated
our successful total synthesis of 1 and 2.2
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Scheme 8. Completion of the total synthesis of clavilactones A (1) and B (2)
Me
OMe
Me
OMe
TPAP, NMO
MS 4A
TBAF
THF, rt
MeCN, rt
O
O
O
OMe
t-Bu
30
OMe OH
67% (2 steps)
O
HO
Si
31
t-Bu
Me
Me
OMe
O
O
CAN
MeCN–H2O, rt
87%
O
O
O
O
OMe
O
O
32
(–)-Clavilactone B (2)
Me
OH
NaBH4
MeOH–H2O, rt
79%
O
O
OH
O
(+)-Clavilactone A (
1
)
Total Synthesis and Structural Revision of Clavilactone D. In 2014, Li and coꢀworkers
achieved the total syntheses of the originally proposed structure of clavilactone D ((±)ꢀ4) and its
regioisomer (±)ꢀ33, as well as of (±)ꢀ1 and (±)ꢀ2 (Figure 3).8 However, the spectroscopic data of
neither (±)ꢀ4 nor (±)ꢀ33 matched those of natural clavilactone D. In addition, the natural product
was reported to be a red solid, but the synthetic samples of (±)ꢀ4 and (±)ꢀ33 were yellow solids. The
Yoshimitsu group similarly reported an inconsistency in the proposed structure of 4 during a
symposium.27 We were intrigued to elucidate the correct structure of clavilactone D. Before
beginning the synthetic study, we carefully evaluated the NMR data of (±)ꢀ4 and (±)ꢀ33 reported by
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the Li group8 and the original data for the natural product.3 As compared with Hꢀ3 (δ 6.15) for (±)ꢀ4
or Hꢀ2 (δ 6.17) for (±)ꢀ33, the corresponding proton signal of the natural product appeared at a
higher field (δ 5.90). Similarly, Cꢀ2 and Cꢀ3 (δ 101.7 and 148.8) for the natural product were
observed at a higher field than those of (±)ꢀ4 (δ 109.2 and 157.7) and (±)ꢀ33 (δ 109.5 and 157.4).
These significant differences in NMR data indicated that the natural product has a stronger
electronꢀdonating group in the quinone ring than the hydroxy group. In addition, we were
suspicious of the molecular weight of clavilactone D. The molecular ion (m/z 302) observed using
lowꢀresolution mass spectrometry by chemical ionization (CI) using CH4 was assigned to M+,
although [M+H]+ should be observed as the molecular ion in CIMS, and highꢀresolution mass
spectrometry data were not reported.3 Therefore, we suspected that the molecular weight is in fact
one less than the proposed weight, and that MW = 301 is correct. In the event, we newly proposed
structures 34 and 6, containing an amino group at Cꢀ2 or Cꢀ3 instead of the hydroxy group, for
natural clavilactone D. Because the original assignment of the position of the substituent was
unreliable,28 we embarked on synthesizing structures 34 and 6 for unambiguous identification.
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Figure 3. The original and the newly proposed structures of clavilactone D
For the synthesis of 34 and 6, we expected that the ROM/RCM strategy would again serve as
an efficient means to elaborate the clavilactone skeleton. From a retrosynthetic perspective, two
regioisomers of pentaꢀsubstituted benzene 39 and 40 would be suitable starting materials as they
contain a nitro group as a precursor of the amino group (Scheme 9). Unexpectedly, the preparation
of 39 was not straightforward. Using a known procedure,29 2,5ꢀdimethoxybenzaldehyde (35) was
regioselectively nitrated to 36. Exhaustive attempts to achieve the critical regioselective
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bromination of 36 were unsuccessful. However, we found that compound 37 underwent the desired
bromination reaction. Thus, treatment of dimethyl ether 36 with concentrated sulfuric acid
selectively hydrolyzed the methyl ether30 to furnish monomethyl ether 37, which was subjected to
bromination with pyridinium tribromide to produce 38 as a single isomer. The methylation of 38
provided the pentaꢀsubstituted benzene 39. On the other hand, the regioisomer 40 was effectively
obtained by nitration of the aforementioned 14 with complete regioselectivity.
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Scheme 9. Synthesis of the two regioisomers 39 and 40
With the two regioisomers 39 and 40 in hand, we exploited our synthetic route for clavilactone
B (2) to achieve the syntheses of newly proposed structures (±)ꢀ34 and (±)ꢀ6. As shown in Scheme
10, the same sequence of reactions was performed in two routes (a series for (±)ꢀ34 and b series for
(±)ꢀ6). Treatment of 39 or 40 with Grignard reagent afforded the allylic alcohol (±)ꢀ41a/b,31 which
was acylated with anhydride 20 to provide cyclobutenecarboxylate (±)ꢀ42a/b. The oneꢀpot
ROM/RCM reaction proceeded to produce γꢀbutenolide (±)ꢀ43a/b in good yield. After conversion
to silylene acetal (±)ꢀ44a/b by reduction and protection, selective epoxidation was achieved to
provide epoxide (±)ꢀ45a/b. Stille coupling with allylstannane 28 afforded diene (±)ꢀ46a/b, which
was subjected to the RCM reaction to construct the 10ꢀmembered carbocycle (±)ꢀ47a/b. At this
stage, the nitro group was chemoselectively reduced under transfer hydrogenation conditions,
without disturbing the olefin, and the resulting amine was protected as tꢀbutyl carbamate (±)ꢀ48a/b.
Removal of the silylene acetal followed by reconstruction of the γꢀlactone provided (±)ꢀ49a/b.
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Scheme 10. Synthesis of γꢀlactone (±)ꢀ49a and (±)ꢀ49b
5
6
7
8
9
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17
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60
The final task was the formation of the quinone ring (Scheme 11). Treatment of dimethyl ether
(±)ꢀ49a with CAN, followed by removal of the Boc group, furnished the target molecule (±)ꢀ34.
Similarly, target (±)ꢀ6 was obtained from (±)ꢀ49b. This time both compounds were red solids and
their NMR spectra had many similarities, but the chemical shifts of (±)ꢀ34 showed some differences
with the published natural product data.3 For example, the signal peaks of Hꢀ6, Hꢀ13, and Cꢀ5 (δ
6.13, 3.61, and 144.7 for (±)ꢀ34) disagreed with the corresponding peaks of the natural product (δ
5.99, 3.76, and 151.3). In contrast, we were gratified to find that the NMR data of synthetic (±)ꢀ6
matched those of the natural product. These findings indicated that the structure of clavilactone D
should be revised to be 6.32 To verify the structural misassignment, we reviewed the original NMR
spectra of natural clavilactone D.33 Although a broad signal peak at δ 6.59 had been disregarded in
the 1H NMR spectrum as being due to impurities, it should be assigned to –NH2. In addition, a cross
peak of the proton in the quinone ring with Cꢀ5 was more strongly observed than a cross peak with
3
Cꢀ14 in the HMBC spectrum. Therefore, the stronger peak had been assigned to JCH, leading to
misjudgment of the position of the proton in the quinone ring to Hꢀ3.
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Scheme 11. Structural revision of clavilactone D
4
5
6
7
8
9
Me
OMe
Me
13
1) CAN
MeOH–H2O, rt
O
BocHN
H2N
2) TFA
CH2Cl2, rt
6
3
5
O
O
O
O
OMe
O
O
54%
O
(±)-49a
(±)-34
10
11
12
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Me
Me
1) CAN
MeOH–H2O, rt
OMe
O
14
2
13
2) TFA
CH2Cl2, rt
6
BocHN
H2N
5
O
O
O
O
OMe
O
O
65%
O
(±)-49b
(±)-6
Revised structure of
Clavilactone D
NMR data (synthetic samples)
NMR data (ref 3)
(±)-34
(±)-6
for natural
(δ 5.90)
(δ 5.99)
(δ 3.76)
(δ 101.7)
(δ 148.8)
(δ 151.3)
H-3 (δ 5.86)
H-6 (δ 6.13)
H-13 (δ 3.61)
H-2 (δ 5.90)
H-6 (δ 5.99)
H-13 (δ 3.76)
C-2 (δ 101.8)
C-3 (δ 148.9)
C-5 (δ 151.3)
C-3 (δ 101.2)
C-2 (δ 149.0)
C-5 (δ 144.7)
Having accomplished our structural revision, we finally turned to the asymmetric synthesis of
natural (+)ꢀclavilactone D (6). As described in Scheme 5, the enantioselective alkynylation of
aldehyde 40 was performed using You conditions18 (Scheme 12). The alkynylated product 50 was
obtained in slightly lower enantiomeric excess (75% ee) than 17 (85% ee), but recrystallization
increased the ee to 91%. Removal of the trimethylsilyl group from 50 and subsequent Lindlar
hydrogenation of alkyne 51 provided enantioenriched allylic alcohol 41b, whose absolute
1
configuration was confirmed by H NMR analysis of the MTPA ester 52.19 We subsequently
repeated all the steps of the racemic synthesis and achieved the total synthesis of (+)ꢀclavilactone D
(6). The properties of the synthetic sample were identical in all respects to those reported for the
natural product.3
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Scheme 12. Asymmetric total synthesis of (+)ꢀclavilactone D (6)
4
5
6
TMS
(S)-BINOL, Et2Zn
N-methylimidazole
Ti(Oi-Pr)4
OMe
OMe
Br
Br
TMS
7
8
O2N
CHO
O2N
CH2Cl2, rt
64%
OMe
OMe OH
50 (75% ee)
(91% ee)
9
40
recryst.
10
11
12
13
14
15
16
17
18
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60
OMe
OMe
Br
H2, Lindlar cat.
Py
Br
K2CO3
MeOH, rt
96%
EtOAc, rt
95%
O2N
O2N
OMe OH
OMe OH
51
41b
Me
O
H2N
O
O
O
O
(+)-Clavilactone D (6)
after recryst. >99% ee
OMe
(R)-MTPA
DCC, DMAP
Br
–0.15
+0.03
O2N
41b
–0.04
–0.09
CH2Cl2, rt
83%
OMe OMTPA
52
ꢁδ values = δS–δR (ppm)
Conclusion
We have achieved the total syntheses of (+)ꢀclavilactone A (1), (–)ꢀclavilactone B (2), and
(+)ꢀclavilactone D (6). Although several total syntheses of clavilactones have been reported, our
publication is, to date, the only synthesis of the natural enantiomers. A key feature of the synthesis
is a ROM/RCM reaction, which offered a novel means to construct the γꢀbutenolide skeleton and
provided a rare example of a cyclobutenecarboxylate being used as a substrate for metathesis in a
total synthesis. Furthermore, we conclude that the true structure of natural clavilactone D is 6, with
an amino group at Cꢀ3, as demonstrated by the synthesis of the two newly proposed structures
(±)ꢀ34 and (±)ꢀ6. Finally, the asymmetric synthesis of 6 was accomplished. Our results demonstrate
that total synthesis can play an important role in the structural elucidation of natural products.34
Following the total synthesis, we started collaborative research with a biology group and found a
new actin polymerization inhibitor by screening synthetic analogs.35 Extension of the ROM/RCM
strategy to the synthesis of other γꢀlactone compounds and further biological studies on this class of
natural products are currently underway.
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Experimental Section
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2-Bromo-3,6-dimethoxybenzaldehyde (14). To a cooled (0 °C) stirred solution of 13 (2.46 g,
11.3 mmol) in DMF (110 mL) were added K2CO3 (4.71 g, 34.1 mmol) and Me2SO4 (3.2 mL, 34
mmol). After being stirred at room temperature for 1.5 h, the mixture was diluted with EtOAc (170
mL) and washed with 1 M aqueous HCl (70 mL), H2O (100 mL) and saturated brine (100 mL),
respectively. The organic layer was dried and concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel (EtOAc/hexane, 1:10) to provide 1.63 g (59%) of
14 and 230 mg (9%) of monoꢀmethyl ether. Compound 14 was obtained as pale yellow crystals: mp
10
11
12
13
14
15
16
17
18
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50
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60
1
98.5–100 °C; TLC Rf 0.36 (EtOAc/hexane, 1:2); IR (KBr) 2959, 1691, 1567 cm–1; H NMR (500
MHz, CDCl3) δ 3.87 (s, 3H), 3.89 (s, 3H), 6.93 (d, 1H, J = 9.2 Hz), 7.07 (d, 1H, J = 9.2 Hz), 10.41
(s, 1H); 13C NMR (125 MHz, CDCl3) δ 56.6, 57.2, 111.5 (2C), 117.1 (2C), 150.4, 155.4, 190.9;
HRMS (EI/double focusing) calcd for C9H9O3Br (M+) m/z 243.9735, found 243.9746.
rac-1-(2-Bromo-3,6-dimethoxyphenyl)prop-2-en-1-ol ((±)-10). To a cooled (–78 °C) stirred
solution of 14 (1.60 g, 6.55 mmol) in THF (70 mL) was added vinylmagnesium bromide (0.82 M
solution in THF, 13.1 mL, 11 mmol). The mixture was stirred at –78 °C for 40 min, quenched with
saturated aqueous NH4Cl (100 mL) and extracted with EtOAc (30 mL × 3). The combined extracts
were washed with saturated brine (50 mL), dried and concentrated under reduced pressure. The
residue was purified by column chromatography on silica gel (EtOAc/hexane, 1:15) to provide 1.75
g (98%) of (±)ꢀ10 as a colorless oil: TLC Rf 0.41 (EtOAc/hexane, 1:2); IR (KBr) 3536, 2939, 1575
cm–1; 1H NMR (500 MHz, CDCl3) δ 3.84 (s, 3H), 3.85 (s, 3H), 4.17 (d, 1H, J = 10.8 Hz, OH), 5.12
(dt, 1H, J = 10.5, 1.4 Hz), 5.26 (dt, 1H, J = 17.3, 1.4 Hz), 5.77 (br dd, 1H, J = 10.8, 5.2 Hz), 6.14
(ddd, 1H, J = 17.3, 10.5, 5.2 Hz), 6.79 (d, 1H, J = 9.1 Hz), 6.85 (d, 1H, J = 9.1 Hz); 13C NMR (125
MHz, CDCl3) δ 56.3, 56.8, 75.1, 110.7, 110.9, 113.8, 114.4, 131.3, 138.6, 150.7, 152.0; HRMS
(EI/double focusing) calcd for C11H13O3Br (M+) m/z 272.0048, found 272.0048.
rac-1-(2-Bromo-3,6-dimethoxyphenyl)prop-2-enyl
cyclobut-1-enecarboxylate
((±)-9).
Mixed anhydride 15 was prepared by the following method. To a cooled (0 °C) stirred solution of
cyclobutenecarboxylic acid (11) (237 mg, 2.42 mmol) in THF (5 mL) were added PivCl (0.30 mL,
2.4 mmol) and Et3N (0.70 mL, 5.0 mmol). After being stirred at 0 °C for 30 min, the mixture was
filtered to remove Et3N·HCl. The filtrate was concentrated under reduced pressure to provide 15,
which was used immediately without further purification.
The following reaction was carried out under Ar. To a cooled (–78 °C) stirred solution of (±)ꢀ10
(406 mg, 1.49 mmol) in THF (4 mL) was added NaHMDS (1.04 M solution in THF, 2.0 mL, 2.1
mmol). The mixture was stirred at –78 °C for 30 min, and 15 prepared above was added. After
being stirred at –78 °C for 30 min, the mixture was quenched with saturated aqueous NH4Cl (20
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mL) and extracted with EtOAc (10 mL × 3). The combined extracts were washed with saturated
aqueous NaHCO3 (10 mL) and saturated brine (10 mL), respectively, dried and concentrated under
reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc/hexane,
1:20) to provide 372 mg (71%) of (±)ꢀ9 and 132 mg (25%) of pivaloyl ester. Compound (±)ꢀ9 was
obtained as white crystals: mp 77–80 °C; TLC Rf 0.50 (EtOAc/hexane, 1:2); IR (KBr) 2963, 1704,
1572 cm–1; 1H NMR (500 MHz, CDCl3) δ 2.45 (t, 2H, J = 3.0 Hz), 2.73 (t, 2H, J = 3.0 Hz), 3.83 (s,
3H), 3.84 (s, 3H), 5.22 (d, 1H, J = 10.4 Hz), 5.32 (d, 1H, J = 16.9 Hz), 6.30 (ddd, 1H, J = 16.9, 10.4,
6.2 Hz), 6.81 (s, 1H), 6.83 (d, 1H, J = 9.1 Hz), 6.86 (d, 1H, J = 9.1 Hz), 7.00 (d, 1H, J = 6.2 Hz);
13C NMR (125 MHz, CDCl3) δ 27.1, 29.1, 56.9, 57.1, 72.8, 111.8, 112.0, 114.3, 117.3, 128.5, 134.4,
138.7, 146.8, 150.7, 152.8, 161.3; HRMS (EI/double focusing) calcd for C16H17O4Br (M+) m/z
352.0310, found 352.0308.
10
11
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14
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rac-5-(2-Bromo-3,6-dimethoxyphenyl)-3-(but-3-enyl)-5H-furan-2-one ((±)-8) and its dimer
((±)-16). To a heated (80 °C) stirred solution of (±)ꢀ9 (166 mg, 0.470 mmol) in degassed toluene
(400 mL) was added a solution of Grubbs catalyst 1st generation (21.6 mg, 26.2 ꢀmol) in degassed
toluene (70 mL) using syringe pump over a period of 3.5 h with bubbling Ar. After completion of
the addition, the mixture was stirred for further 1 h, quenched with DMSO (0.1 mL) and
concentrated under reduced pressure. The residue was purified by column chromatography on silica
gel (EtOAc/hexane, 1:5) to provide 45.8 mg (28%) of (±)ꢀ8, 23.2 mg (15%) of (±)ꢀ16, and 77.5 mg
of the recovered (±)ꢀ9. Compound (±)ꢀ8 was obtained as a pale yellow oil: TLC Rf 0.35
1
(EtOAc/hexane, 1:2); IR (neat) 2938, 1756, 1578 cm–1; H NMR (500 MHz, CDCl3) δ 2.32–2.49
(m, 4H), 3.69 (s, 3H), 3.86 (s, 3H), 5.02 (dq, 1H, J = 10.4, 1.5 Hz), 5.09 (dd, 1H, J = 17.0, 1.5 Hz),
5.85 (ddt, 1H, J = 17.0, 10.4, 6.4 Hz), 6.63 (q, 1H, J = 1.7 Hz), 6.81 (d, 1H, J = 8.9 Hz), 6.89 (d, 1H,
J = 8.9 Hz), 7.02 (q, 1H, J = 1.7 Hz); 13C NMR (125 MHz, CDCl3) δ 24.6, 31.4, 56.6, 57.0, 80.5,
111.5, 112.9, 115.2, 115.6, 122.8, 133.7, 137.1, 145.8, 150.5, 153.6, 174.6; HRMS (EI/double
focusing) calcd for C16H17O4Br (M+) m/z 352.0310, found 352.0307. Compound (±)ꢀ16 (ca. 1:1
diastereomeric mixture) was obtained as a pale yellow oil: TLC Rf 0.25 (EtOAc/hexane, 1:1); IR
1
(neat) 2937, 1755, 1576 cm–1; H NMR (500 MHz, CDCl3) δ 2.27–2.40 (m, 8H), 3.685 (s, 3H),
3.692 (s, 3H×1/2), 3.695 (s, 3H×1/2), 3.85 (s, 6H), 5.46 (t, 2H×1/2, J = 4.0 Hz), 5.52 (t, 2H×1/2, J =
3.4 Hz), 6.63 (m, 2H), 6.80 (d, 1H×1/2, J = 9.0 Hz), 6.806 (d, 1H×1/2, J = 9.0 Hz), 6.813 (d,
1H×1/2, J = 9.0 Hz), 6.82 (d, 1H×1/2, J = 9.0 Hz), 6.88 (d, 2H, J = 9.0 Hz), 6.99 (m, 2H×1/2), 7.03
(m, 2H×1/2); 13C NMR (125 MHz, CDCl3) δ 25.2 (2C×1/2), 25.3 (2C×1/2), 30.3 (2C), 56.56
(2C×1/2), 56.62 (2C×1/2), 57.0 (2C), 80.4 (2C), 111.5 (2C×1/2), 111.6 (2C×1/2), 112.9 (2C), 115.1
(2C×1/2), 115.2 (2C×1/2), 122.65 (2C×1/2). 122.71 (2C×1/2), 129.4 (2C×1/2), 129.8 (2C×1/2),
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133.6 (2C×1/2), 133.7 (2C×1/2), 145.8 (2C×1/2), 145.9 (2C×1/2), 150.5 (2C), 153.5 (2C), 174.5
(2C); LRMS (EI/double focusing) calcd for C30H30O8Br2 (M+) m/z 676, found 676.
6
7
8
9
Synthesis of (±)-8 from (±)-16. To a heated (80 °C) stirred solution of (±)ꢀ16 (73.6 mg, 0.108
mmol) in degassed toluene (9 mL) was added slowly a solution of Grubbs catalyst 2nd generation
(5.0 mg, 5.9 ꢀmol) in degassed toluene (2 mL). The mixture was stirred under atmospheric ethylene
at 80 °C for 1 h and concentrated under reduced pressure. The residue was purified by column
chromatography on silica gel (EtOAc/hexane, 1:5) to provide 67.6 mg (88%) of (±)ꢀ8 as a pale
yellow oil.
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(1S)-1-(2-Bromo-3,6-dimethoxyphenyl)-3-(trimethylsilyl)prop-2-yn-1-ol (17). The following
reaction was carried out under Ar. To a stirred solution of (S)ꢀBINOL (2.37 g, 8.29 mmol) in
CH2Cl2 (150 mL) were added Nꢀmethylimidazole (0.33 mL, 4.1 mmol), trimethylsilylacetylene (23
mL, 166 mmol) and Et2Zn (1.00 M solution in hexane, 166 mL, 166 mmol), respectively. The
mixture was stirred at room temperature for 24 h, and Ti(OiꢀPr)4 (6.2 mL, 21 mmol) was added. The
mixture was stirred at room temperature for 1 h, and then a solution of 14 (2.03 g, 8.28 mmol) in
CH2Cl2 (15 mL) was added. After being stirred at room temperature for 15 min, the mixture was
quenched with saturated aqueous NH4Cl (50 mL) at –78 °C and diluted with H2O (50 mL). The
precipitated solids were removed by filtration through a pad of Celite and washed well with CH2Cl2.
The filtrate and washings were combined and the organic layer was separated. The aqueous layer
was extracted with CH2Cl2 (50 mL × 3). The combined organic layers were washed with saturated
brine (50 mL), dried and concentrated under reduced pressure. The residue was purified by column
chromatography on silica gel (EtOAc/hexane, 1:30) to provide 2.20 g (77%, 85% ee) of 17 as white
crystals and (S)ꢀBINOL was quantitatively recovered.
A solution of the obtained 17 (85% ee, 2.20 g) in acetone/hexane (1:20) was left to stand. The
racemate (±)ꢀ17 preferentially crystallized out and the filtrate was concentrated under reduced
pressure to provide 1.75 g (80%) of optically pure 17 (>99% ee) as white crystals: mp 82–84 °C;
TLC Rf 0.54 (EtOAc/hexane, 1:2); [α]26 –11.2 (c 1.78, CHCl3); IR (KBr) 3546, 2960, 2175 cm–1;
D
1H NMR (500 MHz, CDCl3) δ 0.14 (s, 9H), 3.84 (s, 3H), 3.90 (s, 3H), 4.09 (d, 1H, J = 11.4 Hz,
OH), 5.96 (d, 1H, J = 11.4 Hz), 6.82 (d, 1H, J = 9.0 Hz), 6.89 (d, 1H, J = 9.0 Hz); 13C NMR (125
MHz, CDCl3) δ –0.2 (3C), 56.8, 56.9, 63.5, 89.0, 104.8, 111.3, 112.0, 113.1, 130.7, 150.7, 152.3;
HRMS (EI/double focusing) calcd for C14H19O3BrSi (M+) m/z 342.0287, found 342.0287; HPLC
analysis (column, Daicel Chiralcel OJꢀH 0.46 cm
Φ × 25 cm, 2ꢀpropanol/hexane = 1:15, flow rate =
0.5 mL/min); tR (min) = 31.4 for 17, 46.1 for entꢀ17.
(1S)-1-(2-Bromo-3,6-dimethoxyphenyl)prop-2-yn-1-ol (18). To a cooled (0 °C) stirred
solution of 17 (1.03 g, 3.00 mmol) in MeOH (30 mL) was added K2CO3 (234 mg, 1.69 mmol). The
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mixture was stirred at room temperature for 2.5 h, diluted with H2O (60 mL) and extracted with
CH2Cl2 (30 mL × 6). The combined extracts were dried and concentrated under reduced pressure.
The residue was purified by column chromatography on silica gel (EtOAc/hexane, 1:10) to provide
814 mg (100%) of 18 as white crystals: mp 44–47 °C; TLC Rf 0.41 (EtOAc/hexane, 1:2); [α]26
D
9
+5.9 (c 1.74, CHCl3); IR (KBr) 3537, 3289, 2949 cm–1; 1H NMR (500 MHz, CDCl3) δ 2.51 (d, 1H,
10
11
12
13
14
15
16
17
18
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J = 2.3 Hz), 3.85 (s, 3H), 3.92 (s, 3H), 4.29 (d, 1H, J = 11.5 Hz, OH), 6.01 (dd, 1H, J = 11.5, 2.3
13
Hz), 6.83 (d, 1H, J = 8.9 Hz), 6.90 (d, 1H, J = 8.9 Hz); C NMR (125 MHz, CDCl3) δ 56.7, 56.9,
63.2, 72.4, 83.2, 111.4, 111.5, 113.0, 129.8, 150.7, 152.1; HRMS (EI/double focusing) calcd for
C11H11O3Br (M+) m/z 269.9892, found 269.9904.
(1S)-1-(2-Bromo-3,6-dimethoxyphenyl)prop-2-en-1-ol (10). A solution of 18 (814 mg, 3.00
mmol) in EtOAc (30 mL) was stirred under atmospheric hydrogen at room temperature for 1.5 h in
the presence of Lindlar catalyst (86.9 mg) and pyridine (0.12 mL, 1.49 mmol). Additional Lindlar
catalyst (total 221 mg) was added in several portions during the course of the reaction. The mixture
was stirred under atmospheric hydrogen at room temperature for total 7 h. The catalyst was
removed by filtration through a Celite pad and washed well with EtOAc. The combined filtrate and
washings were concentrated under reduced pressure. The residue was purified by column
chromatography on silica gel (EtOAc/hexane, 1:10) to provide 820 mg (100%) of 10 as white
crystals: mp 53–54 °C; [α]27D –7.5 (c 1.12, CHCl3).
Mixture of (1S)-1-(2-Bromo-3,6-dimethoxyphenyl)prop-2-enyl (2R)-3,3,3-trifluoro-2-
methoxy-2-phenylpropanoate and its diastereomer (19). To a cooled (0 °C) stirred solution of 10
(36% ee, 6.6 mg, 24 ꢀmol) in CH2Cl2 (1 mL) were added (R)ꢀMTPA (11.4 mg, 48.7 ꢀmol), DCC
(15.4 mg, 74.6 ꢀmol) and DMAP (5.8 mg, 47 ꢀmol). The mixture was stirred at room temperature
for 2.5 h, and (R)ꢀMTPA (12.2 mg, 52.0 ꢀmol), DCC (16.2 mg, 78.5 ꢀmol) and DMAP (6.5 mg, 53
ꢀmol) were added. After being stirred at room temperature for 2 h, the mixture was diluted with
EtOAc (2 mL). The precipitated solids were removed by filtration through a pad of Celite and
washed well with EtOAc. The combined filtrate and washings were washed with saturated brine (15
mL), dried and concentrated under reduced pressure. The residue was purified by column
chromatography on silica gel (EtOAc/hexane, 1:30) to provide 9.0 mg (76%) of a mixture of 19R
1
and entꢀ19S (19R/entꢀ19S = ca. 2:1) as white solids: TLC Rf 0.51 (EtOAc/hexane, 1:2); H NMR
(500 MHz, CDCl3) for compound 19R δ 3.57 (s, 3H), 3.846 (s, 3H), 3.851 (s, 3H), 5.25 (dt, 1H, J =
10.3, 1.2 Hz), 5.43 (dt, 1H, J = 17.4, 1.2 Hz), 6.36 (ddd, 1H, J = 17.4, 10.3, 6.9 Hz), 6.75 (d, 1H, J
= 9.0 Hz), 6.84 (d, 1H, J = 9.0 Hz), 7.11 (d, 1H, J = 6.9 Hz), 7.31–7.57 (m, 5H); for compound
entꢀ19S δ 3.50 (s, 3H), 3.846 (s, 3H), 3.851 (s, 3H), 5.21 (dt, 1H, J = 10.5, 1.2 Hz), 5.35 (dt, 1H, J =
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Hz), 7.17 (d, 1H, J = 6.5 Hz), 7.31–7.57 (m, 5H).
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(1S)-1-(2-Bromo-3,6-dimethoxyphenyl)prop-2-enyl
cyclobut-1-enecarboxylate
(9).
Anhydride 20 was prepared by the following method. To a cooled (0 °C) stirred solution of
cyclobutenecarboxylic acid (11) (1.46 g, 14.9 mmol) were added Et3N (2.5 mL, 18 mmol) and
triphosgene (894 mg, 3.01 mmol). The mixture was stirred at 0 °C for 10 min and at room
temperature for 40 min. Then argon was bubbled through the mixture for 10 min. The mixture was
concentrated under reduced pressure and diluted with THF. The precipitated solids were removed
by filtration and washed well with THF. The combined filtrate and washings were concentrated
under reduced pressure. The residue was purified by column chromatography on silica gel
(EtOAc/hexane, 1:5) to provide 1.18 g (88%) of 20 as a colorless oil, which was used immediately
in the next step.
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The following reaction was carried out under Ar. To a cooled (0 °C) stirred solution of iꢀPr2NH
(0.63 mL, 4.5 mmol) in THF (4 mL) was added nꢀBuLi (2.69 M solution in hexane, 1.7 mL, 4.6
mmol). The mixture was stirred at 0 °C for 30 min and cooled to –78 °C. A solution of 10 (814 mg,
2.98 mmol) in THF (4 mL) was added and the mixture was stirred at –78 °C for 30 min. Then a
solution of 20 (1.14 g, 6.41 mmol) in THF (4 mL) was added. After being stirred at –78 °C for 45
min and at 0 °C for 5 min, the mixture was quenched with saturated aqueous NH4Cl (30 mL),
diluted with H2O (15 mL) and extracted with EtOAc (30 mL × 3). The combined extracts were
washed with saturated aqueous NaHCO3 (30 mL) and saturated brine (30 mL), respectively, dried
and concentrated under reduced pressure. The residue was purified by column chromatography on
silica gel (EtOAc/hexane, 1:50) to provide 892 mg (85%) of 9 as a colorless oil: [α]25 +36.8 (c
D
0.920, CHCl3).
(5S)-5-(2-Bromo-3,6-dimethoxyphenyl)-3-(but-3-enyl)-5H-furan-2-one (8). To a heated
(80 °C) stirred solution of 9 (540 mg, 1.53 mmol) in degassed toluene (80 mL) was added a solution
of Grubbs catalyst 1st generation (101 mg, 0.123 mmol) in degassed toluene (60 mL) using syringe
pump over a period of 5 h with bubbling Ar. While the Grubbs catalyst was added, a solution of
2,6ꢀdichloroꢀ1,4ꢀbenzoquinone (21) (56 mg × 4, 0.32 mmol × 4) in degassed toluene (2 mL × 4)
was also added every 1 h. After completion of the addition, a solution of Grubbs catalyst 2nd
generation (52 mg, 0.061 mmol) in degassed toluene (10 mL) was added. The mixture was stirred
under atmospheric ethylene at 80 °C for 1 h and concentrated under reduced pressure. The residue
was purified by column chromatography on silica gel (EtOAc/hexane, 1:10) to provide 439 mg
(81%) of 8 as white crystals: mp 42–45 °C; [α]26D –120 (c 0.970, CHCl3).
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(4S)-4-(2-Bromo-3,6-dimethoxyphenyl)-6-(but-3-enyl)-2,2-di-tert-butyl-4,7-dihydro-1,3,2-
dioxasilepine (24). The following reaction was carried out under Ar. To a cooled (–78 °C) stirred
solution of 8 (250 mg, 0.708 mmol) in THF (7 mL) was added DIBALꢀH (1.0 M solution in toluene,
1.4 mL, 1.4 mmol). The mixture was stirred at –78 °C for 2 h and at 0 °C for 1.5 h, and DIBALꢀH
(1.0 M solution in toluene, 1.4 mL, 1.4 mmol) was added at –78 °C. The mixture was stirred at –
78 °C for 30 min and at 0 °C for 1 h, and DIBALꢀH (1.0 M solution in toluene, 1.4 mL, 1.4 mmol)
was added at –78 °C. The mixture was stirred at –78 °C for 30 min and at 0 °C for 1 h, and
DIBALꢀH (1.0 M solution in toluene, 1.4 mL, 1.4 mmol) was added at –78 °C. After being stirred at
–78 °C for 30 min, at 0 °C for 1 h, the mixture was quenched with H2O (10 mL). The precipitated
solids were removed by filtration through a pad of Celite and washed well with CH2Cl2. The
combined filtrate and washings were concentrated under reduced pressure to provide crude 23,
which was used in the next step without further purification.
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The following reaction was carried out under Ar. To a cooled (–78 °C) stirred solution of crude
23 obtained above in CH2Cl2 (7 mL) were added pyridine (0.34 mL, 4.2 mmol) and tꢀBu2Si(OTf)2
(0.46 mL, 1.4 mmol). After being stirred at –78 °C for 20 min, at 0 °C for 25 min and at room
temperature for 15 min, the mixture was quenched with saturated aqueous NH4Cl (20 mL) and
extracted with CH2Cl2 (30 mL × 3). The combined extracts were dried and concentrated under
reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc/hexane,
1:100) to provide 239 mg (68% for 2 steps) of 24 as a colorless oil: TLC Rf 0.76 (EtOAc/hexane,
1:2); [α]27D +16.5 (c 0.460, CHCl3); IR (neat) 2934, 1576 cm–1; 1H NMR (500 MHz, CDCl3) δ 1.05
(s, 9H), 1.06 (s, 9H), 2.04–2.05 (m, 2H), 2.15–2.19 (m, 2H), 3.78 (s, 3H), 3.86 (s, 3H), 4.56 (d, 1H,
J = 14.9 Hz), 4.69 (d, 1H, J = 14.9 Hz), 4.93 (dd, 1H, J = 10.3, 1.7 Hz), 5.00 (dd, 1H, J = 16.9, 1.7
Hz), 5.60 (br s, 1H), 5.81 (ddt, 1H, J =16.9, 10.3, 6.5 Hz), 6.63 (br s, 1H), 6.81 (d, 1H, J = 9.0 Hz),
6.84 (d, 1H, J = 9.0 Hz); 13C NMR (125 MHz, CDCl3, 50 °C) δ 21.1, 21.5, 27.8 (3C), 27.9 (3C),
32.5, 36.2, 56.5, 57.0 (2C), 66.8, 111.2, 111.5, 114.6, 114.8, 129.2, 133.2, 138.2, 141.2, 150.8,
151.3; HRMS (EI/double focusing) calcd for C24H37O4BrSi (M+) m/z 496.1644, found 496.1640.
(4R,5R,6S)-4-(2-Bromo-3,6-dimethoxyphenyl)-6-(but-3-enyl)-2,2-di-tert-butyl-5,6-epoxy-
1,3,2-dioxasilepane (25) and di-epoxide 26. To a cooled (0 °C) stirred solution of 24 (85.2 mg,
0.171 mmol) in CH2Cl2 (4 mL) was added mꢀCPBA (65%, 44.0 mg, 0.166 mmol). The mixture was
stirred at 0 °C for 3 h and at room temperature for 3.5 h, and mꢀCPBA (65%, 12.6 mg, 0.0475
mmol) was added at 0 °C. The mixture was stirred at 0 °C for 30 min and at room temperature for 1
h, and mꢀCPBA (65%, 15.0 mg, 0.0565 mmol) was added at 0 °C. After being stirred at 0 °C for 30
min and at room temperature for 1 h, the mixture was quenched with 10 wt% aqueous Na2S2O3 (10
mL) and extracted with CH2Cl2 (10 mL × 3). The combined extracts were dried and concentrated
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under reduced pressure. The residue was purified by column chromatography on silica gel
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(EtOAc/hexane, 1:20) to provide 44.7 mg (51%) of 25 and 29.6 mg (33%) of 26. Compound 25 was
obtained as a colorless oil: TLC Rf 0.68 (EtOAc/hexane, 1:2); [α]24 +42.2 (c 1.37, CHCl3); IR
D
1
(neat) 2936, 1577 cm–1; H NMR (500 MHz, CDCl3) δ 1.04 (s, 9H), 1.06 (s, 9H), 1.66 (m, 1H),
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2.14–2.20 (m, 3H), 3.75 (d, 1H, J = 7.3 Hz), 3.82 (s, 3H), 3.86 (s, 3H), 4.16 (d, 1H, J = 12.2 Hz),
4.36 (d, 1H, J = 12.2 Hz), 4.96 (dd, 1H, J = 10.1, 1.6 Hz), 5.03 (dd, 1H, J = 16.9, 1.6 Hz), 5.81 (d,
1H, J = 7.3 Hz), 5.82 (ddt, 1H, J =16.9, 10.1, 6.2 Hz), 6.86 (d, 1H, J = 9.2 Hz), 6.88 (d, 1H, J = 9.2
Hz); 13C NMR (125 MHz, CDCl3) δ 20.5, 22.7, 27.1 (3C), 27.8 (3C), 28.1, 33.2, 56.3, 57.0 (2C),
63.2, 64.0, 67.5, 111.1, 111.9, 114.8 (2C), 129.9, 138.0, 150.4, 153.1; HRMS (EI/double focusing)
calcd for C20H28O5BrSi (M+–tꢀC4H9) m/z 455.0889, found 455.0887. Compound 26 (ca. 1:1
diastereomeric mixture) was obtained as white crystals: mp 87–90 °C; TLC Rf 0.50 (EtOAc/hexane,
1:2); [α]25D +33.3 (c 1.37, CHCl3); IR (neat) 2936, 1577 cm–1; 1H NMR (500 MHz, CDCl3) δ 1.04
(s, 9H), 1.05 (s, 9H), 1.58–1.79 (m, 4H), 2.46–2.48 (m, 1H), 2.73–2.76 (m, 1H), 2.92–2.96 (m, 1H),
3.745 (d, 1H × 1/2, J = 7.2 Hz), 3.752 (d, 1H × 1/2, J = 7.2 Hz), 3.82 (s, 3H), 3.86 (s, 3H), 4.16 (d,
1H × 1/2, J = 12.2 Hz), 4.17 (d, 1H × 1/2, J = 12.2 Hz), 4.34 (d, 1H × 1/2, J = 12.2 Hz), 4.35 (d, 1H
× 1/2, J = 12.2 Hz), 5.80 (d, 1H × 1/2, J = 7.2 Hz), 5.81 (d, 1H × 1/2, J = 7.2 Hz), 6.86 (d, 1H, J =
9.2 Hz), 6.88 (d, 1H, J = 9.2 Hz); 13C NMR (125 MHz, CDCl3) δ 20.5, 22.7, 27.1 (3C), 27.8 (3C),
29.9 (1/2C), 30.0 (1/2C), 47.1 (1/2C), 47.3 (1/2C), 51.9, 56.3, 57.0 (2C), 63.3 (1/2C), 63.4 (1/2C),
63.7 (1/2C), 63.8 (1/2C), 67.3, 67.5, 111.2, 112.0 (2C), 129.8, 150.4, 153.1; HRMS (EI/double
focusing) calcd for C24H37O6BrSi (M+) m/z 528.1543, found 528.1541.
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(4R,5R,6S)-6-(But-3-enyl)-2,2-di-tert-butyl-4-[3,6-dimethoxy-2-(2-methylprop-2-enyl)-
phenyl]-5,6-epoxy-1,3,2-dioxasilepane (29). The following reaction was carried out under Ar. To a
stirred solution of 25 (196 mg, 0.381 mmol) and CuCl (38.9 mg, 0.393 mmol) in degassed
1,4ꢀdioxane (3 mL) were added a solution of Pd(PPh3)4 (88.5 mg, 0.0766 mmol) in degassed
1,4ꢀdioxane (6 mL) and a solution of tributylmethallylstannane (28) (546 mg, 1.58 mmol) in
degassed 1,4ꢀdioxane (3 mL). The mixture was stirred at 80 °C for 1 h and at 100 °C for 20 h,
diluted with 1 M aqueous KF (50 mL) and extracted with EtOAc (30 mL × 3). The combined
extracts were dried and concentrated under reduced pressure. The residue was purified by column
chromatography on silica gel (EtOAc/hexane, 1:100) to provide 123 mg (66%) of 29 as a colorless
oil: TLC Rf 0.70 (EtOAc/hexane, 1:4); [α]25 +37.2 (c 0.285, CHCl3); IR (neat) 2935, 1597 cm–1;
D
1H NMR (500 MHz, CDCl3) δ 1.00 (s, 9H), 1.05 (s, 9H), 1.62 (m, 1H), 1.82 (s, 3H), 2.04–2.17 (m,
3H), 3.49 (d, 1H, J = 16.9 Hz), 3.55 (d, 1H, J = 7.2 Hz), 3.63 (d, 1H, J = 16.9 Hz), 3.76 (s, 3H),
3.79 (s, 3H), 4.09 (d, 1H, J = 12.3 Hz), 4.31 (s, 1H), 4.32 (d, 1H, J = 12.3 Hz), 4.75 (s, 1H), 4.95
(dd, 1H, J = 10.3, 1.4 Hz), 5.02 (dd, 1H, J = 16.9, 1.4 Hz), 5.47 (br, 1H), 5.81 (ddt, 1H, J =16.9,
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10.3, 6.0 Hz), 6.80 (d, 1H, J = 9.0 Hz), 6.83 (d, 1H, J = 9.0 Hz); 13C NMR (125 MHz, CDCl3) δ
20.4, 22.7, 23.6, 27.1 (3C), 27.8 (3C), 28.0, 33.2, 34.0, 56.0, 56.4 (2C), 64.1, 64.2, 67.6, 109.9,
110.6, 111.0, 114.8, 128.7, 129.3, 138.0, 144.6, 152.1, 152.2; HRMS (EI/double focusing) calcd for
C28H44O5Si (M+) m/z 488.2958, found 488.2961.
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(5R,6R,7S,10Z)-14,14-Di-tert-butyl-6,7-epoxy-1,4-dimethoxy-11-methyl-5,6,7,8,9,12-
hexahydro-5,7-(epoxysilanooxymethano)benzo[10]annulene (30). The following reaction was
carried out with bubbling Ar. To a heated (80 °C) stirred solution of 29 (73.5 mg, 0.150 mmol) in
degassed toluene (70 mL) was added a solution of Grubbs catalyst 2nd generation (25.6 mg, 30.2
ꢀmol) in degassed toluene (70 mL) using syringe pump over a period of 9 h. While the Grubbs
catalyst was added, a solution of 2,6ꢀdichloroꢀ1,4ꢀbenzoquinone (21) (2.7 mg × 4, 15 ꢀmol × 4) in
degassed toluene (2 mL × 4) was also added every 2 h. After completion of the addition, the mixture
was stirred at 80 °C for further 9 h and concentrated under reduced pressure. The residue was
diluted with 10wt% aqueous Na2S2O3 (80 mL) and extracted with EtOAc (30 mL × 3). The
combined extracts were dried and concentrated under reduced pressure. The residue was purified by
column chromatography on silica gel (EtOAc/hexane, 1:100) to provide 57.5 mg (83%) of 30 as a
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yellow oil: TLC Rf 0.74 (EtOAc/hexane, 1:4); [α]26 +111 (c 1.97, CHCl3); IR (neat) 2936, 1596
D
cm–1; 1H NMR (500 MHz, CDCl3) δ 0.99 (s, 9H), 1.10 (s, 9H), 1.53 (s, 3H), 1.58 (m, 1H), 1.90 (m,
1H), 2.02 (m, 1H), 2.31 (m, 1H), 3.64 (br d, 1H, J = 14.6 Hz), 3.70 (s, 1H), 3.78 (s, 3H), 3.79 (s,
3H), 3.96 (d, 1H, J = 14.6 Hz), 4.17 (d, 1H, J = 13.8 Hz), 4.79 (d, 1H, J = 13.8 Hz), 5.25 (t, 1H, J =
8.3 Hz), 6.36 (s, 1H), 6.77 (d, 1H, J = 8.9 Hz), 6.81 (d, 1H, J = 8.9 Hz); 13C NMR (125 MHz,
CDCl3) δ 21.0, 21.3, 22.4, 23.8, 27.8, 28.3 (3C), 28.4 (3C), 35.2, 55.3, 56.1, 63.5, 64.9, 66.17,
66.19, 109.3, 110.0, 124.8, 128.3, 132.3, 136.0, 150.8, 152.9; HRMS (EI/double focusing) calcd for
C26H40O5Si (M+) m/z 460.2645, found 460.2645.
Dimethyl ether of (+)-clavilactone A (32). To a cooled (0 °C) stirred solution of 30 (57.5 mg,
0.125 mmol) in THF (3 mL) was added TBAF (1.0 M solution in THF, 0.63 mL, 0.63 mmol). The
mixture was stirred at room temperature for 30 min, and TBAF (1.0 M solution in THF, 0.63 mL,
0.63 mmol) was added. After being stirred at room temperature for further 18 h, the mixture was
diluted with H2O (5 mL) and extracted with CH2Cl2 (10 mL × 3). The combined extracts were
washed with saturated brine (10 mL), dried and concentrated under reduced pressure to provide
crude 31, which was used in the next step without further purification.
The following reaction was carried out under Ar. To a cooled (0 °C) stirred solution of crude 31
obtained above in MeCN (2 mL) were added molecular sieves 4A powder (48.0 mg), NMO (44.0
mg, 0.376 mmol) and TPAP (6.6 mg, 0.019 mmol). After being stirred at room temperature for 1 h,
the mixture was concentrated under reduced pressure. The residue was purified by column
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chromatography on silica gel (EtOAc/hexane, 1:40) to provide 26.5 mg (67% for 2 steps) of 32 as
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white crystals: mp 167–170 °C (lit.2 168–172 °C); TLC Rf 0.37 (EtOAc/hexane, 1:4); [α]26 +107
D
(c 1.57, MeOH) (lit.2 +111 (c 0.1, MeOH)); IR (neat) 2940, 1776, 1595 cm–1; 1H NMR (500 MHz,
CDCl3) δ 1.27 (m, 1H), 1.49 (s, 3H), 2.17 (m, 1H), 2.48 (m, 1H), 2.72 (m, 1H), 3.02 (d, 1H, J =
15.2 Hz), 3.76 (br d, 1H, J = 15.2 Hz), 3.79 (s, 3H), 3.81 (s, 3H), 4.01 (br s, 1H), 5.25 (t, 1H, J =
7.9 Hz), 6.38 (d, 1H, J = 0.6 Hz), 6.83 (d, 1H, J = 9.0 Hz), 6.93 (d, 1H, J = 9.0 Hz); 13C NMR (125
MHz, CDCl3) δ 21.3, 22.5, 25.1, 27.3, 55.9, 56.6, 61.6, 63.7, 74.4, 110.2, 112.9, 121.9, 122.2, 130.3,
137.9, 152.5, 152.9, 172.3; HRMS (EI/double focusing) calcd for C18H20O5 (M+) m/z 316.1311,
found 316.1311.
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(–)-Clavilactone B (2). To a cooled (0 °C) stirred solution of 32 (14.1 mg, 44.6 ꢀmol) in MeCN
(1 mL) was added a solution of CAN (75.7 mg, 138 ꢀmol) in H2O (0.5 mL). The mixture was
stirred at room temperature for 10 min, and a solution of CAN (25.0 mg, 45.6 ꢀmol) in H2O (0.2
mL) was added at 0 °C. After being stirred at room temperature for 10 min, the mixture was diluted
with H2O (5 mL) and extracted with CH2Cl2 (10 mL × 4). The combined extracts were dried and
concentrated under reduced pressure. The residue was purified by column chromatography on silica
gel (EtOAc/hexane, 1:10) to provide 11.1 mg (87%) of 2 as yellow amorphous solids: TLC Rf 0.21
(EtOAc/hexane, 1:4); [α]26 –42.6 (c 1.11, CHCl3) (lit.2 –55 (c 0.15, CHCl3); lit.5 +42 (c 0.77,
D
CHCl3) for entꢀ2); IR (neat) 2937, 1783, 1658, 1602 cm–1; 1H NMR (500 MHz, CDCl3) δ 1.29 (m,
1H), 1.49 (s, 3H), 2.26 (m, 1H), 2.39 (m, 1H), 2.72 (m, 1H), 2.96 (d, 1H, J = 13.8 Hz), 3.63 (d, 1H,
J = 13.8 Hz), 3.97 (s, 1H), 5.35 (m, 1H), 6.06 (s, 1H), 6.92 (d, 1H, J = 10.0 Hz), 6.95 (d, 1H, J =
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10.0 Hz); H NMR (500 MHz, (CD3)2CO) δ 1.36 (m, 1H), 1.56 (br s, 3H), 2.30 (m, 1H), 2.38 (m,
1H), 2.63 (m, 1H), 2.96 (br d, 1H, J = 13.9 Hz), 3.64 (br d, 1H, J = 13.9 Hz), 4.44 (br s, 1H), 5.42
(m, 1H), 5.97 (br s, 1H), 7.05 (d, 1H, J = 10.1 Hz), 7.08 (d, 1H, J = 10.1 Hz); 13C NMR (125 MHz,
CDCl3) δ 22.7, 22.8, 24.6, 26.8, 60.4, 62.6, 71.6, 124.2, 134.7, 136.3, 136.7, 136.8, 149.1, 171.2,
184.7, 186.4; HRMS (EI/double focusing) calcd for C16H14O5 (M+) m/z 286.0841, found 286.0842.
(+)-Clavilactone A (1). To a cooled (0 °C) stirred solution of 2 (11.6 mg, 40.5 ꢀmol) in
MeOH/H2O (5:1, 1 mL) was added NaBH4 (1.8 mg, 48 ꢀmol). The mixture was stirred at room
temperature for 10 min, diluted with 1 M aqueous HCl (2 mL) and extracted with CH2Cl2 (10 mL ×
3). The combined extracts were dried and concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel (EtOAc/hexane, 1:5) to provide 9.2 mg (79%) of 1
as yellow crystals: mp 179–182 °C (lit.2 176 °C); TLC Rf 0.33 (EtOAc/hexane, 1:1); [α]25D +100 (c
1
0.46, MeOH) (lit.2 +81 (c 0.2, MeOH)); IR (KBr) 3461, 3419, 2933, 1722 cm–1; H NMR (500
MHz, (CD3)2CO) δ 1.29 (m, 1H), 1.60 (s, 3H), 2.18 (m, 1H), 2.42 (m, 1H), 2.60 (m, 1H), 3.03 (d,
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1H, J = 15.0 Hz), 3.70 (d, 1H, J = 15.0 Hz), 4.20 (s, 1H), 5.30 (t, 1H, J = 7.9 Hz), 6.30 (s, 1H), 6.79
(d, 1H, J = 8.8 Hz), 6.89 (d, 1H, J = 8.8 Hz), 8.14 (s, 1H, OH), 8.43 (s, 1H, OH); 13C NMR (125
MHz, (CD3)2CO) δ 21.7, 23.1, 25.8, 28.0, 62.1, 64.3, 75.9, 115.4, 118.4, 121.0, 122.5, 127.9, 139.0,
150.40, 150.43, 173.1; HRMS (EI/double focusing) calcd for C16H16O5 (M+) m/z 288.0998, found
288.0997.
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5-Hydroxy-2-methoxy-4-nitrobenzaldehyde (37). A solution of 36 (515 mg, 2.44 mmol) in
concentrated sulfuric acid (4.9 mL) was stirred at 50 °C for 40 h and poured into ice (30 g). The
acidic aqueous solution was neutralized with 20 wt% aqueous NaOH (40 mL) and extracted with
EtOAc (200 mL × 7). The combined extracts were dried and concentrated under reduced pressure.
The residue was purified by column chromatography on silica gel (acetone/hexane, 1:20) to provide
147 mg (31%) of 37 and 236 mg (46%) of recovered 36. Compound 37 was obtained as orange
crystals: mp 165–166 °C; TLC Rf 0.65 (EtOAc/hexane, 1:1); IR (KBr) 3306, 2948, 1698, 1526 cm–
1; H NMR (400 MHz, CDCl3) δ 3.98 (s, 3H), 7.61 (s, 1H), 7.68 (s, 1H), 10.09 (s, 1H), 10.47 (s,
1
1H); 13C NMR (125 MHz, CDCl3) δ 56.6, 107.0, 120.2, 131.8, 136.3, 149.1, 153.7, 188.2; HRMS
(ESI/TOF) calcd for C8H8NO5 (M+H+) m/z 198.0402, found 198.0399.
2-Bromo-3-hydroxy-6-methoxy-4-nitrobenzaldehyde (38). The following reaction was
carried out under Ar. To a cooled (–30 °C) stirred solution of 37 (301 mg, 1.53 mmol) in pyridine (8
mL) were added molecular sieves 4A powder (309 mg) and pyridine·HBr3 (744 mg, 2.33 mmol).
The mixture was stirred at –30 °C for 30 min, and pyridine·HBr3 (274 mg, 0.857 mmol) was added.
The mixture was stirred at –30 °C for 20 min, and pyridine·HBr3 (110 mg, 0.344 mmol) was added.
After being stirred at –30 °C for 20 min, the mixture was quenched with 10 wt% aqueous Na2S2O3
(30 mL) and extracted with CH2Cl2 (50 mL × 8). The combined extracts were dried and
concentrated under reduced pressure. The residue was purified by column chromatography on silica
gel (EtOAc/hexane, 1:10) to provide 365 mg (87%) of 38 as orange crystals: mp 144–146 °C; TLC
Rf 0.41 (EtOAc/hexane, 1:1); IR (KBr) 3264, 2943, 1689, 1522 cm–1; 1H NMR (400 MHz, CDCl3)
δ 3.94 (s, 3H), 7.67 (s, 1H), 10.31 (s, 1H), 10.85 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 57.0, 105.7,
115.6, 132.8, 134.9, 147.0, 152.4, 189.4; HRMS (ESI/TOF) calcd for C8H7NO5Br (M+H+) m/z
275.9508, found 275.9503.
2-Bromo-3,6-dimethoxy-4-nitrobenzaldehyde (39). To a cooled (0 °C) stirred solution of 38
(403 mg, 1.46 mmol) in DMF (15 mL) were added K2CO3 (608 mg, 4.40 mmol) and MeI (0.18 mL,
2.9 mmol). After being stirred at room temperature for 14 h, the mixture was diluted with H2O (20
mL) and extracted with CH2Cl2 (60 mL × 3). The combined extracts were dried and concentrated
under reduced pressure. The residue was purified by column chromatography on silica gel
(EtOAc/hexane, 1:5) to provide 424 mg (100%) of 39 as pale yellow crystals: mp 148–149 °C; TLC
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Rf 0.60 (EtOAc/hexane, 1:1); IR (KBr) 2948, 1696, 1525 cm–1; 1H NMR (400 MHz, CDCl3) δ 3.96
(s, 3H), 3.99 (s, 3H), 7.34 (s, 1H), 10.33 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 57.1, 63.2, 107.1,
122.3, 128.5, 144.7, 147.2, 156.7, 189.1; HRMS (ESI/TOF) calcd for C9H9NO5Br (M+H+) m/z
289.9664, found 289.9663.
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2-Bromo-3,6-dimethoxy-5-nitrobenzaldehyde (40). To a cooled (0 °C) stirred solution of 14
(1.37 g, 5.59 mmol) in CH2Cl2 (70 mL) was added concentrated nitric acid (60%, 6.65 mL, 87.4
mmol). After being stirred at room temperature for 2.5 h, the mixture was diluted with H2O (150
mL) and extracted with CH2Cl2 (70 mL × 3). The combined extracts were dried and concentrated
under reduced pressure. The residue was purified by column chromatography on silica gel
(EtOAc/hexane, 1:10) to provide 1.56 g (96%) of 40 as pale yellow crystals: mp 146–148 °C; TLC
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Rf 0.56 (EtOAc/hexane, 1:2); IR (KBr) 2950, 1710, 1524 cm–1; H NMR (400 MHz, CDCl3) δ
3.989 (s, 3H), 3.991 (s, 3H), 7.54 (s, 1H), 10.32 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 57.4, 65.8,
110.4, 119.9, 132.6, 143.6, 147.9, 152.7, 189.3; HRMS (ESI/TOF) calcd for C9H9NO5Br (M+H+)
m/z 289.9664, found 289.9665.
rac-1-(2-Bromo-3,6-dimethoxy-4-nitrophenyl)prop-2-en-1-ol ((±)-41a). The following
reaction was carried out under Ar. To a cooled (–78 °C) stirred solution of 39 (503 mg, 1.73 mmol)
in THF (35 mL) was added vinylmagnesium bromide (0.80 M solution in THF, 3.3 mL, 2.6 mmol).
The mixture was stirred at –78 °C for 20 min, and vinylmagnesium bromide (0.80 M solution in
THF, 1.0 mL, 0.80 mmol) was added at –78 °C. After being stirred at –78 °C for 30 min, the
mixture was quenched with saturated aqueous NH4Cl (40 mL), diluted with H2O (20 mL), and
extracted with EtOAc (100 mL × 3). The combined extracts were dried and concentrated under
reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc/hexane,
1:10) to provide 402 mg (73%) of (±)ꢀ41a and 90.0 mg (18%) of recovered 39. Compound (±)ꢀ41a
was obtained as a yellow oil: TLC Rf 0.58 (EtOAc/hexane, 1:1); IR (neat) 3556, 2941, 1529 cm–1;
1H NMR (400 MHz, CDCl3) δ 3.83 (d, 1H, J = 12.0 Hz, OH), 3.94 (s, 3H), 3.97 (s, 3H), 5.20 (d, 1H,
J = 10.3 Hz), 5.29 (d, 1H, J = 17.0 Hz), 5.77 (dd, 1H, J = 12.0, 5.4 Hz), 6.11 (ddd, 1H, J = 17.0,
10.3, 5.4 Hz), 7.38 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 56.8, 62.9, 75.2, 107.0, 116.0, 122.2,
136.9, 137.2, 143.5, 145.4, 153.7; HRMS (ESI/TOF) calcd for C11H13NO5Br (M+H+) m/z 317.9977,
found 317.9989.
rac-1-(2-Bromo-3,6-dimethoxy-5-nitrophenyl)prop-2-en-1-ol ((±)-41b). As described for the
preparation of (±)ꢀ41a, compound 40 (508 mg, 1.75 mmol) was converted to 430 mg (77%) of
(±)ꢀ41b: yellow crystals, mp 53–54 °C; TLC Rf 0.47 (EtOAc/hexane, 1:2); IR (KBr) 3398, 2951,
1526 cm–1; 1H NMR (400 MHz, CDCl3) δ 3.79 (d, 1H, J = 10.8 Hz, OH), 3.85 (s, 3H), 3.95 (s, 3H),
5.28 (ddd, 1H, J = 10.6, 1.8, 1.2 Hz), 5.33 (ddd, 1H, J = 17.2, 1.8, 1.2 Hz), 5.88 (ddt, 1H, J = 10.8,
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4.2, 1.8 Hz), 6.18 (ddd, 1H, J = 17.2, 10.6, 4.2 Hz), 7.36 (s, 1H); 13C NMR (125 MHz, CDCl3) δ
57.2, 64.0, 74.2, 106.6, 115.4, 119.4, 138.7, 139.4, 142.3, 146.7, 152.4; HRMS (ESI/TOF) calcd for
C11H13NO5Br (M+H+) m/z 317.9977, found 317.9979.
rac-1-(2-Bromo-3,6-dimethoxy-4-nitrophenyl)prop-2-enyl
cyclobut-1-enecarboxylate
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((±)-42a). The following reaction was carried out under Ar. To a cooled (–78 °C) stirred solution of
(±)ꢀ41a (388 mg, 1.22 mmol) in THF (20 mL) was added NaHMDS (1.10 M solution in THF, 2.2
mL, 2.4 mmol). The mixture was stirred at –78 °C for 15 min, and a solution of 20 (483 mg, 2.71
mmol) in THF (8 mL) was added. After being stirred at –78 °C for 30 min, the mixture was
quenched with saturated aqueous NH4Cl (40 mL), diluted with H2O (20 mL) and extracted with
EtOAc (100 mL × 3). The combined extracts were dried and concentrated under reduced pressure.
The residue was purified by column chromatography on silica gel (EtOAc/hexane, 1:30) to provide
387 mg (80%) of (±)ꢀ42a as a yellow oil: TLC Rf 0.54 (EtOAc/hexane, 1:2); IR (neat) 2943, 1714,
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1530 cm–1; H NMR (400 MHz, CDCl3) δ 2.48 (td, 2H, J = 3.2, 1.2 Hz), 2.74 (t, 2H, J = 3.2 Hz),
3.91 (s, 3H), 3.96 (s, 3H), 5.28 (dt, 1H, J = 10.3, 1.3 Hz), 5.37 (dt, 1H, J = 17.6, 1.3 Hz), 6.24 (ddd,
1H, J = 17.6, 10.3, 6.4 Hz), 6.84 (t, 1H, J = 1.2 Hz), 6.91 (dt, 1H, J = 6.4, 1.3 Hz), 7.32 (s, 1H); 13C
NMR (125 MHz, CDCl3) δ 27.5, 29.3, 57.0, 62.9, 72.7, 107.0, 118.7, 122.7, 133.1, 133.6, 138.3,
144.1, 145.1, 147.8, 154.3, 161.2; HRMS (ESI/TOF) calcd for C16H17NO6Br (M+H+) m/z 398.0239,
found 398.0236.
rac-1-(2-Bromo-3,6-dimethoxy-5-nitrophenyl)prop-2-enyl
cyclobut-1-enecarboxylate
((±)-42b). As described for the preparation of (±)ꢀ42a, compound (±)ꢀ41b (414 mg, 1.30 mmol)
was converted to 437 mg (84%) of (±)ꢀ42b: a yellow oil, TLC Rf 0.59 (EtOAc/hexane, 1:2); IR
(neat) 2939, 1719, 1529 cm–1; 1H NMR (400 MHz, CDCl3) δ 2.49 (td, 2H, J = 3.2, 1.2 Hz), 2.75 (t,
2H, J = 3.2 Hz), 3.93 (s, 3H), 3.94 (s, 3H), 5.30 (br d, 1H, J = 10.5 Hz), 5.37 (br d, 1H, J = 17.2 Hz),
6.29 (ddd, 1H, J = 17.2, 10.5, 6.0 Hz), 6.86 (br s, 1H), 6.98 (dt, 1H, J = 6.0, 1.5 Hz), 7.37 (s, 1H);
13C NMR (125 MHz, CDCl3) δ 27.5, 29.3, 57.2, 63.9, 72.9, 107.3, 118.6, 120.1, 133.6, 136.3, 138.2,
142.8, 146.9, 148.1, 152.6, 161.1; HRMS (ESI/TOF) calcd for C16H17NO6Br (M+H+) m/z 398.0239,
found 398.0240.
rac-5-(2-Bromo-3,6-dimethoxy-4-nitrophenyl)-3-(but-3-enyl)-5H-furan-2-one ((±)-43a). To
a heated (80 °C) stirred solution of (±)ꢀ42a (362 mg, 0.909 mmol) in degassed toluene (60 mL) was
added a solution of Grubbs catalyst 1st generation (152 mg, 0.185 mmol) in degassed toluene (30
mL) using syringe pump over a period of 3 h with bubbling Ar. While the Grubbs catalyst was
added, a solution of 2,6ꢀdichloroꢀ1,4ꢀbenzoquinone (17.5 mg × 4, 98.9 ꢀmol × 4) in degassed
toluene (1 mL × 4) was also added every 50 min. After completion of the addition, a solution of
Grubbs catalyst 2nd generation (41.2 mg, 48.5 ꢀmol) in degassed toluene (1 mL) was added. The
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mixture was stirred under atmospheric ethylene at 80 °C for 45 min, quenched with DMSO (1 mL),
stirred for 12 h, and concentrated under reduced pressure. The residue was purified by column
chromatography on silica gel (EtOAc/hexane, 1:80) to provide 290 mg (80%) of (±)ꢀ43a as a
yellow oil: TLC Rf 0.37 (EtOAc/hexane, 1:2); IR (neat) 2944, 1762, 1533 cm–1; 1H NMR (400 MHz,
CDCl3) δ 2.34ꢀ2.43 (m, 2H), 2.47ꢀ2.51 (m, 2H), 3.80 (s, 3H), 3.97 (s, 3H), 5.04 (dd, 1H, J = 10.5,
1.4 Hz), 5.09 (dd, 1H, J = 17.2, 1.4 Hz), 5.83 (ddt, 1H, J = 17.2, 10.5, 6.5 Hz), 6.59 (q, 1H, J = 1.7
Hz), 7.00 (q, 1H, J = 1.7 Hz), 7.29 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 24.8, 31.4, 56.9, 63.1,
79.8, 107.0, 116.0, 123.6, 128.1, 135.0, 137.0, 144.4, 144.8, 144.9, 155.1, 174.1; HRMS (ESI/TOF)
calcd for C16H17NO6Br (M+H+) m/z 398.0239, found 398.0256.
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rac-5-(2-Bromo-3,6-dimethoxy-5-nitrophenyl)-3-(but-3-enyl)-5H-furan-2-one ((±)-43b). As
described for the preparation of (±)ꢀ43a, compound (±)ꢀ42b (202 mg, 0.507 mmol) was converted
to 165 mg (82%) of (±)ꢀ43b: a yellow oil, TLC Rf 0.46 (EtOAc/hexane, 1:2); IR (neat) 2945, 1761,
1530 cm–1; 1H NMR (400 MHz, CDCl3) δ 2.34ꢀ2.41 (m, 2H), 2.48ꢀ2.51 (m, 2H), 3.77 (s, 3H), 3.96
(s, 3H), 5.04 (dd, 1H, J = 10.5, 1.6 Hz), 5.10 (dd, 1H, J = 17.0, 1.6 Hz), 5.84 (ddt, 1H, J = 17.0,
10.5, 6.4 Hz), 6.60 (q, 1H, J = 1.6 Hz), 7.08 (q, 1H, J = 1.6 Hz), 7.43 (s, 1H); 13C NMR (125 MHz,
CDCl3) δ 24.8, 31.3, 57.3, 64.3, 79.8, 108.3, 116.1, 120.7, 131.0, 134.3, 136.9, 143.0, 145.4, 147.5,
152.6, 173.9; HRMS (ESI/TOF) calcd for C16H17NO6Br (M+H+) m/z 398.0239, found 398.0229.
rac-4-(2-Bromo-3,6-dimethoxy-4-nitrophenyl)-6-(but-3-enyl)-2,2-di-tert-butyl-4,7-dihydro-
1,3,2-dioxasilepine ((±)-44a). The following reaction was carried out under Ar. To a cooled (0 °C)
stirred solution of (±)ꢀ43a (134 mg, 0.337 mmol) in THF (7 mL) was added DIBALꢀH (1.03 M
solution in hexane, 3.5 mL, 3.6 mmol). After being stirred at 0 °C for 2 h, the mixture was
quenched with H2O (2 mL). The precipitated solids were removed by filtration through a pad of
Celite and washed well with CH2Cl2. The combined filtrate and washings were concentrated under
reduced pressure to provide crude diol (131 mg), which was used in the next step without further
purification.
The following reaction was carried out under Ar. To a cooled (0 °C) stirred solution of crude
diol (131 mg) obtained above in CH2Cl2 (7 mL) were added pyridine (0.22 mL, 2.7 mmol) and
tꢀBu2Si(OTf)2 (0.22 mL, 0.68 mmol). After being stirred at room temperature for 30 min, the
mixture was quenched with saturated aqueous NaHCO3 (30 mL), diluted with H2O (20 mL), and
extracted with CH2Cl2 (30 mL × 3). The combined extracts were dried and concentrated under
reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc/hexane,
1:200) to provide 134 mg (73% for 2 steps) of (±)ꢀ44a as a yellow oil: TLC Rf 0.64 (EtOAc/hexane,
1:4); IR (neat) 2935, 1530 cm–1; 1H NMR (400 MHz, CDCl3) δ 1.05 (s, 9H), 1.06 (s, 9H), 2.03ꢀ2.06
(m, 2H), 2.14ꢀ2.20 (m, 2H), 3.86 (s, 3H), 3.99 (s, 3H), 4.56 (d, 1H, J = 15.6 Hz), 4.70 (d, 1H, J =
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1H, J = 17.2, 10.2, 6.6 Hz), 6.61 (br, 1H), 7.33 (s, 1H); C NMR (125 MHz, CDCl3) δ 21.3, 21.6,
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27.8 (3C), 27.9 (3C), 32.5, 36.1, 56.5, 62.9 (2C), 67.3, 106.6, 115.1 (2C), 122.7, 127.3, 138.0, 138.1,
142.6, 143.7, 152.5 (br); HRMS (ESI/TOF) calcd for C24H37NO6SiBr (M+H+) m/z 542.1574, found
542.1573.
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rac-4-(2-Bromo-3,6-dimethoxy-5-nitrophenyl)-6-(but-3-enyl)-2,2-di-tert-butyl-4,7-dihydro-
1,3,2-dioxasilepine ((±)-44b). As described for the preparation of (±)ꢀ44a, compound (±)ꢀ43b (157
mg, 0.394 mmol) was converted to 138 mg (65% for 2 steps) of (±)ꢀ44b: pale yellow crystals, mp
1
123–125 °C; TLC Rf 0.63 (EtOAc/hexane, 1:4); IR (KBr) 2933, 1534 cm–1; H NMR (400 MHz,
CDCl3) δ 1.05 (s, 9H), 1.07 (s, 9H), 2.02ꢀ2.06 (m, 2H), 2.14ꢀ2.19 (m, 2H), 3.86 (s, 3H), 3.94 (s, 3H),
4.67 (br s, 2H), 4.94 (dd, 1H, J = 10.1, 1.3 Hz), 5.00 (dd, 1H, J = 17.0, 1.3 Hz), 5.62 (d, 1H, J = 4.0
13
Hz), 5.77 (ddt, 1H, J = 17.0, 10.1, 6.7 Hz), 6.64 (d, 1H, J = 4.0 Hz), 7.34 (s, 1H); C NMR (125
MHz, CDCl3) δ 21.3, 21.6, 27.9 (3C), 28.0 (3C), 32.5, 35.5, 57.1 (2C), 64.3, 67.8, 106.5, 115.2 (2C),
120.0, 127.6, 137.9, 140.6, 143.0, 143.3, 152.7 (br); HRMS (ESI/TOF) calcd for C24H37NO6SiBr
(M+H+) m/z 542.1574, found 542.1588.
rac-(4R,5R,6S)-4-(2-Bromo-3,6-dimethoxy-4-nitrophenyl)-6-(but-3-enyl)-2,2-di-tert-butyl-
5,6-epoxy-1,3,2-dioxasilepane ((±)-45a). To a cooled (0 °C) stirred solution of (±)ꢀ44a (571 mg,
1.05 mmol) in CH2Cl2 (20 mL) were added aqueous phosphate buffer (0.5 M aqueous
Na2HPO4/NaH2PO4, 1:1, 20 mL) and mꢀCPBA (65%, 287 mg, 1.08 mmol). The mixture was stirred
at 0 °C for 10 min and at room temperature for 1.5 h, and mꢀCPBA (65%, 143 mg, 0.539 mmol)
was added at 0 °C. After being stirred at 0 °C for 10 min and at room temperature for 2 h, the
mixture was quenched with 10 wt% aqueous Na2S2O3 (50 mL) and extracted with CH2Cl2 (50 mL ×
4). The combined extracts were washed with saturated aqueous NaHCO3 (100 mL), dried and
concentrated under reduced pressure. The residue was purified by column chromatography on silica
gel (EtOAc/hexane, 1:100) to provide 272 mg (45%) of (±)ꢀ45a, 80.9 mg (13%) of regioisomer,
124 mg (20%) of diꢀepoxide, and 127 mg (21%) of (±)ꢀ44a. The recovered (±)ꢀ44a (127 mg) was
treated by the same procedure to provide additional (±)ꢀ45a (44.0 mg), regioisomer (12.6 mg), and
diꢀepoxide (53.0 mg). In total, 316 mg (54% for 2 cycles) of (±)ꢀ45a, 93.5 mg (16% for 2 cycles) of
regioisomer, and 177 mg (30% for 2 cycles) of diꢀepoxide were obtained. Compound (±)ꢀ45a was
obtained as pale yellow crystals: mp 114–116 °C; TLC Rf 0.60 (EtOAc/hexane, 1:4); IR (KBr) 2935,
1
1530 cm–1; H NMR (400 MHz, CDCl3) δ 1.04 (s, 9H), 1.06 (s, 9H), 1.66 (m, 1H), 2.11ꢀ2.22 (m,
3H), 3.67 (d, 1H, J = 7.2 Hz), 3.92 (s, 3H), 3.98 (s, 3H), 4.14 (d, 1H, J = 12.6 Hz), 4.38 (d, 1H, J =
12.6 Hz), 4.98 (dd, 1H, J = 10.4, 1.7 Hz), 5.04 (dd, 1H, J = 17.2, 1.7 Hz), 5.78 (d, 1H, J = 7.2 Hz),
5.82 (ddt, 1H, J = 17.2, 10.4, 6.6 Hz), 7.38 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 20.6, 22.9, 27.2
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