Divergent synthesis of bioactive resorcinols isolated from the fruiting bodies of hericium erinaceum: Total syntheses of hericenones A, B, and I, hericenols B-D, and erinacerins A and B

Article abstract of DOI:10.1021/jo500795z

Total syntheses of 5'- and 7'-oxidized geranyl resorcylates isolated from the fruiting bodies of Hericium erinaceum and the submerged cultures of a Stereum species were achieved. Our synthesis features derivatization of a suitably functionalized 5'-oxidized geranyl phthalide as a common intermediate, which was obtained by Stille coupling between the phthalide core and the side chain, into a series of natural products by divergent functional group manipulations. The crucial C5'-oxygen functionality was installed at the initial stage by alkylation by an α-cyano ethoxyethyl ether. From a common synthetic intermediate, eight total syntheses including hericenones A, B, and I, hericenols B-D, and erinacerins A and B were achieved (hericenol B and erinacerin B were synthesized as racemates). The structure of hericenone B established in the isolation paper was unambiguously revised as the carbonyl regioisomer at the lactam moiety.

Full text of DOI:10.1021/jo500795z

Article
pubs.acs.org/joc
Divergent Synthesis of Bioactive Resorcinols Isolated from the
Fruiting Bodies of Hericium erinaceum: Total Syntheses of
Hericenones A, B, and I, Hericenols B−D, and Erinacerins A and B
Shoji Kobayashi,* Hidetsugu Tamanoi, Yuichi Hasegawa, Yusuke Segawa, and Araki Masuyama
Department of Applied Chemistry, Faculty of Engineering, Osaka Institute of Technology, 5-16-1 Ohmiya, Asahi-ku, Osaka 535-8585,
Japan
S
* Supporting Information
ABSTRACT: Total syntheses of 5′- and 7′-oxidized geranyl resorcylates isolated from the fruiting bodies of Hericium erinaceum
and the submerged cultures of a Stereum species were achieved. Our synthesis features derivatization of a suitably functionalized
5′-oxidized geranyl phthalide as a common intermediate, which was obtained by Stille coupling between the phthalide core and
the side chain, into a series of natural products by divergent functional group manipulations. The crucial C5′-oxygen functionality
was installed at the initial stage by alkylation by an α-cyano ethoxyethyl ether. From a common synthetic intermediate, eight total
syntheses including hericenones A, B, and I, hericenols B−D, and erinacerins A and B were achieved (hericenol B and erinacerin
B were synthesized as racemates). The structure of hericenone B established in the isolation paper was unambiguously revised as
the carbonyl regioisomer at the lactam moiety.
In 1990, Kawagishi et al. first isolated low-molecular-weight
ingredients from the fruiting bodies of H. erinaceum and named
them hericenones A and B.2 Stimulated by their discovery, a
number of structurally related molecules were isolated from
natural sources, including the hericenones,3 hericerin,4
hericenes,5 hericenols,6 and erinacerins.7 All of these molecules
possess a geranyl side chain attached to a resorcinol framework
as a common structure and exhibit a wide variety of biological
activities, including antitumor,2a antibacterial,6 stimulation of
nerve-growth-factor (NGF) synthesis,3a,b suppression of
endoplasmic reticulum (ER) stress,3c inhibition of collagen-
induced platelet aggregation,8 and plant growth regulation.4a
Therefore, the members of the geranyl resorcylate family are
considered to be key players that define the function of H.
erinaceum. However, in spite of the discovery of these intriguing
INTRODUCTION
■
An edible mushroom, Hericium erinaceum, called Yamabush-
itake in Japanese, has long been used in traditional Chinese
medicine and is now widely available as a health food
supplement, especially in East Asia and Europe. Various
forms of H. erinaceum, including perishables, lyophilized solids,
powders, and tablets, are available in stores. The increasing
demand for this mushroom is mostly due to its effects on
cognitive function, partially demonstrated by a double-blind
placebo-controlled clinical trial with dozens of patients
diagnosed with mild cognitive impairment.1 According to
Mori’s report,1 a group given H. erinaceum showed significantly
increased scores on the cognitive function scale in comparison
with the placebo group. Their study also showed no adverse
effects of H. erinaceum. Consequently, H. erinaceum can be
regarded as a useful food for the prevention of dementia
without any adverse effects.
Received: April 8, 2014
Published: May 15, 2014
© 2014 American Chemical Society
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Figure 1. Structure relationships among naturally occurring geranyl resorcylates. The purple dashed arrows indicate achievements in this report.
biological activities, inclusive structure−activity relationships
(SAR) for the broad range of geranyl resorcylates are still
unknown. In addition, limited supplies and cumbersome
purification procedures for the active ingredients from natural
sources have impeded more detailed pharmacological and
pharmacokinetic studies at the in vivo level. In this context,
synthetic studies of this class of natural products have been
explored for SAR studies and to supply materials for further
research.2b,4d,e,9,10
In their pioneering work, Rao et al. first synthesized
hericenone A by using a Diels−Alder reaction for the
construction of the aromatic unit and subsequent elongation
of the side chain.2b Importantly, their research resulted in the
conclusion that the actual structure of hericenone A was the
carbonyl regioisomer of the proposed structure. They also
suggested from the NMR research that hericenone B had a
structure similar to that of revised hericenone A, while
confirmation by total synthesis had not been achieved. After
19 years, we reported the total syntheses of hericenone J,
hericene A, and hericerin by a strategy composed of a one-pot
multifunctionalization reaction and a Stille coupling (vide
infra).4d,9 Around the same time, Barrett et al. reported efficient
total syntheses of hericenone J and hericenol A via
regioselective palladium(0)-catalyzed decarboxylative geranyl
migration and aromatization sequence as the key steps.10 More
recently, the Miranda group reported a short-step synthesis of
hericerin using an ether−phenol rearrangement and Pd(OAc)2-
catalyzed carbonylative ring closure.4e However, previous
reports except for Rao’s achievement focused only on the
synthesis of the geranyl-substituted resorcinols lacking an
oxygen functionality on their side chains.
racemates. This study also implied that hericenols C and D are
artifacts resulting from degradation of hericenol B. In addition,
the total synthesis of hericenone B led to the revision of the
structure of the natural product as the carbonyl regioisomer of
the original assignment.
RESULTS AND DISCUSSION
■
Figure 1 shows the structure relationships among naturally
occurring geranyl resorcylates. The members are categorized on
the basis of the substitution patterns of the resorcinol core.
They contain a variety of functional groups, including alcohols,
ethers, aldehydes, ketones, esters, lactones, and lactams, as well
as a pentasubstituted benzene ring, which makes their syntheses
more challenging despite their compact structures. The side
chains can be categorized into two general groups, one
containing an oxygen functionality at the C5′ or the C7′
position and one without. In our recent achievements, the C5′-
deoxo series including hericenone J, hericene A, and hericerin
were synthesized by using the geranyl phthalide 1a as a
common precursor.4d,9 This intermediate was readily prepared
by a Michael−Claisen condensation, a CuBr2-mediated one-pot
multifunctionalization, and a CsF-assisted Stille coupling as key
reactions (Scheme 1).9 However, synthesis of the C5′-oxidized
series remained unexplored because it was anticipated that the
regioselective oxidation of the geranyl-containing products at
the late stage of the synthesis would be difficult due to the
presence of multiple allylic carbons. Therefore, we planned to
incorporate the oxygen functionality at the early stage to
prepare C5′-oxidized natural products such as hericenones A−I,
hericenol B, and erinacerins.
With ready availability and step economy in mind, 3-methyl-
2-butenal (8) and isoprene (9) were chosen as starting
materials (Scheme 2). Our initial plan was to use a dithiane as
the protecting group of the C5′-carbonyl and build up the side
chain (7) via alkylation.11 This approach emerged from Rao’s
In this article, we report the divergent total syntheses of eight
natural products, hericenones A, B, and I, hericenols B−D, and
erinacerins A and B, all of which include an oxygen
functionality on their side chains. Among these eight natural
products, hericenol B and erinacerin B were synthesized as
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The alternate plan for the synthesis of the side chain was to
use a cyanohydrin derivative as the alkylation precursor18 and
to protect the C5′-functional group as the silyl ether, a fluoride-
removable protective group, as it was later found that the C5′-
allylic alcohol was highly susceptible to acidic conditions (vide
infra). Thus, the ethoxyethyl (EE)-protected cyanohydrin 14
was readily prepared from 8 in three conventional steps
(Scheme 4). The benzoyl-protected allylic bromide 15 was
synthesized from isoprene (9) via bromination and substitution
according to the literature.19,20 The key alkylation18 was
achieved by adding LiN(TMS)2 to a mixture of 14 (1 equiv)
and 15 (1 equiv). Remarkably, alkylation was complete within
30 min at −78 °C, providing the desired product 16 in
quantitative yield. The EE group of 16 was removed by acidic
methanol, and subsequent treatment with Et3N generated the
corresponding ketone, which was reduced without isolation by
Scheme 1. Previous Synthesis of the Geranyl Phthalide 1a
NaBH in the presence of CeCl ·7H O (Luche reduction) to
̈
4
3
2
Scheme 2. Retrosynthesis of the Side Chain
afford the C5′-allylic alcohol. It should be noted that the ketone
intermediate was unstable to basic treatment and a brief
exposure to Et3N (preferably less than 10 min) was essential to
suppress undesired elimination of benzoate, which resulted in
the formation of a conjugated trienone. Next, TBS protection
of the resultant alcohol provided the corresponding silyl ether,
the benzoyl group of which was removed by DIBAL to provide
allylic alcohol 17 in 55% overall yield from 15. One-pot
stannylation14 of 17 afforded the requisite allylstannane 7b in
90% yield. Although the total synthetic steps were increased in
comparison to those with the dithiane-based strategy, several
cleaner, high-yielding reactions allowed for gram-scale prepara-
tion of the side chain.
With the two coupling partners in hand, the divergent
synthesis of the C5′-oxidized geranyl resorcylates began with
the assembly of allylstannane 7b and the MOM-protected aryl
bromide 69 under modified Stille coupling conditions.16 In
comparison to the dithiane substrate 7a, 7b was reactive to
coupling conditions and the desired product 18a was formed in
moderate yield. It is noteworthy that the TBS ether was
tolerated by the CsF-mediated coupling conditions. As the silyl
protective group at C5′ was appropriate for subsequent
transformations, further exploration was dedicated to opti-
mization of the phenolic protective group. While various
phthalides with different protective groups were screened,
results for the coupling reaction could not be improved by
protection with EE (4% yield), acetyl (0% yield), TBS (0%
yield), or 2-(trimethylsilyl)ethoxymethyl (SEM) (42% yield).
Accordingly, we carried the MOM-protected substrate 18a
forward.
total synthesis of hericenone A, in which the side chain was
elaborated by the dithiane chemistry.2b
Thus, dithioacetal 1012 obtained by thioacetalization of 8 was
lithiated by n-BuLi at −20 °C and then alkylated with allyl
bromide 1113 prepared in three steps from 9 to provide the
desired product 12 in 90% yield (Scheme 3). It was critical to
Scheme 3. Dithiane-Based Strategy To Prepare the Common
Intermediate 13
Among the C5′-oxidized natural resorcinols, we selected
hericenone A as the initial target. While the isolation and
structure determination of hericenone A were first achieved in
1990, its structure was later revised by Rao et al. as the carbonyl
regioisomer of the original structure.2 Thus, the lactone moiety
of 18a was reduced by LiAlH4 and then reoxidized with
Ag2CO3 on Celite (Fetizon oxidation)21 to provide the
carbonyl-inverted lactone 20 as the major product (74% in
two steps), accompanied by its isomer 18a (23% in two steps).
Further research indicated that the allylic ether portion of 20
was highly susceptible to acidic conditions. For instance, when
20 was exposed to MOM deprotection conditions with Me2BBr
at −78 °C,9,22 rapid formation of triene 22 resulted. Hence, the
TBS group of 20 was first removed by TBAF and the resultant
C5′-alcohol was oxidized with PhI(OAc)2/2-azaadamantane N-
oxyl (AZADO)23 to provide the corresponding ketone 21. As a
keep the reaction temperature at −78 °C during alkylation to
obtain a high yield. After deprotection, the resulting alcohol was
converted into allylstannane 7a by a one-pot method.14 The
Stille coupling15 between 7a and the phthalide core 69 was
problematic, however. Even under the optimized conditions
established in coupling between 6 and geranyl tributyltin (cf.
Scheme 19,16), no coupling product 13 was detected. While the
precise cause of this failure is as yet not known, it is speculated
that the neighboring thioketal moiety reduces the activity of the
catalyst possibly through intramolecular coordination between
sulfur and the allylpalladium that was formed by trans-
metalation of the allylstannane. Since further screening of the
coupling conditions was not fruitful and conversion of thioketal
(e.g., 12) to the corresponding ketal or ketone resulted in low
yield,17 the dithiane-based strategy was abandoned.
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Scheme 4. Total Syntheses of Hericenones A and I, ( )-Hericenol B, and ( )-Erinacerin B
result of screening the oxidation conditions applied to such an
electron-rich resorcinol, PhI(OAc)2/AZADO was found to be
superior to PhI(OAc)2/TEMPO,24 Dess−Martin period-
inane,25 and Swern conditions.26 Removal of the MOM
protective group in 21 with Me2BBr in the presence of excess
amylene27 gave a mixture of two products, including hericenone
A (23) and its bromide-conjugated addition product at C7′.
The mixture was subsequently treated with Et3N to induce β-
elimination of the bromide to furnish hericenone A (23) in
78% overall yield from 21. The spectral data for the synthetic
product 23 were identical with those reported in previous
papers.2
We next turned our attention to the synthesis of hericenone
I,3c as it can be presumed that it was biosynthetically generated
from hericenone A via acid-catalyzed cyclization. Thus,
synthetic hericenone A (23) was treated with a couple of
acids to induce cyclization. While 23 was inactive to PPTS in
CH2Cl2, it gradually cyclized into hericenone I (24) upon
treatment with CSA at 70 °C. The cyclization was almost
complete after 3 days, and 24 was isolated in 74% yield. The
spectral data for 24 were exactly the same as those for the
natural product,3c which constituted the first total synthesis of
hericenone I.
oxidation of the parent C5′-deoxy molecule or enzymatic
asymmetric reduction of hericenone A. Before addressing this
intriguing issue, we undertook the racemic synthesis of
erinacerin B. To promote selective 1,2-reduction, the synthetic
hericenone A (23) was submitted to Luche conditions.
̈
Reduction proceeded within 1 min, and ( )-erinacerin B
(25) was isolated in 73% yield. While the NMR data for natural
erinacerin B were measured in CDCl3,7 our synthetic sample
was only slightly soluble in CDCl3, which did not permit
comparison of the 13C NMR spectra in the same solvent.
Furthermore, our research proved that 25 gradually degraded in
CDCl3. It can be presumed that the instability of 25 arises from
the allylic alcohol structure of the side chain.
Next, our research was directed to the synthesis of hericenol
B derived from submerged cultures of a Streum species.6 As the
labile nature of ( )-erinacerin B (25) became apparent, we
decided to synthesize ( )-hericenol B from the key
intermediate 18a instead of 25. After extensive screening of
deprotection conditions acceptable for such an acid-labile C5′-
siloxy-containing substrate, the combination of TiCl4 and Et3N
in the presence of excess amylene proved the best. This
combination reproducibly generated the deprotected phenol
18b without affecting the C5′-allylic ether portion. The lactone
moiety of 18b was then reduced with LiAlH4, and the TBS
group of the resulting triol 19b was removed by TBAF to
provide ( )-hericenol B (26) in 84% isolated yield over two
steps. The spectral data, except for the optical rotation values,
The structure of erinacerin B isolated by Kikuchi et al. in
20057 is a reduced form of hericenone A. Notably this
compound was isolated as an optically active molecule with a
positive specific optical rotation. This implies that biosyntheti-
cally erinacerin B is generated by enzymatic asymmetric
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Scheme 5. Total Syntheses of Hericenols C and D
for the synthetic compound (26) and the natural product6 were
all identical.
Scheme 6. Total Syntheses of Hericenone B and Erinacerin
A
We next focused on the synthesis of hericenols C and D,6
since it can be supposed that they are derived biosynthetically
from hericenol B via allylic and benzylic substitutions. In the
course of our investigations on model substrates, we
serendipitously observed that such substitution reactions were
triggered by acid catalysts. Encouraged by our original findings,
synthetic ( )-hericenol B (26) was treated with PPTS in
MeOH after silica gel treatment28 (Scheme 5). As expected,
hericenol D was generated in 65% yield, accompanied by the
formation of the C5′-methoxy substituted product 29 (27%
yield). TLC analyses indicated that allylic substitution at the
side chain moiety was rapid, while substitution at the benzylic
position gradually occurred over hours to days. The rationale
for the regioselective substitution at the upper benzyl alcohol
lies in the formation of the o-quinone methide intermediates i
and ii generated by acid-catalyzed dehydration of 26. When the
solvent was replaced by MeOH/H2O (1/1), a small amount of
hericenol C (28) was formed (22% yield) along with hericenol
D (27) (17% yield) and their regioisomers 30 (8% yield) and
29 (10% yield). Anke and Sterner et al. had performed repeated
silica gel column chromatographic separations followed by
preparative HPLC in the isolation of the hericenols.6 The
samples were eluted with a linear gradient of H2O/MeOH.6
Given these observations, it is possible that hericenols C and D
might be artifacts resulting from degradation of hericenol B.
However, it cannot completely be ruled out that these
compounds actually occur in natural sources.
Next, we focused our attention on the synthesis of lactam-
containing natural products such as hericenone B and
erinacerin A. Recently, we achieved the first total synthesis of
hericerin, a 5′-deoxo analogue of hericenone B, and confirmed
that the actual structure of hericerin was the carbonyl
regioisomer of the reported structure.4d Our data were later
supported by Miranda’s total synthesis, in which the structure
of the synthetic sample was unambiguously established by X-ray
crystallographic analysis.4e As the structure and the spectro-
scopic data for hericenone B are highly correlated with those of
hericerin, we were convinced that natural hericenone B had an
inverse carbonyl group as well. With this expectation in mind,
the synthesis commenced with the carbonyl-inverted phthalide
20 (Scheme 6). Whereas either direct lactamization under
thermal conditions4d,29 or Me3Al-mediated amidation4d,30
resulted in mostly decomposition of the substrate, application
of the transamidation conditions with boric acid developed by
Nguyen et al.31 provided amide 31 in 95% yield. It should be
mentioned that such a mild amidation has a great deal of
potential for acid-sensitive substrates, as shown in this case.
Next, a two-step cyclization sequence4d,32 afforded the expected
lactam 33, which was subjected to deprotection and oxidation23
to provide ketone 35. As established earlier, final deprotection
of the phenolic hydroxyl group was undertaken with Me2BBr in
the presence of excess amylene to suppress undesired addition
of HBr to the C2′−C3′ double bond. This careful procedure
successfully furnished hericenone B (36) after treatment with
Et3N in 61% yield. The 1H and 13C NMR data for the synthetic
compound 36 were in accordance with those reported in the
literature,2a which unambiguously revised the structure of
hericenone B. Very recently, Lee and co-workers isolated the
same product from the fruiting bodies of H. erinaceum and
named it isohericenone.33 Our data are also in good agreement
with their spectral data. Accordingly, it is suggested that the two
natural products isolated by different researchers are probably
identical.
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Erinacerin A, discovered in 2005,7 can be regarded as a
cyclized product of newly identified hericenone B (36).
Therefore, we undertook an acid-catalyzed cyclization of 36.
TLC analysis indicated gradual generation of erinacerin A (37)
over a few days. Isolation by chromatography provided 37 in
almost quantitative yield. The spectral data for the synthetic
sample (37) matched the previously published physical data.7
In summary, we have achieved total syntheses of eight
natural products derived from H. erinaceum and a Stereum
species. Our strategy was based on divergent assembly of a
geranyl resorcylate library using the suitably protected C5′-
oxygen incorporated geranyl phthalide 18a as a common
intermediate. This intermediate (18a) was efficiently prepared
by a CuBr2-mediated multifunctionalization reaction and a CsF-
assisted Stille coupling reaction as key reactions. The C5′-
oxygen functionality was installed by alkylation of a
cyanohydrin ether, which was later protected as the TBS
ether until final transformations. From a common synthetic
intermediate, total syntheses of hericenones A (23), B (36),
and I (24), hericenols B (26), C (28) and D (27), and
erinacerins A (37) and B (25) were achieved. Among the eight
natural products, hericenol B and erinacerin B were synthesized
as racemates. The reported structure for hericenone B was
unambiguously revised. Moreover, this study showed that
hericenols C and D could be generated from hericenol B via
allylic and benzylic substitutions. The present investigation not
only provides a natural product library for SAR studies but also
offers information to deduce the biosynthetic pathway of
naturally occurring geranyl resorcylates. The syntheses of other
members of this family are ongoing in our laboratory.
15) to give the title compound 12 (1.09 g, 3.17 mmol, 90%) as a pale
yellow oil: H NMR (300 MHz, CDCl3) δ 5.52−5.47 (m, 2H), 4.64
1
(dd, 1H, J = 4.4, 3.2 Hz), 4.22 (dd, 1H, J = 12, 8.8 Hz), 4.09 (dd, 1H, J
= 12, 7.2 Hz), 3.91−3.86 (m, 1H), 3.52−3.47 (m, 1H), 2.91−2.78 (m,
4H), 2.82 (s, 2H), 2.04−1.48 (m, 8H), 1.95 (d, 3H, J = 1.2 Hz), 1.77
(d, 3H, J = 1.2 Hz), 1.58 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
138.7, 135.6, 128.0, 127.0, 97.7, 63.4, 62.5, 52.8, 50.5, 30.9, 28.0, 27.7,
25.6, 25.5, 19.8, 19.5, 18.3; FT-IR (film on ZnSe) 2938, 1652, 1442,
1384, 1354, 1320, 1275, 1200, 1183, 1158, 1117 cm−1; HRMS (ESI-
pos) m/z calcd for C18H31O2S2 [M + H]+ 343.1760, found 343.1756.
(E)-Tributyl(3-methyl-4-(2-(2-methylprop-1-en-1-yl)-1,3-di-
thian-2-yl)but-2-en-1-yl)stannane (7a). To a solution of 12 (1.06
g, 3.09 mmol) in MeOH (31 mL) was added PPTS (156 mg, 0.621
mmol). The mixture was stirred for 1.5 h at room temperature and
then warmed to 50 °C and stirred for 45 min. Et3N (866 μL, 6.21
mmol) was added, and the resulting mixture was concentrated. The
residue was purified by flash chromatography (n-hexane/EtOAc = 5)
to give the corresponding alcohol (760 mg, 2.94 mmol, 95%) as a pale
1
yellow oil: H NMR (400 MHz, CDCl3) δ 5.57 (td, 1H, J = 6.8, 1.2
Hz), 5.51 (br s, 1H), 4.18 (d, 2H, J = 6.4 Hz), 2.93−2.78 (m, 4H),
2.80 (s, 2H), 2.05−1.92 (m, 2H), 1.95 (d, 3H, J = 1.2 Hz), 1.78 (s,
6H); 13C NMR (75 MHz, CDCl3) δ 138.6, 134.6, 129.6, 128.0, 59.3,
52.7, 50.3, 27.9, 27.7, 25.3, 19.4, 18.2; FT-IR (film on ZnSe) 3400,
2929, 2902, 1652, 1441, 1423, 1383, 1356, 1275, 1242, 1194, 1124,
1091 cm−1; HRMS (FAB) m/z calcd for C13H23OS2 [M + H]+
259.1190, found 259.1193. To a solution of the alcohol (424 mg, 1.64
mmol) in THF (3.3 mL) was added n-BuLi (1.54 M solution in
hexane, 1.07 mL, 1.65 mmol) at −78 °C. After the mixture was stirred
for 30 min, MsCl (130 μL, 1.64 mmol) was added. After the mixture
was stirred for 75 min, n-Bu3SnLi in THF (10 mL) was added
dropwise (n-Bu3SnLi was prepared as follows: to a solution of i-Pr2NH
(700 μL, 5.00 mmol) in THF (5.5 mL) was added n-BuLi (1.53 M
solution in hexane, 3.20 mL, 4.93 mmol) at 0 °C; after the mixture was
stirred for 50 min at 0 °C, n-Bu3SnH (1.42 g, 4.89 mmol) in THF (4.5
mL) was added and the mixture was stirred for 40 min at 0 °C). After
it was stirred for 2 h at −78 °C, the solution was warmed to room
temperature and quenched after 3.5 h with H2O. The resulting mixture
was extracted with EtOAc (3×), and the combined organic layer was
washed with brine, dried over anhydrous MgSO4, and concentrated.
The residue was purified by flash chromatography (hexane/Et3N = 50
→ hexane/EtOAc/Et3N = 100/1/2) to give allylstannane 7a (649 mg,
EXPERIMENTAL SECTION
■
General Techniques. All reactions utilizing air- or moisture-
sensitive reagents were performed under an atmosphere of argon.
Commercially available dry solvents were used for DMF, CH2Cl2,
THF, and MeOH. Triethylamine and 1,2-dichloroethane were distilled
from CaH2. Reactions were monitored by thin-layer chromatography
(TLC) carried out on 0.25 mm silica gel plates (60-F254) that were
analyzed by fluorescence upon 254 nm irradiation or by staining with
p-anisaldeyde/AcOH/H2SO4/EtOH, 12MoO3·H3PO4/EtOH, or
(NH4)6Mo7O24·4H2O/H2SO4. The products were purified by either
open chromatography on silica gel (spherical, neutral, 70−230 μm) or
flash chromatography on silica gel (spherical, neutral, 40−50 μm) and,
if necessary, HPLC equipped with a prepacked column using hexane/
EtOAc as eluent. NMR spectra were recorded with a 300 MHz (1H,
300 MHz; 13C, 75 MHz) or a 400 MHz (1H, 400 MHz; 13C, 100
MHz) spectrometer and referenced to the solvent peak at 7.26 ppm
(1H) and 77.16 ppm (13C) for CDCl3. Splitting patterns are indicated
as follows: br, broad; s, singlet; d, doublet; t, triplet; q, quartet; sept,
septet; m, multiplet. Infrared spectra were recorded with a FT/IR
spectrometer and reported as wavenumbers (cm−1). Low- and high-
resolution FAB mass spectra were recorded with a double-focusing
magnetic sector mass spectrometer in positive or negative ion mode.
High-resolution ESI, APCI, and APPI mass spectra were recorded with
an Orbitrap analyzer in positive or negative ion mode.
1
1.22 mmol, 74%) as a colorless oil: H NMR (300 MHz, CDCl3) δ
5.51 (br t, 1H, J = 6.6 Hz), 5.51 (br s, 1H), 2.93−2.72 (m, 6H), 2.04−
1.85 (m, 2H), 1.95 (d, 3H, J = 1.2 Hz), 1.76 (d, 3H, J = 1.2 Hz), 1.65
(br s, 3H), 1.70−1.43 (m, 8H), 1.34−1.22 (m, 6H), 0.91−0.82 (m,
15H); 13C NMR (75 MHz, CDCl3) δ 137.9, 129.7, 128.6, 124.6, 53.8,
50.6, 29.3, 27.9, 27.7, 27.5, 25.7, 19.4, 17.7, 13.8, 11.3, 9.7; FT-IR (film
on ZnSe) 2952, 2926, 2871, 2852, 1647, 1464, 1156, 1442, 1422, 1375,
1355, 1292, 1274, 1243, 1194, 1118 cm−1. Anal. Calcd for C25H48S2Sn:
C, 56.50; H, 9.10. Found: C, 56.53; H, 8.78.
2-(1-Ethoxyethoxy)-4-methylpent-3-enenitrile (14). To a
solution of 3-methyl-2-butenal (8; 20.0 g, 238 mmol) in CH2Cl2
(119 mL) were added TMSCN (32.7 mL, 262 mmol) and Et3N (3.3
mL, 23.8 mmol) The mixture was stirred at room temperature for 7 h
and concentrated. The resulting α-cyano TMS ether (48.6 g) was
dissolved in THF (95 mL), to which was added 1 M aqueous HCl (24
mL). The mixture was stirred at room temperature for 30 min and
extracted with EtOAc (3×). The combined organic layer was washed
with brine, dried over anhydrous MgSO4, and concentrated to give the
corresponding cyanohydrin (43.0 g) as a yellow oil. To a solution of
crude cyanohydrin (43.0 g) in CH2Cl2 (119 mL) were added ethyl
vinyl ether (114 mL, 1.19 mol) and PPTS (5.85 g, 23.8 mmol). The
solution was stirred at room temperature for 1.5 h, which was followed
by the addition of Et3N (33.0 mL, 238 mmol). The resulting mixture
was concentrated and purified by open chromatography (hexane/
EtOAc = 10) to give the title compound 14 (44.5 g, quant) as a pale
pink oil: 1H NMR (400 MHz, CDCl3) δ 5.37−5.28 (m, 1H), 5.13 (d,
0.5H, J = 8.7 Hz), 5.03 (d, 0.5H, J = 9.0 Hz), 4.96 (q, 0.5H, J = 5.4
Hz), 4.88 (q, 0.5H, J = 5.4 Hz), 3.70−3.46 (m, 2H), 1.79 (d, 3H, J =
0.9 Hz), 1.74 (d, 3H, J = 1.5 Hz), 1.39 (d, 3H, J = 5.7 Hz), 1.36 (d,
(E)-2-((3-Methyl-4-(2-(2-methylprop-1-en-1-yl)-1,3-dithian-
2-yl)but-2-en-1-yl)oxy)tetrahydro-2H-pyran (12). To a solution
of dithiane 1012 (1.22 g, 7.02 mmol) in THF (34 mL) was added n-
BuLi (1.63 M in hexane, 4.30 mL, 7.02 mmol) at −20 °C. After it was
stirred for 2 h at −20 °C, the reaction mixture was cooled to −78 °C
followed by the addition of allyl bromide 1113 (874 mg, 3.51 mmol) in
THF (20 mL). After it was stirred for 14 h at −78 °C, the reaction
mixture was quenched with 1 M aqueous HCl. The resulting mixture
was extracted with hexane (3×), and the combined organic layer was
washed with brine, dried over anhydrous Na2SO4, and concentrated.
The residue was purified by flash chromatography (n-hexane/EtOAc =
5232
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3H, J = 5.4 Hz), 1.22 (t, 3H, J = 7.2 Hz, EE), 1.21 (t, 3H, J = 7.2 Hz,
EE); 13C NMR (100 MHz, CDCl3) δ 141.5, 141.4, 118.9, 118.7, 118.2,
117.9, 98.8, 98.5, 60.8, 60.6, 59.9, 59.2, 25.7, 19.6, 18.5, 15.3, 15.1; FT-
IR (film on ZnSe) 2979, 2937, 2918, 2237, 1675, 1445, 1387, 1379,
1342, 1310, 1200, 1141, 1082 cm−1; HRMS (ESI-pos) m/z calcd for
C10H17O2NNa [M + Na]+ 206.1152, found 206.1152.
the MeOH was removed by evaporation, and the residue was treated
with EtOAc. The precipitate was carefully removed by decantation and
filtration through a pad of Celite. The combined filtrate was
concentrated and extracted with EtOAc (5×). The combined organic
layer was washed with brine, dried over anhydrous MgSO4, and
concentrated to give the corresponding allylic alcohol (16.6 g) as a
yellow oil, which was used for the next reaction without further
purification. The analytical sample was obtained by flash chromatog-
(E)-4-Bromo-3-methylbut-2-en-1-yl Benzoate (15).19 To a
solution of isoprene (9; 31.1 mL, 309 mmol) in 1-chlorobutane (309
mL) was added bromine (24.7 g, 155 mmol) through a dropping
funnel over 20 min at −40 °C. After it was stirred for 2.5 h at −40 °C,
the reaction mixture was warmed to room temperature and the
solution was poured into water. The organic layer was washed
successively with aqueous Na2S2O3 solution, aqueous saturated
NaHCO3 solution, and brine. The resulting organic layer was dried
over anhydrous MgSO4 and concentrated to give (E)-1,4-dibromo-2-
methyl-2-butene (29.4 g) as a yellow oil. To a solution of the above
product (27.9 g) in DMF (245 mL) was added sodium benzoate (19.4
g, 135 mmol) at 0 °C. The mixture was stirred for 3.5 h at room
temperature and 0.5 h at 40 °C. An additional portion of sodium
benzoate (1.79 g, 12.2 mmol) was added at 0 °C, and the stirring was
continued for 1 h at 40 °C. The reaction mixture was quenched by the
addition of water and extracted with EtOAc (3×). The combined
organic layer was washed with water and brine, dried over anhydrous
MgSO4, and concentrated. The residue was purified by repeated flash
chromatography (n-hexane → n-hexane/EtOAc = 60 → 30 → 10 then
n-hexane/EtOAc = 500 → 300 → 100 → 30 → 10) to give the title
compound 15 (18.5 g, 68.9 mmol, 47% for two steps) as a colorless
1
raphy (n-hexane/EtOAc = 5): H NMR (300 MHz, CDCl3) δ 8.02−
7.97 (m, 2H), 7.52−7.45 (m, 1H), 7.40−7.33 (m, 2H), 5.51 (br t, 1H,
J = 6.9 Hz), 5.16−5.10 (m, 1H), 4.80 (br d, 2H, J = 6.6 Hz), 4.51−
4.43 (m, 1H), 2.27 (dd, 1H, J = 14, 8.1 Hz), 2.15 (br dd, 1H, J = 14,
5.7 Hz), 1.77 (br s, 3H), 1.65 (br s, 3H), 1.62 (br s, 3H); 13C NMR
(75 MHz, CDCl3) δ 166.5, 138.8, 134.7, 132.8, 130.3, 129.5, 128.2,
127.5, 121.6, 66.4, 61.6, 47.7, 25.6, 18.1, 16.8; FT-IR (film on ZnSe)
3422, 3061, 3031, 2972, 2931, 1720, 1602, 1585, 1451, 1377, 1340,
1315, 1273, 1176, 1111 cm−1; HRMS (FAB) m/z calcd for C17H23O3
[M + H]+ 275.1647, found 275.1639. To a solution of the crude
alcohol (16.6 g) in DMF (61 mL) were added imidazole (12.4 g, 182
mmol) and TBSCl (10.9 g, 72.6 mmol). The mixture was stirred for 30
min at 40 °C and then cooled to 0 °C and diluted with n-hexane and
water. The resulting mixture was extracted with n-hexane (2×), and
the combined organic layer was washed with brine, dried over
anhydrous MgSO4, and concentrated to give the corresponding TBS
ether (23.9 g) as a pale yellow oil, which was used for the next reaction
without further purification. The analytical sample was obtained by
1
flash chromatography (n-hexane/EtOAc = 50): H NMR (300 MHz,
1
CDCl3) δ 8.07−8.03 (m, 2H), 7.57−7.51 (m, 1H), 7.45−7.39 (m,
2H), 5.50 (br t, 1H, J = 7.2 Hz), 5.11 (dqq, 2H, J = 8.7, 1.5, 1.2 Hz),
4.83 (d, 1H, J = 6.9 Hz), 4.82 (d, 1H, J = 7.2 Hz), 4.47 (ddd, 1H, J =
8.7, 7.5, 5.4 Hz), 2.27 (dd, 1H, J = 13, 7.5 Hz), 2.10 (dd, 1H, J = 13,
5.4 Hz), 1.79 (br s, 3H), 1.66 (d, 3H, J = 1.2 Hz), 1.60 (d, 3H, J = 1.5
Hz), 0.85 (s, 9H), 0.01 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 166.7,
139.4, 132.9, 131.3, 130.6, 129.7, 129.3, 128.3, 121.2, 68.8, 61.9, 48.6,
25.9, 25.7, 18.3, 17.5, −4.2, −4.8; FT-IR (film on ZnSe) 3063, 3033,
2929, 2856, 1721, 1674, 1603, 1586, 1472, 1461, 1451, 1376, 1361,
1332, 1314, 1270, 1176, 1107 cm−1; HRMS (ESI-pos) m/z calcd for
C23H36O3NaSi [M + Na]+ 411.2326, found 411.2325. To a solution of
the crude TBS ether (23.9 g) in CH2Cl2 (121 mL) was added
DIBALH (1.0 M in n-hexane, 133 mL, 133 mmol) at −78 °C. The
mixture was stirred for 1 h at −78 °C and quenched with aqueous
Rochelle salt solution. The resulting mixture was diluted with n-hexane
and stirred vigorously at room temperature for 14 h. The organic layer
was separated, and the aqueous phase was extracted with EtOAc (4×).
The combined organic layer was washed with brine, dried over
anhydrous MgSO4, and concentrated. The residue was purified by
repeated open chromatography (n-hexane → n-hexane/EtOAc = 50 →
20 → 10 → 5 then n-hexane → n-hexane/EtOAc = 100 → 50 → 30 →
20 → 10 → 5) to give allylic alcohol 17 (10.8 g, 37.8 mmol, 55% for
oil: H NMR (300 MHz, CDCl3) δ 8.07−8.03 (m, 2H), 7.59−7.54
(m, 1H), 7.47−7.41 (m, 2H), 5.86 (br t, 1H, J = 6.0 Hz), 4.86 (br d,
2H, J = 6.6 Hz), 3.98 (br s, 2H), 1.92 (br s, 3H); 13C NMR (75 MHz,
CDCl3) δ 166.5, 137.5, 133.2, 130.2, 129.8, 128.5, 124.4, 61.5, 39.6,
15.4; FT-IR (film on ZnSe) 3062, 3032, 2956, 1721, 1602, 1585, 1491,
1451, 1388, 1380, 1335, 1314, 1271, 1221, 1201, 1176, 1111 cm−1;
HRMS (FAB) m/z calcd for C12H14BrO2 [M + H]+ 269.0177, found
269.0150.
(E)-5-Cyano-5-(1-ethoxyethoxy)-3,7-dimethylocta-2,6-dien-
1-yl Benzoate (16). To a solution of α-cyano ether 14 (12.6 g, 68.9
mmol) and allylic bromide 15 (18.5 g, 68.9 mmol) in THF (138 mL)
was added (TMS)2NLi (1.0 M solution in THF, 82.7 mL, 82.7 mmol)
at −78 °C. After it was stirred for 30 min at −78 °C, the reaction
mixture was quenched with saturated aqueous NH4Cl solution. Most
of the THF was removed by evaporation, and the residue was
extracted with hexane (2×). The combined organic layer was washed
with phosphate buffer (pH 3.9) and brine and dried over anhydrous
MgSO4. Concentration of the solution gave the alkylation product 16
(27.4 g) as a pale yellow oil, which was used for the next reaction
without further purification. The analytical sample was obtained by
1
flash chromatography (n-hexane/EtOAc = 20 → 10): H NMR (300
MHz, CDCl3, 2/1 diastereomeric mixture) δ 8.05−8.01 (m, 2H),
7.56−7.50 (m, 1H), 7.44−7.38 (m, 2H), 5.72−5.65 (m, 1H), 5.30−
5.28 (m, 0.33H), 5.14−5.11 (m, 0.67H), 5.02 (q, 0.67H, J = 5.4 Hz),
4.96 (q, 0.33H, 5.4 Hz), 4.86 (d, 2H, J = 6.9 Hz), 3.67−3.40 (m, 2H),
2.79−2.53 (m, 2H), 1.96−1.88 (m, 6H), 1.77−1.76 (m, 3H), 1.37 (d,
1H, J = 5.1 Hz), 1.31 (d, 2H, J = 5.4 Hz), 1.20 (t, 2H, J = 6.9 Hz), 1.16
(t, 1H, J = 6.9 Hz); 13C NMR (75 MHz, CDCl3, 2/1 diastereomeric
mixture) δ 166.5, 140.9, 139.1, 135.5, 132.9, 130.4, 129.6, 128.4, 125.6,
125.5, 123.1, 121.6, 120.3, 119.5, 98.5, 97.2, 74.4, 73.4, 61.5, 61.4, 60.0,
50.7, 50.2, 27.3, 27.2, 21.1, 20.8, 19.0, 18.9, 18.5, 18.4, 15.2, 15.0; FT-
IR (film on ZnSe) 3062, 2978, 2934, 2227, 1720, 1665, 1602, 1585,
1451, 1382, 1342, 1314, 1271, 1176 cm−1; HRMS (FAB) m/z calcd
for C22H30NO4 [M + H]+ 372.2175, found 372.2183.
(E)-5-((tert-Butyldimethylsilyl)oxy)-3,7-dimethylocta-2,6-
dien-1-ol (17). To a solution of crude 16 (27.4 g) in MeOH (138
mL) was added TsOH·H2O (1.31 g, 6.89 mmol). After it was stirred
for 20 min at room temperature, the solution was cooled to 0 °C
followed by the addition of Et3N (14.3 mL, 103 mmol). After the
mixture was stirred for 10 min at 0 °C, a solution of CeCl3·7H2O (51.3
g, 138 mmol) in MeOH (138 mL) and NaBH4 (6.52 g, 172 mmol)
were successively added. After it was stirred for 15 min at 0 °C, the
reaction mixture was quenched with phosphate buffer (pH 7). Most of
1
four steps) as a pale yellow oil: H NMR (300 MHz, CDCl3) δ 5.39
(br t, 1H, J = 6.9 Hz), 5.08 (dsept, 1H, J = 8.4, 1.5 Hz), 4.42 (ddd, 1H,
J = 8.4, 7.8, 5.4 Hz), 4.10 (br d, 2H, J = 6.9 Hz), 2.19 (dd, 1H, J = 13,
7.8 Hz), 2.03 (dd, 1H, J = 13, 5.4 Hz), 1.67 (br s, 3H), 1.65 (d, 3H, J =
1.5 Hz), 1.58 (d, 3H, J = 1.5 Hz), 0.83 (s, 9H), −0.02 (s, 3H), −0.04
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 136.5, 131.2, 129.4, 126.4,
69.0, 59.4, 48.6, 25.9, 25.7, 18.3, 17.1, −4.2, −4.8; FT-IR (film on
ZnSe) 3352, 2956, 2929, 2857, 1673, 1473, 1463, 1444, 1376, 1361,
1254, 1074 cm−1; HRMS (ESI-pos) m/z calcd for C16H32O2NaSi [M
+ Na]+ 307.2064, found 307.2059.
(E)-tert-Butyl((2,6-dimethyl-8-(tributylstannyl)octa-2,6-dien-
4-yl)oxy)dimethylsilane (7b). To a solution of alcohol 17 (3.95 g,
13.9 mmol) in THF (46 mL) was added n-BuLi (1.60 M solution in
hexane, 8.67 mL, 13.9 mmol) at −78 °C. After the mixture was stirred
for 35 min, MsCl (1.10 mL, 13.9 mmol) was added. After this mixture
was stirred for 35 min, n-Bu3SnLi in THF was added (n-Bu3SnLi was
prepared as follows: to a solution of i-Pr2NH (6.24 mL, 44.4 mmol) in
THF (26 mL) was added n-BuLi (1.60 M solution in hexane, 26.0 mL,
41.6 mmol) at 0 °C; after the mixture was stirred for 25 min at 0 °C, n-
Bu3SnH (12.1 g, 41.6 mmol) in THF (15 mL) was added and the
mixture was stirred for 30 min at 0 °C). After it was stirred for 2 h at
5233
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−78 °C, the solution was gradually warmed to −40 °C over 3.5 h and
quenched with phosphate buffer (pH 7). The resulting mixture was
extracted with n-hexane (3×), and the combined organic layer was
washed with brine, dried over anhydrous MgSO4, and concentrated.
The residue was purified by repeated open chromatography (hexane/
Et3N = 100) to give allylstannane 7b (6.92 g, 12.4 mmol, 90%) as a
HRMS (FAB) m/z calcd for C26H39O6Si [M − CH3]+ 475.2516,
found 475.2509.
(E)-5-(3,7-Dimethyl-5-oxoocta-2,6-dien-1-yl)-6-methoxy-4-
(methoxymethoxy)isobenzofuran-1(3H)-one (21). To a solution
of TBS ether 20 (52.2 mg, 0.106 mmol) in THF (2.1 mL) was added
TBAF (1 M solution in THF, 638 μL, 0.638 mmol). The mixture was
stirred for 7 h at 40 °C and directly subjected to flash chromatography
(n-hexane/EtOAc = 1) to give the corresponding alcohol (49.0 mg) as
1
colorless oil: H NMR (300 MHz, CDCl3) δ 5.30 (br t, 1H, J = 8.4
Hz), 5.10 (dsept, 1H, J = 9.0, 1.2 Hz), 4.39 (dt, 1H, J = 9.0, 6.3 Hz),
2.20 (dd, 1H, J = 13, 6.6 Hz), 2.03 (dd, 1H, J = 13, 6.3 Hz), 1.67 (d,
3H, J = 1.2 Hz), 1.60 (d, 3H, J = 1.2 Hz), 1.57 (br s, 3H), 1.71−1.42
(m, 8H), 1.35−1.23 (m, 6H), 0.91−0.80 (m, 15H), 0.86 (s, 9H), 0.02
(s, 3H), 0.00 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 131.0, 129.8,
126.1, 125.9, 69.5, 49.1, 29.4, 27.5, 26.1, 25.9, 18.4, 16.7, 13.9, 10.8,
9.5, −4.1, −4.6; FT-IR (film on ZnSe) 2956, 2927, 2856, 1676, 1463,
1376, 1360, 1254, 1119, 1073 cm−1; HRMS (APPI-pos) m/z calcd for
C28H58ONaSiSn [M + Na]+ 581.3171, found 581.3178.
1
a colorless viscous oil: H NMR (300 MHz, CDCl3) δ 7.12 (s, 1H),
5.35 (s, 2H), 5.23 (br t, 1H, J = 6.9 Hz), 5.10 (dsept, 1H, J = 8.7, 1.2
Hz), 5.06 (s, 2H), 4.41 (td, 1H, J = 8.1, 5.4 Hz), 3.87 (s, 3H), 3.52 (s,
3H), 3.50 (dd, 1H, J = 14, 7.2 Hz), 3.43 (dd, 1H, J = 14, 6.9 Hz),
2.19−2.04 (m, 2H), 1.81 (br s, 3H), 1.67 (d, 3H, J = 1.2 Hz), 1.65 (d,
3H, J = 1.2 Hz); 13C NMR (75 MHz, CDCl3) δ 171.3, 159.7, 150.4,
135.0, 132.7, 129.0, 128.5, 127.5, 125.7, 125.6, 101.8, 97.2, 69.2, 65.9,
56.9, 56.3, 48.2, 25.8, 23.8, 18.3, 16.4; FT-IR (film on ZnSe) 3510,
2965, 2931, 1766, 1618, 1469, 1434, 1401, 1332, 1231, 1210, 1154,
1112 cm−1; HRMS (ESI-neg) m/z calcd for C21H28O6Cl [M + Cl]−
411.1580, found 411.1594. To a solution of the above alcohol (49.0
mg) in CH2Cl2 (1 mL) were added PhI(OAc)2 (206 mg, 0.638 mmol)
and 2-azaadamantane N-oxyl (1.6 mg, 0.011 mmol). The mixture was
stirred for 3 h at room temperature followed by the addition of
PhI(OAc)2 (103 mg, 0.319 mmol). After 40 min, the solution was
diluted with CH2Cl2 (2 mL) and quenched successively with saturated
aqueous NaHCO3 solution and saturated aqueous Na2S2O3 solution.
After it was stirred for 1.2 h, the mixture was extracted with EtOAc
(3×), and the combined organic layer was washed with brine, dried
over anhydrous MgSO4, and concentrated. The residue was purified by
flash chromatography (hexane/EtOAc = 3) to give ketone 21 (30.8
(E)-6-(5-((tert-Butyldimethylsilyl)oxy)-3,7-dimethylocta-2,6-
dien-1-yl)-5-methoxy-7-(methoxymethoxy)isobenzofuran-
1(3H)-one (18a). In a 20 mL two-necked round-bottom flask were
placed aryl bromide 6 (170 mg, 0.560 mmol), allylstannane 7b (624
mg, 1.12 mmol), (Ph3P)2PdCl2 (39.9 mg, 0.0569 mmol), and CsF
(169 mg, 1.11 mmol). DMF (2.8 mL) was added, and the mixture was
heated to 85 °C and stirred for 24 h. The precipitate that formed was
removed by filtration through a pad of Celite, and the filtrate was
extracted with EtOAc (3×) and water. The combined organic layer
was washed with brine, dried over anhydrous MgSO4, and
concentrated. The residue was purified by flash chromatography
(hexane/EtOAc = 3) to give the coupling product 18a (141 mg, 0.287
mmol, 51%) as a colorless solid: mp 83−85 °C; 1H NMR (300 MHz,
CDCl3) δ 6.64 (s, 1H), 5.36 (s, 2H), 5.20 (br t, 1H, J = 7.2 Hz), 5.16
(s, 2H), 5.04 (br d, 1H, J = 8.4 Hz), 4.42−4.34 (m, 1H), 3.88 (s, 3H),
3.57 (s, 3H), 3.43 (d, 1H, J = 7.2 Hz), 3.42 (d, 1H, J = 6.6 Hz), 2.13
(dd, 1H, J = 13, 7.5 Hz), 1.97 (dd, 1H, J = 13, 5.7 Hz), 1.78 (br s, 3H),
1.59 (d, 3H, J = 1.2 Hz), 1.54 (d, 3H, J = 1.2 Hz), 0.80 (s, 9H), −0.05
(s, 3H), −0.06 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 169.3, 164.2,
155.0, 148.6, 132.5, 130.8, 129.5, 124.7, 124.5, 109.2, 101.1, 99.0, 69.0,
68.7, 57.9, 56.2, 48.9, 25.9, 25.7, 23.1, 18.24, 18.18, 17.1, −4.3, −4.9;
FT-IR (film on ZnSe) 3100, 2929, 2856, 1739, 1606, 1471, 1431,
1404, 1366, 1336, 1303, 1292, 1251, 1233, 1206, 1158, 1126 cm−1;
HRMS (ESI-pos) m/z calcd for C27H42O6NaSi [M + Na]+ 513.2643,
found 513.2638.
(E)-5-(5-((tert-Butyldimethylsilyl)oxy)-3,7-dimethylocta-2,6-
dien-1-yl)-6-methoxy-4-(methoxymethoxy)isobenzofuran-
1(3H)-one (20). To a solution of lactone 18a (399 mg, 0.608 mmol)
in THF (6.1 mL) was added LiAlH4 (70.2 mg, 1.85 mmol) at 0 °C.
After it was stirred for 5 min at 0 °C, the reaction mixture was
quenched by the slow addition of water, EtOAc, and aqueous Rochelle
salt solution. The resulting mixture was stirred at room temperature
for 1 h and then extracted with EtOAc (3×). The combined organic
layer was washed with brine, dried over anhydrous MgSO4, and
concentrated to give diol 19a (384 mg) as a pale yellow oil. To a
solution of crude diol 19a (384 mg) in toluene (7.7 mL) was added
Ag2CO3 on Celite (ca. 50 wt %, 1.08 g, ca. 1.94 mmol). The
suspension was heated at reflux and stirred for 3 h. The precipitate was
removed by filtration through a pad of Celite and washed with EtOAc,
and the filtrate was concentrated. The residue was purified by flash
chromatography (n-hexane/EtOAc = 3) to give phthalide 20 (220 mg,
0.448 mmol, 74% for two steps) as a pale yellow viscous oil and
phthalide 18a (69.9 mg, 0.143 mmol, 23%) as a pale yellow solid. Data
for 20: 1H NMR (300 MHz, CDCl3) δ 7.12 (s, 1H), 5.36 (s, 2H), 5.15
(br t, 1H, J = 7.2 Hz), 5.05 (s, 2H), 5.01 (br d, 1H, J = 7.2 Hz), 4.38
(td, 1H, J = 7.8, 5.7 Hz), 3.87 (s, 3H), 3.53 (s, 3H), 3.43 (d, 2H, J =
7.2 Hz), 2.14 (dd, 1H, J = 13, 7.5 Hz), 1.97 (dd, 1H, J = 13, 5.1 Hz),
1.78 (d, 3H, J = 1.2 Hz), 1.60 (d, 3H, J = 1.2 Hz), 1.54 (d, 3H, J = 1.2
Hz), 0.80 (s, 9H), −0.05 (s, 3H), −0.07 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 171.6, 159.7, 150.5, 133.0, 130.9, 129.6, 129.2, 129.1, 125.5,
124.2, 101.8, 97.3, 69.3, 68.9, 57.0, 56.3, 49.0, 26.1, 26.0, 25.8, 23.9,
18.3, 17.2, −4.2, −4.8; FT-IR (film on ZnSe) 2929, 2856, 1766, 1675,
1618, 1471, 1433, 1399, 1361, 1331, 1254, 1231, 1205, 1155 cm−1;
1
mg, 0.0823 mmol, 77% for two steps) as a pale yellow oil: H NMR
(300 MHz, CDCl3) δ 7.12 (s, 1H), 6.05 (sept, 1H, J = 1.2 Hz), 5.36 (s,
2H), 5.24 (br t, 1H, J = 7.2 Hz), 5.06 (s, 2H), 3.87 (s, 3H), 3.52 (s,
3H), 3.50 (d, 2H, J = 7.6 Hz), 3.01 (s, 2H), 2.11 (d, 3H, J = 1.2 Hz),
1.83 (d, 3H, J = 0.9 Hz), 1.78 (br s, 3H); 13C NMR (75 MHz, CDCl3)
δ 199.2, 171.4, 159.7, 155.9, 150.4, 130.7, 129.0, 128.4, 126.2, 125.6,
122.9, 101.7, 97.2, 69.2, 56.9, 56.2, 55.4, 27.8, 23.9, 20.8, 16.7; FT-IR
(film on ZnSe) 2938, 2913, 2845, 1766, 1686, 1618, 1469, 1434, 1401,
1382, 1356, 1332, 1231, 1209, 1154, 1112 cm−1; HRMS (ESI-pos) m/
z calcd for C21H27O6 [M + H]+ 375.1802, found 375.1794.
(E)-5-(3,7-Dimethyl-5-oxoocta-2,6-dien-1-yl)-4-hydroxy-6-
methoxyisobenzofuran-1(3H)-one (Hericenone A, 23). To a
solution of ketone 21 (18.6 mg, 49.7 μmol) in CH2Cl2 (1 mL) were
added successively amylene (149 μL, 1.40 mmol) and Me2BBr (0.5 M
solution in CH2Cl2, 149 μL, 74.5 μmol) at −78 °C. After 1 h at −78
°C, the reaction was quenched with saturated aqueous NaHCO3
solution. The resulting mixture was extracted with EtOAc (3×), and
the combined organic layer was washed with brine, dried over
anhydrous MgSO4, and concentrated. The residue (20.4 mg) was
dissolved in CH2Cl2 (1 mL) and treated with Et3N (41.3 μL, 298
μmol) for 1 h at 0 °C. The resulting mixture was directly subjected to
flash chromatography (n-hexane/EtOAc = 3 → 2) to give hericenone
A (23; 12.8 mg, 38.7 μmol, 78%) as a colorless solid: mp 134−136 °C;
1H NMR (300 MHz, CDCl3) δ 6.96 (s, 1H), 6.09 (sept, 1H, J = 1.2
Hz), 5.30 (br t, 1H, J = 7.2 Hz), 5.24 (s, 2H), 3.86 (s, 3H), 3.58 (d,
2H, J = 7.2 Hz), 3.18 (s, 2H), 2.17 (d, 3H, J = 1.2 Hz), 1.90 (d, 3H, J =
1.2 Hz), 1.81 (br s, 3H); 13C NMR (75 MHz, CDCl3) δ 199.2, 172.0,
159.3, 157.7, 150.7, 133.8, 128.3, 125.9, 125.2, 123.2, 121.4, 98.6, 68.4,
56.3, 54.5, 28.0, 23.5, 21.2, 17.3; FT-IR (film on ZnSe) 3248, 2940,
2842, 1765, 1666, 1595, 1470, 1381, 1348, 1330, 1265, 1237, 1206
cm−1; HRMS (FAB) m/z calcd for C19H23O5 [M + H]+ 331.1545,
found 331.1551.
5-Methoxy-2-methyl-2-(4-methyl-2-oxopent-3-en-1-yl)-3,4-
dihydro-2H-furo[3,4-h]chromen-7(9H)-one (Hericenone I, 24).
To a solution of hericenone A (23; 7.4 mg, 22 μmol) in ClCH2CH2Cl
(1 mL) was added CSA (10.5 mg, 45.2 μmol). The mixture was stirred
for 67 h at 70 °C and directly subjected to flash chromatography (n-
hexane/EtOAc = 3) to give hericenone I (24; 5.5 mg, 17 μmol, 74%)
as a colorless viscous oil: 1H NMR (300 MHz, CDCl3) δ 6.89 (s, 1H),
6.05 (sept, 1H, J = 1.2 Hz), 5.18 (d, 1H, J = 15 Hz), 5.11 (d, 1H, J =
15 Hz), 3.87 (s, 3H), 2.78 (d, 1H, J = 14 Hz), 2.71 (dd, 2H, J = 6.9,
5234
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6.6 Hz), 2.65 (d, 1H, J = 14 Hz), 2.15 (d, 3H, J = 1.2 Hz), 2.05 (dt,
1H, J = 14, 6.6 Hz), 1.94 (dt, 1H, J = 14, 6.9 Hz), 1.88 (d, 3H, J = 1.2
Hz), 1.42 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 197.9, 171.9, 159.4,
156.4, 148.5, 128.1, 125.1, 125.0, 116.8, 97.0, 76.6, 68.1, 56.1, 52.3,
30.4, 28.0, 24.8, 21.0, 17.7; FT-IR (film on ZnSe) 2977, 2939, 2882,
2844, 1766, 1681, 1618, 1474, 1439, 1380, 1342, 1308, 1240, 1204,
1157, 1101 cm−1; HRMS (FAB) m/z calcd for C19H23O5 [M + H]+
331.1545, found 331.1551.
(E)-4-Hydroxy-5-(5-Hydroxy-3,7-dimethylocta-2,6-dien-1-
yl)-6-methoxyisobenzofuran-1(3H)-one (( )-Erinacerin B, 25).
To a solution of 23 (12.8 mg, 0.0387 mmol) in MeOH (1 mL) and
THF (0.3 mL) was added CeCl3·7H2O (43.3 mg, 0.116 mmol). After
5 min, NaBH4 (4.9 mg, 0.13 mmol) was added and the mixture was
stirred at room temperature for 10 min. The reaction mixture was
concentrated to ca. 0.5 mL and directly subjected to flash
chromatography (n-hexane/EtOAc = 3 → 1) to give ( )-erinacerin
B (25; 9.4 mg, 0.0283 mmol, 73%) as a colorless solid: mp 134−135
°C; 1H NMR (300 MHz, DMSO-d6) δ 9.90 (s, 1H), 6.87 (s, 1H), 5.23
(s, 2H), 5.09 (br t, 1H, J = 6.9 Hz), 4.97 (br d, 1H, J = 8.6 Hz), 4.31
(br d, 1H, J = 4.6 Hz), 4.26−4.17 (m, 1H), 3.40−3.25 (m, 2H), 3.33
(s, 3H), 2.07 (dd, 1H, J = 13, 6.6 Hz), 1.88 (dd, 1H, J = 13, 6.9 Hz),
1.73 (s, 3H), 1.53 (s, 3H), 1.48 (s, 3H); 13C NMR (75 MHz, DMSO-
d6) δ 170.9, 159.1, 149.4, 132.1, 130.9, 129.6, 126.7, 123.7, 123.5,
123.0, 97.4, 68.2, 65.9, 56.0, 48.1, 25.3, 22.5, 17.8, 16.6; FT-IR (film on
ZnSe) 1183, 2927, 1723, 1624, 1594, 1471, 1457, 1437, 1355, 1328,
1313, 1237, 1225, 1168 cm−1; HRMS (ESI-neg) m/z calcd for
C19H23O5 [M − H]− 331.1551, found 331.1561.
Hz), 2.15 (dd, 1H, J = 14, 4.8 Hz), 2.08 (dd, 1H, J = 13, 8.4 Hz), 1.82
(s, 3H), 1.70 (br s, 3H), 1.68 (br s, 3H); 13C NMR (75 MHz, CDCl3)
δ 157.5, 155.6, 137.2, 135.2, 132.6, 127.4, 127.0, 117.6, 116.7, 103.8,
65.8, 64.0, 58.8, 55.8, 48.2, 25.9, 22.5, 18.3, 16.3; FT-IR (film on ZnSe)
3319, 2968, 2930, 1617, 1585, 1508, 1426, 1375, 1319, 1220, 1167,
1114, 1008 cm−1; HRMS (ESI-neg) m/z calcd for C19H27O5 [M −
H]− 335.1864, found 335.1873.
3-(Hydroxymethyl)-5-methoxy-6-((2E,5E)-7-methoxy-3,7-di-
methylocta-2,5-dien-1-yl)-2-(methoxymethyl)phenol (Herice-
nol D, 27) and (E)-3-(Hydroxymethyl)-5-methoxy-6-(5-me-
thoxy-3,7-dimethylocta-2,6-dien-1-yl)-2-(methoxymethyl)-
phenol (29). To a solution of ( )-hericenol B (26; 7.2 mg, 0.021
mmol) in MeOH (1 mL) was added silica gel (103 mg, spherical,
neutral, 63−210 μm). The suspension was stirred at room temperature
for 23 h. Then, PPTS (5.3 mg, 0.021 mmol) was added and the
resulting mixture was stirred for 48 h. The reaction mixture was
directly subjected to flash chromatography (n-hexane/EtOAc = 1) to
give hericenol D (27) (0.7 mg) and a 2.3:1 mixture of 27 and 29 (6.2
mg). Calculated yields of 27 and 29 were 65% and 27%, respectively.
The mixture was purified by normal-phase HPLC using n-hexane/
EtOAc as eluent for data analyses. Data for hericenol D (27): colorless
1
oil; H NMR (300 MHz, CDCl3) δ 7.34 (s, 1H), 6.46 (s, 1H), 5.51
(dt, 1H, J = 15.6, 6.3 Hz), 5.41 (d, 1H, J = 15.6 Hz), 5.27 (br t, 1H, J =
7.2 Hz), 4.73 (s, 2H), 4.60 (s, 2H), 3.81 (s, 3H), 3.44 (s, 3H), 3.40 (d,
2H, J = 7.2 Hz), 3.13 (s, 3H), 2.71 (d, 2H, J = 6.3 Hz), 1.77 (br s, 3H),
1.24 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 157.8, 155.7, 137.8,
136.8, 135.1, 128.6, 123.4, 116.5, 114.3, 103.7, 75.0, 68.7, 64.4, 58.2,
55.8, 50.4, 43.0, 26.0, 22.4, 16.2; FT-IR (film on ZnSe) 3350, 2928,
2855, 1618, 1586, 1508, 1464, 1426, 1378, 1362, 1319, 1287, 1257,
1220, 1188, 1167, 1117, 1076 cm−1; HRMS (ESI-neg) m/z calcd for
C21H31O5 [M − H]− 363.2177, found 363.2193. Data for 29: colorless
oil; 1H NMR (300 MHz, CDCl3) δ 6.96 (s, 1H), 6.48 (s, 1H), 5.24 (br
t, 1H, J = 7.2 Hz), 4.95 (dsept, 1H, J = 9.0, 1.2 Hz), 4.70 (s, 2H), 4.60
(s, 2H), 4.00 (dt, 1H, J = 9.0, 6.9 Hz), 3.81 (s, 3H), 3.42 (s, 3H) 3.40
(d, 2H, J = 7.2 Hz), 3.22 (s, 3H), 2.31 (br dd, 2H, J = 13, 6.6 Hz), 2.07
(br dd, 2H, J = 13, 6.6 Hz), 1.80 (d, 3H, J = 1.5 Hz), 1.72 (d, 3H, J =
1.2 Hz), 1.65 (d, 3H, J = 1.2 Hz); 13C NMR (75 MHz, CDCl3) δ
157.7, 155.7, 138.8, 136.4, 134.2, 125.9, 124.8, 116.0, 115.2, 104.0,
75.9, 67.7, 64.5, 58.0, 55.81, 55.76, 46.0, 26.0, 22.6, 18.4, 16.7; FT-IR
(film on ZnSe) 3382, 2962, 2928, 2859, 1617, 1585, 1508, 1465, 1148,
1424, 1375, 1261 cm−1; HRMS (ESI-neg) m/z calcd for C21H32O5Cl
[M + Cl]− 399.1944, found 399.1955.
2-((2E,5E)-7-Hydroxy-3,7-dimethylocta-2,5-dien-1-yl)-5-(hy-
droxymethyl)-3-methoxy-6-(methoxymethyl)phenol (Herice-
nol C, 28). To a solution of ( )-hericenol B (26; 8.2 mg, 0.024
mmol) in MeOH (0.7 mL) and water (0.7 mL) was added silica gel
(100 mg, spherical, neutral, 63−210 μm). The suspension was stirred
at room temperature for 24 h. Then, PPTS (17.2 mg, 0.068 mmol)
was added and the resulting mixture was stirred at room temperature
for 95 h. The reaction mixture was directly subjected to flash
chromatography (n-hexane/EtOAc = 1.5 → 1 → 0.5) to give a 1.6:1
mixture of hericenol D (27) and its isomer 29 (2.4 mg) and a 2.8:1
mixture of hericenol C (28) and its isomer 30 (2.6 mg). Calculated
yields of 27−30 were 17%, 22%, 10% and 8%, respectively. The
mixtures were purified by normal-phase HPLC using n-hexane/EtOAc
as eluent for data analyses. Data for hericenol C (28): colorless oil; 1H
NMR (300 MHz, CDCl3) δ 7.32 (s, 1H), 6.46 (s, 1H), 5.66−5.54 (m,
2H), 5.25 (br t, 1H, J = 6.9 Hz), 4.73 (s, 2H), 4.60 (s, 2H), 3.82 (s,
3H), 3.44 (s, 3H), 3.39 (br d, 2H, J = 6.9 Hz), 2.68 (br d, 2H, J = 5.1
Hz), 1.76 (s, 3H), 1.30 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 157.8,
155.7, 139.5, 137.9, 135.4, 125.3, 123.3, 116.4, 114.3, 103.7, 70.9, 68.7,
64.4, 58.2, 55.8, 42.6, 29.93, 29.86, 22.4, 16.2; FT-IR (film on ZnSe)
3369, 2967, 2925, 2855, 1618, 1586, 1507, 1465, 1424, 1378, 1319,
1289, 1221, 1190, 1116 cm−1; HRMS (ESI-neg) m/z calcd for
C20H29O5 [M − H]− 349.2020, found 349.2035. Data for 30: colorless
oil; 1H NMR (300 MHz, CDCl3) δ 7.61 (s, 1H), 6.44 (s, 1H), 5.32 (br
t, 1H, J = 6.6 Hz), 5.12 (br d, 1H, J = 8.7 Hz), 4.74 (s, 2H), 4.60 (s,
2H), 4.42 (td, 1H, J = 8.4, 5.1 Hz), 3.81 (s, 3H), 3.44 (s, 3H) 3.40 (d,
2H, J = 7.2 Hz), 2.18−2.05 (m, 2H), 1.83 (br s, 3H), 1.70 (d, 3H, J =
0.9 Hz), 1.68 (d, 3H, J = 1.2 Hz); FT-IR (film on ZnSe) 3372, 2929,
(E)-6-(5-((tert-Butyldimethylsilyl)oxy)-3,7-dimethylocta-2,6-
dien-1-yl)-7-hydroxy-5-methoxyisobenzofuran-1(3H)-one
(18b). To a solution of MOM ether 18a (103 mg, 0.209 mmol) and
amylene (666 μL, 6.27 mmol) in CH2Cl2 (7 mL) were added Et3N
(175 μL, 1.26 mmol) and TiCl4 (1.0 M solution in CH2Cl2, 418 μL,
0.418 mmol) in this order at −78 °C. After it was stirred for 6 min at
−78 °C, the reaction mixture was quenched with saturated aqueous
NaHCO3 solution. The resulting mixture was extracted with EtOAc
(2×), and the combined organic layer was washed with brine, dried
over anhydrous MgSO4, and concentrated. The residue was purified by
flash chromatography (n-hexane/EtOAc = 8) to give phenol 18b (60.8
mg, 0.136 mmol, 65%) as a colorless viscous oil: 1H NMR (300 MHz,
CDCl3) δ 7.70 (s, 1H), 6.47 (s, 1H), 5.22 (s, 2H), 5.20 (br t, 1H, J =
7.2 Hz), 5.04 (dsept, 1H, J = 8.7, 1.2 Hz), 4.37 (td, 1H, J = 7.8, 5.7
Hz), 3.88 (s, 3H), 3.33 (d, 2H, J = 7.2 Hz), 2.14 (dd, 1H, J = 13, 7.5
Hz), 1.97 (dd, 1H, J = 13, 5.4 Hz), 1.78 (d, 3H, J = 0.9 Hz), 1.60 (d,
3H, J = 1.2 Hz), 1.54 (d, 3H, J = 1.2 Hz), 0.79 (s, 9H), −0.05 (s, 3H),
−0.07; 13C NMR (75 MHz, CDCl3) δ 173.0, 164.9, 154.6, 146.0,
132.6, 130.7, 129.6, 124.2, 116.9, 104.3, 96.1, 70.5, 68.9, 56.2, 48.9,
25.9, 25.7, 21.8, 18.3, 18.2, 17.0, −4.3, −4.9; FT-IR (film on ZnSe)
3424, 2955, 2929, 2855, 1732, 1632, 1616, 1499, 1469, 1375, 1345,
1317, 1289, 1253, 1204, 1173, 1127, 1077 cm−1; HRMS (ESI-neg) m/
z calcd for C25H37O5Si [M − H]− 445.2416, found 445.2431.
(E)-(3-Hydroxy-4-(5-hydroxy-3,7-dimethylocta-2,6-dien-1-
yl)-5-methoxy-1,2-phenylene)dimethanol (Hericenol B, 26). To
a solution of lactone 18b (46.3 mg, 0.104 mmol) in THF (3.5 mL)
was added LiAlH4 (11.8 mg, 0.311 mmol) at 0 °C. The mixture was
stirred at room temperature for 3 h and quenched by the addition of
water (0.4 mL), Et2O (5 mL), and 1 M aqueous HCl (0.4 mL) in that
order at 0 °C. The resulting mixture was extracted with Et2O (3×).
The combined organic layer was washed with saturated aqueous
NaHCO3 solution and brine, dried over anhydrous MgSO4, and
concentrated to give diol 19b (52.2 mg) as a pale yellow oil. To a
solution of the crude diol 19b (52.2 mg) in THF (3.5 mL) was added
TBAF (1.0 M solution in THF, 520 μL, 0.520 mmol). The mixture
was stirred for 6 h at 40 °C and concentrated to ca. 1 mL. The solution
was directly subjected to flash chromatography (n-hexane/EtOAc = 1
→ EtOAc → EtOAc/MeCN = 5) to give ( )-hericenol B (26; 29.3
mg, 0.0871 mmol, 84% for two steps) as an amber viscous oil and the
recovery of 19b (4.2 mg, 0.0093 mmol, 9%). Data for ( )-hericenol B
1
(26): H NMR (300 MHz, CDCl3) δ 7.45 (br s, 1H), 6.43 (s, 1H),
5.30 (t, 1H, J = 7.2 Hz), 5.11 (d, 1H, J = 8.7 Hz), 4.81 (s, 2H), 4.57 (s,
2H), 4.43 (td, 1H, J = 8.7, 4.5 Hz), 3.80 (s, 3H), 3.41 (d, 2H, J = 7.2
5235
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2857, 1618, 1585, 1508, 1464, 1448, 1426, 1380, 1319, 1290, 1219,
1190, 1167, 1116 cm−1. HRMS (ESI-neg) m/z calcd for C20H29O5 [M
− H]− 349.2020, found 349.2031.
128.9, 128.7, 126.6, 126.2, 124.9, 124.2, 100.9, 97.8, 68.9, 56.9, 56.1,
49.5, 48.9, 44.3, 35.1, 26.0, 25.9, 25.7, 23.7, 18.3, 18.2, 17.1, −4.3.
−4.8; FT-IR (film on ZnSe) 3062, 3027, 2955, 2928, 2856, 1691,
1620, 1597, 1497, 1469, 1434, 1414, 1375, 1360, 1318, 1249, 1218,
1156 cm−1; HRMS (ESI-pos) m/z calcd for C35H52O5NSi [M + H]+
594.3609, found 594.3597.
(E)-4-(5-((tert-Butyldimethylsilyl)oxy)-3,7-dimethylocta-2,6-
dien-1-yl)-2-(hydroxymethyl)-5-methoxy-3-(methoxyme-
thoxy)-N-phenethylbenzamide (31). A mixture of lactone 20 (50.0
mg, 0.102 mmol), 2-phenylethylamine (258 μL, 2.04 mmol), B(OH)3
(12.6 mg, 0.204 mmol), and water (36.7 μL, 2.04 mmol) was stirred at
room temperature for 114 h. The reaction mixture was directly
subjected to flash chromatography (n-hexane/EtOAc = 2) to give
amide 31 (59.4 mg, 0.0971 mmol, 95%) as a pale yellow oil: 1H NMR
(300 MHz, CDCl3) δ 7.51 (t, 1H, J = 5.7 Hz), 7.38−7.19 (m, 5H),
7.01 (s, 1H), 5.11 (br t, 1H, J = 6.6 Hz), 5.05 (br d, 1H, J = 8.7 Hz),
4.97 (d, 1H, J = 6.5 Hz), 4.95 (d, 1H, J = 6.5 Hz), 4.54 (dd, 1H, J = 12,
6.0 Hz), 4.49 (dd, 1H, J = 12, 6.3 Hz), 4.39 (ddd, 1H, J = 8.7, 7.2, 5.7
Hz), 3.88 (br t, 1H, J = 6.3 Hz), 3.82 (s, 3H), 3.73 (td, 2H, J = 7.5, 5.7
Hz), 3.62 (s, 3H), 3.35 (dd, 1H, J = 14, 6.6 Hz), 3.29 (dd, 1H, J = 14,
6.3 Hz), 2.96 (t, 2H, J = 7.5 Hz), 2.15 (dd, 1H, J = 13, 6.9 Hz), 1.98
(dd, 1H, J = 13, 5.7 Hz), 1.76 (br s, 3H), 1.61 (d, 3H, J = 1.2 Hz), 1.55
(d, 3H, J = 1.2 Hz), 0.83 (s, 9H), −0.03 (s, 6H); 13C NMR (75 MHz,
CDCl3) δ 168.8, 158.2, 156.2, 139.1, 136.5, 132.5, 131.0, 129.5, 128.9,
128.7, 126.6, 126.2, 124.8, 124.6, 107.7, 100.5, 69.0, 57.7, 56.9, 55.9,
48.8, 41.5, 35.7, 26.0, 25.7, 23.9, 18.3, 18.2, 17.2, −4.2, −4.8; FT-IR
(film on ZnSe) 3300, 3086, 3063, 3027, 2930, 2856, 1638, 1598, 1500,
1397, 1361, 1330, 1305, 1254, 1221, 1201, 1159 cm−1; HRMS (ESI-
neg) m/z calcd for C35H53O6NClSi [M + Cl]− 646.3336, found
646.3354.
(E)-5-(5-Hydroxy-3,7-dimethylocta-2,6-dien-1-yl)-6-me-
thoxy-4-(methoxymethoxy)-2-phenethylisoindolin-1-one (34).
To a solution of TBS ether 33 (5.0 mg, 8.4 μmol) in THF (1 mL) was
added TBAF (1 M solution in THF, 168 μL, 168 μmol). The mixture
was stirred for 20 h at 40 °C and directly subjected to flash
chromatography (n-hexane/EtOAc = 1) to give alcohol 34 (3.0 mg,
1
6.3 μmol, 74%) as a colorless oil: H NMR (300 MHz, CDCl3) δ
7.32−7.19 (m, 5H), 7.13 (s, 1H), 5.25 (br t, 1H, J = 6.9 Hz), 5.11
(dsept, 1H, J = 8.4, 1.5 Hz), 5.01 (d, 1H, J = 6.6 Hz), 4.99 (d, 1H, J =
6.6 Hz), 4.41 (td, 1H, J = 8.4, 4.8 Hz), 4.23 (s, 2H), 3.87 (s, 3H), 3.85
(t, 2H, J = 7.6 Hz), 3.47 (s, 3H), 3.43 (d, 2H, J = 6.9 Hz), 2.98 (t, 2H,
J = 7.6 Hz), 2.14 (dd, 1H, J = 14, 4.8 Hz), 2.07 (dd, 1H, J = 14, 8.4
Hz), 1.81 (br s, 3H), 1.68 (d, 3H, J = 1.5 Hz), 1.67 (d, 3H, J = 1.5
Hz); 13C NMR (75 MHz, CDCl3) δ 168.3, 159.0, 150.8, 139.0, 135.0,
132.9, 132.0, 128.88, 128.86, 128.7, 127.5, 126.6, 125.6, 124.2, 101.0,
97.8, 65.8, 57.0, 56.2, 49.5, 48.3, 44.3, 35.1, 25.9, 23.7, 18.3, 16.4; FT-
IR (film on ZnSe) 3398, 3062, 3025, 2928, 2855, 1678, 1620, 1598,
1497, 1434, 1417, 1375, 1362, 1318, 1249, 1218 cm−1; HRMS (ESI-
pos) m/z calcd for C29H38O5N [M + H]+ 480.2744, found 480.2735.
(E)-5-(3,7-Dimethyl-5-oxoocta-2,6-dien-1-yl)-6-methoxy-4-
(methoxymethoxy)-2-phenethylisoindolin-1-one (35). To a
solution of alcohol 34 (19.8 mg, 41.3 μmol) in CH2Cl2 (1 mL)
were added PhI(OAc)2 (66.5 mg, 207 μmol) and 2-azaadamantane N-
oxyl (0.4 mg, 2 μmol). After the mixture was stirred for 7 h at room
temperature, PhI(OAc)2 (26.6 mg, 82.6 μmol) and 2-azaadamantane
N-oxyl (1.0 mg, 6.6 μmol) were added. The resulting mixture was
stirred for 30 min and diluted with CH2Cl2 (2 mL). The solution was
quenched successively with saturated aqueous NaHCO3 solution and
saturated aqueous Na2S2O3 solution. The resulting mixture was stirred
for 30 min and extracted with EtOAc (3×). The combined organic
layer was washed with brine, dried over anhydrous MgSO4, and
concentrated. The residue was purified by flash chromatography (n-
hexane/EtOAc = 1) to give ketone 35 (16.6 mg, 34.8 μmol, 84%) as a
(E)-4-(5-((tert-Butyldimethylsilyl)oxy)-3,7-dimethylocta-2,6-
dien-1-yl)-2-(chloromethyl)-5-methoxy-3-(methoxymethoxy)-
N-phenethylbenzamide (32). To a solution of alcohol 31 (30.0 mg,
49.0 μmol) in CH2Cl2 (5.9 mL) were added Et3N (82.1 μL, 588
μmol) and MsCl (19.4 μL, 245 μmol) at 0 °C. The mixture was stirred
for 50 min at 0 °C and quenched with saturated aqueous NaHCO3
solution. The resulting mixture was extracted with EtOAc (3×), and
the combined organic layer was washed with brine, dried over
anhydrous MgSO4, and concentrated. The residue was purified by
flash chromatography (n-hexane/EtOAc = 4) to give chloride 32 (23.6
mg, 37.4 μmol, 76%) as a pale yellow oil: 1H NMR (300 MHz,
CDCl3) δ 7.34−7.20 (m, 5H), 6.71 (s, 1H), 6.23 (t, 1H, J = 5.7 Hz),
5.10 (br t, 1H, J = 6.6 Hz), 5.04 (br d, 1H, J = 8.4 Hz), 5.02 (d, 1H, J =
5.4 Hz), 4.95 (d, 1H, J = 5.4 Hz), 4.81 (s, 2H), 4.39 (dt, 1H, J = 8.4,
6.9 Hz), 3.78 (s, 3H), 3.76 (td, 2H, J = 6.9, 5.7 Hz), 3.62 (s, 3H), 3.37
(dd, 1H, J = 14, 7.6 Hz), 3.30 (dd, 1H, J = 14, 6.2 Hz), 2.97 (t, 2H, J =
6.9 Hz), 2.15 (dd, 1H, J = 13, 6.9 Hz), 1.75 (br s, 3H), 1.62 (d, 3H, J =
1.2 Hz), 1.55 (d, 3H, J = 1.2 Hz), 0.83 (s, 9H), −0.03 (s, 6H); 13C
NMR (75 MHz, CDCl3) δ 168.8, 159.1, 155.8, 138.8, 136.6, 132.7,
131.0, 129.5, 128.9, 128.8, 126.7, 126.4, 124.8, 121.1, 106.6, 100.8,
69.0, 57.7, 55.8, 48.8, 41.2, 39.7, 35.5, 26.01, 25.96, 25.7, 23.9, 18.3,
18.2, 17.2, −4.2, −4.8; FT-IR (film on ZnSe) 3297, 3062, 3027, 2928,
2855, 1641, 1597, 1573, 1533, 1497, 1463, 1455, 1395, 1361, 1333,
1303, 1255, 1217, 1160 cm−1; HRMS (ESI-neg) m/z calcd for
C35H52O5NCl2Si [M + Cl]− 664.2997, found 664.3026.
1
pale yellow oil: H NMR (300 MHz, CDCl3) δ 7.32−7.18 (m, 5H),
7.13 (s, 1H), 6.06 (br s, 1H), 5.26 (br t, 1H, J = 6.5 Hz), 5.00 (s, 2H),
4.24 (s, 2H), 3.87 (s, 3H), 3.85 (t, 2H, J = 7.2 Hz), 3.47 (s, 3H), 3.46
(d, 2H, J = 6.5 Hz), 3.01 (s, 2H), 2.98 (t, 2H, J = 7.2 Hz), 2.12 (d, 3H,
J = 0.9 Hz), 1.83 (d, 3H, J = 1.5 Hz), 1.78 (br s, 3H); 13C NMR (75
MHz, CDCl3) δ 199.4, 168.4, 159.1, 155.7, 150.9, 139.0, 132.8, 130.1,
128.9, 128.7, 127.1, 126.6, 125.6, 124.3, 122.9, 101.0, 97.9, 56.9, 56.2,
55.5, 49.6, 44.3, 35.1, 27.8, 23.8, 20.8, 16.6; FT-IR (film on ZnSe)
3062, 3026, 2932, 2858, 1687, 1683, 1619, 1469, 1455, 1435, 1415,
1382, 1358, 1318, 1247, 1220, 1189, 1154, 1115 cm−1; HRMS (FAB)
m/z calcd for C29H36NO5 [M + H]+ 478.2593, found 478.2551.
(E)-4-Hydroxy-5-(5-hydroxy-3,7-dimethylocta-2,6-dien-1-yl)-
6-methoxy-2-phenethylisoindolin-1-one (Hericenone B, 36).
To a solution of ketone 35 (13.6 mg, 28.5 μmol) in CH2Cl2 (2 mL)
were added amylene (90.8 μL, 0.86 mmol) and Me2BBr (0.5 M
solution in CH2Cl2, 85 μL, 43 μmol) at −78 °C. After the mixture was
stirred for 1 h at −78 °C, additional Me2BBr (0.5 M solution in
CH2Cl2, 29 μL, 15 μmol) was added. After it was stirred for 2 h at −78
°C, the reaction mixture was quenched with saturated aqueous
NaHCO3 solution. The resulting mixture was extracted with EtOAc
(3×), and the combined organic layer was washed with brine, dried
over anhydrous MgSO4, and concentrated. The residue was purified by
flash chromatography (n-hexane/EtOAc = 1) to give an 1.1:1
inseparable mixture of hericenone B (36) and its bromide-conjugated
addition product at C7′ (10.3 mg). The mixture was dissolved in
CH2Cl2 (1 mL) and treated with Et3N (19.8 μL, 143 μmol) for 1 h at
0 °C. The resulting solution was directly subjected to flash
chromatography (n-hexane/EtOAc = 1) to give the product (8.3
(E)-5-(5-((tert-Butyldimethylsilyl)oxy)-3,7-dimethylocta-2,6-
dien-1-yl)-6-methoxy-4-(methoxymethoxy)-2-phenethylisoin-
dolin-1-one (33). To a solution of chloride 32 (6.1 mg, 9.7 μmol) in
DMF (1 mL) was added NaH (60% dispersion in mineral oil, ca. 10
mg) at 0 °C. The mixture was stirred for 25 min at 0 °C and quenched
with water. The resulting mixture was extracted EtOAc (3×), and the
combined organic layer was washed with brine, dried over anhydrous
MgSO4, and concentrated. The residue was purified by flash
chromatography (n-hexane/EtOAc = 2) to give lactam 33 (5.0 mg,
1
8.4 μmol, 87%) as a colorless oil: H NMR (300 MHz, CDCl3) δ
7.32−7.18 (m, 5H), 7.12 (s, 1H), 5.15 (br t, 1H, J = 6.5 Hz), 5.04
(dsept, 1H, J = 8.7, 1.2 Hz), 4.99 (s, 2H), 4.37 (ddd, 1H, J = 8.7, 7.5,
5.7 Hz), 4.23 (s, 2H), 3.86 (s, 3H), 3.85 (t, 2H, J = 7.2 Hz), 3.47 (s,
3H), 3.41 (dd, 1H, J = 14, 6.6 Hz), 3.35 (dd, 2H, J = 14, 6.6 Hz), 2.98
(t, 2H, J = 7.2 Hz), 2.14 (dd, 1H, J = 13, 7.5 Hz), 1.97 (dd, 1H, J = 13,
5.7 Hz), 1.77 (d, 3H, J = 1.2 Hz), 1.59 (d, 3H, J = 1.2 Hz), 1.53 (d, 3H
J = 1.2 Hz), 0.81 (s, 9H), −0.05 (s, 3H), −0.06 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 168.4, 159.0, 150.9, 139.0, 132.6, 132.2, 130.8, 129.5,
1
mg). The H NMR indicated that the ratio of 36 and its bromide-
conjugated addition product was 1.8:1. The mixture was again
dissolved in CD2Cl2 (0.75 mL) and treated with Et3N (15.9 μL, 115
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μmol) at room temperature. The reaction was monitored by 1H NMR,
which indicated that most of the bromide was consumed after 5 h. The
solution was subjected to flash chromatography (n-hexane/EtOAc =
1) to give hericenone B (36; 7.5 mg, 17 μmol, 61%) as a colorless oil.
The sample was further purified by normal-phase HPLC using n-
hexane/EtOAc as eluent for data analysis: 1H NMR (300 MHz,
CDCl3) δ 7.31−7.17 (m, 5H), 6.96 (s, 1H), 6.61 (br s, 1H), 6.07 (br s,
1H), 5.30 (br t, 1H, J = 7.2 Hz), 4.20 (s, 2H), 3.84 (s, 3H), 3.84 (t,
2H, J = 7.5 Hz), 3.56 (d, 2H, J = 7.2 Hz), 3.14 (s, 2H), 2.97 (t, 2H, J =
7.5 Hz), 2.16 (d, 3H, J = 0.9 Hz), 1.88 (d, 3H, J = 0.9 Hz), 1.81 (br s,
3H); 13C NMR (75 MHz, CDCl3) δ 199.0, 169.0, 158.5, 157.0, 150.9,
138.9, 133.3, 132.4, 128.8, 128.7, 126.6, 126.5, 123.1, 122.2, 118.3,
97.8, 56.3, 54.7, 48.4, 44.3, 35.0, 27.9, 23.2, 21.1, 17.2; 13C NMR (75
MHz, CDCl3) δ 202.1, 171.1, 160.5, 157.7, 151.3, 140.1, 132.3, 130.6,
129.8, 129.8, 128.6, 127.6, 123.8, 122.3, 121.9, 97.6, 56.3, 56.2, 49.8,
45.4, 35.6, 27.7, 23.8, 20.8, 16.6; FT-IR (film on ZnSe) 3189, 3086,
3063, 3027, 2935, 2861, 1686, 1656, 1622, 1471, 1438, 1365, 1335,
1220, 1192, 1161 cm−1; HRMS (FAB) m/z calcd for C27H32NO4 [M
+ H]+ 434.2331, found 434.2326.
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1
4.0 mg, 9.2 μmol, 100%) as a colorless oil: H NMR (300 MHz,
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CDCl3) δ 7.33−7.19 (m, 5H), 6.90 (s, 1H), 6.04 (sept, 1H, J = 1.2
Hz), 4.17 (d, 1H, J = 17 Hz), 4.11 (d, 1H, J = 17 Hz), 3.87 (s, 3H),
3.84 (t, 1H, J = 7.5 Hz), 3.83 (t, 1H, J = 7.5 Hz), 2.98 (t, 2H, J = 7.5
Hz), 2.76 (d, 1H, J = 14 Hz), 2.69 (t, 1H, J = 6.9 Hz), 2.68 (t, 1H, J =
6.9 Hz), 2.63 (d, 1H, J = 14 Hz), 2.14 (d, 3H, J = 1.2 Hz), 2.02 (dt,
1H, J = 14, 6.6 Hz), 1.90 (dt, 1H, J = 14, 6.9 Hz), 1.84 (d, 3H, J = 1.2
Hz), 1.40 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 198.2, 169.0, 158.6,
155.8, 148.7, 138.9, 132.4, 128.8, 128.7, 126.6, 125.2, 122.0, 113.6,
96.3, 76.0, 56.0, 52.4, 48.1, 44.3, 35.0, 30.7, 28.0, 24.9, 20.9, 17.5; FT-
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1410, 1366, 1319, 1254, 1194, 1155, 1109, 1093 cm−1; HRMS (FAB)
m/z calcd for C27H32NO4 [M + H]+ 434.2331, found 434.2330.
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ASSOCIATED CONTENT
■
S
* Supporting Information
1
Figures and tables giving H and 13C NMR spectra for all new
(12) (a) Poulter, C. D.; Hughes, J. M. J. Am. Chem. Soc. 1977, 99,
3830−3877. (b) Wegener, R.; Schulz, S. Tetrahedron 2002, 58, 315−
319.
synthetic compounds, as well as comparisons of the NMR data
for synthetic compounds and natural products. This material is
available free of charge via the Internet at http://pubs.acs.org.
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(b) Kuk, J.; Kim, B. S.; Jung, H.; Choi, S.; Park, J.-Y.; Koo, S. J. Org.
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AUTHOR INFORMATION
(14) Weigand, S.; Bruckner, R. Synthesis 1996, 475−482.
■
̈
(15) Stille, J. K. Angew. Chem., Int. Ed. 1986, 25, 508−524.
(16) Littke, A. F.; Schwarz, L.; Fu, G. C. J. Am. Chem. Soc. 2002, 124,
6343−6348.
Corresponding Author
*E-mail for S.K.: shoji.kobayashi@oit.ac.jp.
Notes
(17) Numerous conditions, including MeI/CaCO3, HgCl2/CaCO3,
(CF3CO2)IPh, NBS with or without ethylene glycol, or 2,2-dimethyl-
1,3-propanediol in various solvents, were explored. However, the yield
of ketal or ketone did not exceed 45%.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(18) (a) Stork, G.; Maldonado, L. J. Am. Chem. Soc. 1971, 93, 5286−
5287. For selected examples applying alkylation of protected
cyanohydrins for the synthesis of complex molecules, see: (b) Stork,
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(c) Takahashi, T.; Sakamoto, Y.; Doi, T. Tetrahedron Lett. 1992, 33,
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(19) Doi, N.; Seko, S.; Kimura, K.; Takahashi, T. European Patent
EP1231197A1, 2002.
This work was supported in part by a Grant-in-Aid for Scientific
Research (C) (No. 24550124) from the JSPS and the Science
Research Promotion Fund from the Promotion and Mutual Aid
Corporation for Private Schools of Japan. We are grateful to
Mr. Taiki Shimomura and Mr. Yuki Hashino for preparation of
intermediates and to Ms. Sayaka Kado, Center for Analytical
Instrumentation, Chiba University, for measurement of ESI and
APPI mass spectrometry. We also thank to Prof. Yoshiharu
Iwabuchi and Mr. Yusuke Sasano, Graduate School of
Pharmaceutical Science, Tohoku University, for provision of
AZADO, and to Ms. Ayako Sato, A Rabbit Science Japan Co.,
Ltd., for measurement of elemental analysis.
(20) After many trials, the benzoyl group was found to be the best
protecting group for the terminal alcohol in terms of alkylation yield,
removability, and compatibility with other functional groups. We also
succeeded in the direct synthesis of 15 by treating isoprene (9) with
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NBS in AcOH at 100 °C for 1 h. However, a non-negligible amount of
the regioisomer could not be separated from 15 by silica gel
chromatography. Therefore, we resorted to the two-step method
shown in Scheme 4.
(21) (a) Fetizon, M.; Golfier, M. C. R. Acad. Sci., Ser. C 1968, 267,
900. (b) McKillop, A.; Young, D. W. Synthesis 1979, 401−422.
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Chem. Soc. 2006, 128, 8412−8413.
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(27) When the reaction was carried out without amylene, a
considerable amount of byproducts, in which the internal olefin
(C2′−C3′) reacted with HBr (generated possibly from Me2BBr and a
trace amount of water), was occasionally observed. The use of amylene
for a similar purpose is reported in ref 10.
(28) To explore the convertibility of hericenol B to hericenol D upon
exposure to silica gel, synthetic hericenol B (26) was first treated with
silica gel in MeOH. TLC analysis indicated the appearance of
hericenol D (27) after the mixture was stirred for 22 h at ambient
temperature. However, the change was subtle and most of the
hericenol B remained (as judged from TLC). Therefore, PPTS was
subsequently added to enforce conversion.
(29) Shinozuka, T.; Yamamoto, Y.; Hasegawa, T.; Saito, K.; Naito, S.
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(32) We explored a large number of conditions for the cyclization.
The main issue was the N/O selectivity in the cyclization mode. In
most cases on the basis of halogenation−cyclization or Mitsunobu
conditions, O-cyclization preceded N-cyclization. While Tsuritani et al.
reported the N-selective method by use of phosphate reagents, their
conditions were incompatible with our substrate. The N-selective
method is reported in the following reference: Tsuritani, T.; Kii, S.;
Akao, A.; Sano, K.; Nonoyama, N.; Mase, T.; Yasuda, N. Synlett 2006,
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