Asymmetric Synthesis of the Aromatic Fragment of Sespendole

Article abstract of DOI:10.1021/acs.joc.9b01597

Sespendole is an indole sesquiterpene alkaloid bearing two isoprenyl groups, one of which is highly oxidized. Herein, we disclose an eight-step synthesis of the aromatic fragment of sespendole in an optically pure form, starting from 4-bromo-2-fluoronitrobenzene. The key steps were a Claisen rearrangement at room temperature for introduction of the prenyl group and a coupling between the dianion generated from prenylated bromo-N-tosylanilide and a chiral epoxy aldehyde.

Full text of DOI:10.1021/acs.joc.9b01597

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Article
An Asymmetric Synthesis of the Aromatic Fragment of Sespendole
Yoshiki Ono, Atsuo Nakazaki, Kaori Ueki, Keiko Higuchi,
Uraiwan Sriphana, Masaatsu Adachi, and Toshio Nishikawa
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01597 • Publication Date (Web): 03 Jul 2019
Downloaded from http://pubs.acs.org on July 8, 2019
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An Asymmetric Synthesis of the Aromatic Fragment of Sespendole
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Yoshiki Ono, Atsuo Nakazaki, Kaori Ueki, Keiko Higuchi, Uraiwan Sriphana,
Masaatsu Adachi, and Toshio Nishikawa*
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Graduate School of Bioagricultural Sciences, Nagoya University
Furo-cho, Chikusa, Nagoya 464-8601 (Japan)
E-mail: nisikawa@agr.nagoya-u.ac.jp
Abstract: Sespendole is an indole sesquiterpene alkaloid bearing two isoprenyl groups, one of
which is highly oxidized. Herein, we disclose an eight-step synthesis of the aromatic fragment
of sespendole in optically pure form, starting from 4-bromo-2-fluoronitrobenzene. The key
steps were a Claisen rearrangement at room temperature for introduction of the prenyl group,
and a coupling between the dianion generated from prenylated bromo-N-tosylanilide and a
chiral epoxy aldehyde.
i) n-BuLi
ii)
H
OH
Claisen
OH
CHO
rearrangement
D
Br
F
OH
C
Br
OTBS
NHTs
OTf
O
A
O
B
O
E
and
four steps
and
two steps
N
NO2
NHTs
H
O
sespendole
aromatic fragment
Key words: natural product synthesis, sespendole, epoxy aldehyde, Claisen rearrangement,
isoprenyl group
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INTRODUCTION
Sespendole 1 (Figure 1), was isolated by Ōmura and co-workers in 2006 from
Pseudobotrytis terrestris FKA-25,1 and determined to contain a sesquiterpene indole core
structure bearing two isoprenyl units on the benzene of the indole nucleus, one of which is
highly oxygenated.2 Determination of the relative stereochemistry of the side chain was
difficult by spectroscopic methods; we assigned the syn relationship by stereoselective
synthesis of two possible diastereomers of the indole moiety and comparison of their NMR
spectra with those of the natural product.3 Sespendole was found to be a potent inhibitor of
lipid droplet synthesis in macrophages, which leads to arteriosclerosis.4 However, its
mechanism of action was reported to be different from that of terpendole C,5 a structurally
similar diterpene indole, which was reported to inhibit acyl-CoA cholesterol acyltransferase
(ACAT) and acyl-CoA synthase (ACS).4,6 Despite the intriguing nature of its structure and
important biological activity, a total synthesis of sespendole has not been reported, although
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the syntheses of structurally related terpene indole alkaloids have been extensively
investigated.7 Due to our ongoing interest in the structure and biological activity of these
natural products, we have undertaken synthetic studies of sespendole in order to elucidate the
importance of the isoprenyl groups of the indole nucleus, and the molecular mechanism of its
action.
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H
H
OH
O
H
H
H
O
O
D
OH
C
A
OH
B
O
N
E
H
N
O
H
H
O
sespendole (1)
terpendole C
Figure 1. Structures of sependole (1) and terpendole C
RESULTS AND DISCUSSION
Our convergent synthetic plan of sespendole is depicted in Scheme 1. It relies on our
previously reported racemic syntheses of the aromatic fragment 23 and terpene fragment 38
starting from 3-hydroxy-4-nitrobenzaldehyde (4) and Wieland Miescher’s ketone (5),
respectively. This paper describes a new synthetic route of the optically active aromatic
fragment necessary for total synthesis of sespendole.
sespendole 1
( )
HO
H
OTBS
D
OTMS
OTf
+
A
O
E
NO2
OTBS
aromatic fragment 2
terpene fragment 3
OHC
OH
O
NO2
O
4
5
racemic-
Scheme 1. A synthetic plan for sespendole
Due to the concise and highly diastereoselective nature of the racemic synthesis of aromatic
fragment 2 (10 steps from 4, a commercially available material), we initially improved the
synthetic route, and attempted the asymmetric synthesis of several intermediates used therein.
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Unfortunately, all of our attempts to introduce chirality, including kinetic resolution of an allylic
alcohol intermediate by either Sharpless asymmetric epoxidation or acylation by various
lipases; CBS reduction; or asymmetric epoxidation of an enone intermediate, were unsuccessful
(for the details, see SI).
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Accordingly, we designed a new synthetic plan, Scheme 2: The two contiguous stereogenic
centers of a new aromatic fragment 6 would be established by coupling of the known
enantiopure (>99% ee) epoxyaldehyde 79 with the functionalized aryl metal 8. In general,
addition of organometallic reagents to epoxy aldehydes gives a diastereomeric mixture of
products in moderate anti-stereoselectivities, an observation that can be explained by the
Felkin-Anh model.10,11 However, in our preliminary experiments using epoxy aldehyde 7 and
phenyllithium, a moderate syn stereoselectivity (syn-12:anti-12 = 1.9:1) was observed,12
perhaps due to chelation control13 (Scheme 3). We therefore anticipated the same
stereopreference in the coupling between 7 and the aryl metal 8, which we planned to obtain by
aromatic nucleophilic displacement (SNAr mechanism) of 4-bromo-2-fluoronitrobenzene (11)
with 2-methylbut-3-en-2-ol (10) to give 9, followed by a Claisen rearrangement and metal-
halogen exchange.
OH
O
M
OR
OTf
+
H
O
O
NHTs
NHTs
7
6
8
Claisen
rearrangement
Br
F
Br
O
+
OH
10
NO2
SNAr
NO2
11
9
Scheme 2. An alternative plan for the asymmetric synthesis of aromatic fragment 6
O
OH
OH
Ph
PhLi
+
H
Ph
-12
THF, -78 to 0 ºC
(70%)
O
O
O
syn
(1.9:1)
12
anti-
7
(±)-
Li
O
Me
Me
H
O
H
Ph
Scheme 3. Model experiments for the construction of the side chain of sespendole
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Reaction of 4-bromo-2-fluoronitrobenzene (11) with the sodium alkoxide of 2-methylbut-
3-en-2-ol (10) gave 9 (Scheme 4). During silica gel column chromatography of 9, we
unexpectedly found that the rearrangement occurred at room temperature to give the desired
product 13 and unusual by-product 14a. We thus investigated the conditions for the silica gel-
mediated Claisen rearrangement, and found that the use of hexane suspended with silica gel
was the most efficient, giving 13 and 14a in 64% and 9% yield from 11 in two steps.14 The
structure of 14a was initially elucidated by spectroscopic analysis, and later confirmed by X-
ray crystallographic analysis of the corresponding p-nitrobenzoate 14b.15 A possible
mechanism from 9 to 14a is shown in Scheme 5. When the Claisen rearrangement occurs at
the position substituted with nitro group, the nitro group of the resulting intermediate 17
undergoes a [2,3] sigmatropic rearrangement to give 18, which undergoes a second [2,3]
sigmatropic rearrangement to give 19, aromatization of which results in by-product 14a.16 The
desired product 13 of the Claisen rearrangement was transformed to 16 in three steps
comprising protection of the phenol with a TBS group, reduction of the nitro group with Zn-
Cu couple, and protection of the resulting aniline with a tosyl group.
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Br
O
Br
F
SiO2 gel
OH
10
hexane
rt
NaH/THF
NO2
NO2
11
9
NO2
TBSCl
imidazole
Br
+
OR
Br
OH
CH2Cl2
NO2
PNBCl
Et3N,
14a
14b
11
)
R = H (10% from
R = PNB
13
11
)
(64% from
CH2Cl2
(80%)
1) Zn-Cu
EtOH-H2O
Br
OTBS
NO2
Br
OTBS
NHTs
2) TsCl
pyridine
(81% in 3 steps)
16
15
Scheme 4. Synthesis of bromide 16
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Br
O
Br
O
O
[3,3]
[2,3]
[2,3]
NO2
N
O
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17
NO2
H
Br
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Br
O
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14a
N
O
H
O
H
19
18
Scheme 5. A proposed mechanism of formation of byproduct 14a from 9
The synthesis of aromatic fragment 6 by the coupling of bromide 16 and chiral epoxy
aldehyde 7 (>99% ee) was next investigated (Scheme 6). Compound 16 was treated with 2.5
equivalents of n-BuLi in THF at -78 °C for 2 hours to generate the corresponding dianion,
which was reacted with freshly distilled epoxy aldehyde 717 at -78 °C to give a 84% yield of
3.3:1 diastereomeric mixture of 20a and 20b as anticipated.18 The stereoselectivity was slightly
higher than that of the model experiment, probably due to the increased steric hindrance of the
dianion derived from 16 relative to phenyllithium. Although chromatographic separation of this
mixture of stereoisomers was difficult, pure 20a could be obtained in 40% isolated yield by
crystallization from ether. Dess-Martin periodinane (DMP) oxidation of a mixture of 20a and
20b followed by reduction of the resulting ketone with Li(t-BuO)3AlH gave 20b as a single
product in 69% yield, which may be useful for synthesis of a diastereomeric analogue of
sespendole in a future SAR study. Deprotection of the TBS group of the desired diastereomer
20a with TBAF was followed by triflation with Comins’ reagent and Et3N furnished triflate 6,
an optically active aromatic fragment of sespendole. Careful TLC analysis of a series of the
reactions revealed that the first product of the deprotection of the TBS was tosylate 21a, which
readily underwent O to N migration of the Ts group to provide tosylamide 21b under the
conditions of the next triflation,19 or silica gel chromatography of 21a.20
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i) n-BuLi
THF, -78 °C, 2 h
OH
OH
OTBS
NHTs
OTBS
NHTs
16
+
7
ii) , -78°C to rt
O
O
(84%, dr 3.3:1)
20a
20b
(40% isolated)
1) TBAF, THF
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2) Comins’ reagent
Et3N, CH2Cl2
(65% in 2 steps)
TBAF
THF
(73%)
1) DMP, CH2Cl2 (74%)
2) Li(t-BuO)3AlH (69%)
OH
OH
Comins'
reagent
OTf
OR
O
O
Et3N
CH2Cl2
(76%)
NHTs
NHR’
21a:
6
R = Ts, R’ = H
SiO2 gel
chromatography
21b
: R = H, R’ = Ts
Scheme 6. Synthesis of 6, aromatic fragment, by coupling between 16 and 7
To confirm the syn-configuration of 6, we initially planned to convert our previously
reported syn epoxy alcohol (±)-22 to racemic 6 and compare the spectral data (Scheme 7).21
Deprotection of TBS group of (±)-22 followed by triflation yielded 23; however, subsequent
reduction of the nitro group with Zn-Cu and tosylation in pyridine22 did not provide the desired
6, but instead 21b was obtained in 51% yield in two steps based on 1H- and 19F-NMR analyses
of the crude product.23 Thus, the syn-configuration of the epoxide moiety was confirmed by
comparison of NMR spectra of chiral and the racemic 21b.
1) TBAF
THF
OH
OTBS
OTf
OH
O
O
2) Tf2O, Et3N
CH2Cl2
(72% in 2 steps)
NO2
NO2
23
(±)-
22
(±)-
1) Zn-Cu
NH4Cl
EtOH-H2O
2) TsCl
pyridine
OH
OH
OH
OTf
O
O
NHTs
NHTs
6
21b
(±)-
(±)- (0%)
(51% in 2 steps)
Scheme 7. Synthesis of (±)-21b from known syn epoxy alcohol (±)-22
CONCLUSION
In summary, we have developed an eight-step synthesis of the aromatic fragment 6 of
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sespendole from 11, a commercially available starting material, in optically pure form. This
new synthesis is strategically different and more concise than the racemic synthesis we
previously reported. The key steps are a room temperature Claisen rearrangement and syn
selective addition reaction of the highly functionalized aryl lithium to epoxy aldehyde 7. In the
course of this synthetic study, an unusual product of the Claisen rearrangement was identified
and a mechanism for its formation is proposed. This new route is expected to enable easy access
to both sespendole and a variety of its analogs; and studies towards these goals are currently
underway.
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EXPRIMENTAL SECTION
General Experimental Methods: Melting points (mp) were recorded on a Yanaco MP-S3
melting point apparatus and are not corrected. Optical rotations were measured on a JASCO DIP-
370 digital polarimeter. Infrared spectra (IR) were recorded on a JASCO FT/IR-4100
spectrophotometer and are reported in wave number (cm-1). Proton nuclear magnetic resonance
(1H NMR) spectra were recorded on a Bruker Avance-400 (400 MHz) spectrometer. Chemical
shifts of all compounds are reported in ppm relative to the residual, undeuterated solvent (CDCl3
as δ = 7.26). 1H NMR data are reported as follows; chemical shift, integration, multiplicity (s =
singlet, d = doublet, t = triplet, q = quartet, quin = quintet, br = broadened, m = multiplet),
coupling constant, and assignment. Carbon nuclear magnetic resonance (13C{1H} NMR) spectra
were recorded on a Bruker Avance-400 (100 MHz) spectrometer. Chemical shifts are reported
in ppm relative to the residual undeuterated solvent (CDCl3 as δ = 77.0). Fluorine nuclear
magnetic resonance (19F NMR) spectra were recorded on a Bruker Avance-400 (376 MHz)
spectrometer. Chemical shifts of all compounds are reported in ppm in a scale relative to
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C6H6CF3 as an external standard (δ = –63.7). F NMR data are reported as follows; chemical
shift, integration, multiplicity (s = singlet). All NMR spectra were measured at 300 K. High-
resolution mass spectra (HRMS) were recorded on an Applied Biosystems Mariner ESI-TOF
spectrometer for ESI-MS and reported in m/z. Elemental analyses were performed by the
Analytical Laboratory of Graduate School of Bioagricultural Sciences, Nagoya University.
Reactions were monitored by thin layer chromatography (TLC) on 0.25 mm silica gel coated
glass plates 60F254 (Merck, #1.05715.0001) and visualized with UV light (254 nm) and an
appropriate reagent (7% ethanolic phosphomolybdic acid, p-anisaldehyde solution in
H2SO4/AcOH/EtOH, ninhydrin solution in n-BuOH/H2O/H2SO4) followed by heating. For open
column chromatography, silica gel 60 (particle size 0.063-0.200 mm, Merck, #1.07734.9025)
was used. For flash column chromatography, silica gel 60 (spherical, particle size 0.04-0.05 mm,
Kanto, #37562-84) was used. Dry THF and CH2Cl2 were purchased from Kanto chemical Co.,
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Inc. Celite (Hyflo Super-Cel®) was purchased from Nacalai Tesque Co., Inc. All other
commercially available reagents were used as received. All moisture sensitive reactions were
carried out using flame-dried flask under an argon or nitrogen atmosphere.
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syn- and anti-(3,3-Dimethyloxiran-2-yl)(phenyl)methanol (syn-12 and anti-12).
Phenyllithium (1.6 M in n-Bu2O, 0.90 mL, 1.4 mmol) was added to a stirred solution of epoxy
aldehyde 7 (145 mg, 1.44 mmol) in dry THF (2 mL) at -78 C over 30 min. The mixture was
stirred for 30 min, warmed to 0 °C, stirred for another 30 min, and then diluted with ice-cold sat.
NH4Cl solution. The aqueous layer was separated and extracted with EtOAc (30 mL × 3). The
combined organic extracts were washed with brine, dried over anhydrous Na2SO4 and
concentrated in vacuo. The residue was purified by column chromatography (silica gel 5 g,
EtOAc/hexane 1:10 to 1:5) to give a 1.9:1 diastereomeric mixture of 12 (180 mg, 70%) as a
colorless solid. 12 (syn: anti = 1.9:1): 1H NMR (400 MHz, CDCl3):  (ppm) 1.31 (2H, s), 1.37
(1H, s), 1.45 (2H, s), 1.51 (1H, s), 2.95 (1/3H, d, J = 8.5 Hz), 2.98 (2/3H, d, J = 8.5 Hz), 4.57
(1H, d, J = 8.5 Hz), 7.30-7.47 (5H, m). 13C{1H} NMR (100 MHz, CDCl3):  (ppm) 18.9, 19.7*,
24.8, 24.9*, 59.7, 60.1*, 66.5, 68.0*, 72.4, 72.6*, 126.0, 126.0*, 128.1, 128.1*, 128.6, 128.7*,
140.1*, 141.5 (signals of the major syn-12 are indicated as *mark.) HR-MS (ESI, positive): calcd.
For C11H14NaO2 (MNa), 201.0886; Found 201.0891. The NMR data were in good agreement
with those of literature.12
3-Bromo-6-(3-methylbut-2-en-1-yl)-2-nitrophenyl 4-nitrobenzoate (14b).
PNBCl
(96.4 mg, 0.520 mmol) was added to a solution of 14a (97.1 mg, 0.339 mmol) and Et3N (150
L, 1.02 mmol) in dry CH2Cl2 (5 mL) at 0 °C under argon at room temperature and stirred.
After 10 min, the mixture was diluted with sat. NaHCO3 solution. The aqueous layer was
separated and extracted with CH2Cl2 (20 mL x 3). The combined organic extracts were dried
over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by column
chromatography (silica gel 10 g, CH2Cl2/hexane 1:5) to give 14b (115.7 mg, 80%) as a white
1
solid. 14b: mp: 79-84 °C. IR (film): max (cm-1) 1758, 1542, 1349, 1240, 1056, 1013. H
NMR (400 MHz, CDCl3):  (ppm) 1.54 (3H, s), 1.68 (3H, s), 3.25 (2H, d, J = 7.0 Hz), 5.17
(1H, m), 7.33 (1H, d, J = 8.5 Hz), 7.57 (1H, d, J = 8.5 Hz), 8.30 (2H, brd, J = 8.5 Hz), 8.37
13
(2H, brd, J = 8.5 Hz). C{1H} NMR (100 MHz, CDCl3):  (ppm) 17.8, 25.6, 28.8, 111.2,
119.2, 123.9, 131.5, 131.6, 132.5, 132.8, 135.6, 136.3, 141.2, 145.1, 151.3, 161.6. Anal. Calcd
for C18H15BrN2O6: C, 49.67; H, 3.47; N, 6.44. Found: C, 49.58; H, 3.55; N, 6.21.
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3-Bromo-2-(3-methylbut-2-en-1-yl)-6-nitrophenol (13) and 3-bromo-6-(3-methylbut-
2-en-1-yl)-2-nitrophenol (14a). 2-Methyl-3-buten-2-ol (10) (3.60 mL, 34.1 mmol) was
added portion-wise over 10 min to a stirred suspension of 60% NaH (1.86 g, 47.0 mmol) in dry
THF (30 mL) at room temperature. The mixture was refluxed for 30 min, cooled to 0 °C, diluted
with a solution of 4-bromo-2-fluoronitrobenzene (11) (5.01 g, 22.8 mmol) in dry THF (15 mL)
(added dropwise), and then stirred for 3 h at room temperature. The mixture was then diluted
with ice-cold sat. NaHCO3 solution and NaOH (1 N) solution; the aqueous layer was separated
and extracted with EtOAc (100 mL × 5), and the combined organic extracts washed with brine,
dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was used for the next
reaction without purification. Silica gel (42.3 g, Silica gel 60 (particle size 0.063-0.200 mm,
Merck, #1.07734.9025)) was added to a solution of the crude product 9 (6.90 g) in hexane (230
mL). After being stirred vigorously at rt for 12 h, the reaction mixture was filtered through a
sintered glass funnel. The filtrate was concentrated in vacuo. The residue was purified by
column chromatography (silica gel 100 g, CH2Cl2/hexane 1:10 to 1:5) to give 13 (4.14 g, 64%
in 2 steps) as a yellow solid and 14a (651 mg, 10%) as a yellow oil. 13: mp: 84-85 °C. IR
(film): max (cm-1) 2968, 2962, 2361, 1602, 1430, 1268, 1210, 1163, 937. 1H NMR (400 MHz,
CDCl3):  (ppm) 1.70 (3H, d, J = 1.0 Hz), 1.82 (3H, s), 3.61 (2H, d, J = 7.0 Hz), 5.13 (1H, m),
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7.17 (1H, d, J = 9.0 Hz), 7.82 (1H, d, J = 9.0 Hz), 11.16 (1H, s). C{1H} NMR (100 MHz,
CDCl3):  (ppm) 18.2, 25.7, 29.3, 119.1, 122.9, 124.1, 132.7, 132.8, 133.9, 134.2, 153.8. Anal.
Calcd for C11H12BrNO3: C, 46.18; H, 4.23; N, 4.90. Found: C, 46.43; H, 4.14; N, 4.74. 14a:
IR (film): max (cm-1): 2913, 1590, 1539, 1233, 890. 1H NMR (400 MHz, CDCl3):  (ppm) 1.71
(3H, s), 1.76 (3H, s), 3.35 (2H, d, J = 7.5 Hz), 5.26 (1H, m), 7.17 (1H, d, J = 8.0 Hz), 7.21 (1H,
d, J = 8.0 Hz). 13C{1H} NMR (100 MHz, CDCl3):  (ppm) 17.8, 25.7, 28.3, 113.1, 119.9, 126.2,
131.7, 134.4, 135.2, 135.9, 152.6. HR-MS (ESI, positive): calcd. For C11H13BrNO3 (MH),
286.0073; Found 286.0079.
N-(4-Bromo-2-((tert-butyldimethylsilyl)oxy)-3-(3-methylbut-2-en-1-yl)phenyl)-4-
methylbenzenesulfonamide (16). Imidazole (6.50 g, 36.1 mmol) and TBSCl (4.48 g, 43.2
mmol) were added to a solution of 13 (4.14 g, 14.4 mmol) in CH2Cl2 (150 mL) at room
temperature and stirred. After 2 h, the mixture was diluted with water (150 mL). The aqueous
layer was separated and extracted with CH2Cl2 (100 mL × 2). The combined organic extracts
were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was used for the next
reaction without purification. Zn-Cu (8.69 g) was added to a mixture of crude 15 (10.8 g) and
NH4Cl (36.6 g) in EtOH (400 mL) and water (80 mL) at room temperature. The mixture was
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stirred vigorously for 12 h and filtered through a pad of Celite. The filtrate was concentrated to
remove EtOH and some of the water. The residue was suspended with EtOAc (500 mL) and
filtered through a pad of Celite. The filtrate was washed with brine and evaporated. The residue
was used for the next reaction without purification. TsCl (8.32 g, 43.2 mmol) was added to a
solution of crude product (5.56 g) in pyridine (140 mL), portion-wise, at room temperature. The
mixture was stirred. After 15 h, ice-cold water and then toluene were added, and the mixture
concentrated in vacuo. The residue was dissolved in water and EtOAc, and then extracted with
EtOAc (100 mL × 3). The combined extracts were washed with brine, dried over anhydrous
Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography (silica
gel 100 g, EtOAc/hexane 1:5) to give 16 (6.12 g, 81% in 3 steps) as a brown oil. 16: IR (film):
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max (cm-1) 3385, 3118, 2962, 2361, 1951, 1728, 1685, 1608, 1524, 1469. 1H NMR (400 MHz,
CDCl3):  (ppm) 0.21 (6H, s), 1.03 (9H, s), 1.64 (3H, s), 1.66 (3H, s), 2.39 (3H, s), 3.34 (2H, d,
J = 6.0 Hz), 4.83 (1H, m), 6.70 (1H, s) 7.11 (1H, d, J = 9.0 Hz), 7.16 (1H, d, J = 9.0 Hz), 7.23
(2H, d, J = 8.5 Hz), 7.65 (2H, d, J = 8.5 Hz). 13C{1H} NMR (100 MHz, CDCl3):  (ppm) -3.6,
18.2, 18.5, 21.5, 25.6, 25.8, 29.9, 117.8, 120.0, 121.0, 126.5, 127.2, 128.3, 129.6, 132.6, 133.0,
136.2, 143.4, 144.0. Anal. Calcd. for C24H34BrNO3SSi: C, 54.95; H, 6.53; N, 2.67. Found: C,
54.95; H, 6.54; N, 2.66.
Preparation of enantiomerically pure epoxy aldehyde 7 in 4 steps as follows (The scheme is
given as Scheme S7 in the Supporting Information):
1. Synthesis of (2R)-3,3-dimethyl-2-oxiranemethanol.
A flame-dried 500 mL round-
bottomed flask fitted with a thermometer was charged with powdered activated molecular sieves
4A (5.04 g) and dry CH2Cl2 (300 mL). 3-Methyl-2-buten-1-ol (15.0 ml, 149 mmol) was added to
the suspension of D-()-DIPT (1.80 mL, 8.91 mmol) and Ti(O-i-Pr)4 (2.10 mL, 7.43 mmol) at -30
°C and stirred. After 20 min, TBHP (5.05 M toluene solution, 30.0 mL, 152 mmol) was added over
30 min and stirring was continued for 2 h. Bu3P (7.20 mL, 29.6 mmol) was then added to quench
TBHP at -30 °C. Anhydrous citric acid (1.52 g, 14.8 mmol) and Et2O (200 mL) were added to the
reaction mixture at room temperature. The mixture was vigorously stirred for 30 min, then filtered
through filter paper under reduce pressure to remove the molecular sieves. The filtrate was
evaporated. The same scale synthesis of (2R)-3,3-dimethyl-2-oxiranemethanol was conducted
three times by the same procedure. These crude products were combined and then purified by
column chromatography (silica gel 200 g, EtOAc/ hexane 1:5 to 1:1) to give (2R)-3,3-dimethyl-2-
oxiranemethanol (28.8 g, 75%) as a colorless oil. 1H NMR (400 MHz, CDCl3):  (ppm) 1.31 (3H,
s), 1.34 (3H, s), 2.04 (1H, brs), 2.97 (1H, dd, J = 6.5, 4.5 Hz), 3.67 (1H, dd, J = 12.0, 6.5 Hz), 3.83
(1H, d, J = 12.0 Hz). This NMR data matches that of the following literature.9b
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2.
p-Nitrobenzoylation
of
(2R)-3,3-dimethyl-2-oxiranemethanol.
((R)-(3,3-
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dimethyloxiran-2-yl)methyl 4-nitrobenzoate. PNBCl (58.2 g, 314 mmol) was added portion-
wise over 15 min to a solution of (2R)-3,3-dimethyl-2-oxiranemethanol (28.8 g, 282 mmol) and
Et3N (120 mL, 861 mmol) in dry CH2Cl2 (800 mL) at 0 °C and stirred. After being stirred at the
same temperature for 10 min, sat. NaHCO3 solution was poured into the reaction mixture at 0 °C.
The mixture was extracted with CH2Cl2 (800 mL x 3). The combined extracts were evaporated.
EtOAc (200 mL) was added to the residue and the suspension was filtered through a pad of
Super-Cel® under reduce pressure to remove insoluble salts. The filtrate was diluted with water
and extracted with EtOAc (100 mL x 3). The combined extracts were washed with brine, dried
over anhydrous Na2SO4, and concentrated to dryness in vacuo. The residue was dissolved in Et2O
and the solution was cooled at -30 °C to give [(2R)-3,3-dimethyloxiran-2-yl]methyl 4-
nitrobenzoate (22.9 g, 32%, 99% ee) as a pale yellow solid. The enantiomeric excess was
determined by HPLC analysis with chiral HPLC column (DAICEL CHIRALCEL, IC, 50% 2-
propanol in hexane, 1.0 mL/min). 1H-NMR (400 MHz, CDCl3):  (ppm) 1.39 (6H, s), 3.15 (1H,
dd, J = 7.0, 4.0 Hz), 4.30 (1H, dd, J =12.0, 7.0 Hz), 4.66 (1H, dd, J = 12.0, 4.0 Hz), 8.24 (2H,
brd, J = 9.0 Hz) 8.30 (2H, d, J = 9.0 Hz). This NMR data matches that of the following literature.9a
3. Synthesis of (2R)-3,3-dimethyl-2-oxiranemethanol. Sat. NH3 in MeOH solution (250 mL)
was added to a solution of [(2R)-3,3-dimethyloxiran-2-yl]methyl 4-nitrobenzoate (22.9 g, 91.1
mmol) in dry THF (250 mL) at room temperature. After being stirred for 28 h at the same
temperature, the reaction mixture was concentrated. The residue was diluted with MeOH. Insoluble
material was filtered through filter paper under reduce pressure. The same procedure was repeated
twice. The filtrate was purified by column chromatography (silica gel 300 g, EtOAc/hexane 1:5 to
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1:1) to give (2R)-3,3-dimethyl-2-oxiranemethanol (7.62 g, 82%) as colorless oil. H-NMR (400
MHz, CDCl3):  (ppm) 1.30 (3H, s), 1.34 (3H, s), 2.97 (1H, dd, J = 6.0, 4.5 Hz), 3.67 (1H, m),
3.82 (1H, m). This NMR data matches that of the following literature9b
4. Oxidation of (2R)-3,3-dimethyl-2-oxiranemethanol. Et3N (42.0 mL, 297 mmol) and
DMSO (21.0 mL, 297 mmol) was added to a solution of (2R)-3,3-dimethyl-2-oxiranemethanol
(7.62 g, 74.6 mmol) in dry CH2Cl2 (150 mL) at 0 °C. After stirring for 10 min, SO3 pyridine
complex (21.5 g, 135 mmol) was added at same temperature. After stirring for 30 min, the
reaction was quenched with sat. NaHCO3 solution. The mixture was extracted with CH2Cl2 (200
mL x 3). The combined organic layer was washed with 3% CuSO4 solution (50 mL x 5) and
brine. The mixture was stirred with anhydrous Na2SO4 for 1 h, filtered and evaporated. The crude
product was distilled under reduced pressure (52 mmHg, 50 °C) to give 7 (1.55 g, 21%). 7: 1H-
NMR (400 MHz, CDCl3):  (ppm) 1.34 (3H, s), 1.37 (3H, s), 3.10 (1H, d, J = 5.0 Hz), 9.36 (1H,
d, J = 5.0 Hz). This NMR data matches that of the following literature.9b
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N-(2-((tert-butyldimethylsilyl)oxy)-4-((S)-((R)-3,3-dimethyloxiran-2-
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yl)(hydroxy)methyl)-3-(3-methylbut-2-en-1-yl)phenyl)-4-methylbenzenesulfonamide (20a)
and
N-(2-((tert-butyldimethylsilyl)oxy)-4-((R)-((R)-3,3-dimethyloxiran-2-
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yl)(hydroxy)methyl)-3-(3-methylbut-2-en-1-yl)phenyl)-4-methylbenzenesulfonamide (20b).
n-BuLi (2.60 M in hexane; 5.0 mL, 13.0 mmol) was added to a solution of 16 (2.69 g, 5.11 mmol)
in dry THF (50 mL) at -78 °C under positive pressure of argon. The mixture was stirred at -78 °C
for 2 h, and then freshly distilled 7 (1.50 mL, 1.55 g, 15.5 mmol) was added. Stirring was
continued for 30 min. The reaction mixture was allowed to warm to 0 °C over 30 min; and then
left to warm to room temperature, with stirring. After 30 min, the reaction was quenched with
sat. NH4Cl solution and the mixture extracted with EtOAc (200 mL × 3). The combined organic
extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The
residue was purified by column chromatography (silica gel 60 g, EtOAc/hexane 0:1 to 1:5 to 1:2)
to give a 3.3:1 diastereomeric mixture of 20a and 20b (2.34 g, 84%) as a brown solid. The residue
was dissolved in Et2O and the solution was kept at 0 °C for 15 min to give 20a (1.12 g, 40%) as
a white solid. 20a: mp: 141-143 °C. []D28 7.0 (c 1.05, CHCl3). IR (film): max (cm-1) 3385,
2930, 2858, 2360, 1460, 1434, 1385, 1335, 1292, 1263, 1201, 1163, 1091, 1005. 1H NMR (400
MHz, CDCl3):  (ppm) 0.19 (3H, s), 0.22 (3H, s), 1.03 (9H, s), 1.21 (3H, s), 1.30 (3H, s), 1.62
(6H, s), 2.38 (3H, s), 3.06 (1H, d, J = 6.5 Hz), 3.24 (1H, dd, J = 16.0, 6.0 Hz), 3.39 (1H, dd, J =
16.0, 6.0 Hz), 4.56 (1H, dd, J = 6.5, 3.5 Hz), 4.80 (1H, m), 6.79 (1H, s) 7.04 (1H, d, J = 8.5 Hz),
7.23 (2H, d, J = 8.0 Hz), 7.29 (1H, d, J = 8.5 Hz), 7.70 (2H, d, J = 8.0 Hz). 13C{1H} NMR (100
MHz, CDCl3):  (ppm) -3.6, -3.5, 18.0, 18.6, 19.0, 21.5, 24.7, 25.4, 25.5, 25.9, 59.8, 67.4, 68.7,
116.6, 120.8, 123.1, 127.3, 128.7, 129.6, 131.4, 132.4, 136.0, 136.6, 142.5, 143.9. Anal. Calcd
for C29H43NO5SSi: C, 63.82; H, 7.94; N, 2.57. Found: C, 63.83; H, 7.98; N, 2.50.
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Synthesis of pure 20b. Dess-Martin Periodinane (98.2 mg, 0.232 mmol) was added to a
solution of a diastereomeric mixture (syn:anti = 1:1) of 20a and 20b (98.5 mg, 0.180 mmol) in
CH2Cl2 (2 mL) at room temperature and the mixture stirred. After 3 h, saturated aqueous
NaHCO3 solution was added. The mixture was extracted with EtOAc (30 mL × 3) and the
combined extracts washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo.
The residue was purified by column chromatography (silica gel 5 g, EtOAc/hexane 1:10) to give
epoxyketone (72.6 mg, 74%) as a colorless oil. Epoxyketone: []D28 -27.0 (c 1.00, CHCl3). IR
(film): max (cm-1) 2958, 2931, 2859, 2362, 1696, 1590, 1485, 1473, 1438, 1390, 1339, 1305,
1293, 1265, 1243, 1339, 1306, 1293, 1265, 1243, 1163, 1091, 905, 870, 838, 813. 1H NMR (400
MHz, CDCl3):  (ppm) 0.21 (3H,s), 0.23 (3H, s), 1.05 (9H, s), 1.24 (3H, s), 1.50 (3H, s), 1.55
(3H, s), 1.57 (3H, s), 2.39 (3H, s), 3.44 (1H, dd, J = 15.5, 5.0 Hz), 3.68(1H, dd, J = 15.5, 7.5 Hz),
3.69 (1H, s), 4.84 (1H, m), 7.05 (1H, brs), 7.12 (1H, d, J = 8.5 Hz), 7.26 (2H, d, J = 8.5 Hz), 7.31
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(1H, d, J = 8.5 Hz), 7.75 (2H, d, J = 8.5 Hz). 13C{1H} NMR (100 MHz, CDCl3):  (ppm) -3.70,
-3.60, 18.0, 18.3, 18.5, 21.5, 24.4, 25.4, 25.7, 25.8, 61.6, 65.5, 114.0, 122.6, 123.6, 127.2, 129.8,
132.4, 132.4, 133.0, 134.2, 136.3, 142.4, 144.3, 196.8. HR-MS (ESI, positive); calcd. For
C29H41NNaO5SSi (MNa), 566.2367; Found 566.2365. LiAlH(OtBu)3 (1.0 M in THF, 300 L,
0.30 mmol) was added to a solution of epoxyketone (55.5 mg, 0.102 mmol) in THF (2 mL) at -
78 C under a positive pressure of argon and the mixture stirred. After 6 h, saturated aqueous
NH4Cl solution and saturated potassium sodium tartrate solution were added. The mixture was
vigorously stirred for 30 min at room temperature and then extracted with EtOAc (30 mL × 3).
The combined extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated
in vacuo. The residue was purified by column chromatography (silica gel 5 g, EtOAc/hexane
1:10 to 1:5) to give 20b (38.6 mg, 69%) as a colorless oil. 20b: []D28 26.3 (c 1.11, CHCl3).
IR (film): max (cm-1) 3443, 2995, 2960, 2943, 2930, 2359, 1636, 1379, 1333, 1292, 1281, 1261,
1162, 840, 827, 813. 1H NMR (400 MHz, CDCl3):  (ppm) 0.20 (3H, s), 0.21 (3H, s), 1.03 (9H,
s), 1.35 (3H, s), 1.43 (3H, s), 1.64 (6H, s), 1.79 (1H, brs), 2.38 (3H, s), 2.93 (1H, d, J = 7.5 Hz),
3.34 (2H, m, -CH2), 4.68 (1H, d, J = 7.5 Hz), 4.85 (1H, m), 6.80 (1H, brs), 7.15 (1H, d, J = 8.5
Hz), 7.23 (2H, d, J = 8.0 Hz), 7.32 (1H, d, J = 8.5 Hz), 7.70 (2H, d, J = 8.0 Hz). 13C{1H} NMR
(100 MHz, CDCl3):  (ppm) -3.6, -3.5, 18.1, 18.6, 18.8, 21.5, 24.8, 25.4, 25.5, 25.9, 59.7, 66.3,
68.3, 116.5, 120.3, 123.2, 127.2, 128.6, 129.6, 131.5, 132.2, 136.6, 136.6, 142.3, 143.9. HR-MS
(ESI, positive); calcd. For C29H43NNaO5SSi (MNa), 568.2523; Found 568.2526.
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3-((S)-((R)-3,3-dimethyloxiran-2-yl)(hydroxy)methyl)-2-(3-methylbut-2-en-1-yl)-6-(4-
methylphenylsulfonamido)phenyl trifluoromethanesulfonate ((+)-6). TBAF (1.0 M in
THF; 0.2 mL, 0.2 mmol) was added to a solution of 20a (35.5 mg, 0.0650 mmol) in THF (3
mL) at 0 °C under argon. After stirring for 1 h, the mixture was poured into a saturated aqueous
solution of NH4Cl. The aqueous layer was separated and extracted with EtOAc (20 mL × 2).
The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, and
concentrated in vacuo. The residue was used for the next reaction without further purification.
The crude product (35.2 mg) was dissolved in CH2Cl2 (2 mL) and Et3N (25 µL, 0.18 mmol)
and Comin’s reagent (26.2 mg, 0.0667 mmol) was added at rt. The mixture was stirred for 1 h,
and then sat. aqueous NaHCO3 solution was added. The aqueous layer was separated and
extracted with CH2Cl2 (30 mL × 2). The combined organic extracts were washed with brine,
dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by column
chromatography (silica gel 1 g, EtOAc/hexane 1:5) to give (+)-6 (23.6 mg, 65% in 2 steps) as
a colorless solid. ()-6: mp: 92-96 °C. []D28 6.3 (c 0.82, CHCl3). IR (film): max (cm-1) 3385,
2925, 1418, 1339, 1219, 1135. 1H NMR (400 MHz, CDCl3):  (ppm) 1.31 (3H, s), 1.33 (3H, s),
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1.65 (3H, s), 2.40 (3H, s), 3.00 (3H, d, J = 6.5 Hz, 1H), 3.33 (1H, dd, J = 16.0, 5.5 Hz), 3.46
(1H, dd, J = 16.0, 5.5 Hz), 4.67 (1H, dd, J = 6.5, 2.0 Hz), 4.78 (1H, m), 7.00 (1H, brs), 7.24
(2H, d, J = 8.5 Hz), 7.52 (1H, d, J = 8.5 Hz), 7.54 (1H, d, J = 8.5 Hz), 7.65 (2H, d, J = 8.5 Hz).
13C{1H} NMR (100 MHz, CDCl3):  (ppm) 18.0, 18.9, 21.6, 24.6, 25.4, 25.6, 60.5, 66.8, 67.6,
118.3 (q, JC-F = 319 Hz), 120.6, 122.8, 127.4, 127.8, 129.6, 129.7, 133.7, 134.8, 135.9, 138.1,
139.3, 144.4. 19F-NMR (376 MHz, CDCl3)  (ppm) -74.0 (s). HR-MS (ESI, positive): Calcd.
For C24H28F3NNaO7S2 (MNa), 586.1139; Found 586.1151.
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N-(4-((S)-((R)-3,3-dimethyloxiran-2-yl)(hydroxy)methyl)-2-hydroxy-3-(3-methylbut-2-
en-1-yl)phenyl)-4-methylbenzenesulfonamide ((+)-21b). TBAF (1.0 M in THF; 0.2 mL,
0.2 mmol) was added to a solution of 20a (37.0 mg, 0.0678 mmol) in THF (3 mL) at 0 °C under
a positive pressure of argon. After stirring for 1 h, the mixture was poured into a saturated
aqueous solution of NH4Cl. The aqueous layer was separated and extracted with EtOAc (20
mL × 2). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4,
and concentrated in vacuo. The residue was purified by column chromatography (silica gel 1 g,
EtOAc/hexane 1:5) to give ()-21b (21.3 mg, 73% in 2 steps) as a colorless solid. ()-21b: mp:
152 °C. []D28 6.9 (c 0.95, CHCl3). IR (film): max (cm-1) 3504, 3359, 2963, 2624, 2854, 2360,
2341, 1731, 1717, 1597, 1493, 1455, 1378, 1331, 1307, 1261, 1238, 1156, 1091, 1021, 1012.
1H NMR (400 MHz, CDCl3):  (ppm) 1.30 (3H, s), 1.32 (3H, s), 1.71 (3H, s), 1.77 (3H, s), 2.39
(3H, s), 3.04 (1H, d, J = 7.0 Hz), 3.43 (2H, m), 4.64 (1H, d, J = 7.0 Hz), 5.00 (1H, m), 6.17
(1H, brs), 6.68 (1H, brs), 6.87 (1H, d, J = 8.0 Hz), 6.90 (1H, d, J = 8.0 Hz), 7.23 (2H, d, J = 8.0
Hz), 7.64 (2H, d, J = 8.0 Hz). 13C{1H} NMR (100 MHz, CDCl3):  (ppm) 18.0, 19.1, 21.6, 24.7,
25.6, 25.7, 60.4, 67.1, 69.4, 119.1, 121.5, 121.5, 123.7, 126.8, 127.5, 129.6, 135.2, 135.5, 137.3,
144.1, 148.1. Anal. Calcd for C24H28F3NO7S2: C, 51.15; H, 5.01; N, 2.49. Found: C, 51.16; H,
5.11; N, 2.59.
Synthesis of triflate 6 from 21b. Et3N (150 µL, 0.0993 mmol) and Comin’s reagent (16.5 mg,
0.0420 mmol) were added to a solution of the phenol (+)-21b (14.3 mg, 0.0331) in CH2Cl2 (2
mL) at rt under a positive pressure of argon. After stirring for 1 h, the reaction was quenched
with sat. aqueous NaHCO3 solution. The aqueous layer was separated and extracted with CH2Cl2
(30 mL × 2). The combined organic extracts were washed with brine, dried over anhydrous
Na2SO4, and concentrated in vacuo. The residue was purified by preparative TLC (EtOAc/hexane
1:1) to give (+)-6 (12.4 mg, 76%) as a colorless solid.
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3-((S*)-((R*)-3,3-Dimethyloxiran-2-yl)(hydroxy)methyl)-2-(3-methylbut-2-en-1-yl)-6-
nitrophenyl trifluoromethanesulfonate (()-23). TBAF (1.0 M in THF, 4.9 mL, 4.9 mmol)
was added to a solution of ()-223 (522 mg, 1.24 mmol) in THF (12 mL) at 50 C and stirred.
After 14.5 h, the mixture was diluted with water. The mixture was extracted with EtOAc (x 3).
The combined extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated
in vacuo. The residue was used for the next reaction without purification. Et3N (800 L, 5.72
mmol) and Tf2O (200 L, 1.25 mmol) were added to a solution of the residue (352 mg) in CH2Cl2
(12 mL) at -20 C and stirred. After 15 min, the mixture was diluted with sat. NaHCO3 solution.
The mixture was extracted with EtOAc (x 3). The combined organic extracts were washed with
brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by
column chromatography (silica gel 10 g, EtOAc/hexane 1:1) to give ()-23 (394 mg, 72% in 2
steps) as a yellow solid. ()-23: mp: 69-71 °C. IR (film): max (cm-1) 3442, 1636, 1539, 1430,
1410, 1353, 1216, 1135, 890, 848, 826. 1H NMR (400 MHz, CDCl3):  (ppm) 1.35 (3H, s), 1.38
(3H, s), 1.70 (3H, s), 1.75 (3H, s), 2.97 (1H, d, J = 6.0 Hz), 3.08 (1H, brs), 3.51 (1H, dd, J = 16.0,
6.0 Hz), 3.66 (1H, dd, J = 16.0, 6.0 Hz), 4.85 (1H, dd, J = 6.0, 3.0 Hz), 4.96 (1H, m), 7.78 (1H,
d, J = 8.5 Hz), 7.95 (1H, d, J = 8.5 Hz). 13C{1H} NMR (100 MHz, CDCl3):  (ppm) 18.0, 18.9,
24.4, 25.5, 25.8, 61.0, 66.5, 66.9, 116.7, 118.3 (q, JC-F = 315 Hz), 119.7, 120.0, 124.4, 127.3,
135.0, 136.1, 138.2, 142.5, 148.4. 19F NMR (376 MHz, CDCl3)  (ppm) -73.9 (s). Anal. Calcd
for C17H20F3NO7S: C, 46.47; H, 4.59; N,3.19. Found: C, 46.48; H, 4.57; N, 3.14.
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Synthesis of ()-21b from ()-23. Zn-Cu (101 mg) was added to a solution of ()-23 (65.5 mg,
0.149 mmol) and NH4Cl (235 mg) in EtOH (3 mL) and water (0.5 mL) at room temperature.
After being stirred for 30 min, the reaction mixture was filtered through a pad of Celite. The
filtrate was dissolved in water and EtOAc, and then extracted with EtOAc (30 mL × 3). The
combined extracts were washed with brine and dried over anhydrous Na2SO4 and concentrated.
The residue was used for the next reaction without purification. TsCl (45.4 mg, 0.238 mmol) was
added to a solution of the crude product (39.3 mg) in pyridine (3 mL) at room temperature. After
being stirred at the same temperature for 50 min, an ice-cold water was added. The mixture was
dissolved in water and then extracted with EtOAc (30 mL × 3). The combined extracts were
washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was
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purified by column chromatography (silica gel 5 g, EtOAc/hexane 1:5 to 1:2) to give ()-21b
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(32.7 mg, 39% in 2 steps) as a yellow solid. ()-21b: mp: 156-160 °C. H-NMR (400 MHz,
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CDCl3):  (ppm) 1.30 (3H, s), 1.31 (3H, s), 1.71 (3H, s), 1.77 (3H, s), 2.39 (3H, s), 3.04 (1H, d,
J = 7.0 Hz), 3.43 (2H, m), 4.64 (1H, d, J = 7.0 Hz), 5.00 (1H, m), 6.23 (1H, brs), 6.75 (1H, brs),
6.87 (1H, d, J = 8.0 Hz), 6.89 (1H, d, J = 8.0 Hz), 7.22 (2H, d, J = 8.0 Hz), 7.64 (2H, d, J = 8.0
Hz). 13C{1H} NMR (100 MHz, CDCl3):  (ppm) 18.0, 19.1, 21.6, 24.7, 25.5, 25.7, 60.4, 67.1,
69.4, 119.1, 121.5, 121.6, 123.6, 126.9, 127.5, 129.6, 135.1, 135.5, 137.3, 144.0, 148.2.
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Supporting information
The Supporting Information is available free of charge on the ACS Publications website at DOI:
10.1021/acs.joc.XXXXXXX.
Attempts for asymmetric synthesis of intermediates in racemic synthesis of aromatic fragment 2,
comparison of 13C{1H}NMR spectra of a mixture of anti-12 and syn-12 of the literature, scheme
of asymmetric synthesis of epoxy aldehyde 7, X-ray crystallographic data for compound 14b,
and spectral data for all new compounds (PDF)
Crystal data for compound 14b (CIF)
Acknowledgement: This work was supported by a Grant-in-Aid for Scientific Research (B)
(No.16H04915), Grants-in-Aid for Scientific Research on Innovative Areas ‘‘Frontier Research
on Chemical Communication’’ (No.17H06406), and “Middle Molecular Strategy”
(No.18H04400) from MEXT. Y.O. thanks to the Program for Leading Graduate Schools: IGER
Program in Green Natural Sciences from MEXT and the Mizutani Scholarship (Graduate
School of Bioagricultural Sciences, Nagoya University). K.H. was a research fellow of the
Japan Society for the Promotion of Science (DC1). U.S. thanks to the Golden Jubilee PhD
program (Thailand). We also thank Dr. H. Yamada and Dr. S. Ueno for helpful discussion
and technical assistance.
References and Notes:
1.
2.
Yamaguchi, Y.; Masuma, R.; Kim, Y.-P.; Uchida, R.; Tomoda, H.; Ōmura, S. Taxonomy
and secondary metabolites of Pseudobotrytis sp. FKA-25. Mycoscience 2004, 45, 9-16.
Uchida, R.; Kim, Y.-P.; Nagamitsu, T.; Tomoda, H.; Ōmura, S. Structure Elucidation of
Fungal Sespendole, an Inhibitor of Lipid Droplet Synthesis in Macrophages. J.
Antibiot.2006, 59, 338-344.
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Adachi, M.; Higuchi, K.; Thasana, N.; Yamada, H.; Nishikawa, T. Stereocontrolled
Synthesis of an Indole Moiety of Sespendole and Stereochemical Assignment of the Side
Chain. Org. Lett. 2012, 14, 114-117.
Uchida, R.; Kim, Y.-P.; Namatame, I.; Tomoda, H.; Ōmura, S. Sespendole, a New
Inhibitor of Lipid Droplet Synthesis in Macrophages, Produced by Pseudobotrytis
terrestris FKA-25. J. Antibiot. 2006, 59, 93-97.
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5.
(a) Huang, X.-H.; Tomoda, H.; Nishida, H.; Masuma, R.; Ōmura, S. Terpendoles, novel
ACAT inhibitors produced by Albophoma yamanashiensis. I. Production, isolation and
biological properties. J. Antibiot. 1995, 48, 1-4. (b) Huang, X.-H.; Nishida, H.; Tomoda,
H.; Tabata, N.; Shiomi, K.; Yang, D.-J.; Takayanagi, H.; Ōmura, S. Terpendoles, novel
ACAT inhibitors produced by Albophoma yamanashiensis. II. Structure elucidation of
terpendoles A, B, C and D. J. Antibiot. 1995, 48, 5-11, (c) H. Tomoda, N.; Tabata, Yang,
D.-J.; Takayanagi,H.; Ōmura, S. Terpendoles, novel ACAT inhibitors produced by
Albophoma yamanashiensis. III. Production, isolation and structure elucidation of new
components. J. Antibiot. 1995, 48, 793-804.
6.
7.
Ohshiro, T.; Rudel, L. L.; Ōmura, S., Tomoda, H. Selectivity of microbial acyl-CoA:
cholesterol acyltransferase inhibitors toward isozymes. J. Antibiot. 2007, 43, 43-51.
For leading references of synthesis of terpene indole alkaloids, see: (a) Zou, Y.; Smith,
A. B. III. Total synthesis of architecturally complex indole terpenoids: strategic and
tactical evolution. J. Antibiot. 2018, 71, 185-204. (b) Enomoto, M.; Morita, A.; Kuwahara,
S. Total Synthesis of the Tremorgenic Indole Diterpene Paspalinine. Angew. Chem. Int.
Ed. 2012, 51, 12833-12836. (c) Sharpe, R. J.; Johnson, J. S. A Global and Local
Desymmetrization Approach to the Synthesis of Steroidal Alkaloids: Stereocontrolled
Total Synthesis of Paspaline. J. Am. Chem. Soc. 2015, 137, 4968-4971. (d) Sharpe, R. J.;
Johnson, J. S. Asymmetric Total Synthesis of the Indole Diterpene Alkaloid Paspaline. J.
Org. Chem. 2015, 80, 9740-9766. (e) Godfrey, N. A.; Schatz, D. J.; Pronin, S. V. Twelve-
Step Asymmetric Synthesis of (−)-Nodulisporic Acid C. J. Am. Chem. Soc. 2018, 140,
12770-12774. (f) George, D.T.; Kuenstner, E. J.; Pronin, S. V. Synthesis of Emindole SB.
Synlett 2017, 28, 12-18.
8.
9.
Sugino, K.; Nakazaki, A.; Isobe, M.; Nishikawa, T. Synthetic Study on Sespendole, an
Indole Sesquiterpene Alkaloid: Stereocontrolled Synthesis of the Sesquiterpene Segment
Bearing All Requisite Stereogenic Centers. Synlett 2011, 647-650.
(a) Gao, Y.; Klunder, J. M.; Hanson, R. M.; Masamune, H.; Ko, S. Y.; Sharpless, K. B.
Catalytic asymmetric epoxidation and kinetic resolution: modified procedures including
in situ derivatization. J. Am. Chem. Soc. 1987, 109, 5765-5780. (b) Zou, Y.; Lobera, M.;
Snider, B. B. Synthesis of 2,3-Dihydro-3-hydroxy-2-hydroxylalkylbenzofurans from
Epoxy Aldehydes. One-Step Syntheses of Brosimacutin G, Vaginidiol, Vaginol,
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Smyrindiol, Xanthoarnol, and Avicenol A. Biomimetic Syntheses of Angelicin and
Psoralen. J. Org. Chem. 2005, 70, 1761-1770.
10. For several examples of anti-stereoselectivity in addition of organometallic reagent to
epoxy aldehyde, see: (a) Kitamura, M.; Isobe, M.; Ichikawa, Y.; Goto, T. Stereocontrolled
total synthesis of (-)-maytansinol. J. Am. Chem. Soc. 1984, 106, 3252-3257. (b) Iio, H.;
Mizobuchi, T.; Tokoroyama, T. High diastereoselectivity observed in the vinylation
reaction of α, β-epoxy aldehydes with β-silylphosphorous ylide. Tetrahedron Lett. 1987,
28, 2379-2382. (c) Howe, G. P.; Wang, S. Procter, G. Stereoselective additions to α, β-
epoxy-aldehydes; the formation of “non-chelation controlled” products. Tetrahedron Lett.
1987, 28, 2629-2632. (d) Escudier, J.-M.; Baltas, M.; Gorrichon, L. Diastereoselection in
the addition of enolates to chiral α, β-epoxyaldehydes. Tetrahedron Lett. 1991, 32, 5345-
5348. (e) Urabe, H.; Matsuka, T.; Sato, F. (2S,3S)-2,3-epoxy-3-trimethylsilylpropanal as
a new conjunctive reagent. Tetrahedron Lett. 1992, 33, 4179-4182. (e) Righi, G.; Ronconi,
S.; Bonini, C. A Study on the “Non‐Chelation Controlled” Organometallic Addition to
trans α, β‐Epoxy Aldehydes − A Straightforward Stereoselective Synthesis of the Abbot
Amino Dihydroxyethylene Dipeptide Isoster. Eur. J. Org. Chem. 2002, 1573-1577.
11. To our knowledge, only two examples of the reaction of 6 with nucleophiles have
been reported, however, neither nucleophile was an organolithium reagents. See:
Tanaka, M.; Tomioka, K.; Koga, K. Total synthesis of natural (+)-spatol.
Confirmation of the absolute stereostructure. Tetrahedron 1994, 50, 12843-12852,
and ref 9 (b).
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12. The relative configuration of syn-7 was determined by comparison of its NMR data with
that previously reported (See SI). Salvi, L.; Kim, J.G.; Walsh, P. J. Practical Catalytic
Asymmetric Synthesis of Diaryl-, Aryl Heteroaryl-, and Diheteroarylmethanols. J. Am.
Chem. Soc. 2009, 131, 12483-12493.
13. Examples of chelation control in reaction of epoxy aldehyde or ketone: with
organometallic reagents: (a) Oishi, T.; Nakata, T. An introduction of chiral centers into
acyclic systems based on stereoselective ketone reduction. Acc. Chem. Res. 1984, 17,
338-344. (b) Okamoto, S.; Yoshino, T.; Tsujiyama, H.; Sato, F. Synthesis of optically
active γ-trimethylsilyl-β,γ-epoxy tertiary alcohols by the diastereoselective addition
reaction of β-trimethylsilyl-α,β-epoxyketones with Grignard reagents. Tetrahedron Lett.
1991, 32, 5789-5792. (c) Ipaktschi, J.; Heydari, A.; Kalinowski, H.-O. Chelat-
kontrollierte diastereoselektive Addition an α,ß-Epoxy-Aldehyde. Chem. Ber. 1994, 127,
905-909. (d) Urabe, H,; Evin,O. O.; Sato, F. Chelation-Controlled Addition of
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Dialkylzincs to trans-.alpha.,.beta.-Epoxy Aldehydes. J. Org. Chem. 1995, 60, 2660-2661.
(e) Nakamura, K.; Ohmori, K.; Suzuki, K. Stereocontrolled Total Syntheses of (−)-
Rotenone and (−)-Dalpanol by 1,2‐Rearrangement and SNAr Oxycyclizations. Angew.
Chem. Int. Ed. 2017, 56, 182-187.
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14. The Claisen rearrangement of 10 proceeded in refluxing toluene to give the desired
product 13 and by-product 14a in yields of 67% and 10%, respectively.
15. CCDC-1878380 contains the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
16. For a similar rearrangement of nitro group of 6-alkyl-6-nitrocyclohexadienone, see: (a)
Fischer, A.; Henderson, G. N. IPSO nitration: nitration of 2-alkylphenols in acetic
anhydride. Formation of 6-alkyl-6-nitrocyclohexa-2,4-dienones. Tetrahedron Lett. 1980,
21, 4661-4662. (b) Fischer, A.; Mathivanan. N. Formation of dienones on the reaction of
cresols, xylenols, and 2-naphthol with nitrogen dioxide: Observation of keto tautomers
of nitrophenols. Tetrahedron Lett. 1988, 29, 1869-1872.
17. The aldehyde 6 was used within 24 h of distillation, otherwise the yield decreased because
of its instability. The aldehyde turned to viscous oil even when kept in a freezer at -30 °C.
18. In order to improve the stereoselectivity, addition of metal salt such as ZnCl2 and TiCl4
was examined. The reaction in addition of ZnCl2 increased the selectivity to 5:1, however,
the yield decreased to 36%. The reaction with TiCl4 gave a complex mixture of products.
19. When 21a was exposed to the conditions of triflation at -20 °C, migration of the Ts group
was observed without triflation. When the mixture was then warmed to 0 °C, O-triflation
of 21b occurred to 6. Because of the instability of 21a and 21b, compound 6 was
synthesized from 20a without purification of the intermediates.
20. The position of Ts group of 21a and 21b was determined by NOESY spectra.
21. X-ray analysis of compound 20a was unsuccessful because the quality of the crystals was
inadequate.
22. K. Kurita. Selectivity in tosylation of o-aminophenol by choice of tertiary amine. Chem.
Ind. 1974, 345.
23. When the triflate of o-nitrophenol was exposed to the same reaction conditions, removal
of the Tf group was not observed. Thus, removal of the Tf group of 23 might be unusual,
and the mechanism is not clear. We greatly appreciate one of the reviewers for his/her
comment, which led us to note this unexpected reaction and to investigate the details.
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