Asymmetric total syntheses of teretifolione B and methylteretifolione B via Diels-Alder reaction of optically active pyranobenzyne and substituted furans

Article abstract of DOI:10.1016/j.tet.2017.06.050

We report the asymmetric total syntheses of teretifolione B and methylteretifolione B, which are benzochromenes originally isolated from Conospermum plants. The synthesis involves enzymatic asymmetric transesterification of racemic acetoxychromene and construction of the basic framework via Diels-Alder reaction of optically active pyranobenzyne and substituted furans. The absolute configuration of the chiral chromene was unambiguously determined by asymmetric total synthesis of teretifolione B and its characterization. The first asymmetric total synthesis of methylteretifolione B was achieved in a similar manner and its absolute configuration, for which direct proof has not been reported, was established.

Full text of DOI:10.1016/j.tet.2017.06.050

Accepted Manuscript
Asymmetric total syntheses of teretifolione B and methylteretifolione B via Diels-Alder
reaction of optically active pyranobenzyne and substituted furans
Kazuaki Katakawa, Mika Kainuma, Katsuya Suzuki, Saori Tanaka, Takuya Kumamoto
PII:
S0040-4020(17)30693-2
10.1016/j.tet.2017.06.050
TET 28815
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 2 February 2017
Revised Date: 22 June 2017
Accepted Date: 26 June 2017
Please cite this article as: Katakawa K, Kainuma M, Suzuki K, Tanaka S, Kumamoto T, Asymmetric
total syntheses of teretifolione B and methylteretifolione B via Diels-Alder reaction of optically active
pyranobenzyne and substituted furans, Tetrahedron (2017), doi: 10.1016/j.tet.2017.06.050.
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Asymmetric total syntheses of teretifolione B
and methylteretifolione B via Diels-Alder
reaction of optically active pyranobenzyne
and substituted furans
Leave this area blank for abstract info.
Kazuaki Katakawa, Mika Kainuma, Katsuya Suzuki, Saori Tanaka, Takuya Kumamoto*
Department of Synthetic Organic Chemistry, Research Institute of Pharmaceutical Sciences, Musashino
University, 1-1-20 Shinmachi, Nishitokyo City, Tokyo, 202-8585, Japan.

ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Asymmetric total syntheses of teretifolione B and methylteretifolione B via Diels-
Alder reaction of optically active pyranobenzyne and substituted furans
Kazuaki Katakawa, Mika Kainuma, Katsuya Suzuki, Saori Tanaka, Takuya Kumamoto
Department of Synthetic Organic Chemistry, Research Institute of Pharmaceutical Sciences, Musashino University, 1-1-20 Shinmachi, Nishitokyo City, Tokyo,
202-8585, Japan.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
We report the asymmetric total syntheses of teretifolione B and methylteretifolione B, which are
benzochromenes originally isolated from Conospermum plants. The synthesis involves
enzymatic asymmetric transesterification of racemic acetoxychromene and construction of the
basic framework via Diels-Alder reaction of optically active pyranobenzyne and substituted
furans. The absolute configuration of the chiral chromene was unambiguously determined by
asymmetric total synthesis of teretifolione B and its characterization. The first asymmetric total
synthesis of methylteretifolione B was achieved in a similar manner and its absolute
configuration, for which direct proof has not been reported, was established.
Available online
Keywords:
Chromene
Benzyne
Furan
2009 Elsevier Ltd. All rights reserved
.
Quinone
Enzymatic kinetic resolution
Diels-Alder reaction
reaction (DAR) of benzynes and furan as a key step.9,10 We
expected that this strategy would be applicable to the asymmetric
total syntheses of natural angular benzochromenes such as 1–3.
DAR of optically active pyranobenzyne and monomeric or
suitably oligomerized furans can produce desired monomeric 2
and 3 or polymeric benzochromene 1. In this paper, we describe
1. Introduction
Quinone natural products are widely distributed in plants and
microorganisms, and they have diverse biological activities.1
Angular benzochromenes are a small class of natural products
isolated from Conospermum and Pentas plants. Conocurvone (1),
a trimeric benzochromene isolated from Conospermum plants,
has potent anti-HIV activity.2,3 The structure of 1 was elucidated
by spectroscopic analyses, derivatization, and semi-synthesis
from the corresponding monomeric unit, teretifolione B (2).2
Methylteretifolione B (3), a derivative with a methyl group at the
8-position,4 was isolated from the same plant as an another
monomeric benzochromene.5 To date, total synthesis of 1 has not
been achieved.6 In contrast, several total syntheses of monomeric
benzochromenes 2 and 3 have been reported. (±)-2 was
synthesized in the course of structure elucidation,5 and total
synthesis of (+)-2 was achieved by Jacobsen et al. via kinetic
resolution of a fully constructed racemic benzochromene by
asymmetric epoxidation.7 (±)-3 was synthesized by Stagliano
through regioselective ortho metalation.8 For synthesizing an
oligomeric structure like 1, condensation of the monomeric unit,
as in the semi-synthesis, would be a feasible method (Fig. 1).2
We have developed syntheses of quinone natural products,
including the concise synthesis of substituted naphthoquinones
and the total synthesis of a benzochromene, 9-hydroxy-3,3,8-
Fig. 1. Structures of conocurvone (1), teretifolione B (2)
and methylteretifolione B (3).
———
trimethyl-3H-benzo[f]chromene-7,10-dione, via the Diels-Alder
Corresponding author. Tel.: +81-42-468-9278; fax: +81-42-468-9278; e-mail: t_kum632@musashino-u.ac.jp

2
Tetrahedron
the asymmetric total synthesis of teretifolione B (2) and the first
ACCEPTED MANUSCRIPT
Table 1. Examination of catalyst for the synthesis of 7.
asymmetric total synthesis of methylteretifolione B (3) through
preparing the optically active pyranobenzyne moiety via
enzymatic kinetic resolution of racemic acetoxychromene and
DAR with monomeric furans for constructing the basic
framework.
2. Results and Discussion
2.1. Retrosynthetic analysis
Retrosynthetic analysis of 2 and 3 is shown in Scheme 1.
Construction of the benzochromene framework was envisioned
through DAR of pyranobenzyne 4 and monomeric furans 5. The
precursor of benzyne 4, iodotriflate 6, would be accessible from
known chromene 7 via regioselective iodination. Optically active
7 would be obtained from catalytic asymmetric synthesis or
enzymatic kinetic resolution11 of acetate 8 in which a remote
stereogenic center could be recognized.12
Run
1
Catalyst
11
Time (h)
3.0
Yield of 7 (%)
23
40
38
24
33
39
25
2
12
3.0
3
13
3.0
4
14
7.0
5a
6
15
18.0
3.0
16
Scheme 1. Retrosynthetic analysis of 2 and 3.
7
17
22.0
2.2. Establishing the synthetic route for racemic total
synthesis of teretifolione B (2)
a 0.2 eq. of catalyst was used.
(±)-7 was converted to MOM ether 18. Regioselective
iodination14 of 18 and deprotection gave 19, which was converted
to iodotriflate 6 as a benzyne precursor. Substituted furan 5a was
prepared from benzyl tetronate (20) by our previously reported
method (Scheme 2). 9
Lee et al. reported the concise one-step synthesis of racemic
chromene 7 via cyclocondensation of citral (9) and resorcinol
(10) catalyzed by ethylenediamine diacetate (11; EDDA) in
xylene.13 With this method, we obtained (±)-7 in 23% yield
using toluene as a solvent instead of xylene (Table 1, run 1).
Because EDDA is highly hygroscopic and insoluble in low polar
solvents, and the yield of 7 was low, we screened catalysts for
better efficiency in this reaction. We found that ethylenediamine
(12) catalyzed the reaction and gave 7 in slightly higher yield
(40%) compared with 11 (run 2). N,N-Dimethylethylenediamine
(13) showed similar results (run 3); however, a longer reaction
time was required when N,N’-dimethyl derivative 14 was used
(run 4). Piperidine (15) also catalyzed this reaction (run 5). On
the other hand, tetramethylethylenediamine and triethylamine
gave only trace amount of 7 (3~4%). Using chiral diamines, such
DAR of furan 5a with benzyne 4 generated from 6 and n-BuLi
in situ produced a regioisomeric mixture of adducts 21a and 22a
and these compounds isomerized to 23a and 24a spontaneously.
Because of the anticipated instability of hydroquinones 23a and
24a, these compounds were separated by column
chromatography and the isolated hydroquinones were
immediately oxidized to the corresponding quinones 25a and 26a,
respectively. When 25a was purified by normal phase SiO2
column chromatography, a trace amount of cyclized product 27a
was obtained. This class of compounds is generated under
acidic,15 basic,16 and photoirradiation17 conditions. We assumed
that 27a was produced during purification by the acidic nature of
as
(1R,2R)-cyclohexanediamine
(16)
and
(1R,2R)-
diphenylethylenediamine (17), did not result in asymmetric
induction and gave only racemic 7 (runs 6 and 7).
Scheme 2. Preparation of benzyne precursor 6 and furan 5a. Reagents and conditions: (a) MOMCl, NaH, THF, rt, 2 h, 71%;
(b) 1) t-BuLi, Et2O, -25 °C, 10 min to rt, 1 h then I2, rt, 1 h; 2) cat. p-TsOH, EtOH, 50 °C, 24 h, 57% in two steps; (c) Tf2O,
Et3N, CH2Cl2, -78 °C, 2.5 h, 97%; (d) TIPSOTf, Et3N, CH2Cl2, 0 °C, 1 h, 75%.

ACCEPTED MANUSCRIPT
Scheme 3. Construction of benzochromene core by Diels-Alder reaction. Reagents and conditions: (a) 5a, n-BuLi, THF,
-78 °C, 20 min; (b) 1M FeCl3, MeOH – CH2Cl2, rt, 30 min, 25a: 25%; 26a: 35% from 6 respectively.
Table 2. Examination of regioselectivity in DAR.
SiO2 and light exposure. Therefore, crude 25a was purified by
ODS medium-pressure liquid chromatography (MPLC) shielded
with aluminum foil from light and only 25a was obtained without
27a. 26a was obtained in a similar way without cyclization.18
Run
1
Furan
5a
Solvent
THF
Conditions
25a:26a
1:1.8a
1:1.8
1:1.9
1:1.7
1:3.3
1:3.2
1:1.4
1:3.3
-78 °C/20 min
-40 °C/20 min
0 °C/20 min
2
5a
THF
The structures of quinones 25a and 26a were confirmed by
2D-NMR analyses. In the HMBC spectra of 25a, correlations
between a carbonyl carbon (δC 184.3, C7) and aromatic
hydrogens (δH 7.92, d, J = 8.2 Hz, C6-H, δH 6.11, s, C8-H), and
correlations between a quaternary sp2 carbon (δC 126.2, C6a) and
aromatic hydrogens (δH 7.92 and 6.11) were observed. In contrast,
in the HMBC spectra of 26a, correlations between an aromatic
carbon (δC 126.3, C10a), an sp2 methine (δH 7.85, d, J = 10.5 Hz,
C1-H), and the isolated aromatic hydrogen (δH 6.09, s, C9-H)
were observed. These correlations were reasonable for the
assignment of 25a as benzylated 2 and 26a as a regioisomer of
25a (Scheme 3).
3
5a
THF
4
5a
DME
n-Hexane
Toluene
THF
-78 °C/30 min
-78 °C/30 min
-78 °C/30 min
-78 °C/20 min
-78 °C/20 min
5
5a
6
5a
7
28
8
29
THF
a60% yield from 6 as a mixture of 25a and 26a (1:1.7) after purification.
The regioselectivity of the reaction of benzyne 4 and furan 5a
was estimated as 21a:20a = 1:1.7 based on isolated yields of 23a
and 24a. Thus, we examined the effects of the reaction conditions,
such as temperature, solvent, and substituents of furan 5a, on the
regioselectivity of DAR with benzyne 4. The regioselectivity was
evaluated by 1H-NMR analysis of the crude product as a mixture
of quinones 25a and 26a after the DAR followed by oxidation of
the corresponding mixture of unstable hydroquinones 23a and
24a. The regioselectivity was independent of temperature (Table
2, runs 1–3). Next, we examined the solvent effect. DME gave a
similar result to that of THF (run 4); however, the generation of
undesired 26a was increased in less polar solvents such as n-
hexane and toluene (runs 5 and 6).19 The furan substituents
affected the regioselectivity. The ratio of 25a was slightly
improved when TBDPS-protected furan 28 was used (run 7). The
amount of undesired 26a increased when regioisomeric furan 29
was used (run 8).
2, TS1 > TS2). Greater formation of 22a in less polar solvents
was caused by conformational change in the side chain from
closed to open, which decreased the steric repulsion between the
side chain and the TIPS group (TS3 > TS1). The sterically
hindered TBDPS group in furan 28 increased the steric repulsion
We proposed transition state models for the DAR of 4 and 5a
based on our observations. The regioselectivity of the
cycloaddition reaction with benzyne has been discussed in
relation to the electrostatic effect and steric repulsion.20 In our
case, the electrostatic interaction between the high electron
density 5-position in furan and the electrophilic 6-position in
benzyne 421 had the largest effect and resulted in the preferential
formation of undesired isomer 22a, despite the steric repulsion
between the side chain in 4 and the bulky TIPS group in 5a (Fig.
Fig. 2. Plausible transition state models for DAR of 4 and 5a/29.

4
Tetrahedron
ACCEPTED MANUSCRIPT
with the side chain in the closed conformation of 4 and the ratio
Because catalytic asymmetric synthesis of 7 failed, we
of the desired isomer was slightly improved. For furan 29,22 steric
repulsion of the TIPS group and side chain had a larger effect
than the electrostatic effect, possibly because of the additional
steric effect of the TIPS group that was affected by the adjacent
benzyloxy group (TS4).
examined the synthesis of optically active chromenes by
enzymatic kinetic resolution. (±)-7 was acetylated to (±)-8 and
asymmetric hydrolysis24 of (±)-8 using Amano Lipase PS was
examined; however, the optical purity of 7 and recovered 8 were
up to 35% and 18% enantiomeric excess (ee), respectively. In
contrast, asymmetric transesterification of (±)-8 with the same
enzyme in the presence of cyclopentanol25 showed improved
results, which afforded 7 and 8 in 57% and 46% ee, respectively
Finally, 25a was debenzylated under hydrolytic conditions
generally used for the demethylation of quinone methyl ether23 to
give (±)-2, and regioisomer 30a was also obtained in a similar
manner (Scheme 4).
t
(Table 3, run 1). Sterically hindered BuOH gave a similar result
(run 2). In further trials using BuOH, the optical purity of 8 was
t
improved to 73% ee after 2 h (run 3) and 97% ee after 5.5 h (run
4). Fortunately, (±)-7 can be recovered after the complete
racemization of (+)-7 under thermal conditions.26
Next, (-)-8 (95% ee) was prepared on a large scale and
deacetylated to (-)-7 for asymmetric synthesis of (+)-2 through
the above synthetic route. The spectroscopic data and specific
25
rotation ([α]D +73, c 0.1, CH3OH) of synthesized (+)-2 were in
good agreement with those of natural 2 ([α]D +66, c 0.1,
27
CH3OH).2,
The absolute configuration of natural 2 was
independently established by anomalous scattering in the X-ray
analysis of the p-bromobenzoate derivative.2 This result
supported the assignment of the absolute configuration of
acetoxy chromene (-)-8 obtained by kinetic resolution as R.
Scheme 4. Racemic total syntheses of teretifolione B (2) and
its regioisomer 30a. Reagents and conditions: (a) 1M KOH,
EtOH, rt, 25 min, 94%; (b) 1M KOH, EtOH, rt, 1 h, 97%.
2.4. Asymmetric total synthesis of methylteretifolione B
The synthetic route was used for the asymmetric total
synthesis of methylteretifolione B (3). DAR of benzyne 4
generated from (-)-6 and furan 5b afforded a regioisomeric
mixture of hydroquinones 23b and 24b. 23b and 24b isolated by
SiO2 column chromatography were oxidized to quinones 25b and
26b, respectively. Total synthesis of (R)-3 and corresponding
regioisomer 30b was achieved by debenzylation of 25b and 26b.
Lower yields in the final two steps (oxidation and debenzylation)
were observed in the methylteretifolione B series than in the
teretifolione B series. The reason for this result is not clear; it
may be because of the ortho-quinone methide formation via
tautomerism28 of 25b and 26b. The spectroscopic data and
2.3. Synthesis of optically active chromene and determination
of absolute stereochemistry via asymmetric total synthesis of
teretifolione B
Table 3. Asymmetric transesterification of (±)-8.
a
O
(±)-7
c
OH
O
OAc
(±)-8
25
specific rotation ([α]D +35.0, c 0.35, CHCl3) of synthetic (R)-3
were in good agreement with those of natural 3 ([α]D +29.7, c
0.33, CHCl3).29 The absolute configuration of natural 3 was
assumed to be R from literature data;30 however, the process was
complicated and direct proof has not been reported. In this study,
we achieved the asymmetric total synthesis of (+)-3 from (R)-(-)-
8, and the absolute configuration of (+)-3 was determined as R
directly. The structure of 30b was deduced based on 2D-NMR
analyses. HMBC showed that the hydroxy group (δH 7.28, 1H, br
s) and aromatic hydrogen (δH 7.95, 1H, d, J = 8.2 Hz, C6-H)
were correlated with a quinone carbonyl carbon (δC 188.0, C7),
indicating that the hydroxy group was ortho to the carbonyl
carbon and that the aromatic hydrogen was in the peri position to
the same carbonyl group. Thus, 30b has an 8-
hydroxybenzo[f]chromene skeleton, assigned as the regioisomer
of 3 (Scheme 5).
b
d
+
(-)-7
O
OH
O
OAc
(+)-7
(-)-8
Reagents and conditions: (a) Ac2O, pyridine, rt, 4 h, 79%;
(b) Amano Lipase PS, alcohol, toluene, 35 °C (see table);
(c) toluene, reflux, 9 d, 99%; (d) KOH, MeOH, rt, 1 h, quant.
Run
1
Alcohol
Time (h)
Ratio (8:7)a
% ee (8, 7)b
Cyclopentanol 0.5
56:44
46, 57
2
tBuOH
tBuOH
tBuOH
1
59:41
42, 63
3
2
43:57
73, 55
3. Conclusion
4
5.5
26:74
97, 23
We have achieved the asymmetric total syntheses of (+)-2 and
3
with its regioisomers via enzymatic asymmetric
aRatio was estimated by the integration of 1H-NMR of crude products.
transesterification and DAR of a benzyne and furan as key steps.
The absolute configurations of (-)-8 and (+)-3 were
unambiguously determined from asymmetric total synthesis of
bee was estimated by chiral HPLC analysis of crude products.

ACCEPTED MANUSCRIPT
Scheme 5. Asymmetric total syntheses of methylteretifolione B (3) and regioisomer 30b. Reagents and conditions: (a) 5b, n-
BuLi, THF, -78 °C, 25 min; (b) 1M FeCl3, MeOH – CH2Cl2, rt, 40 min, 25b: 28%, 26b: 17% from 6 respectively; (c) 1M KOH,
EtOH, rt, 3: 1 h, 46%, 30b: 1.5 h, 14%.
(+)-2, the absolute configuration of which was determined. The
regioselectivity in DAR of benzyne 4 and furans was examined
to deduce the transition state models, and use of a bulky TBDPS
group as the furan substituent resulted in only slight
improvement in the desired selectivity. We propose this
methodology as a novel synthetic route for optically active
benzochromenes and expect that it will contribute to the
evolution of the total synthesis of 1. Studies of the
regioselectivity in DAR of pyranobenzyne, and total synthesis of
1 and related benzochromene natural products are now underway
in our laboratory.
and stirred at same temperature. After 10 min, citral (0.35 mL,
2.04 mmol) was added and the mixture was refluxed for further 3
h. The solvent was removed in vacuo and the residue was
purified over SiO2 column chromatography (AcOEt : n-hex. = 0 :
100 - 19 : 91) to afford (±)-7 (a yellow oil, 196.8 mg, 40%). The
spectral data, see (-)-7.
4.2.2.
5-Acetoxy-2-methyl-2-(4-methylpent-3-en-1-yl)-2H-
chromene (8). To a stirred solution of (±)-7 (12.4 g, 50.8 mmol)
in pyridine (35.5 mL, 439 mmol), Ac2O (33.5 mL, 354 mmol)
was added and the mixture was stirred at rt for 4 h. The whole
was diluted with AcOEt (600 mL), and sat. NaHCO3 (360 mL)
was added slowly. Organic layer was separated and washed with
5% HCl (1 x 240 mL), brine (1 x 75 mL) and the layer was dried
over Na2SO4. The solvent was removed in vacuo, the residue was
purified over SiO2 column chromatography (AcOEt : n-hex. = 5 :
95) to afford (±)-8 (a yellow oil, 11.6 g, 79%). The spectral data,
see (-)-8.
4. Experimental
4.1. General
Commercially available reagents and anhydrous solvents were
used without further purification. Anhydrous solvents (CH2Cl2
and THF) were purchased from Wako chemicals. Analytical thin
layer chromatography was performed on silica gel 60 F254 plate
from Merck KGaA. Flash chromatography was carried out with
Silica gel 60N (40-50 µm) from Kanto Chemical Co. ODS
MPLC was performed on Ultra Pack ODS-SM from Yamazen
Co.
4.2.3.
(R)-5-Acetoxy-2-methyl-2-(4-methylpent-3-en-1-yl)-2H-
chromene (8). To a stirred solution of (±)-8 (4.74 g, 16.9 mmol)
t
in toluene (126 mL), BuOH (4.8 mL, 50.2 mmol) and Amano
Lipase PS from Burkholderiacepacia (Aldrich, 6.10 g) were
added and the mixture was stirred at 35 °C for 5.5 h. The whole
was filtered through Celite® pad, and the filtrate was
concentrated in vacuo. The residue was purified over SiO2
column chromatography (AcOEt : n-hex. = 5 : 95) to afford (-)-8
(a yellow oil, 847 mg, 18%, 95% ee) and (+)-7 (3.11 g, 75%).
ODS HPLC was performed on Cosmosil 5C18-AR-II 10 x 250
mm from Nacalai Tesque. IR spectra were recorded on a JASCO
FT/IR-4100 spectrophotometer with Attenuated Total
Reflectance Unit ATR PRO450-S. EI-MS was recorded on a
JEOL GC-Mate II and DART-MS was recorded on a JEOL JMS-
1
T100LP in positive ion mode. H- (400 MHz) and 13C- (100
[α]D = -66.2 (c 1.0, CHCl3); IR νmax 1769 cm-1; H-NMR δH
7.07 (1H, t, J = 8.1 Hz), 6.66 (1H, dt, J = 8.1, 0.9 Hz), 6.58 (1H,
dd, J = 8.1, 0.9 Hz), 6.36 (1H, dd, J = 10.1, 0.9 Hz), 5.60 (1H, d,
J = 10.1 Hz), 5.08 (1H, t sept., J = 7.1, 1.3 Hz), 2.32 (3H, s, Ac),
2.17 - 2.02 (2H, m), 1.74 (1H, ddd, J = 14.0, 10.5, 6.0 Hz), 1.65
(1H, ddd, J = 14.0, 10.5, 6.0 Hz), 1.66 (3H, d, J = 1.3 Hz), 1.57
(3H, s), 1.39 (3H, s); 13C-NMR δC 169.1, 154.1, 146.3, 131.8,
130.3, 128.6, 123.9, 116.6, 114.1, 113.9, 78.5, 41.1, 26.3, 25.6,
22.7, 20.8, 17.6 (One sp2 carbon is missing); LRMS (EI) m/z (%)
286 (M+, 62), 271 (17), 229 (24), 203 (97), 161 (100); HRMS
(EI) m/z 286.1568 (calcd. for C18H22O3 286.1569, ∆ - 0.1 mmu).
23
1
MHz) NMR spectra were recorded on a JEOL ECX 400
spectrometer with deuterated chloroform (CDCl3) as a solvent
and tetramethylsilane as an internal reference at room
temperature. Chemical shifts were reported in ppm and J in Hz.
Abbreviations were used for multiplicity: s = singlet, d = doublet,
t = triplet, sept. = septet, m = multiplet.
4.2. Experimental procedures
4.2.1. 2-Methyl-2-(4-methylpent-3-en-1-yl)-2H-chromen-5-ol (7).
Resorcinol (220.8 mg, 2.01 mmol) was suspended in toluene (17
mL) and the mixture was refluxed for 5 min. After dissolution of
resorcinol, ethylenediamine (13.5 µL, 0.202 mmol) was added
4.2.4. (R)-2-Methyl-2-(4-methylpent-3-en-1-yl)-2H-chromen-5-ol
(7). (-)-8 (847 mg, 2.96 mmol) was dissolved in methanolic KOH

6
Tetrahedron
(285 mg (85%, 4.35 mmol) in 11.0 mL) and stirred at rt for 1 h.
dried over Na2SO4. The solvent was removed in vacuo, and the
ACCEPTED MANUSCRIPT
After the solvent was removed in vacuo, H2O (9.0 mL) was
added to the residue and pH was adjusted to 1 with 5% HCl (5.0
mL). The whole was extracted with AcOEt (3 x 45 mL). The
combined organic layer was washed with half sat. NaHCO3 (1 x
20 mL) and brine (1 x 15 mL). The layer was dried over Na2SO4
and the solvent was removed in vacuo. The crude (-)-7 (a yellow
oil, 766 mg, quant.) was subjected to the next step without further
purification. [α]D25 = -86.4 (c 1.0, CHCl3); IR νmax 3385 cm-1; 1H-
NMR δH 6.93 (1H, t, J = 8.0 Hz), 6.65 (1H, d, J = 10.1 Hz), 6.40
(1H, d, J = 8.0 Hz), 6.28 (1H, dd, J = 8.0, 0.9 Hz), 5.55 (1H, d, J
= 10.1 Hz), 5.09 (1H, t sept., J = 7.3, 1.4 Hz), 4.74 (1H, s, -OH),
2.18 - 2.05 (2H, m), 1.74 (1H, ddd, J = 13.7, 10.3, 6.6 Hz), 1.65
(1H, ddd, J = 13.7, 10.3, 6.4 Hz), 1.66 (3H, s), 1.57 (3H, s), 1.39
(3H, s); 13C-NMR δC 154.2, 151.3, 131.7, 128.9, 128.2, 124.1,
116.8, 109.4, 109.1, 107.5, 78.2, 41.0, 26.2, 25.6, 22.7, 17.6;
LRMS (EI) m/z (%) 244 (M+, 26), 229 (10), 161 (100); HRMS
(EI) m/z 244.1481 (calcd. for C16H20O2 244.1463, ∆ +1.8 mmu).
residue was purified over SiO2 column chromatography (AcOEt :
n-hex. = 5 : 95) to afford (-)-19 (a yellow oil, 87.8 mg, 47% from
(-)-18). [α]D = -41.6 (c 1.0, CHCl3); IR νmax 3385 cm-1; H-
NMR δH 7.31 (1H, t, J = 8.7 Hz), 6.69 (1H, d, J = 10.1 Hz), 6.24
(1H, dd, J = 8.7, 0.9 Hz), 5.55 (1H, d, J = 10.1 Hz), 5.21 (1H, s, -
OH), 5.08 (1H, t sept., J = 7.1, 1.4 Hz), 2.16 - 2.02 (2H, m), 1.73
(1H, ddd, J = 14.0, 10.1, 6.6 Hz), 1.64 (1H, ddd, J = 14.0, 10.1,
6.4 Hz), 1.66 (3H, d, J = 1.4 Hz), 1.57 (3H, s), 1.38 (3H, s); 13C-
NMR δC 154.9, 150.1, 136.5, 131.8, 128.7, 123.9, 117.6, 111.4,
109.5, 78.6, 74.7, 41.1, 26.3, 25.7, 22.7, 17.6; LRMS (EI) m/z
(%) 370 (M+, 12), 287 (100), 160 (17); HRMS (EI) m/z 370.0442
(calcd. for C16H19IO2 370.0430, ∆ +1.2 mmu).
25
1
4.2.7.
(R)-6-Iodo-2-methyl-2-(4-methylpent-3-en-1-yl)-2H-
chromen-5-yl trifluoromethanesulfonate (6). To a solution of (-)-
19 (75.6 mg, 0.204 mmol) in CH2Cl2 (0.5 mL) was added Et3N
(0.06 mL, 0.430 mmol), and the mixture was cooled to -78 °C.
Tf2O (0.04 mL, 0.238 mmol) was added and stirred for 20 min.
After quenched with H2O (0.3 mL), the mixture was warmed to
rt. Additional H2O (0.3 mL) was added, and the whole was
extracted with Et2O (1 x 5.0 mL, 2 x 2.5 mL). The combined
organic layer was washed with brine (1 x 0.6 mL), dried over
Na2SO4 and the solvent was removed in vacuo. The residue was
combined with another crude product, which was obtained from
87.8 mg (0.237 mmol) of (-)-19, and was purified over SiO2
column chromatography (CHCl3 : n-hex. = 1 : 9) to afford (-)-6 (a
colorless oil, 180 mg, 81%). [α]D26 = -39.7 (c 1.0, CHCl3); IR no
4.2.5. (R)-5-(Methoxymethoxy)-2-methyl-2-(4-methylpent-3-en-1-
yl)-2H-chromene (18). To an ice-cooled stirred solution of (-)-7
(766 mg, 3.14 mmol) in CH2Cl2 (8.0 mL), iPr2NEt (0.88 mL, 5.05
mmol) and MOMCl (0.33 mL, 4.35 mmol) were added. The
reaction mixture was warmed to rt and stirred for 4.5 h. The
mixture was poured into ice water (7.5 mL), and the whole was
extracted with AcOEt (2 x 40 mL, 1 x 20 mL). The combined
organic layer was washed with brine (7.5 mL) and dried over
Na2SO4. The solvent was removed in vacuo, and the residue was
purified over SiO2 column chromatography (AcOEt : n-hex. = 5 :
95 - 15 : 85) to afford (-)-18 (a yellow oil, 639 mg, 71%, 82%
brsm) and (-)-7 (107 mg, 14%). [α]D25 = -66.0 (c 1.0, CHCl3); IR
no characteristic absorption; 1H-NMR δH 7.01 (1H, t, J = 8.2 Hz),
6.71 (1H, d, J = 10.1 Hz), 6.59 (1H, dd, J = 8.2, 0.9 Hz), 6.47
(1H, d, J = 8.2 Hz), 5.54 (1H, d, J = 10.1 Hz), 5.18 (2H, s), 5.09
(1H, t sept., J = 7.3, 1.4 Hz), 3.49 (3H, s), 2.18 - 2.03 (2H, m),
1.73 (1H, ddd, J = 14.1, 10.2, 6.4 Hz), 1.65 (1H, ddd, J = 14.1,
10.5, 6.2 Hz), 1.66 (3H, d, J = 0.9 Hz), 1.57 (3H, s), 1.39 (3H, s);
13C-NMR δC 154.0, 152.8, 131.6, 128.9, 128.3, 124.1, 117.2,
111.4, 110.2, 106.4, 94.7, 78.0, 56.1, 41.1, 26.3, 25.6, 22.7, 17.6;
LRMS (EI) m/z (%) 288 (M+, 31), 273 (16), 205 (100), 175 (49),
161 (52); HRMS (EI) m/z 288.1722 (calcd. for C18H24O3
286.1726, ∆ -0.4 mmu).
1
characteristic absorption; H-NMR δH 7.56 (1H, d, J = 8.5 Hz),
6.60 (1H, d, J = 8.5 Hz), 6.59 (1H, d, J = 10.3 Hz), 5.73 (1H, d, J
= 10.3 Hz), 5.07 (1H, t sept., J = 7.1, 1.4 Hz), 2.15 - 1.99 (2H,
m), 1.77 (1H, ddd, J = 13.9, 10.3, 6.4 Hz), 1.66 (1H, ddd, J =
13.9, 10.8, 6.2 Hz), 1.66 (3H, d, J = 0.9 Hz), 1.56 (3H, s), 1.41
(3H, s); 13C-NMR δC 155.0, 145.2, 139.4, 132.2, 132.1, 123.5,
118.5 (q, J = 319 Hz), 118.2, 117.3, 116.8, 79.2, 77.2, 40.9, 26.2,
25.7, 22.6, 17.6; LRMS (EI) m/z (%) 502 (M+, 14), 487 (4), 419
(82), 286 (100); HRMS (EI) m/z 501.9924 (calcd. for
C17F3H18IO4S 501.9923, ∆ + 0.1 mmu).
4.2.8. 4-Benzyloxy-2-triisopropylsiloxyfuran (5a). To a solution
of 4-benzyloxy-5H-furan-2-one (100 mg, 0.526 mmol) and Et3N
(0.10 mL, 0.717 mmol) in CH2Cl2 (0.5 mL), TIPSOTf (0.15 mL,
0.558 mmol) was added at 0 °C and the whole was stirred at 0 °C
for 1 h. The mixture was diluted with hexane (anhydrous, 2.5
mL), washed with ice-cooled half sat. NaHCO3 (2 x 1 mL) and
ice-cooled brine (1 x 1 mL), and dried over MgSO4. The solvent
was removed in vacuo and the residue was suspended in hexane
(anhydrous, 1.5 mL) then filtered. The filtrate was concentrated
in vacuo to give a mixture of 5a and TIPSOH in 1 : 0.25 (a
colorless oil, 154 mg, 89% w/w purity, 75% yield as 5a). IR νmax
4.2.6.
(R)-6-Iodo-2-methyl-2-(4-methylpent-3-en-1-yl)-2H-
chromen-5-ol (19). (-)-18 (146 mg, 0.505 mmol) was dissolved in
THF (3.0 mL) and cooled to -78 °C. After 10 min, n-BuLi (1.55
M in n-hex., 0.46 mL, 0.713 mmol) was added. After 10 min, the
reaction mixture was warmed to rt and stirred for 40 min. After
the mixture was cooled to -78 °C for 10 min, a solution of I2 (154
mg, 0.606 mmol) in THF (1.1 mL) was added. The mixture was
stirred at -78 °C for 10 min, then it was warmed to rt and stirred
for 1 h. Sat. NH4Cl (1.5 mL) was added to the mixture and the
whole was extracted with AcOEt (1 x 10 mL, 2 x 3.0 mL). The
combined organic layer was washed with 5%Na2S2O3 (1 x 5.0
mL), brine (1 x 1.5 mL) and dried over Na2SO4. The solvent was
removed in vacuo, and the residue was subjected to next reaction
without further purification.
1621 cm-1; H-NMR δH 7.42 - 7.30 (5H, m), 6.53 (1H, d, J = 1.4
1
Hz), 5.10 (1H, d, J = 1.4 Hz), 4.82 (2H, s), 1.29 - 1.20 (3H, m),
1.09 (18H, d, J = 7.1 Hz); 13C-NMR δC 155.1, 149.3, 136.7,
128.5, 128.1, 127.7, 113.0, 79.3, 71.9, 17.5, 12.1; HRMS
(DART+) m/z 347.2038 (M+H, calcd. for C20H31O3Si 347.2043,
∆ -0.5 mmu).
The residue described above was dissolved in ethanolic solution
of p-TsOH monohydrate (35.9 mg (0.185 mmol) in 3.3 mL) and
warmed to 50 °C. After the reaction mixture was stirred for 2 h,
solvent was removed in vacuo. The residue was dissolved in
AcOEt (8 mL) and washed with H2O (1 x 2 mL). After the
aqueous layer was extracted with AcOEt (2 x 4.0 mL), the
combined organic layer was washed with brine (1 x 2.0 mL) and
4.2.9. (R)-9-(Benzyloxy)-3-methyl-3-(4-methylpent-3-en-1-yl)-7-
((triisopropylsilyl)oxy)-3H-benzo[f]chromen-10-ol (23a) and
(R)-8-(benzyloxy)-3-methyl-3-(4-methylpent-3-en-1-yl)-10-
((triisopropylsilyl)oxy)-3H-benzo[f]chromen-7-ol (24a). To a
solution of 5a (159 mg, 90% w/w purity, 0.412 mmol) in THF
(1.0 mL) was added a solution of (-)-6 (172 mg, 0.343 mmol,

94% ee) in THF (3.5 mL) and cooled to -78 °C. n-BuLi (1.42 M
*interchangeable; HRMS (DART+) m/z 415.1929 (M+H, calcd.
for C27H27O4 415.1909, ∆ +2.0 mmu).
ACCEPTED MANUSCRIPT
in n-hex., 0.48 mL, 0.682 mmol) was added and the mixture was
stirred for 20 min. After quenched with H2O (3.5 mL), the
mixture was warmed to rt. The whole was extracted with AcOEt
(2 x 10 mL, 1 x 5 mL) and the combined organic layer was
washed with H2O and brine (1 x 1.5 mL each) and dried over
Na2SO4. The solvent was removed in vacuo and the residue was
purified over SiO2 column chromatography (CH2Cl2 : n-hex. = 2 :
8 - 5 : 5) to afford 23a (a pale red oil, 50.2 mg, 26%) and 24a (a
yellowish brown oil, 89.1 mg, 45%), respectively. The obtained
hydroquinones were oxidized immediately.
4.2.12. (R)-8-(Benzyloxy)-3-methyl-3-(4-methylpent-3-en-1-yl)-
3H-benzo[f]chromene-7,10-dione (26a). 26a was prepared from
24a (89.1 mg, 0.156 mmol) in similar conditions described at
compound 25a. The crude material was purified by ODS MPLC
(CH3CN : H2O = 9 : 1) to afford 26a (a yellow oil, 53.2 mg, 37%
25
from (-)-6). [α]D = +43.1 (c 0.62, CHCl3); IR νmax 1669, 1644,
1613 cm-1; 1H-NMR δH 8.00 (1H, d, J = 8.5 Hz, C6-H), 7.85 (1H,
d, J = 10.5 Hz, C1-H), 7.44 - 7.32 (5H, m, Ar-H), 7.02 (1H, dd, J
= 8.5, 0.7 Hz, C5-H), 6.09 (1H, s, C9-H), 5.87 (1H, d, J = 10.5
Hz, C2-H), 5.10 (2H, s, -OCH2Ph), 5.07 (1H, t sept., J = 7.2, 1.4
Hz, C3’-H), 2.09 (2H, m, C2’-H2), 1.78 (1H, ddd, J = 14.0, 9.2,
7.2 Hz, C1’-H), 1.69 (1H, ddd, J = 14.0, 9.9, 6.6 Hz, C1’-H),
1.65 (3H, d, J = 1.1 Hz, C4’-CH3), 1.55 (3H, s, C4’-CH3), 1.43
(3H, s, C3-CH3); 13C-NMR δC 187.8 (C10), 179.2 (C7), 159.8
(C4a), 158.2 (C8), 134.3 (Ar), 133.7 (C2), 132.1 (C4’), 129.2
(C6), 128.8 (Ar), 128.6 (Ar), 127.5 (Ar), 126.3 (C10a), 125.4
(C6a), 123.5 (C3’), 120.5 (C10b), 120.4 (C5*), 120.3 (C1*),
112.5 (C9), 79.5 (C3), 70.9 (-OCH2Ph), 41.3 (C1’), 26.7 (C3-
CH3), 25.6 (C4’-CH3), 22.6 (C2’), 17.6 (C4’-CH3)
*interchangeable; HRMS (DART+) m/z 415.1892 (M+H, calcd.
for C27H27O4 415.1909, ∆ -1.7 mmu).
4.2.10. (R)-9-(Benzyloxy)-3-methyl-3-(4-methylpent-3-en-1-yl)-
3H-benzo[f]chromene-7,10-dione (25a). To a solution of 23a
(50.2 mg, 0.0876 mmol) in MeOH (1.8 mL) - CH2Cl2 (0.4 mL)
was added aq. 1M FeCl3 (0.18 mL, 0.18 mmol) and the mixture
was stirred for 30 min at rt. H2O (3.0 mL) was added and the
whole was extracted with CH2Cl2 (2 x 10 mL, 1 x 5 mL). The
combined organic layer was washed with H2O and brine (1 x 2
mL each), and dried over Na2SO4. The solvent was removed in
vacuo and the residue was purified by ODS MPLC (CH3CN :
H2O = 9 : 1) to afford 25a (an orange oil, 34.0 mg, 24% from (-)-
6). [α]D25 = +49.6 (c 0.61, CHCl3); IR νmax 1676, 1644, 1615 cm-
1; H-NMR δH 7.92 (1H, d, J = 8.4 Hz, C6-H), 7.80 (1H, d, J =
1
10.5 Hz, C1-H), 7.45 - 7.33 (5H, m, Ar-H), 7.06 (1H, dd, J = 8.4,
0.7 Hz, C5-H), 6.11 (1H, s, C8-H), 5.90 (1H, d, J = 10.5 Hz, C2-
H), 5.09 (2H, s, -OCH2Ar), 5.07 (1H, t sept., J = 7.2, 1.5 Hz, C3’-
H), 2.13 - 2.07 (2H, m, C2’-H2), 1.78 (1H, ddd, J = 14.0, 9.4, 7.0
Hz, C1’-H), 1.68 (1H, ddd, J = 14.0, 10.1, 6.5 Hz, C1’-H), 1.65
(3H, d, J = 0.9 Hz, C4’-CH3), 1.55 (3H, s, C4’-CH3), 1.43 (3H, s,
C3-CH3); 13C-NMR δC 184.2 (C7), 182.3 (C10), 159.4 (C9),
158.6 (C4a), 134.4 (C2), 134.3 (Ar), 132.1 (C4’), 128.8 (Ar),
128.6 (Ar), 128.1 (C6), 127.5 (Ar), 126.1 (C6a), 125.5 (C10a),
123.5 (C3’), 121.4 (C5), 121.2 (C10b), 120.2 (C1), 109.6 (C8),
79.2 (C3), 71.0 (-OCH2Ph), 41.2 (C1’), 26.5 (C3-CH3), 25.6
(C4’-CH3), 22.6 (C2’), 17.6 (C4’-CH3); HRMS (DART+) m/z
415.1891 (M+H, calcd. for C27H27O4 415.1909, ∆ -1.8 mmu).
4.2.13. General procedure for the examination of regioselectivity
in DAR of 4 and furans. To a solution of (±)-6 (50 mg, 0.10
mmol) in solvent (0.3 mL) was added a solution of furan (0.12
mmol) in solvent (1.0 mL) and cooled. n-BuLi (1.5 M in n-hex.,
0.13 mL, 0.20 mmol) was added and the mixture was stirred for
30 min. After the reaction was quenched with H2O (1.0 mL), the
mixture was warmed to rt. The whole was extracted with AcOEt
(3 x 5 mL) and the combined organic layer was washed with H2O
and brine (1 x 1 mL each) and dried over Na2SO4. The solvent
was removed in vacuo and the residue was dissolved in MeOH
(1.4 mL) - CH2Cl2 (0.3 mL). Aqueous 1M FeCl3 (0.14 mL, 0.14
mmol) was added to the solution, and the mixture was stirred for
30 min. H2O (3.0 mL) was added and the whole was extracted
with CH2Cl2 (2 x 10 mL, 1 x 5 mL). The combined organic layer
was washed with H2O and brine (1 x 2 mL each), and dried over
Na2SO4. The solvent was removed in vacuo and the residue was
analyzed by 1H-NMR.
4.2.11. 9-(Benzyloxy)-1,1,3a-trimethyl-1a,2,3,3a-tetrahydro-1H-
4-oxacyclobuta[3,4]indeno[5,6-a]naphthalene-7,10(1a1H,10cH)-
dione (27a). (±)-23a (43.3 mg, 0.0756 mmol) which was
obtained from 5a (161 mg, 89% w/w purity, 0.414 mmol) and
(±)-6 (174 mg, 0.346 mmol), was treated with 1M FeCl3 (0.15
mL, 0.15 mmol) in MeOH (1.5 mL) - CH2Cl2 (0.3 mL). The
crude product was obtained in similar manner described at 25a
and was purified over SiO2 column chromatography (AcOEt : n-
hex. = 15 : 85) to afford 25a containing trace amount of 27a. A
portion of the mixture (4.0 mg) was purified by ODS HPLC
(CH3CN : H2O = 8 : 2) to afford 25a (2.0 mg, estimated yield
41%) and 27a (yellow solids, 0.1 mg, estimated yield 2%). IR
νmax 1684, 1647, 1618 cm-1; 1H-NMR δH 7.95 (1H, d, J = 8.2 Hz,
C6-H), 7.44-7.33 (5H, m, Ar-H), 7.18 (1H, d, J = 8.2 Hz, C5-H),
6.09 (1H, s, C8-H), 5.14 (1H, d, J = 12.3 Hz, -OCH2Ph), 5.09
(1H, d, J = 12.3 Hz, -OCH2Ph), 4.20 (1H, d, J = 9.4 Hz, C10c-
H), 2.63 (1H, t, J = 9.2 Hz, C1a1-H), 2.50 (1H, dt, J = 3.9, 8.2
Hz, C1a-H), 1.99 (1H, dt, J = 6.0, 12.1 Hz, C3-H), 1.82-1.65
(3H, m, C2-H2, C3-H), 1.63 (3H, s, C1-CH3), 1.32 (3H, s, C3a-
CH3), 0.52 (3H, s, C1-CH3); 13C-NMR δC 184.7 (C7), 181.8
(C10), 159.54 (C4a*), 159.49 (C9*), 134.4 (Ar), 129.9 (C10a),
128.9 (Ar), 128.7 (Ar), 128.4 (C10b), 127.5 (Ar), 127.1 (C6a),
126.4 (C6), 124.2 (C5), 109.5 (C8), 84.9 (C3a), 71.1 (-CH2Ph),
47.2 (C1a), 41.8 (C1), 40.6 (C3), 39.8 (C1a1), 37.9 (C10c), 34.4
(C1-CH3), 25.6 (C3a-CH3), 25.2 (C2), 19.0 (C1-CH3)
4.2.14. 2-tert-Butyldiphenylsiloxy-4-benzyloxyfuran (28). 28 (a
brown oil, 234.7 mg, quant.) was prepared from 4-benzyloxy-5H-
furan-2-one (100 mg, 0.527 mmol) in similar conditions
described at compound 5a. IR νmax 1616 cm-1; 1H-NMR δH 7.71 -
7.68 (4H, m), 7.47 - 7.29 (11H, m), 6.50 (1H, d, J = 1.3 Hz), 4.76
(1H, d, J = 1.3 Hz), 4.73 (2H, s), 1.11 (9H, s); 13C-NMR δC 154.4,
149.0, 135.4, 131.6, 130.2, 128.5, 128.0, 127.8, 127.7, 113.4,
80.2, 71.9, 26.4, 19.3; HRMS (DART+) m/z 429.1892 (M+H,
calcd. for C27H29O3Si 429.1886, ∆ +0.6 mmu).
4.2.15.
(3R,4R)-3,4-Dihydroxytetrahydrofuran-2-one.
Title
compound was synthesized from
D-araboascorbic acid along with
a report of Pavlik et al (see reference 20a). The obtained residue
was extracted with hot AcOEt repeatedly, and the combined
extract was concentrated. The crude material was recrystallized
from AcOEt to give title compound. Mp 102 - 103 °C.
4.2.16. 3-(Benzyloxy)furan-2(5H)-one. To a mixture of (3R,4R)-
3,4-dihydroxytetrahydrofuran-2-one (592 mg, 5.02 mmol) and

8
Tetrahedron
Ag2O (5.22 g, 22.5 mmol) in DMF (7.5 mL) was added BnBr
(C2’), 17.6 (C4’-CH3); HRMS (DART+) m/z 325.1424 (M+H,
ACCEPTED MANUSCRIPT
(2.0 mL, 16.8 mmol) and was stirred at 70 °C for 16 h. The
whole was filtered through Celite® pad, and the filtrate was
concentrated in vacuo. The residue was purified over SiO2
column chromatography (AcOEt : n-hex. = 30 : 70 - 50 : 50) to
afford title compound (brown amorphous solids, 348 mg, 36%).
Mp 80 - 82 °C; IR νmax 1763, 1653 cm-1; 1H-NMR δH 7.41 - 7.32
(5H, m), 6.14 (1H, t, J = 2.1 Hz), 5.04 (2H, s), 4.75 (2H, d, J =
2.1 Hz); 13C-NMR δC 168.1, 145.6, 134.8, 128.7, 128.6, 127.6,
114.2, 72.8, 67.5; HRMS (DART+) m/z 191.0701 (M+H, calcd.
for C11H11O3 191.0708, ∆ -0.7 mmu).
calcd. for C20H21O4 325.1440, ∆ -1.6 mmu).
4.2.20. (R)-9-(Benzyloxy)-3,8-dimethyl-3-(4-methylpent-3-en-1-
yl)-7-((triisopropylsilyl)oxy)-3H-benzo[f]chromen-10-ol
and (R)-8-(benzyloxy)-3,9-dimethyl-3-(4-methylpent-3-en-1-yl)-
10-((triisopropylsilyl)oxy)-3H-benzo[f]chromen-7-ol (24b).
(23b)
Hydroquinones 23b and 24b were prepared by Diels-Alder
reaction of furan 5b (459 mg, 89% w/w purity, 1.13 mmol) and
benzyne derived from (-)-6 (472 mg, 0.940 mmol) in similar
conditions described at compound 23a and 24a. The crude
material was purified over SiO2 column chromatography (CHCl3
: n-hex. = 2 : 8 - 5 : 5) to afford 23b (a red oil, 166 mg, 30%) and
24b (a yellow oil, 245 mg, 44%). The obtained hydroquinones
were oxidized immediately.
4.2.17. 2-Triisopropylsilyloxy-3-benzyloxyfuran (29). A mixture
of 29 and TIPSOH in 1 : 0.23 (a yellow oil, 169.2 mg, 90% w/w
purity, 84% yield as 29) was prepared from 3-(benzyloxy)furan-
2(5H)-one (99.6 mg, 0.524 mmol) in similar conditions described
at compound 5a. IR νmax 1665 cm-1; 1H-NMR δH 7.40 - 7.27 (5H,
m), 6.59 (1H, d, J = 2.5 Hz), 6.15 (1H, d, J = 2.5 Hz), 4.91 (2H,
s), 1.29 - 1.20 (3H, m), 1.09 (18H, d, J = 7.3 Hz); 13C-NMR δC
144.6, 137.7, 128.6, 128.3, 127.8, 121.7, 107.0, 74.5, 17.5, 12.3
(one sp2 carbon is missing); HRMS (DART+) m/z 347.2028
(M+H, calcd. for C20H31O3Si 347.2043, ∆ -1.5 mmu).
4.2.21. (R)-9-(Benzyloxy)-3,8-dimethyl-3-(4-methylpent-3-en-1-
yl)-3H-benzo[f]chromene-7,10-dione (25b). 25b was prepared
from 23b (166 mg, 0.284 mmol) in similar conditions described
at compound 25a. The crude material was purified by ODS
MPLC (CH3CN : H2O = 9 : 1) to afford 25b (an orange oil, 151
25
mg, 28% from 6). [α]D = +48.0 (c 0.99, CHCl3); IR νmax 1646
cm-1; 1H-NMR δH 7.91 (1H, d, J = 8.5 Hz), 7.77 (1H, d, J = 10.4
Hz), 7.44 - 7.31 (5H, m), 7.02 (1H, d, J = 8.5 Hz), 5.90 (1H, d, J
= 10.4 Hz), 5.30 (2H, s), 5.08 (1H, tt, J = 7.2, 1.3 Hz), 2.16 - 2.06
(2H, m), 1.99 (3H, s), 1.82 - 1.68 (2H, m), 1.66 (3H, s), 1.57 (3H,
s), 1.42 (3H, s); 13C-NMR δC 185.0, 183.7, 158.6, 157.3, 136.8,
134.0, 132.1, 131.6, 128.6, 128.4, 128.3, 126.3, 126.0, 123.6,
120.9, 120.7, 120.3, 79.2, 74.8, 41.2, 26.5, 25.6, 22.6, 17.6, 9.4
(one sp2 carbon is missing); LRMS (EI) m/z (%) 428 (M+, 6), 359
(15), 346 (17), 345 (67), 255 (100), 227 (36), 105 (26); HRMS
(EI) m/z 428.1993 (calcd. for C28H28O4 428.1988, ∆ -0.5 mmu).
4.2.18. (R)-(+)-Teretifolione B (2). To a solution of 25a (12.2
mg, 0.0294 mmol) in EtOH (1.0 mL) was added 1M KOH (0.20
mL, 0.200 mmol) and the mixture was stirred at rt for 30 min. 5%
HCl (1.0 mL) was added and the whole was extracted with
AcOEt (1 x 10 mL, 2 x 5 mL). The combined organic layer was
washed with brine (1 x 2 mL), dried over Na2SO4 and the solvent
was removed in vacuo. The residue was dissolved in CH3CN :
H2O = 1 : 1 (5.0 mL) and the solvent was removed in vacuo. This
operation was repeated four times for azeotropic removal of
BnOH with H2O. The residue was purified over SiO2 column
chromatography (MeOH : CHCl3 = 0 : 100 - 1 : 99) to afford 2
4.2.22. (R)-8-(Benzyloxy)-3,9-dimethyl-3-(4-methylpent-3-en-1-
yl)-3H-benzo[f]chromene-7,10-dione (26b). 26b was prepared
from 24b (245 mg, 0.417 mmol) in similar conditions described
at compound 25a. The crude material was purified over ODS
MPLC (CH3CN : H2O = 9 : 1) to afford 26b (an orange oil, 68.4
25
(an orange oil, 7.5 mg, 79%, 93% ee). [α]D = +73.4 (c 0.10,
MeOH); IR νmax 3357, 1652 cm-1; H-NMR δH 7.97 (1H, d, J =
1
8.4 Hz), 7.83 (1H, d, J = 10.5 Hz), 7.50 (1H, br s), 7.10 (1H, d, J
= 8.4 Hz), 6.26 (1H, s), 5.96 (1H, d, J = 10.5 Hz), 5.08 (1H, t
sept., J = 7.1, 1.3 Hz), 2.18 - 2.02 (2H, m), 1.80 (1H, ddd, J =
14.0, 9.6, 6.8 Hz), 1.71 (1H, ddd, J = 14.0, 10.2, 6.4 Hz), 1.66
(3H, s), 1.56 (3H, s), 1.48 (3H, s); 13C-NMR δC 184.4, 184.0,
158.2, 156.3, 135.5, 132.2, 128.7, 127.0, 123.4, 123.3, 122.2,
121.6, 120.0, 109.0, 79.4, 41.2, 26.6, 25.6, 22.6, 17.6; HRMS
(DART+) m/z 325.1424 (M+H, calcd. for C20H21O4 325.1440, ∆ -
1.6 mmu).
26
mg, 84%, 17% from 6). [α]D = +49.5 (c 0.98, CHCl3); IR νmax
1656 cm-1; 1H-NMR δH 7.93 (1H, d, J = 8.5 Hz), 7.81 (1H, d, J =
10.5 Hz), 7.45 - 7.41 (2H, m), 7.39 - 7.31 (3H, m), 7.01 (1H, dd,
J = 8.5, 0.7 Hz), 5.87 (1H, d, J = 10.5 Hz), 5.40 (2H, s), 5.07
(1H, t sept., J = 7.1, 1.4 Hz), 2.09 (2H, m), 1.98 (3H, s), 1.78
(1H, ddd, J = 13.9, 9.3, 7.2 Hz), 1.68 (1H, ddd, J = 13.9, 10.1,
6.4 Hz), 1.65 (3H, d, J = 0.9 Hz), 1.56 (3H, s), 1.43 (3H, s); 13C-
NMR δC 188.4, 180.6, 159.3, 155.7, 136.9, 133.8, 133.6, 132.1,
128.54, 128.50, 128.3, 126.6, 125.7, 123.6, 120.5, 120.4, 79.3,
74.8, 41.2, 26.6, 25.6, 22.6, 17.6, 9.8 (two sp2 carbons are
missing); LRMS (EI) m/z (%) 428 (M+, 6), 345 (100), 269 (16),
255 (30), 226 (25), 91 (83); HRMS (EI) m/z 428.1990 (calcd. for
C28H28O4 428.1988, ∆ +0.2 mmu).
4.2.19. (R)-8-Hydroxy-3-methyl-3-(4-methylpent-3-en-1-yl)-3H-
benzo[f]chromene-7,10-dione (30a). 30a was prepared from 26a
(11.7 mg, 0.0282 mmol) in similar conditions described at
compound 2. The crude material was purified over SiO2 column
chromatography (MeOH : CHCl3 = 0 : 100 - 1 : 99) to afford 30a
25
(an orange oil, 9.1 mg, 99%, 94% ee). [α]D = +57.1 (c 0.10,
4.2.23. (R)-(+)-Methylteretifolione B (3). 3 was prepared from
25b (18.6 mg, 0.0434 mmol) in similar conditions described at
compound 2. The crude material was purified over SiO2 column
chromatography (AcOEt : n-hex. = 1 : 9) to afford 3 (an orange
MeOH); IR νmax 3330, 1647 cm-1; H-NMR δH 7.98 (1H, d, J =
1
8.5 Hz, C6-H), 7.90 (1H, dd, J = 10.5, 0.7 Hz, C1-H), 7.02 (1H,
dd, J = 8.5, 0.7 Hz, C5-H), 6.22 (1H, s, C9-H), 5.90 (1H, d, J =
10.5 Hz, C2-H), 5.07 (1H, t sept., J = 7.1, 1.4 Hz, C3’-H), 2.14 -
2.05 (2H, m, C2’-H), 1.80 (1H, ddd, J = 14.0, 8.8, 7.6 Hz, C1’-
H), 1.69 (1H, ddd, J = 14.0, 9.6, 6.9 Hz, C1’-H), 1.65 (3H, d, J =
1.1 Hz, C4’-CH3), 1.56 (3H, s, C4’-CH3), 1.45 (3H, s, C3’-CH3);
13C-NMR δC 188.1 (C10), 180.7 (C7), 161.0 (C4a), 155.3 (C8),
134.0 (C2), 132.2 (C4’), 129.2 (C6), 127.2 (C10a), 123.44 (C3’),
123.36 (C6a), 121.3 (C10b), 120.3 (C1), 120.1 (C5), 111.6 (C9),
79.8 (C3), 41.4 (C1’), 26.8 (C3-CH3), 25.6 (C4’-CH3), 22.6
25
oil, 6.8 mg, 46%, 95% ee). [α]D = +35.0 (c 0.35, CHCl3); IR
νmax 3359, 1654, 1625 cm-1; 1H-NMR δH 7.98 (1H, d, J = 8.2 Hz),
7.84 (1H, d, J = 10.8 Hz), 7.44 (1H, s, -OH), 7.06 (1H, dd, J =
8.2, 0.9 Hz), 5.94 (1H, d, J = 10.8 Hz), 5.08 (1H, t sept., J = 7.1,
1.4 Hz), 2.14 - 2.07 (2H, m), 2.07 (3H, s), 1.79 (1H, ddd, J =
13.9, 9.4, 6.9 Hz), 1.69 (1H, ddd, J = 13.9, 10.2, 6.6 Hz), 1.65
(3H, d, J = 1.4 Hz), 1.56 (3H, s), 1.44 (3H, s); 13C-NMR δC

Malinakova, H. C.; Stagliano, K. W. J. Org. Chem. 2006, 71,
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7. Vander Velde, S. L.; Jacobsen, E. N. J. Org. Chem. 1995, 60,
5380.
8. Stagliano, K. W.; Malinakova, H. C. Tetrahedron Lett. 1998, 39,
4941.
184.5, 183.3, 158.0, 153.3, 135.1, 132.2, 128.8, 127.0, 123.5,
123.3, 121.7, 121.3, 120.1, 118.6, 79.3, 41.3, 26.6, 25.6, 22.6,
17.6, 8.6; LRMS (EI) m/z (%) 338 (M+, 22), 323 (6), 255 (100),
227 (36); HRMS (EI) m/z 338.1517 (calcd. for C21H22O4
338.1518, ∆ -0.1 mmu).
ACCEPTED MANUSCRIPT
9. Katakawa, K.; Yonenaga, D.; Terada, T.; Aida, N.; Sakamoto, A.;
Hoshino, K.; Kumamoto, T. Heterocycles 2014, 88, 817.
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Chem. Pharm. Bull. 2014, 62, 820.
11. (a) Fogassy, E.; Nógrádi, M.; Kozma, D.; Egri, G.; Pálovics, E.;
Kiss, V. Org. Biomol. Chem. 2006, 4, 3011. (b) Sugai, T. Curr.
Org. Chem. 1999, 3, 373.
12. Blasco, M. A.; Gröger, H. Bioorg. Med. Chem. 2014, 22, 5539.
13. Lee, Y. R.; Choi, J. H.; Yoon, S. H. Tetrahedron Lett. 2005, 46,
7539. We examined solvents to improve the yield of 7, however,
benzene and toluene gave same result as those of this report. 7 was
not obtained in CH2Cl2 and DMF.
4.2. 24. (R)-8-Hydroxy-3,9-dimethyl-3-(4-methylpent-3-en-1-yl)-
3H-benzo[f]chromene-7,10-dione (30b). 30b was prepared from
26b (19.5 mg, 0.0455 mmol) in similar conditions described at
compound 2. The crude material was purified over SiO2 column
chromatography (AcOEt : n-hex. = 8 : 92) to afford 30b (an
25
orange oil, 2.2 mg, 14%, 97% ee). [α]D = +74.7 (c 0.24,
1
CHCl3); IR (ATR) νmax 3342, 1645 cm-1; H-NMR δH 7.95 (1H,
d, J = 8.2 Hz, C6-H), 7.90 (1H, dd, J = 10.5, 0.9 Hz, C1-H), 7.28,
(1H, br s, -OH), 6.99 (1H, dd, J = 8.2, 0.9 Hz, C5-H), 5.89 (1H,
d, J = 10.5 Hz, C2-H), 5.07 (1H, t sept., J = 7.1, 1.4 Hz, C3’-H),
2.09 (2H, m, C2’-H2), 2.05 (3H, s, C9-CH3), 1.79 (1H, ddd, J =
14.2, 9.4, 7.1 Hz, C1’-H), 1.69 (1H, ddd, J = 14.2, 10.1, 6.9 Hz,
C1’-H), 1.65 (3H, d, J = 0.9 Hz, C4’-CH3), 1.56 (3H, s, C4’-
CH3), 1.44 (3H, s, C3-CH3); 13C-NMR δC 188.0 (C10), 180.1
(C7), 160.6 (C4a), 152.2 (C8), 133.8 (C2), 132.2 (C4’), 128.7
(C6), 127.4 (C10a), 123.5 (C3’), 123.4 (C6a), 121.4 (C10b),
120.8 (C9), 120.6 (C1), 119.9 (C5), 79.6 (C3), 41.3 (C1’), 26.7
(C3-CH3), 25.7 (C4’-CH3), 22.6 (C2’), 17.6 (C4’-CH3), 8.9 (C9-
CH3); LRMS (EI) m/z (%) 338 (M+, 11), 279 (15), 255 (100), 227
(22), 167 (35); HRMS (EI) m/z 338.1517 (calcd. for C21H22O4
338.1518, ∆ -0.1 mmu).
14. Snieckus, V. Chem. Rev. 1990, 90, 879.
15. (a) Kurdyumov, A. V.; Hsung, R. P. J. Am. Chem. Soc. 2006, 128,
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2013, 15, 3130.
16. Mondal, M.; Puranik, V. G.; Argade, N. P. J. Org. Chem. 2007,
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2003, 5, 3935. (b) Kang, Y.; Mei, Y.; Du, Y.; Jin, Z. Org. Lett.
2003, 5, 4481.
18. S1 the cyclized product from 26a, was found to generate during
the repeated SiO2 column chromatography. Spectroscopic data,
see Supplementary material.
19. DAR of 2,2-Dimethyl-2H-chromene type benzyne and furan 5b
showed similar regioselectivity in various solvents such as Et2O,
THF, toluene and DME (see ref. 10).
20. Selected recent reviews on benzyne: (a) Yoshida, S.; Hosoya, T.
Chem. Lett. 2015, 44, 1450. (b) Miyabe, H. Molecules 2015, 20,
12558. (c) Dubrovskiy, A. V.; Markina, N. A.; Larock, R. C. Org.
Biomol. Chem. 2013, 11, 191. (d) Ikawa, T.; Tokiwa, H.; Akai, S.
J. Synth. Org. Chem. Jpn. 2012, 70, 1123. (e) Tadross, P. M.;
Stoltz, B. M. Chem. Rev. 2012, 112, 3550.
21. Regioselectivity in 4-methoxybenzyne: (a) Tadross, P. M.;
Gilmore, C. D.; Bugga, P.; Virgil, S. C.; Stoltz, B. M. Org. Lett.
2010, 12, 1224. (b) Yoshida, H.; Yoshida, R.; Takai, K. Angew.
Chem. Int. Ed. 2013, 52, 8629. (c) Ikawa, T.; Kaneko, H.; Masuda,
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Acknowledgement
We thank Professor Takeshi Sugai, Keio University, Japan, for
his kind technical suggestion on enzymatic resolution. This work
was partly supported by The Uehara Memorial Foundation and a
Grant from Musashino Joshi-Gakuin.
22. Furan
29
was
prepared
from
(3R,4R)-3,4-
Supplementary material
dihydroxytetrahydrofuran-2-one in two steps. (3R,4R)-3,4-
dihydroxytetrahydrofuran-2-one: (a) Pavlik, C.; Onorato, A.;
Castro, S.; Morton, M.; Peczuh, M.; Smith, M. B. Org. Lett. 2009,
11, 3722. (b) Golden, K. C.; Gregg, B. T.; Quinn, J. F.
Tetrahedron Lett. 2010, 51, 4010.
Supplementary data (Experimental procedures for synthesis of
(±)-2, experimental data of S1, H and 13C NMR spectra and
1
chiral HPLC chromatograms) associated with this article can be
found in the online version, at
23. McErlean, C. S. P.; Moody, C. J. J. Org. Chem. 2007, 72, 10298.
24. Related examples of asymmetric hydrolysis of similar chromenes:
Goujon, J. Y.; Zammattio, F.; Kirschleger, B. Tetrahedron:
Asymmetry 2000, 11, 2409.
References and notes
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