Total Synthesis of Bis-anthraquinone Antibiotic BE-43472B

Article abstract of DOI:10.1055/s-0037-1610136

This is a full account of our synthetic endeavor on the total synthesis of bis-anthraquinone antibiotic BE-43472B, an unusual octacyclic aromatic polyketide with a bis-anthraquinone scaffold. Three key steps enabled a facile access to the anthraquinone unit corresponding to the ABCF rings; (1) cyclo-condensation or -addition of benzonitrile oxides with cyclic enone derivatives, (2) benzoin cyclization for the stereoselective ring fusion with an angular hydroxy group, and (3) pinacol rearrangement for stereoselective installation of the angular aryl group. Other keys for the success include, (4) diastereoselective methylation of a lactol derivative, and (5) late-stage installation of the C3 hydroxy group through stereoselective oxirane ring formation via halohydrin derivatives. Whereas oxidation of the double bond in the enone with an adjacent 1,3-diketone moiety failed, the projected oxidation was achieved with the alkene keeping the isoxazole moiety intact as a 1,3-diketone equivalent. In the racemic total synthesis, X-ray crystal structure analysis of the target was achieved, proving the three-dimensional architecture for the first time. The asymmetric total synthesis was also achieved by exploiting a cycloadduct of the nitrile oxide and the enantiomerically pure cyclohexenone, which was convertible to the common intermediate via dehydrogenation followed by alkoxycarbonylation.

Full text of DOI:10.1055/s-0037-1610136

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–Z
feature
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Y. Yamashita et al.
Feature
Synthesis
Total Synthesis of Bis-anthraquinone Antibiotic BE-43472B
Yu Yamashita
Yoichi Hirano
Akiomi Takada
Hiroshi Takikawa1
Keisuke Suzuki*
Department of Chemistry, Tokyo Institute of Technology,
O-okayama, Meguro-ku, Tokyo 152-8551, Japan
ksuzuki@chem.titech.ac.jp
Received: 10.03.2018
Accepted after revision: 18.04.2018
Published online: 14.05.2018
tent inhibitory activities against a panel of drug-resistant
bacteria, including MSSA, MRSA, and VRE.2,3b Of particular
importance is that BE-43472B (2) even shows strong bacte-
ricidal activities to these bacteria.
DOI: 10.1055/s-0037-1610136; Art ID: ss-2018-z0170-fa
Abstract This is a full account of our synthetic endeavor on the total
synthesis of bis-anthraquinone antibiotic BE-43472B, an unusual octa-
cyclic aromatic polyketide with a bis-anthraquinone scaffold. Three key
steps enabled a facile access to the anthraquinone unit corresponding
to the ABCF rings; (1) cyclo-condensation or -addition of benzonitrile
oxides with cyclic enone derivatives, (2) benzoin cyclization for the ste-
reoselective ring fusion with an angular hydroxy group, and (3) pinacol
rearrangement for stereoselective installation of the angular aryl group.
Other keys for the success include, (4) diastereoselective methylation of
a lactol derivative, and (5) late-stage installation of the C3 hydroxy
group through stereoselective oxirane ring formation via halohydrin de-
rivatives. Whereas oxidation of the double bond in the enone with an
adjacent 1,3-diketone moiety failed, the projected oxidation was
achieved with the alkene keeping the isoxazole moiety intact as a 1,3-
diketone equivalent. In the racemic total synthesis, X-ray crystal struc-
ture analysis of the target was achieved, proving the three-dimensional
architecture for the first time. The asymmetric total synthesis was also
achieved by exploiting a cycloadduct of the nitrile oxide and the enan-
tiomerically pure cyclohexenone, which was convertible to the com-
mon intermediate via dehydrogenation followed by alkoxycarbonyla-
tion.
OH
O
HO
R1
R2
OH
Me
BE-43472A (1)
BE-43472B (2)
BE-43472C (3)
BE-43472D (4)
OH
H
H
O
O
R1
Me
H
O
R2O
Me
OH
H
Me
Me
O
Figure 1 Structures of BE-43472 antibiotics
From the structural viewpoint, BE-43472B (2) showcas-
es an exquisite molecular architecture that is derived from
the type-II polyketide biogenesis (Figure 2).4 First, it mani-
fests a unique dimeric anthraquinone scaffold5 in terms of
the position connecting two units: whereas common bis-
anthraquinones often have a biaryl connection as exempli-
fied by cassiamin A, and asphodelin [Figure 2 (A)], the an-
thraquinone moieties hidden in 2, i.e., the ABC rings and
FGH rings, are interconnected at the angular position (C4a
in A).6 Secondly, these units are fused together through a bi-
cyclic system, composed of two five-membered hetero-
cycles (D and E rings), constituting a complex octacyclic
framework. Finally, the molecular complexity is further in-
creased by the five contiguous stereogenic centers, among
which is notable the C3 with a labile hydroxy group prone
to the elimination: seminal works by Rowley revealed that 2
underwent the partial C2–C3 dehydration, even when kept
standing at ambient temperature in a neutral media [Figure
2 (B)].3a Note that the C3 hydroxy group is essential for the
Key words antibiotics, bis-anthraquinone, isoxazole, natural prod-
ucts, total synthesis
Introduction
Antitumor antibiotics BE-43472A–D (1–4) constitute a
class of bis-anthraquinone natural products, originally iso-
lated by the Banyu research group in 1996 from the culture
broth of Streptomyces sp. A43472 (Figure 1).2 After a decade,
they were rediscovered by the Rowley group from a marine
creature, Caribbean ascidian (Ecteinascidia turbinata) col-
lected at La Parguera, Puerto Rico.3 In addition to significant
antitumor activities on several cancer cell lines, such as
DLD-1, PC-13, and MKN-45, these compounds exhibit po-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–Z

B
Y. Yamashita et al.
Feature
Synthesis
biological activity; indeed, the dehydrated product exhibit-
ed a pronounced decrease in the inhibitory effect on MRSA
in comparison with 2.3b
The intriguing biological properties as well as the struc-
tural novelty have stimulated the study on the total synthe-
sis of 2. Nicolaou achieved the first asymmetric total syn-
Biographical Sketches
Yu Yamashita was born in
1984 in Osaka, Japan. He ob-
tained his BS degree in 2008 at
Kwansei Gakuin University (Prof.
Shigeo Katsumura). He received
his M.Sc. (2010) and D.Sc.
(2013) at the Tokyo Institute of
Technology under the supervi-
sion of Prof. Keisuke Suzuki. In
2013 he moved to Otsuka Phar-
maceutical Co., Ltd.
Yoichi Hirano was born in
1989 in Tokyo, Japan. He re-
ceived his BS (2011), M.Sc.
(2013), and D.Sc. (2016) at the
Tokyo Institute of Technology
under the supervision of Prof.
Keisuke Suzuki. He is currently
working in Shionogi & Co., Ltd
as a process chemist.
Akiomi Takada was born in
1973 in Hokkaido, Japan. He ob-
tained his B.Sc. (1996) and
M.Sc. (1998) at Yamagata Uni-
versity (Prof. Yasuhisa Senda).
He then began his career at
FUJIFILM Finechemicals Co., Ltd.
In 2007, he began his doctoral
studies at the Tokyo Institute of
Technology and received his
D.Sc. (2011) under the super-
vision of Prof. Keisuke Suzuki.
Currently he is a research man-
ager at the Organic Synthesis
Research Laboratory, FUJIFILM
Finechemicals Co., Ltd.
Hiroshi Takikawa was born in
1980 in Hiroshima, Japan. He
obtained his B.Eng. in 2003 at
Nagoya University (Prof. Hisashi
Yamamoto and Prof. Kazuaki
Ishihara). He received his M.Sc.
(2005) and D.Sc. (2008) at the
Tokyo Institute of Technology
under the supervision of Prof.
Keisuke Suzuki. After working as
a postdoctoral fellow at the Max
Planck Institute for Coal Re-
search with Prof. Alois Fürstner
(2008–2009), he returned to
Tokyo Institute of Technology in
2009 as an Assistant Professor,
and in 2017 moved to Kyoto
University as Lecturer.
Keisuke Suzuki was born in
1954 in Kanagawa, Japan. He
received his D.Sc. in 1983 at the
University of Tokyo (Prof. Teruaki
Mukaiyama), and became a Re-
search Associate (the late Prof.
Gen-ichi Tsuchihashi) at Keio
University (1983), where he was
promoted to Lecturer (1987),
Associate Professor (1989), and
Professor (1994). He moved to
his current position at Depart-
ment of Chemistry, Tokyo Insti-
tute of Technology in 1996. He
spent his sabbatical as a Visiting
Professor at ETH, Zürich (1990–
1991; Prof. D. Seebach) and
Regensburg (June to August
2010; Prof. O. Reiser).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–Z

C
Y. Yamashita et al.
Feature
Synthesis
Figure 2 Naturally occurring bis-anthraquinones, a computer-generated molecular model of (+)-BE-43472B [(+)-2] (fully optimized at the B3LYP/6-
31G* level, Spartan 14, carbon, gray; oxygen, red; hydrogens, omitted), and an origami model of (+)-2 (courtesy of Prof. S.-C. Hung, Academia Sinica,
Taiwan) (top). Bis-anthraquinones with a biaryl connection (A) and dehydration of (+)-BE-43472B (B) (bottom)
thesis, which was accomplished via 21 steps in 1.0% yield by
exploiting the cascade sequence consisting of a Diels–Alder
reaction, a hemiketal formation, and a nucleophilic aromat-
ic ipso substitution.7 Subsequently, we achieved the second
total synthesis of rac-2,8 featuring the isoxazole-based
polyketide assembly strategy (vide infra).
In this article, we describe the full account of our syn-
thetic endeavor toward 2 with particular emphasis upon
strategy and tactics developed during the course of this
study.
follows, where an isoxazole is exploited not only as a 1,3-
diketone surrogate, but also as a ‘guiding functionality’ to
install an angular substituent.
Step 1 is the preparation of the isoxazole intermediate
III from benzonitrile oxide I by the cyclocondensation9 with
1,3-diketone IIa or the cycloaddition to cyclohexenone IIb
followed by dehydrogenation.10
Step 2 serves as the stereogenerating stage, that is, enan-
tio- or diastereoselective benzoin cyclization of keto-alde-
hyde III by using (chiral or achiral) N-heterocyclic carbene
catalysts (NHCs), providing linear tricycle IV having an an-
gular hydroxy group.11 The synthetic utility of IV has been
highlighted by our successful total syntheses of several
polycyclic type-II polyketide metabolites.8,12
Results and Discussion
Strategy for the Construction of the Polyketide
Framework with an Angular Substituent
In the present context, α-ketol IV would allow installa-
tion of the angular substituent via two steps, i.e., steps 3
and 4. Step 3 is the diastereoselective nucleophilic addition
of anions (R′′–) to ketone IV to afford cis-diol VI most proba-
bly through deprotonated intermediate V, where R′′– ap-
proaches from the opposite side of the angular alkoxide due
to electronic repulsion.
Step 4 is the key pinacol rearrangement of cis-diol VI:
the 1,2-shift of the pendant substituent proceeds in a regio-
selective and stereospecific manner via cationic species VII,
thereby establishing the angular quaternary stereogenic
center in tetracycle VIII.13
The major challenge in this whole synthetic venture
was construction of the densely oxygenated polycyclic bis-
anthraquinone skeleton, requiring effective approaches to
the introduction and management of the sensitive func-
tional arrays. Particularly challenging was the issue of the
inter-anthraquinone connection at the angular position
that is characteristic to this class of natural products. With
relevance to this, we have developed an efficient approach
to an angularly substituted polycyclic intermediate VIII
(Scheme 1). Our approach consists of a four-step protocol as
Particularly notable are two features of this rearrange-
ment: First, among the two hydroxy groups that appear to
be equally susceptible to acid activation, the angular
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–Z

D
Y. Yamashita et al.
Feature
Synthesis
O–
+
N
RO
C
OR’
RO
N
O
RO
N
O
RO
O
N
O
RO
N
O
RO
O
B
O
HO
OR’
X
Lewis
acid
NHC
R” –
I
A
C
step 1
step 2
step 3
step 4
+
O
OH
HO
OH
R”
R”
O
R”
O
III
IV
VI
VIII
VIII'
O
RO
N
O
RO
N
O
IIa (X = OH)
IIb (X = H)
+
O–
HO
O
R”
VII
V
Scheme 1 Four-step strategy for the anthraquinone substructure with the angular aryl substituents
hydroxy group is selectively eliminated to generate VII
thanks to the extremely high α-cation stabilizing ability of
an isoxazole (vide infra). Second, the pinacol rearrangement
is stereospecific; the R′′ group in VI undergoes the 1,2-shift
in a completely suprafacial manner to afford VIII. Viewing
isoxazoles as 1,3-diketone equivalents,14 isoxazole VIII can
be regarded as an anthraquinone surrogate VIII′ corre-
sponding to the ABC rings of 2.
Note that the origin of the regioselectivity is in the ex-
cellent ability of an isoxazole to facilitate the formation of
an adjacent carbenium ion. This α-cation-stabilizing effect
of isoxazoles has been underappreciated, while it is sub-
stantial as further recognized by the SN1-type substitution
of α-ketol B (Scheme 2).15 In the presence of a Lewis acid, a
chiral, non-racemic ketol B eliminates to give a cation inter-
mediate and is captured by nucleophiles to afford ketone C
in completely racemic form. This is a remarkable fact, given
that cation formation at the α-position to a carbonyl group
is a disfavored process.16
tacyclic framework, and 3. stereocontrolled installation of
the C3 hydroxy group. The last issue seemed particularly
challenging given the pronounced lability of 2 , i.e., the facile
dehydration (vide supra). Thus, we reasoned that the C3
hydroxy group should be introduced at a late synthetic stage.
As the immediate precursor, epoxide 5 was envisaged
for the late-stage installation of the C3 hydroxy group, by
assuming a reductive opening of the oxirane ring under
mild conditions.17 Epoxide 5 was traced back to olefin 6,
which was expected to favor the α-face selective nucleo-
philic epoxidation. The requisite stereocontrol would be pos-
sible in view of the steric hindrance provided by the angular
anthraquinone unit that would block the β-face. To con-
struct the anthraquinone moiety in 6, we envisioned a
Diels–Alder reaction of chloroquinone 7 with siloxydiene 8,
where a chloro group would secure the requisite regioselec-
tivity.18 Naphthoquinone 7 could be traced back to naph-
thalene 9 by assuming the C2–C3 unsaturation and oxida-
tion of the G ring. The 13-methyl group on the tetrahydro-
furan ring in 9 could be installed by the hydrogenation of
olefin 10, in which the α-face would be more accessible
thanks to the bulky angular naphthyl group. Enol ether 10,
having an isoxazole as a 1,3-diketone surrogate (shown in
blue), could be available from lactone 11 via methylena-
tion.19 Further disconnections of 11 at the central spiro-
acetal and the lactone suggested keto ester 12 as an early
synthetic intermediate, which could be further dissected
into α-ketol 13 and naphthalene derivative 14.
RO
N
O
RO
N
O
RO
N
O
Lewis
acid
R’–
+
OH
R’
O
O
O
B
C
Scheme 2 Isoxazole-assisted SN1 substitution
Initial Approach Towards BE-43472B: Retrosynthetic
Analysis
Our early synthetic efforts concluded that the strategy
indeed enabled a rapid access to enone 6 having a full car-
bon framework of BE-43472B (2). However, the intrinsically
poor reactivity of the C2–C3 double bond in 6 when conju-
gated with the 1,3-diketone moiety hampered the project-
ed reaction, as will be discussed later.
Scheme 3 shows our retrosynthetic analysis of rac-2
based on the strategy stated above. Three major issues in
the planning were: 1. C–C bond formation (C4a–C7′) at the
highly hindered angular position, 2. construction of the oc-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–Z

E
Y. Yamashita et al.
Feature
Synthesis
MeO
OH
O
O
MeO
OH
O
O
MeO
OH
O
OH
O
HO
2
3
O
4a
3
OH
Me
Me
OMe
OH
Me
Me
O
H
O
H
O
O
H
O
O
H
O
Me
Me
O
Me
O
O
O
O
Me
7'
H
O
HO
Me
HO
Me
HO
Cl
TMSO
Me
Me
–OOR
Me
OMe
O
O
O
O
Me
rac-2
5
6
7
8
MeO
N
O
MeO
N
O
MeO
N
O
O
MeO
OH
O
O
MeO
N
O
2
3
Me
CO2Et
OH
O
Me
Me
Me
Me
13
O
O
H
O
H
O
O
H
CO2Et
HO
O
Me
MeO
Cl
+
MeO
MeO
Cl
pinacol
13
OMe OMOM
Br
MeO
Cl
G
Cl
Cl
OMe
OMe
OMe
OMe
12
11
9
10
OMe
14
Scheme 3 Retrosynthetic analysis of (±)-BE-43472B (rac-2)
OH
MeO
MeO
N
O
MeO
Synthesis of Building Blocks and Union via Pinacol
Rearrangement
CHO
O
H
O
a,b
c
Scheme 4 illustrates the preparation of α-ketol 13,
which commenced with commercially available aldehyde
15. Protection of the formyl group in 15 as a propylidene
acetal followed by ortho-lithiation and trapping with N-
formylpiperidine afforded aldehyde 16 in 75% yield (2
steps). After conversion of 16 into oxime 17, treatment with
NCS and Et3N gave stable nitrile oxide 18 in 94% yield,
which was subjected to cyclocondensation promoted by
powdered 4-Å molecular sieves9c with 1,3-diketone 1920 to
give isoxazole 20. The acetal moiety in 20 was hydrolyzed
to keto-aldehyde 21, which was treated with a catalytic
amount of thiazolium salt 2221 and DBU, allowing smooth
benzoin cyclization to give ketol 13 as a single diastereo-
mer.22
O
O
15
16
17
MeO
N
O
O–
+
N
MeO
C
O
e
f
d
O
O
O
Me
O
CO2Et
18
20
MeO
O
N
O
MeO
N
O
O
g
O
Me
Me
OH
CO2Et
CO2Et
21
13
Preparation of naphthyl bromide 14 from the known 3-
chlorojuglone (23) is shown in Scheme 5.23 After MOM pro-
tection of the phenol in 23, the resulting naphthoquinone
24 was subjected to reductive dimethylation to give naph-
thalene 25 in 83% yield. Although we had planned a direct
conversion of 25 into bromide 14 by ortho-bromination, all
attempts failed due to the poor regioselectivity and the la-
bility of the MOM group. At this juncture, an indirect, but
efficient protocol was devised: removal of the MOM protec-
tion in 25 by treatment with TFA afforded naphthol 26 in
89% yield. Regioselective bromination24 of 26 using 1,3-di-
O
Me
HO
Br–
Et
+
S
N
O
Me
CO2Et
22
19
Scheme 4 Synthesis of α-ketol 13. Reagents and conditions: (a)
HO(CH2)3OH, PPTS, toluene, reflux, 4.5 h (94%); (b) n-BuLi, cyclohex-
ane, 0 °C, 3 h; N-formylpiperidine, 0 °C, 20 min (80%); (c) NH2OH·HCl,
K2CO3, MeOH, H2O, 0 °C, 1.5 h (96%); (d) NCS, Et3N, CHCl3, r.t., 50 min
(94%); (e) 19, 4-Å molecular sieves (powdered), i-PrOH, 50 °C, 10 h; (f)
2 M HCl, acetone, r.t., 10.5 h (61% for 2 steps); (g) 22, DBU, t-BuOH, 40
°C, 30 min (81%).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–Z

F
Y. Yamashita et al.
Feature
Synthesis
MeO
N
O
O
O
HO
O
O
OMOM
OMe OMOM
Cl
Cl
Cl
b
a
c
MeO
N
O
Me
OH
CO2Et
O
OMe
Me
b
13
23
24
25
HO
MOMO
OH
CO2Et
OMe OMOM
Br
MeO
Cl
OMe OH
OMe OH
OMe OMOM
a
Cl
Cl
Br
Cl
Br
Cl
OMe
N
d
e
(see text)
OMe
28
14
OMe
OMe
OMe
26
27
14
MeO
O
MeO
N
O
Scheme 5 Synthesis of naphthalene 14. Reagents and conditions: (a)
MOMCl, i-Pr2NEt, CH2Cl2, r.t., 1 h (97%); (b) Na2S2O4, n-Bu4NBr (cat.),
THF, H2O, 0 °C → r.t., 30 min, then Me2SO4, KOH, r.t., 2 h (83%); (c) TFA,
CH2Cl2, 0 °C, 2.5 h (89%); (d) DBDMH, CHCl3, 0 °C → r.t., 4 h (96%); (e)
MOMCl, NaH, DMF, 0 °C → r.t., 30 min (99%).
Me
+
Me
c
HO
HO
O
CO2Et
CO2Et
HO
MeO
Cl
MeO
Cl
OMe
OMe
bromo-5,5-dimethylhydantoin (DBDMH) followed by re-
protection gave naphthalene 14 in excellent yield.
29
12
Having two building blocks 13 and 14 in hand, the stage
was set for the key C–C bond formation at the angular posi-
tion via two steps (Scheme 6). The first step was the nucleo-
philic addition of the naphthyllithium species, generated
from bromide 14, to ketone 13, where the temperature
control was the key to success: upon treatment of 14 with
t-BuLi at –78 °C (THF, 10 min), the halogen–lithium ex-
change smoothly proceeded to generate the corresponding
naphthyllithium species, to which was added 13 at various
temperatures. The addition was sluggish at –78 °C, and a
substantial amount of 13 was recovered unreacted (ca.
20%). On the other hand, serious decomposition of the ad-
duct 28 was noted when the temperature was raised to
0 °C. Eventually, however, the issue was solved by conduct-
ing the addition at –40 °C to afford 28 in quantitative yield.
With the requisite cis-diol 28 in hand, the second step,
i.e., the key pinacol rearrangement, was examined. How-
ever, the attempted 1,2-shift proved problematic by em-
ploying the Lewis acid that had been used in the previous
model study (Scheme 6, bottom).13 For example, when
BF3·OEt2 was used, the unexpected formation of the boric
acid derivative D was noted, implying the in situ formation
of the nonproductive complex E via the ligand exchange of
BF3 with the vicinal diol in 28. Hoping to avoid such unde-
sired complexation, we examined the use of Brønsted acids,
and TfOH proved effective. Exposure of 28 to TfOH (25
mol%, CH2Cl2, r.t.) gave the desired ketone 12 in 96% yield
via the suprafacial 1,2-shift of the pendant naphthyl group,
where concomitant removal of the MOM group occurred.
Of particular importance in this transformation was the
perfect regioselectivity, where the angular hydroxy group
was selectively eliminated to generate cation intermediate
29 thanks to the significant α-cation stabilizing ability of
isoxazole moiety in 29 (vide supra).
MeO
N
O
D: R = OH
E: R = F
Me
Ar
O
B
O
CO2Et
R
Scheme 6 Synthesis of ketone 12. Reagents and conditions: (a) 14,
t-BuLi, THF, –78 °C, 10 min; (b) –40 °C, 20 min (quant.); (c) TfOH
(25 mol%), CH2Cl2, r.t., 13 h (96%).
Construction of the D and E Rings: Diastereo-
selective Installation of the 13-Methyl Group
Having ketone 12 in hand, the next stage was the elabo-
ration of the D and E rings. After some experimentation, the
projected conversion was nicely achieved by beginning with
a dual 5-membered ring construction via the hemiacetal
formation followed by the ester exchange (Scheme 7).
While no reaction proceeded under basic conditions (NaH,
DMF, 80 °C), an acid catalyst nicely promoted the reaction;
upon heating of ketone 12 in toluene in the presence of CSA
(3.5 equiv, 110 °C, 1 h), lactone 11 was obtained in 98% yield
via hemiacetal intermediate 30.
The next task was the installation of the 13-methyl
group, which was nicely achieved by a two-step protocol,
i.e., methylenation followed by the hydrogenation: upon
treatment of lactone 11 with Petasis reagent19 (toluene, 90
°C), the methylenation gradually proceeded to give enol
ether 10 in 56% yield accompanied by enaminone 31 in 20%
yield. Formation of 31 caused no problem for our purpose,
as both 10 and 31 would be converted into the saturated
product 32 by the following hydrogenation. Indeed, hydro-
genation of 10 and 31 (H2, Raney Ni, MeOH, THF, r.t.) afford-
ed 32 in 72% and 67% yield, respectively.25 Rigorous stereo-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–Z

G
Y. Yamashita et al.
Feature
Synthesis
selectivity could be rationalized by the steric hindrance of
the bulky naphthalene moiety occupying the β side of the
reacting C=C bond.
yield. The Diels–Alder reaction of 34 with Brassard’s diene
(8)18 proceeded in a regioselective manner to afford the cor-
responding cycloadduct, which was treated with acidic sili-
ca gel to give anthraquinone 35 in 87% yield.27
Having constructed the full carbon framework, the next
task was the hydrolysis of enaminone 35 into the corre-
sponding 1,3-diketone 6. However, it turned out that the
enaminone moiety was completely resistant to hydrolysis,
in that no reaction occurred either under conventional
acidic (10 M H2SO4, 90 °C) or basic conditions (1 M NaOH,
90 °C). Faced with this problem, we came up with an idea to
apply diazotization conditions,12b,28 hoping that the
reaction would proceed via diazonium intermediate F
followed by displacement of the diazonio group with a
hydroxy group to afford 6. After considerable optimization,
we were able to obtain 6 in 54% yield by using a combina-
tion of t-BuONO and TfOH (DMSO, r.t., 80 min).
MeO
N
O
MeO
N
O
Me
Me
a
O
OH
CO2Et
CO2Et
O
HO
MeO
Cl
MeO
Cl
OMe
OMe
12
30
MeO
N
O
MeO
N
O
Me
Me
b
O
O
H
O
O
H
Bz
MeO
Cl
O
MeO
Cl
MeO
NH2
O
MeO HN
O
2
3
OMe
OMe
Me
Me
a,b
c,d
O
O
H
O
O
H
11
10
MeO
Cl
Me
MeO
Me
MeO
NH2
O
MeO
NH2
O
Cl
OMe
OMe
32
33
Me
Me
D
c
E
O
O
H
O
O
H
MeO
NH2
O
MeO
NH2
O
MeO
Cl
MeO
Cl
Me
13
Me
Me
O
O
H
OMe
O
O
H
OMe
f
e
O
Me
O
Me
32
31
HO
Me
Scheme 7 Synthesis of enaminone 32. Reagents and conditions:
(a) (±)-CSA, toluene, reflux, 1 h (98%); (b) Cp2TiMe2, toluene, THF,
90 °C, 1.5 h (56% for 10, 20% for 31); (c) H2, Raney Ni, MeOH/THF (1:1),
r.t., 2 h (72% from 10, 67% from 31).
Cl
O
O
34
35
MeO
OH
O
Construction of Bis-anthraquinone Framework:
Synthesis of Precursor Toward BE-43472B
N
N+
MeO
O
OTMS
OMe
Me
O
O
H
Having constructed the D and E rings, we next exam-
ined: 1. the installation of the C2–C3 double bond, and 2.
the construction of the whole carbon framework (Scheme
8).
Benzoylation of the amino group in enaminone 32 fol-
lowed by the Mukaiyama oxidation26 [LDA; PhS(Cl)=Nt-Bu,
–78 °C] afforded enone 33 in 91% yield. Note that the prior
N-benzoylation was essential for the efficient enolate
formation. Oxidation of naphthalene 33 with CAN
[MeCN/CH2Cl2/H2O (4:2:1), r.t.] followed by acidic removal
of the N-benzoyl group gave naphthoquinone 34 in 62%
O
Me
Me
HO
Me
Me
O
O
H
Me
8
O
F
6
Scheme 8 Synthesis of anthraquinone 6. Reagents and conditions: (a)
BzCl, pyridine, CH2Cl2, r.t., 2 d (92%); (b) LDA, THF, –78 °C → r.t., 80 min;
PhS(Cl)=Nt-Bu, –78 °C, 30 min (91%); (c) CAN, MeCN, CH2Cl2, H2O, r.t.,
20 min (68%); (d) 10 M aq H2SO4, 60 °C, 25 min (91%); (e) 8, benzene,
THF, r.t., 11 h; silica gel, r.t., 24 h (87%); (f) t-BuONO, TfOH, DMSO, r.t.,
80 min (54%).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–Z

H
Y. Yamashita et al.
Feature
Synthesis
Attempts at Installing the C3 Hydroxy Group
not surprising, given a higher nucleophilicity of the C9a po-
sition rather than that of the C2–C3 olefin. Although the
C2–C3 olefin in G might potentially undergo nucleophilic
epoxidation, all attempts failed, due probably to the low re-
activity and/or the base lability of G. At this point, we even-
tually decided to abandon this synthetic route.
Having diketone 6 in hand, the remaining problem to-
ward the total synthesis was the stereocontrolled installa-
tion of the C3 hydroxy group, which would be hopefully re-
alized by epoxidation of the C2–C3 olefin followed by the
reductive opening (Scheme 9).
However, the issue turned out to be the low reactivity of
the C2–C3 double bond; despite numerous efforts, we were
unable to find suitable reaction conditions to oxidize the
C2–C3 olefin. Scheme 9 (A), (B), and (C) summarize the re-
sults and rationales for these frustratingly poor reactivity.
We initially focused on nucleophilic epoxidations, hop-
ing that the C1 carbonyl of 1,3-diketone would enhance the
electrophilicity at the C3 position in 6, and therefore wel-
coming the incoming peroxide anion [Scheme 9 (A)]. How-
ever, all attempts failed to obtain the corresponding epox-
ide 5. Our rationale here is that the 1,3-diketone is depro-
tonated under the basic reaction conditions, leading to the
low reactivity of the adjacent C2–C3 double bond towards
nucleophiles. Extensive variation of the reaction parame-
ters (oxidants, bases, temperature, etc.) failed to give any
positive results. The O-protection of the 1,3-diketone moi-
ety by a methoxymethyl, pivaloyl, and tert-butoxycarbonyl
groups also proved ineffective, giving no epoxidized prod-
uct [Scheme 9 (B)].
The Second-Generation Approach
Although we failed to achieve the requisite oxidation of
the C2–C3 olefin, we came to believe that the oxidation
should be implemented, if conducted before unveiling the
1,3-diketone moiety. Scheme 10 shows the second-genera-
tion plan based on this assumption, where olefin IX having
the isoxazole moiety (marked in blue) was set as the key in-
termediate. We envisaged that the C2–C3 olefin in IX would
be more electron-rich than that next to the 1,3-diketo
structure in olefin 6,30 allowing hopefully the electrophilic
epoxidation to give epoxide X. Isoxazole X would be con-
verted into diketone XI, and the epoxide moiety in XI would
hopefully be unmasked via reductive ring opening to fur-
nish alcohol XII, a direct intermediate before the final tar-
get. A prior installation of the C3 hydroxy group (X → XIII)
would not be suitable, in that the resulting tertiary alcohol
in XIII would not survive under the acid hydrolysis (vide
supra).
MeO
OH
O
MeO
OH
O
Alternative Approach for Introducing the 13-Methyl
Group
2
3
1
O
Me
Me
epoxidation
In order to realize this scenario, however, we confronted
an additional issue on introduction of the 13-methyl group
(Scheme 11). In the previous approach, the 13-methyl
group was introduced via hydrogenation of the C11–C13
enol ether moiety, where a concomitant N–O bond cleavage
of the isoxazole moiety was unavoidable [Scheme 11 (A)].
To circumvent the issue, we devised an alternative two-
step protocol to keep the isoxazole moiety intact [Scheme
11 (B)].
Specifically, we envisioned that nucleophilic addition of
a methyl anion species to lactone H would give the corre-
sponding hemiacetal, which would undergo hydride reduc-
tion under Lewis acidic conditions to afford isoxazole I. Our
hope was that the angular aryl substituent would block the
β-face of the intermediary oxocarbenium, allowing the
hydride delivery from the α-side.
To prove our hypothesis, a model study was carried out
using lactone 36. However, we encountered an unexpected
stereochemical outcome (Scheme 12). Treatment of 36 with
MeLi gave hemiacetal 37 in 89% yield, which was then sub-
jected to silane reduction [BF3·OEt2 (1 equiv) and Et3SiH (10
equiv), CH2Cl2, –78 °C → r.t.] to afford the methylated prod-
uct as a single diastereomer (29% yield). However, careful
structural assignment revealed that the product proved to
be isoxazole α-38 having the wrong stereochemistry at C11.
O
O
H
O
O
H
Me
Me
O
O
HO
Me
HO
Me
O
O
6
5
(A)
(B)
R
O–
O
O
9
O
9
ROOH
NaOH
1
6
6
5
Me
Me
O
O
H
O
O
H
Me
Me
(C)
O
O
O
O
OH
OH
ROOH
NaOH
2
3
9a
DMDO
O
Me
Me
O
O
H
O
O
H
Me
Me
G
Scheme 9 Unsuccessful trials for installing the C3 hydroxy group
We then turned our attention to electrophilic epoxida-
tions; however, all attempts were unfruitful [Scheme 9 (C)]:
when diketone 6 was treated with dimethyldioxirane (DM-
DO),29 α-hydroxy-β-diketone G was obtained, which was
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–Z

I
Y. Yamashita et al.
Feature
Synthesis
RO
N
O
RO
N
O
RO
N
O
2
3
O
OH
Me
electrophilic
epoxidation
Me
reductive
Me
ring-opening
O
O
H
O
O
H
O
O
H
Me
Me
Me
O
O
O
HO
Me
HO
Me
HO
Me
O
O
O
X
XIII
IX
1) N–O cleavage
2) hydrolysis
1) N–O cleavage
2) hydrolysis
RO
OH
O
O
MeO
OH
O
RO
OH
O
2
O
3
3
OH
Me
Me
reductive
Me
H
ring-opening
O
O
O
H
O
O
H
Me
Me
Me
O
O
O
HO
Me
HO
Me
HO
Me
O
O
O
XII
6
XI
Scheme 10 The second-generation approach for installing the C3 hydroxy group
Although disappointing, this stereochemical outcome
gave us a guideline to obtain the desired diastereomer β-38;
given nucleophiles should approach from the β-face, we
could safely expect that β-38 would be obtained by invert-
ing the order of the two transformations, which proved in-
deed the case. Hydride reduction of lactone 36 by DIBAL-H
(CH2Cl2, –100 °C) followed by acetylation of the resulting
hemiacetal 39 gave a separable mixture of β-acetate β-40
and α-acetate α-40 in 97% yield (β-40/α-40 5.5:1), among
which β-40 was subjected to the key methylation reaction.
After screening various combinations of methylating
agents (Me2Zn, Me3Al) and Lewis acids (BF3·OEt2, TMSOTf,
TiCl4), we found that the use of Me3Al and TMSOTf led to
complete conversion.31 To our delight, completely stereo-
selective methylation of β-40 was achieved under carefully
optimized conditions with three key requirements: 1. the
presence of water, 2. the use of TMSOTf as a Lewis acid, and
3. a precise ratio of the reagents. Thus, treatment of β-40
with Me3Al (7.5 equiv), H2O (4.5 equiv), and TMSOTf (10
equiv) (CH2Cl2, –78 °C → r.t.) afforded β-38 with complete
diastereoselectivity in 91% yield. The stereostructure of β-
38 was unambiguously determined by X-ray crystallogra-
phy (Scheme 12).32
A)
[H2]
MeO
N
O
MeO
NH2
O
Me
Me
11
O
O
H
O
O
H
Me
13
[H2]
B)
RO
N
O
RO
N
O
O
Me–
Lewis acid
Me
Me
H
O
O
H
O
Me
OH
O
H
RO
N
O
RO
N
O
I
O
H–
Me
Me
O
O
H
O
H
+
Me
Me
Before going further, it would be appropriate briefly to
account the detail of the optimization study (Table 1). Upon
treatment of β-40 with Me3Al (15 equiv) and TMSOTf (20
equiv), the desired β-isomer 38 was obtained as a sole
product (entry 1). However, this was not the end of the sto-
ry in that we suffered from poor reproducibility of the yield
Scheme 11 Alternative approach for installing the 13-methyl group
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–Z

J
Y. Yamashita et al.
Feature
Synthesis
Scheme 12 Alternative strategy for installing the 13-methyl group. Reagents and conditions: (a) MeLi, THF, –78 °C, 1 h (89%); (b) Et3SiH, BF3·OEt2,
CH2Cl2, –78 °C → r.t., 6 h (29%); (c) DIBAL-H, CH2Cl2, –100 °C, 15 min (82%); (d) Ac2O, pyridine, DMAP, CH2Cl2, r.t., 3 h (97%, β-40/α-40 5.5:1); (e) Me3Al
(7.5 equiv), H2O (4.5 equiv), TMSOTf (10 equiv), CH2Cl2, –78 °C → r.t., 9 h (91%).
and diastereoselectivity; the yields of β-38 fluctuated in the
range of 43% to 82% with concomitant formation of the un-
desired α-38.
tries 3 and 4), reduction of the amounts of three reagents
without changing the ratio gave β-38 in 89% yield without
formation of α-38 (entry 5).
After numerous unfruitful experiments, we finally
found that the addition of water33 was the key to securing
the diastereoselectivity; the reaction in the presence of wa-
ter (9 equiv) afforded β-38 as the sole product in 85% yield
(entry 2). Additional experiments revealed that the precise
ratio of three reagents is also important; while decreased
amount of TMSOTf led to poorer diastereoselectivity (en-
Having promising results from the model study, we re-
tackled the total synthesis from suitably functionalized in-
termediate 11 (Scheme 13). Lactone 11 was reduced by
DIBAL-H (CH2Cl2, –100 °C), and the resulting hemiacetal
was converted into β-acetate 41 as the major diastereomer
(β-41/α-41 11:1) in 84% yield in two steps. Pleasingly, the
protocol for installing the 13-methyl group also worked
nicely for acetate β-41 (Me3Al, H2O, TMSOTf), giving the
methylated product 42 in 92% yield. The isomeric acetate α-
41 also gave 42 in 96% yield under identical reaction condi-
tions. The stereochemistry of 42 was unambiguously deter-
mined by X-ray analysis.32
For introducing the C2–C3 double bond, we prelimi-
narily examined the lithiation at the C2 position of 42 by
n-BuLi,34 where the extent of the lithiation was assessed by
quenching with MeOD. While no lithiation proceeded in
THF, the reaction was dramatically promoted by the use of
DMPU as a co-solvent. After numerous experiments, we
eventually found a suitable set of conditions: by lithiation
of 42 with n-BuLi (1.5 equiv) in a mixed solvent [THF/DMPU
(5:1)] at –90 °C (30 min) followed by adding MeOD, a highly
deuterated product (91% D incorporation) was obtained in
86% yield. Note that trapping by MeOD occurred in non-
stereoselective manner, giving two stereoisomeric products
α-D-42 and β-D-42 in nearly equal proportion.
Table 1 Methylation of β-Acetate β-40
MeO
N
O
MeO
N
O
Me3Al, TMSOTf
H2O
Me
Me
O
O
H
O
O
H
CH2Cl2
Me
OAc
–78 °C→r.t., time
β-40
β-38
Entry Reagents (equiv)
Time (h) Yield (%)
Ratio β/α
Me3Al
TMSOTf H2O
β-38
α-38
a
a
a
1
15
15
15
15
7.5
20
20
10
0
–
24
24
17
19
22
–
–
–
2
9
85
86
73
89
0
7
only β
12:1
3b
4b
5
9
9
16
0
4.7:1
only β
Having found the suitable conditions, we examined the
C2–C3 olefination of isoxazole 42. Mukaiyama oxidation26
was ineffective and gave olefin 44 in only 27% yield with re-
covered starting material 42 (50% recovery).
10
4.5
a The yield of β-38 fluctuated, varying between 43% (β/α 2.5:1) and 82%
(β/α 1:0) (see text).
b –78 → 12 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–Z

K
Y. Yamashita et al.
Feature
Synthesis
MeO
N
O
MeO
N
O
MeO
N
O
MeO
N
O
R1
2
R2
Me
Me
Me
Me
e
d
a,b
c
O
O
H
O
O
H
O
O
H
H
O
O
OAc
Me
MeO
Cl
MeO
Cl
O
Me
MeO
Cl
MeO
Cl
OMe
OMe
OMe
OMe
42 (X-ray)
11
β-41
α-D-42: R1 = H, R2 = D
β-D-42: R1 = D, R2 = H
α-43: R1 = H, R2 = SePh
β-43: R1 = SePh, R2 = H
MeO
N
O
MeO
N
O
MeO
N
O
2
3
Me
Me
Me
N
O
O–
Se+Ph
g
O
O
H
Me
f
OTMS
O
O
H
Me
O
O
H
Me
2
O
MeO
Cl
O
OMe
HO
H
3
Cl
Me
Me
anti
O
O
H
O
Me
OMe
O
8
Me
J
44
45
46
Scheme 13 Synthesis of anthraquinone 46. Reagents and conditions: (a) DIBAL-H, CH2Cl2, –100 °C, 20 min; (b) Ac2O, pyridine, DMAP, CH2Cl2, r.t., 3 h
(84%, 2 steps, β-41/α-41 11:1); (c) Me3Al, H2O, TMSOTf, CH2Cl2, –78 °C → r.t., 12 h (92%); (d) n-BuLi (1.5 equiv), THF/DMPU (5:1), –100 → –90 °C, 30
min; MeOD, –90 °C, 10 min [86%, 91% D (α-D-42/β-D-42/42 50:41:9)] or PhSeBr, –90 °C, 10 min (38% for α-43, 38% for β-43); (e) NaIO4, NaHCO3, THF,
H2O, r.t., 14 h (quant. from α-43); H2O2, NaHCO3, THF, H2O, r.t., 14 h (85% from β-43); (f) CAN-silica gel, CH2Cl2, H2O, r.t., 10 min (88%); (g) 8, benzene,
CH2Cl2, 0 °C → r.t., 3.5 h; silica gel, benzene, CH2Cl2, r.t., 2 h; K2CO3, MeOH, CH2Cl2, 0 °C, 20 min (94%).
Pleasingly, the protocol based on selenoxide elimina-
tion35 proved effective. Lithiation of isoxazole 42 (vide su-
pra) and subsequent treatment with PhSeBr gave a separa-
ble mixture of two diastereomeric selenides α-43 and β-43
(α-43/β-43 1:1) in 76% combined yield. Upon oxidation,
both selenides α-43 and β-43 converged into olefin 44 in
high yield under different conditions; oxidation of α-43
with NaIO4 (NaHCO3, THF, H2O, r.t., 12 h) followed by spon-
taneous syn-elimination gave olefin 44 in quantitative yield.
β-43 seems a challenging substrate, considering its anti-
relationship between the selenoxide moiety and the adja-
cent C3 proton in the possible intermediate J. Pleasingly,
however, by treatment with H2O2 (NaHCO3, THF, H2O, r.t., 14
h), β-43 underwent slow, but steady olefination to give 44
in 85% yield. We assumed that the success was the result of
a base-induced epimerization at C2;36 due to the enhanced
acidity of the C2 proton by the presence of both the iso-
B)
A)
MeO
N
O
MeO
N
O
2
3
O
OR
Me
Me
N
O
O
H
Me
O
O
H
Me
DMDO
O
O
O
O
D
C
H
O
CH2Cl2, r.t.
HO
Me
HO
Me
Me
Me
25% (73% recovery)
H
O
O
46
47
C)
RO
N
O
RO
N
O
O
Me
Br
OH
Me
Br+
H2O
base
Me
Br+
Me
O
O
H
O
O
H
Me
Me
Scheme 14 Problems and solution for installing the C3-hydroxy group
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–Z

L
Y. Yamashita et al.
Feature
Synthesis
xazole and the selenoxide moieties, β-selenoxide J might be
interconvertible with the corresponding α-selenoxide, pro-
viding 44 via syn-elimination.
saccharin (49) in acetic acid (r.t., 9 h), the starting material
was fully converted to give three products, among which
two isomeric bromo-acetates were obtained.
Oxidation of naphthalene 44 with CAN–silica gel37 af-
forded naphthoquinone 45 in 88% yield. The Diels–Alder re-
action of 45 with siloxydiene 8 gave, after successive treat-
ment with silica gel and K2CO3,27 anthraquinone 46 in 94%
yield.
AcO
N
O
MeO
N
O
8
A
3
Me
Me
a,b
O
O
H
O
O
H
Me
O
Me
O
AcO
Me
HO
Me
Key Epoxide Formation via Halohydrin Formation
1’
H
O
O
The stage was set for the pivotal electrophilic epoxida-
tion (Scheme 14). We initially focused on the reactivity.
However, the real issue was the stereocontrol: upon treat-
ment of olefin 46 with DMDO29 (CH2Cl2, r.t.), the reaction
gradually proceeded to give, albeit in low conversion, the
epoxidized compound 47 in 25% (73% recovery) as a single
diastereomer. To our dismay, however, the product proved
to be the wrong stereoisomer, β-epoxide 47 [Scheme 14
(A)].
This outcome gave insight into the molecular geometry
in the vicinity of the double bond [Scheme 14 (B)]. The fact
that the β-face seems to be exposed to the approaching re-
agent could be rationalized by the convex–concave nature
of the fused CD ring system.
At this juncture, we focused on the epoxide formation
via a halohydrin intermediate, expecting that the formation
of a β-halonium ion followed by capture by an oxygen nu-
cleophile from the α-side would give a halohydrin derivative
that would be converted into the α-epoxide [Scheme 14
(C)].
Along these lines, a preliminary model experiment was
conducted, where an additional issue arose (Scheme 15).
Use of the strong halogenating reagent invoked an unde-
sired aromatic halogenation on the A and H rings, which led
us to focus on introduction of an electron-withdrawing
group to the C8 and C1′ hydroxy groups. Thus, diacetate 48
was prepared from isoxazole 46 via demethylation (BBr3,
CH2Cl2) followed by acetylation (Ac2O, TMSOTf, CH2Cl2)
(Scheme 15).38
46
48
AcO
N
O
OH
Me
Br
O
O
O
H
c
N
Br
Me
O
S
AcO
Me
O
O
49
O
50
Scheme 15 Synthesis of bromohydrin 50. Reagents and conditions: (a)
BBr3, CH2Cl2, –78 → –10 °C, 3 h; (b) Ac2O, TMSOTf, CH2Cl2, r.t., 30 min
(77%, 2 steps); (c) 49, MeCN/H2O (4:1), r.t., 2 h (1%).
Pleasingly, careful structural analysis revealed these
products to be 2-acetate 51 (65% yield) and 3-acetate 52
(20% yield). The structures of 51 and 52 were deduced by
the NOE correlations shown in Figure 3. Formation of anti-
Markovnikov product 51 was unexpected, but rationalized
by the extreme steric hindrance of the α-side at the C3 po-
sition (inside of the concave pocket), thereby forcing the ox-
ygen nucleophile to attack the C2 position, albeit electroni-
cally unfavorable [Scheme 16 (A)]. However, both com-
pounds 51 and 52 would be converted into the α-epoxide. A
small amount of allylic bromide 53 was also noted (6%
yield), which might be produced via a radical bromination.
The projected halohydrin formation proved challenging,
as the double bond next to the isoxazole was also still unre-
active; no reaction proceeded when olefin 48 was treated
with conventional brominating agents, such as NBS and
DBDMH [MeCN/water (4:1)]. Pleasingly, however, the use of
N-bromosaccharin (49),39 a stronger brominating agent,
gave a promising result; upon treatment of 48 with 49
[MeCN/H2O (4:1), r.t., 2 h], a polar spot appeared on TLC [Rf
0.5, hexane/EtOAc (2:3)]. After exhaustive purification by
preparative TLC followed by reversed-phase HPLC, a trace
amount of bromohydrin 50 having an α-hydroxy group was
isolated.
Figure 3 Structures of bromo-acetates 51 and 52. Several hydrogens
are omitted for clarity.
For optimization, we focused on the acid activation of
the brominating agent,40 for which we initially used acetic
acid (Scheme 16). Upon exposure of olefin 48 to N-bromo-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–Z

M
Y. Yamashita et al.
Feature
Synthesis
AcO
N
O
AcO
N
O
AcO
N
O
2
OAc
Me
Br
3
OAc
Br
Br
Me
a
O
O
H
Me
O
O
H
Me
O
O
H
Me
+
+
O
O
O
AcO
Me
AcO
Me
AcO
Me
AcO
N
O
O
O
O
Me
O
O
H
51
52
53
Me
O
AcO
Me
AcO
N
O
AcO
N
O
OCHO
Me
Br
(A)
OCHO
O
Br
Me
OAc
O
O
H
O
O
H
48
b
+
N
Me
Me
O
O
Br+
O
O
AcO
Me
AcO
Me
H
O
3
2
Me
Me
H
O
O
HOAc
54
55
Scheme 16 The investigation for the formation of halohydrin derivatives. Reagents and conditions: (a) N-bromosaccharin (49), AcOH, r.t., 9 h (65% for
51, 20% for 52, 6% for 53); (b) N-bromosaccharin (49), HCOOH, 10 °C, 30 min (71% for 54, 29% for 55).
OH
N
O
O
N
OH
OH
N
O
O
O
O
N
O
N
O
Me
Me
Me
OCHO
Me
Br
K2CO3
O
O
H
Me
O
O
H
Me
O
OMe
O
H
Me
+
+
OCHO
+
O
O
MeO
MeOH
0 °C
20 min
Br
Me
HO
Me
HO
Me
HO
Me
H
H
54
55
O
O
O
54:55 = 2.5:1
56
57
26%
58
12%
20%
O–
#1 isoxazole → benzisoxazole rearrangement
N
O
O
N
OH
AcO
N
O
#1
K2CO3
MeOH
O
O
A
O
AcO
N
O
Me
Me
Me
OCHO
Me
O
O
H
Me
O
O
H
Me
O
O
H
Me
A
Br
K
57
#2
O
O
H
Me
O
#2 acetal formation
AcO
MeOH
MeO
O
OMe
O
OMe
O
O
H
O
AcO
MeO
O
–OAc–
K2CO3
MeOH
O
HO
Me
AcO
O
9’
Me
1’
54
H
O
O
O
O
Me
Me
Me
L
M
58
Scheme 17 Oxirane formation from bromoformates 54 and 55 (top) and proposed mechanism for the formation of byproducts (bottom)
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–Z

N
Y. Yamashita et al.
Feature
Synthesis
Further improvement was achieved by using a stronger
carboxylic acid, i.e., formic acid (pKa = 3.75), instead of ace-
tic acid (pKa = 4.76). Thus, the reaction in formic acid (10 °C,
30 min) proceeded much faster than that in acetic acid (r.t.,
9 h, vide supra) to give a regioisomeric mixture of bromo-
formates 54 and 55 in quantitative yield. The mixture, thus
obtained, was used in the following reaction without any
purification, in that both isomers were unstable on silica
gel and underwent decomposition.
A mixture of bromoformates 54 and 55 was subjected to
the crucial epoxide formation (Scheme 17). Contrary to our
expectation, however, simple base treatment of the mixture
led to the formation of several different products; upon
treatment of bromoformates 54 and 55 with K2CO3 in
MeOH (0 °C, 20 min), three major spots were observed on
TLC. Purification by preparative TLC [CH2Cl2/MeOH (85:1)]
gave the desired α-epoxide 56 in only 20% yield (2 steps),
along with other two products. Careful NMR analyses iden-
tified these compounds as benzisoxazole 57 (26% yield) and
acetal 58 (12% yield).41
tion of the acetoxy group to lead to quinonemethide M, be-
ing trapped by methanol to give acetal 58.43
Endgame: Total Synthesis of BE-43472B
This unfavorable result led us to focus on a Boc group, a
base-tolerant protecting group, for protection of the two
phenols (Scheme 18). Thus, bis-carbonate 59 was prepared
via two steps from 46, which was treated with N-bromosac-
charin (49) and HCOOH (CH2Cl2, 0 °C, 20 min) to give a re-
gioisomeric mixture of bromo-formates 60 and 61 (60/61
1.8:1), ready for the pivotal oxirane formation.
Pleasingly, we found that use of Na2CO3 in MeOH real-
ized a clean reaction (r.t., 1.5 h), affording epoxide 62 as the
sole product in 83% yield (two steps). Having achieved suc-
cessful construction of the α-epoxide, the remaining tasks
toward the total synthesis were: 1. unmasking the isoxazole
to give the 1,3-diketone, 2. reductive opening of the oxirane
ring, and 3. deprotection.
After the two Boc groups in 62 were removed, the isox-
azole moiety was cleaved with Mo(CO)644 [MeCN/H2O (5:1),
85 °C] to give enaminone 63 (Scheme 18). Our previous ex-
perience suggested that prior protection of C8-OH was es-
sential. Thus, after the selective protection of the phenol in
63 with a benzyl group, the enaminone moiety was hydro-
lyzed by using t-BuONO and TfOH12b,28 to give diketone 64
in 61% yield. Epoxide 64 was subjected to reductive ring
opening under the Miyashita conditions17 (PhSeSePh,
NaBH4, EtOH) to give the corresponding alcohol, which was
treated with BBr3 (CH2Cl2, –78 → –55 °C). Fortunately, in
Our rationale for the formation of 57 and 58 is as follows
(Scheme 17, bottom).
1. Isoxazole → benzisoxazole rearrangement:42 The ace-
tyl group on the A-ring undergoes basic methanolysis to
form phenoxide K, which further undergoes nucleophilic
substitution at the nitrogen atom of the isoxazole moiety to
give benzisoxazole 57.
2. Acetal formation: Addition of methanol to the C9′
carbonyl group triggers migration of an acetyl group on
C1′-OH to generate phenoxide L, which undergoes elimina-
BocO
N
O
BocO
N
O
MeO
N
O
BocO
N
O
OCHO
Me
Br
2
3
OCHO
Me
Me
Br
Me
O
H
Me
O
O
H
Me
c
O
O
O
H
d
a,b
O
O
H
Me
+
Me
O
O
O
O
BocO
Me
BocO
Me
HO
Me
BocO
Me
O
O
O
O
46
59
60
61
OH
O
HO
BocO
N
O
OH NH2
8
O
BnO
OH
O
O
O
O
O
3
OH
Me
Me
Me
Me
O
O
H
O
O
H
O
O
H
Me
i,j
g,h
O
H
Me
e,f
O
Me
O
Me
O
O
HO
Me
BocO
Me
HO
Me
HO
Me
O
( )-BE-43472B (rac-2)
O
O
O
62
63
64
Scheme 18 Synthesis of (±)-BE-43472B (rac-2). Reagents and conditions: (a) BBr3, CH2Cl2, –78 → –10 °C, 3 h; (b) Boc2O, DMAP, CH2Cl2, –20 °C, 20 min
(82%, 2 steps); (c) N-bromosaccharin (49), HCOOH, CH2Cl2, 0 °C, 20 min (60/61 1.8:1); (d) Na2CO3, MeOH, r.t., 1.5 h (83%, 2 steps); (e) TFA, CH2Cl2, r.t.,
2 h; (f) Mo(CO)6, MeCN/H2O (5:1), 85 °C, 40 min (97%, 2 steps); (g) BnBr, Ag2O, DMF, r.t., 1 h (93%); (h) t-BuONO, TfOH, DMSO, r.t., 40 min (61%); (i)
PhSeSePh, NaBH4, AcOH, EtOH, THF, 0 °C, 20 min (82%); (j) BBr3, CH2Cl2, –78 → –55 °C, 1 h (76%).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–Z

O
Y. Yamashita et al.
Feature
Synthesis
contrast to the pronounced lability of the tertiary alcohol,3a
the Lewis acidic conditions smoothly detached the benzyl
group at low temperature without elimination of the C3
hydroxy group to afford the long-sought target rac-2. The
synthetic material was identical in all respects (1H, 13C NMR,
IR, HRMS) to the natural sample, which was kindly provid-
ed by Banyu Pharmaceutical Co., Ltd.
In the course of NMR experiments (CDCl3), we unex-
pectedly found small yellow plate-like crystals (mp 211–
213 °C) attached to the inside wall of the NMR tube, which,
fortunately, proved suitable for X-ray diffraction analysis,
revealing the three-dimensional architecture of rac-2 (Fig-
ure 4).32
Asymmetric Total Synthesis of BE-43472B
Figure 4 X-ray crystal structure of (±)-BE-43472B (rac-2); hydrogen
atoms are omitted for clarity
Having completed the racemic total synthesis, we em-
barked on the asymmetric synthesis (Scheme 19). Based on
the above-mentioned synthetic route, we initially con-
ceived that chiral, non-racemic diketone 19′ as the starting
material [Scheme 19 (A)]. However, this idea was ruled out
by the poor availability of 19′. We thus turned our attention
to isoxazole 65 missing the ester moiety, which would be
(A)
+
N
MeO
O–
O
OH
O
HO
C
O
+
C
O
C
O
Me
OH
Me
MeO
N
O
CO2Et
O
O
H
18
19’
O
Me
4
HO
Me
O
O
Me
MeO
N
O
O
CO2Et
O
C
strategic
simplification
20’
O
Me
O
Me
O
O
Me
[ref. 45]
(+)-BE-43472B [(+)-2]
O
(+)-pulegone
66
readily available
65
(B)
MeO
O
N
O
O
MeO
N
O
MeO
N
O
O–
+
N
MeO
H
C
O
c,d
a
b
H
O
O
+
O
Me
Me
O
O
Me
O
Me
CO2Et
O
O
99% ee
18
66
67
65
(+)-21
OH
O
HO
(C)
HOMO
HOMO
LUMO
MeO
N
O
MeO
O–
MeO
O–
+
+
N
OH
Me
N
C
R
C
LUMO
O
e
O
O
H
O
Me
Me
R
HO
OH
CO2Et
O
Me
O
Me
disfavored
(–)-13
O
99% ee
favored
Me
(+)-BE-43472B [(+)-2]
Scheme 19 Asymmetric synthesis of (+)-2. Reagents and conditions: (a) 66 (1.5 equiv), toluene, r.t., 53 h; (b) MnO2, toluene, reflux, 20 min (75%,
2 steps); (c) (EtO)2CO, NaH, THF, reflux, 2 h; (d) 2 M HCl, acetone, r.t., 11 h, 87% for 2 steps; (e) 22, DBU, t-BuOH, 40 °C, 30 min, 80%.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–Z

P
Y. Yamashita et al.
Feature
Synthesis
accessible by the 1,3-dipolar cycloaddition of chiral cyclo-
hexenone 66 with nitrile oxide 18 followed by the dehydro-
genation. Note that enone 66 is readily available in enantio-
merically pure form from (+)-pulegone, a commercially
available chiral pool.45
Cycloaddition of nitrile oxide 18 with chiral enone 66
proceeded in regioselective manner to give isoxazoline 67,
which was in situ treated by MnO2 to effect dehydrogena-
tion to give isoxazole 65 (75% yield, two steps) [Scheme 19
(B)]. The regioselectivity could be rationalized by the fron-
tier orbital terms, where the primary orbital interaction be-
tween the HOMO of 18 and the LUMO of 66 is decisive
[Scheme 19 (C)]. The HOMO coefficient is the largest at the
oxygen atom of nitrile oxide 18 and that of LUMO is at the
β-carbon of enone 66.
With the requisite isoxazole 65 in hand, installation of
the ester moiety was examined. Upon treatment of 65 with
NaH (2.1 equiv) and diethyl carbonate (2.2 equiv) in THF
under reflux, an ethoxycarbonylation proceeded in a
complete diastereoselective manner to give, after acid
hydrolysis, keto-aldehyde (+)-21 in 87% (2 steps). Cycliza-
tion of (+)-21 (22, DBU, t-BuOH, 40 °C, 30 min) afforded
α-ketol (–)-13 in 80% as a single diastereomer, whose
enantiomeric excess (>99% ee) was evidenced by chiral
HPLC analysis.
ceived. Cyclohexane, DMF, DMSO, DMPU, N-formylpiperidine, tolu-
ene, and CH2Cl2 were distilled prior to use according to standard
protocols. Other reagents were used without further purification as
received from commercial suppliers. For TLC analysis, Merck pre-
coated plates (TLC silica gel 60 F254, Art 5715, 0.25 mm) were used.
Silica-gel preparative thin-layer chromatography (PTLC) was per-
formed using plates prepared from Merck silica gel 60 PF254 (Art
7747). For flash column chromatography, silica gel 60N (Spherical,
neutral, 63–210 μm) from Kanto Chemical was used. Higher-accuracy
purifications were performed by a Yamazen Smart Flash EPCLC W-
Prep 2XY system. Melting point (mp) determinations were performed
by using a Yanaco MP-500 instrument or a Mettler Toledo MP70 melt-
ing point system, and are uncorrected. 1H and 13C NMR were mea-
sured on a Jeol JNM ECX-400 (400 MHz), Bruker DRX-500 (500 MHz),
or Bruker AV-600 (600 MHz) spectrometer in the solvent indicated.
Infrared spectra were recorded on a Perkin–Elmer Spectrum 100 FTIR
or Thermo Scientific Nicolet iS5 FT-IR spectrometer. Attenuated total
reflectance Fourier-transform infrared (ATR-FTIR) spectra were re-
corded by using a Perkin–Elmer Spectrum 100 FTIR spectrometer
equipped with a universal ATR sampling accessory or a Thermo Sci-
entific Nicolet iS5 FT-IR spectrometer equipped with a universal ATR
sampling accessory (iD5 ATR). Optical rotations ([α]D) were measured
on a Jasco P-3000 polarimeter. Elemental analyses were recorded on
an Elementar vario MICRO cube analyzer. HPLC analyses were per-
formed by using a Jasco PU-2086 instrument with UV detection at
254 nm. HRMS were obtained with a Bruker Daltonics micrOTOF-QII.
X-ray crystallographic data were recorded with a Rigaku RAXIS-RAP-
ID diffractometer. Unless otherwise indicated, analytical data for ra-
cemic samples are documented. Analytical data (mp and [α]D) for op-
tically pure samples are noted with those of racemic samples.
The same series of transformations as those described
above for the racemic materials gave (+)-2 in an optically
pure form, thus achieving the asymmetric total synthesis.
Synthesis of Keto-aldehyde 21
20
To a solution of nitrile oxide 188 (5.03 g, 21.4 mmol) and diketone
1920 (6.35 g, 32.0 mmol) in i-PrOH (71 mL) was added powdered 4-Å
molecular sieves (21.4 g, 1.00 g/mmol). The mixture was heated to
50 °C and maintained at this temperature for 10 h. After cooling to r.t.,
the mixture was filtered through Celite pad (washed with EtOAc) and
concentrated in vacuo. To a solution of this crude material, including
isoxazole 20, in acetone (128 mL) was added 2 M HCl (85 mL) at r.t.
After stirring for 10.5 h, the reaction was quenched by the addition of
sat. aq NaHCO3 at 0 °C. The mixture was extracted with EtOAc (3 ×),
and the combined organic extracts were washed with brine, dried
(Na2SO4), and concentrated in vacuo. Trituration (Et2O/MeOH) gave
keto-aldehyde 21 [2.70 g, 35% (2 steps)] as a white solid. The mother
liquor was concentrated in vacuo, and the residue was purified by
flash column chromatography (silica gel, hexane/EtOAc 5:1 → 2:1) to
afford additional 21 as a white solid [1.95 g, 26%; total yield = 61%
(2 steps)]. Rf 0.45 (hexane/EtOAc 1:1); rac-21: mp 133–135 °C
(Et2O/MeOH, white solid); (+)-21 (optically pure): mp 142–143 °C
(EtOAc/hexane, pale yellow solid); [α]D20 +12.5 (c 1.00, CHCl3).
The optical rotation of synthetic sample {[α]D +550 (c
20
0.85, CHCl3)} was identical to the natural sample {[α]D
+560 (c 0.85, CHCl3)}.
It turned out that, contrary to rac-2 (vide supra), we
failed to obtain single crystals of the enantiopure sample.46
A higher crystalline nature of rac-2 than (+)-2 was attribut-
ed to a well-known tendency for racemic mixtures of
organic molecules, called Wallach’ rule.47
Conclusion
Total synthesis of BE-43472B (2) has been achieved in
racemic form (27 steps, 3.0% yield), and enantioselective
form (28 steps, 3.0% yield), by utilizing the cycloaddition of
nitrile oxide with enantiomerically pure enone. The syn-
thesis features: 1. pinacol rearrangement to install the an-
gular naphthyl group, 2. a diastereoselective methylation of
a lactol derivative, and 3. the late-stage installation of the
labile hydroxy group through an epoxide. By using this syn-
thetic strategy, it should be possible to synthesize various
congeners with potential biological activities.
IR (KBr): 2964, 1740, 1696, 1596, 1274, 1068, 1018, 913 cm–1
.
1H NMR (600 MHz, CDCl3, a mixture of two rotamers, conspicuous
signals of the minor rotamer are marked with an asterisk): δ = 1.18–
1.31 (m, 7 H), 1.31* (d, J = 6.9 Hz, 1 H), 2.78* (br s, 1 H), 2.84 (dd, J =
17.5, 10.0 Hz, 1 H), 2.95 (br s, 1 H), 3.12* (dd, J = 17.7, 4.9 Hz, 1 H),
3.21* (dd, J = 17.7, 11.0 Hz, 1 H), 3.20–3.31 (m, 2 H), 3.45* (br s, 1 H),
3.79 (br s, 3 H), 4.11–4.27 (m, 2 H), 7.20–7.26 (m, 1 H), 7.56–7.65 (m,
2 H), 9.87 (s, 1 H).
All reactions utilizing air- or moisture-sensitive reagents were per-
formed in dried glassware under an atmosphere of dry argon. Ethere-
al solvents (anhydrous; Kanto Chemical Co., Inc.) were used as re-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–Z

Q
Y. Yamashita et al.
Feature
Synthesis
13C NMR (150 MHz, CDCl3, without distinction of two rotamers):
δ = 14.1, 19.6, 19.7, 29.8, 29.9, 33.2, 33.4, 56.2, 61.4, 61.5, 61.6, 61.9,
115.4, 116.2, 116.5, 117.7, 118.2, 120.9, 121.7, 131.5, 136.1, 154.3,
154.5, 158.2, 158.3, 168.9, 169.2, 179.8, 186.3, 190.4, 190.6.
1H NMR (600 MHz, CDCl3): δ = 0.96 (d, J = 6.7 Hz, 3 H), 1.36 (dd, J = 7.0,
7.0 Hz, 3 H), 1.92 (br s, 1 H), 2.19 (dd, J = 17.5, 11.0 Hz, 1 H), 2.74–2.87
(m, 1 H), 2.97 (dd, J = 17.5, 5.2 Hz, 1 H), 3.64 (br s, 3 H), 3.88 (s, 3 H),
3.92 (br s, 3 H), 4.03 (s, 3 H), 4.19 (dq, J = 11.0, 7.0 Hz, 1 H), 4.40 (br s,
1 H), 4.65 (br s, 1 H), 5.00 (br s, 1 H), 5.45 (br s, 1 H), 6.64 (br s, 1 H),
6.78 (s, 1 H), 6.95 (d, J = 8.3 Hz, 1 H), 7.40 (dd, J = 8.3, 8.3 Hz, 1 H),
7.51–7.75 (m, 2 H), 8.40 (br s, 1 H).
Anal. Calcd for C19H19NO6: C, 63.86; H, 5.36; N, 3.92. Found: C, 64.00;
H, 5.62; N, 3.85.
13C NMR (150 MHz, CDCl3): δ = 14.2, 18.5, 29.9, 30.7, 52.3, 56.0, 56.2,
58.7, 60.9, 61.6, 72.6, 83.0, 103.5, 107.0, 110.6, 113.2, 114.3, 119.3,
120.8, 123.0, 125.2, 126.3, 126.9, 130.5, 131.9, 144.1, 147.7, 148.1,
151.8, 155.7, 157.3, 167.6, 172.5.
Synthesis of α-Ketol 13
The preparation of the racemic sample is representative: A mixture of
keto-aldehyde 21 (30.8 g, 86.2 mmol) and thiazolium salt 22 (2.17 g,
8.61 mmol) in t-BuOH (861 mL) was degassed by N2 bubbling and al-
lowed to warm up to 40 °C. To the mixture was added DBU (2.57 mL,
17.2 mmol) dropwise at this temperature. After stirring for 30 min, a
white solid precipitated. The mixture was cooled to 0 °C, and the re-
action was quenched by the addition of sat. aq NH4Cl. The mixture
was concentrated in vacuo to remove t-BuOH and then extracted with
CH2Cl2 (3 ×). The combined organic extracts were washed with brine,
dried (Na2SO4), and concentrated in vacuo. Trituration (Et2O/MeOH)
gave α-ketol 13 (22.7 g, 74%) as a white solid. The mother liquor was
concentrated in vacuo, and the residue was purified by flash column
chromatography (silica gel, hexane/EtOAc 1:1) followed by trituration
(Et2O/MeOH) to afford additional 13 as a white solid (2.17 g, 7%; total
yield = 81%); Rf 0.4 (hexane/EtOAc 1:1); rac-13: mp 180 °C (dec., CH-
Cl3/Et2O, colorless prisms); (–)-13 (optically pure): mp 154–155 °C
(CHCl3/hexane, colorless prisms); [α]D20 –26 (c 0.40, CHCl3).
Anal. Calcd for C33H34ClNO10: C, 61.92; H, 5.35; N, 2.19. Found: C,
62.22; H, 5.59; N, 2.19.
Synthesis of Naphthol 12
The preparation of racemic sample is representative: To a solution of
diol 28 (1.29 g, 2.02 mmol) in CH2Cl2 (20 mL) was slowly added a solu-
tion of TfOH (47 μL, 0.53 mmol) in CH2Cl2 (2.0 mL) at 0 °C, and the
reaction was allowed to warm up to r.t. After stirring for 13 h, the re-
action was quenched by the addition of sat. aq NaHCO3 at 0 °C. The
mixture was extracted with CH2Cl2 (3 ×), and the combined organic
extracts were washed with brine, dried (Na2SO4), and concentrated in
vacuo. The residue was purified by flash column chromatography (sil-
ica gel, hexane/EtOAc 1:1) to afford naphthol 12 (1.12 g, 96%) as a
white solid; Rf 0.33 (hexane/EtOAc 1:1); rac-12: mp 246 °C (dec.,
CHCl3/Et2O, colorless prisms); (+)-12 (optically pure): white amor-
phous solid, [α]D20 +310 (c 0.84, CHCl3).
IR (KBr): 3412, 2971, 2938, 1702, 1577, 1272, 1199, 800, 771 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 1.22 (d, J = 7.2 Hz, 3 H), 1.42 (dd, J = 7.2,
6.8 Hz, 3 H), 2.38–2.52 (m, 2 H), 2.88–3.02 (m, 1 H), 3.14 (dd, J = 18.0,
5.4 Hz, 1 H), 4.05 (s, 3 H), 4.32–4.46 (m, 2 H), 5.69 (s, 1 H), 7.26 (d, J =
8.4 Hz, 1 H), 7.50 (dd, J = 8.4, 7.8 Hz, 1 H), 7.60 (d, J = 7.8 Hz, 1 H).
13C NMR (150 MHz, CDCl3): δ = 14.1, 18.6, 29.6, 31.0, 48.5, 56.4, 61.5,
69.0, 113.1, 116.9, 117.0, 121.8, 131.8, 132.9, 153.4, 156.7, 169.6,
176.4, 195.0.
IR (ATR): 3293, 2975, 2935, 2839, 1728, 1704, 1594, 1575, 1341, 1323,
1273, 1244, 1212, 1191, 1154, 1047, 795 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 0.73 (d, J = 7.2 Hz, 3 H), 1.16 (dd, J = 7.4,
7.4 Hz, 3 H), 2.62 (d, J = 17.4 Hz, 1 H), 2.80–2.94 (m, 2 H), 3.86 (s, 3 H),
4.01 (s, 3 H), 4.07 (s, 3 H), 4.04–4.13 (m, 2 H), 4.65 (d, J = 1.4 Hz, 1 H),
6.66 (s, 1 H), 7.08 (d, J = 9.0 Hz, 1 H), 7.11 (d, J = 7.8 Hz, 1 H), 7.29 (dd,
J = 8.4, 7.8 Hz, 1 H), 7.34 (d, J = 7.8 Hz, 1 H), 7.43 (d, J = 9.0 Hz, 1 H),
10.38 (s, 1 H).
Anal. Calcd for C19H19NO6: C, 63.86; H, 5.36; N, 3.92. Found: C, 63.64;
H, 5.48; N, 3.86.
13C NMR (150 MHz, CDCl3): δ = 14.0, 22.3, 27.0, 32.4, 46.7, 52.3, 55.8,
56.3, 60.7, 62.7, 106.5, 112.9, 114.0, 115.5, 117.0, 118.0, 118.2, 121.5,
122.3, 126.7, 127.1, 131.3, 134.5, 144.9, 152.3, 152.8, 154.5, 156.1,
166.0, 173.0, 192.3.
Synthesis of Diol 28
The preparation of the racemic sample is representative: To a solution
of naphthalene 14 (1.29 g, 3.58 mmol) in THF (10 mL) was added 1.59
M t-BuLi in pentane (4.5 mL, 7.2 mmol) slowly at –78 °C. After stirring
for 10 min, a suspension of α-ketol 13 (365 mg, 1.02 mmol) in THF
(5.0 mL) was added slowly to the mixture via cannula. The reaction
was allowed to warm up to –40 °C, and stirring was continued for 20
min at this temperature before quenching by the addition of sat. aq
NH4Cl. The mixture was extracted with EtOAc (3 ×), and the combined
organic extracts were washed with brine, dried (Na2SO4), and concen-
trated in vacuo. The residue was purified by flash column chromatog-
raphy (silica gel, hexane/EtOAc 7:1 → 2:1) to afford diol 28 (654 mg,
quant.) as a white solid and naphthalene 25 (505 mg, ca. 70%, con-
taining some impurities).
Anal. Calcd for C31H28ClNO8: C, 64.42; H, 4.88; N, 2.42. Found: C,
64.40; H, 5.12; N, 2.42.
Synthesis of Lactone 11
To a suspension of naphthol 12 (38.2 g, 66.1 mmol) in toluene (661
mL) was added (±)-CSA (53.7 g, 0.231 mol). The mixture was heated at
110 °C for 1 h. After cooling to 0 °C, the reaction was quenched by the
addition of sat. aq NaHCO3. The mixture was extracted with EtOAc
(3 ×), and the combined organic extracts were washed with brine,
dried (Na2SO4), and concentrated in vacuo. Trituration (Et2O/EtOAc)
gave lactone 11 (30.5 g, 87%) as a white solid. The mother liquor was
concentrated in vacuo, and the residue was purified by flash column
chromatography (silica gel, hexane/EtOAc 1:1) to afford additional 11
as a white solid (3.99 g, 11%; total yield = 98%); Rf 0.61 (hexane/EtOAc
1:2); rac-11: mp 274–278 °C (CHCl3/Et2O, white solid); (+)-11 (opti-
cally pure): white amorphous solid, [α]D20 +296 (c 1.06, CHCl3).
When the reaction was conducted with naphthalene 14 (1.62 g, 4.48
mmol, 2 equiv) and 1.65 M t-BuLi in pentane (5.2 mL, 8.6 mmol, 4
equiv) to α-ketol 13 (800 mg, 2.24 mmol), the yield of diol 28 was 90%
(1.29 g); Rf 0.43 (hexane/EtOAc 1:2); rac-28: mp 193–194 °C
(CHCl3/Et2O, colorless prisms); (+)-28 (optically pure): white amor-
phous solid; [α]D20 +352 (c 1.08, CHCl3).
IR (ATR): 2964, 2935, 2839, 1795, 1676, 1581, 1522, 1457, 1411, 1361,
IR (ATR): 3522, 3300, 2975, 2939, 2837, 1712, 1414, 1327, 1268, 1250,
1333, 1282, 1177, 1045, 1034, 1006, 978, 955 cm–1
.
1044, 911, 887 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–Z

R
Y. Yamashita et al.
Feature
Synthesis
1H NMR (600 MHz, CDCl3): δ = 1.45 (d, J = 7.0 Hz, 3 H), 2.36–2.49 (m, 1
H), 2.88 (dd, J = 16.3, 9.1 Hz, 1 H), 3.05 (d, J = 5.9 Hz, 1 H), 3.26 (dd, J =
16.3, 6.2 Hz, 1 H), 3.92 (s, 3 H), 3.99 (s, 3 H), 4.00 (s, 3 H), 6.74 (s, 1 H),
7.06 (d, J = 8.3 Hz, 1 H), 7.11 (d, J = 8.5 Hz, 1 H), 7.53 (dd, J = 8.3, 8.0 Hz,
1 H), 7.82 (d, J = 8.5 Hz, 1 H), 7.83 (d, J = 8.0 Hz, 1 H).
13C NMR (150 MHz, CDCl3): δ = 22.7, 30.2, 35.3, 50.2, 54.0, 56.0, 56.2,
62.2, 106.8, 109.5, 113.1, 114.0, 114.2, 117.5, 117.7, 119.9, 121.2,
124.8, 126.8, 127.4, 132.1, 134.8, 144.1, 151.1, 152.0, 153.4, 156.5,
170.8, 175.5.
1H NMR (400 MHz, CDCl3): δ = 1.21 (d, J = 6.8 Hz, 3 H), 2.05–2.18 (m, 1
H), 2.45 (dd, J = 15.6, 3.9 Hz, 1 H), 2.78 (dd, J = 15.6, 14.2 Hz, 1 H),
2.99–3.06 (m, 1 H), 3.90 (s, 3 H), 3.91 (s, 3 H), 3.95 (s, 3 H), 4.17 (dd, J =
2.4, 2.0 Hz, 1 H), 4.54 (dd, J = 2.4, 2.4 Hz, 1 H), 6.65 (s, 1 H), 6.99 (d, J =
8.3 Hz, 1 H), 7.22 (d, J = 8.8 Hz, 1 H), 7.52 (dd, J = 8.8, 8.3 Hz, 1 H), 7.72
(d, J = 8.8 Hz, 1 H), 7.84 (d, J = 8.3 Hz, 1 H), 8.32 (br d, J = 5.8 Hz, 1 H),
11.60 (br d, J = 5.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 22.6, 34.7, 46.9, 54.8, 55.9, 56.4, 57.2,
62.2, 83.5, 93.5, 105.8, 113.3, 115.7, 116.0, 117.3, 118.0, 121.0, 121.1,
123.7, 126.7, 133.0, 133.2, 136.4, 144.2, 149.6, 152.0, 154.2, 158.5,
165.7, 197.8.
Anal. Calcd for C29H22ClNO7: C, 65.48; H, 4.17; N, 2.63. Found: C,
65.37; H, 4.47; N, 2.59.
HRMS (ESI): m/z [M + H]+ calcd for C30H27ClNO6: 532.1509; found:
532.1521.
Synthesis of Enol Ethers 10 and 31
Petasis reagent was prepared according to the literature procedure19
To a suspension of Cp2TiCl2 (5.00 g, 20.1 mmol) in toluene (54.2 mL)
was added 3.0 M MeMgCl in THF (15 mL, 46 mmol) dropwise at –10 °C.
After stirring for 1 h at 0 °C, the resulting orange slurry was diluted
with toluene (25 mL), and quenched by transferring into a flask con-
taining 6% aq NH4Cl solution (14 mL) via a cannula under an atmo-
sphere of argon at 0 °C. The mixture was poured into a separatory
funnel with toluene, and the aqueous phase was separated. The com-
bined organic extracts were sequentially washed with cold water
(3 ×) and brine (3 ×) each, then dried (Na2SO4), and concentrated in
vacuo. The resulting orange toluene solution was assayed by 1H NMR
to be 42 wt% dimethyltitanocene (3.73 g, 83%). The reagent was dilut-
ed with THF (29.9 mL). This Petasis reagent (0.50 M in toluene and
THF) was used in the following experiment.
Synthesis of Enaminone 32
Enol ether 10 (50.0 mg, 0.0945 mmol) was dissolved in THF/MeOH
(1:1, 10 mL). The reaction was performed using H-Cube (reaction pa-
rameter; flow rate of 1 mL/min and temperature of 25 °C, full hydro-
gen mode). The mixture was allowed to continuously flow through
the prepacked Raney Ni cartridge, 30 mm CarCart® (4 ×). The mixture
was concentrated in vacuo, and the residue was purified by PTLC
(CHCl3/MeOH/Et3N 100:2:1) to afford enaminone 32 (36.1 mg, 72%) as
a yellow solid; Rf 0.34 (hexane/EtOAc 1:1); mp 154–158 °C (CHCl3/Et2O,
yellow prisms).
IR (ATR): 3424, 3088, 2952, 2845, 1614, 1582, 1486, 1437, 1409, 1302,
1261, 1252, 1049, 807 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.05 (d, J = 6.9 Hz, 3 H), 1.58 (d, J = 6.4
Hz, 3 H), 1.80–1.94 (m, 1 H), 2.17 (dd, J = 8.7, 6.9 Hz, 1 H), 2.43 (dd, J =
15.6, 3.7 Hz, 1 H), 2.71 (dd, J = 15.6, 14.2 Hz, 1 H), 3.90 (s, 6 H), 3.96 (s,
3 H), 4.32 (dq, J = 6.9, 6.4 Hz, 1 H), 6.64 (s, 1 H), 6.94 (dd, J = 8.2, 0.9 Hz,
1 H), 7.19 (d, J = 8.7 Hz, 1 H), 7.48 (dd, J = 8.2, 7.8 Hz, 1 H), 7.68 (d, J =
8.7 Hz, 1 H), 7.80 (dd, J = 7.8, 0.9 Hz, 1 H), 8.30 (br d, J = 5.7 Hz, 1 H),
11.6 (br d, J = 5.7 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 21.8, 23.6, 34.5, 46.8, 55.9, 56.4, 56.8,
62.1, 64.4, 86.5, 94.6, 105.6, 112.8, 115.3, 115.4, 117.4, 120.3, 121.1,
121.1, 123.4, 126.7, 132.8, 134.4, 138.2, 144.4, 149.3, 152.1, 154.3,
158.4, 198.2.
To a solution of lactone 11 (100 mg, 0.188 mmol) in toluene (1.9 mL)
was added Petasis reagent (0.50 M in toluene and THF, 2.26 mL, 1.13
mmol) at r.t. The mixture was heated at 90 °C for 1.5 h. The solution
was cooled to r.t., and diluted with hexane (5.0 mL). The resulting
slurry was filtered through a Celite pad. Concentration of the filtrate
provided crude product, which was purified by PTLC (hexane/EtOAc/
CH2Cl2 3:1:1) to give enol ether 10 (58.6 mg, 56%) and enol ether 31
(20.3 mg, 20%) both as a yellow solid.
Enol Ether 10
Rf 0.48 (hexane/EtOAc 1:1); mp 271 °C (dec., CHCl3/Et2O, light yellow
prisms).
Anal. Calcd for C30H28ClNO6: C, 67.48; H, 5.29; N, 2.62. Found: C,
67.65; H, 5.46; N, 2.38.
IR (ATR): 2980, 2837, 1673, 1580, 1411, 1358, 1333, 1289, 1274, 1045,
937, 912, 814, 755, 739 cm–1
.
Synthesis of Enone 33
1H NMR (400 MHz, CDCl3): δ = 1.39 (d, J = 7.4 Hz, 3 H), 2.24–2.37 (m, 1
H), 2.83 (dd, J = 16.9, 8.2 Hz, 1 H), 3.10–3.20 (m, 2 H), 3.91 (s, 3 H),
3.97 (s, 3 H), 4.01 (s, 3 H), 4.08 (dd, J = 2.8, 2.8 Hz, 1 H), 4.52 (dd, J =
2.8, 2.8 Hz, 1 H), 6.70 (s, 1 H), 7.01 (dd, J = 8.7, 0.9 Hz, 1 H), 7.15 (d, J =
8.7 Hz, 1 H), 7.47 (dd, J = 8.7, 8.2 Hz, 1 H), 7.74 (d, J = 8.7 Hz, 1 H), 7.82
(dd, J = 8.2, 0.9 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 22.6, 29.4, 35.4, 52.1, 54.6, 55.9, 56.2,
62.2, 85.2, 106.3, 109.7, 112.5, 114.4, 116.4, 117.5, 119.1, 120.79,
120.83, 124.1, 127.2, 127.7, 131.8, 136.6, 144.3, 151.1, 152.0, 154.4,
156.4, 164.3, 170.1.
To a solution of enaminone 32 (471 mg, 0.883 mmol) in CH2Cl2 (5 mL)
were added pyridine (710 μL, 8.83 mmol) and BzCl (160 μL, 1.32
mmol) at 0 °C. After stirring for 48 h at r.t., to the mixture was added
N,N-dimethylpropanediamine (550 μL, 4.42 mmol) at 0 °C. After stir-
ring for 1.5 h, the reaction was stopped by the addition of sat. aq
NH4Cl at 0 °C. The mixture was extracted with CH2Cl2 (3 ×), and the
combined organic extracts were washed with brine, dried (Na2SO4),
and concentrated in vacuo. Trituration (Et2O/CH2Cl2) gave amide S-1
(521 mg, 92%) as a white solid.
To a solution of i-Pr2NH (125 μL, 0.896 mmol) in THF (3.4 mL) was
added 1.65 M n-BuLi in hexane (0.52 mL, 0.86 mmol) at –78 °C. The
solution was allowed to warm up to 0 °C, and stirred for 30 min. The
mixture was cooled to –78 °C, and then a solution of S-1 (220 mg,
0.344 mmol) in THF (5.0 mL) was added. The mixture was allowed to
warm up to 0 °C over 45 min, and stirred for 35 min at 0 °C. A solution
of N-tert-butylbenzenesulfinimidoyl chloride (220 mg, 1.02 mmol) in
THF (1.5 mL) was added at –78 °C. After stirring for 30 min at this
temperature, the reaction was quenched by the addition of sat. aq
NH4Cl. The mixture was extracted with EtOAc (3 ×), and the combined
HRMS (ESI): m/z [M + H]+ calcd for C30H25ClNO6: 530.1352; found:
530.1365.
Enol Ether 31
Rf 0.35 (hexane/EtOAc 1:1); mp 273 °C (dec., CHCl3/Et2O, yellow
prisms).
IR (ATR): 3435, 3085, 2980, 1664, 1611, 1580, 1485, 1409, 1320, 1264,
1044, 810, 745 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–Z

S
Y. Yamashita et al.
Feature
Synthesis
organic extracts were washed with brine, dried (Na2SO4), and concen-
trated in vacuo. The residue was purified by PTLC (CHCl3/MeOH/Et3N
100:2:1) to afford enone 33 (199 mg, 91%) as a yellow solid.
Naphthoquinone S-2
Rf 0.48 (hexane/EtOAc 1:1).
IR (ATR): 3381, 2974, 2934, 1680, 1607, 1586, 1557, 1453, 1432, 1299,
1278, 1260, 1219, 1051, 795, 705 cm–1
.
Amide S-1
1H NMR (400 MHz, CDCl3): δ = 1.66 (d, J = 6.4 Hz, 3 H), 2.00 (s, 3 H),
2.84 (d, J = 10.2 Hz, 1 H), 3.58 (s, 3 H), 4.59 (dq, J = 10.2, 6.4 Hz, 1 H),
6.21–6.24 (m, 1 H), 6.84 (d, J = 8.3 Hz, 1 H), 7.12 (s, 1 H), 7.34 (d, J = 7.8
Hz, 1 H), 7.44 (dd, J = 8.3, 7.8 Hz, 1 H), 7.47–7.54 (m, 2 H), 7.54–7.62
(m, 2 H), 7.66 (d, J = 7.8 Hz, 1 H), 7.97–8.04 (m, 2 H), 12.56 (s, 1 H).
Rf 0.39 (hexane/EtOAc 1:1); mp 182–183 °C (CHCl3/Et2O, colorless
prisms).
IR (ATR): 3441, 2937, 2874, 2840, 1688, 1582, 1515, 1454, 1411, 1312,
1213, 1050, 1037, 1018, 949, 918, 818, 798, 707 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.11 (d, J = 6.4 Hz, 3 H), 1.60 (d, J = 6.9
Hz, 3 H), 2.20 (dd, J = 10.6, 5.0 Hz, 1 H), 2.26–2.40 (m, 1 H), 2.49 (dd,
J = 17.7, 13.3 Hz, 1 H), 2.81 (dd, J = 17.7, 3.2 Hz, 1 H), 3.75 (s, 3 H), 3.90
(s, 3 H), 3.98 (s, 3 H), 4.45 (dq, J = 5.0, 6.9 Hz, 1 H), 6.67 (s, 1 H), 6.88
(d, J = 7.8 Hz, 1 H), 7.10 (d, J = 8.7 Hz, 1 H), 7.42 (dd, J = 8.2, 8.2 Hz, 1
H), 7.45–7.58 (m, 3 H), 7.68 (d, J = 8.7 Hz, 1 H), 7.77 (dd, J = 7.8, 0.9 Hz,
1 H), 7.89–7.95 (m, 2 H), 11.42 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 21.3, 24.2, 55.9, 57.8, 59.8, 85.0, 106.7,
112.5, 115.1, 116.8, 119.4, 120.9, 121.2, 127.6, 127.9, 128.8, 129.2,
132.4, 132.7, 133.1, 134.1, 134.8, 135.1, 141.7, 144.0, 147.0, 152.3,
156.4, 157.5, 166.4, 175.3, 182.0, 187.8.
Anal. Calcd for C35H24ClNO7: C, 69.37; H, 3.99; N, 2.31. Found: C,
69.29; H, 4.19; N, 2.12.
13C NMR (100 MHz, CDCl3): δ = 20.3, 24.4, 32.6, 45.9, 55.9, 56.3, 57.3,
62.1, 65.4, 84.9, 105.9, 112.6, 115.8, 117.2, 117.4, 117.6, 120.2, 120.4,
120.5, 123.7, 126.8, 127.3, 128.7, 131.6, 131.8, 132.0, 134.0, 134.7,
135.6, 144.4, 149.3, 152.0, 156.4, 165.5, 203.1.
Enaminone 34
Rf 0.30 (hexane/EtOAc 1:3).
IR (ATR): 3418, 3084, 2968, 2929, 2847, 1670, 1662, 1601, 1585, 1558,
1482, 1456, 1428, 1306, 1279, 1222, 1052, 933, 852, 807, 783 cm–1
.
Anal. Calcd for C37H32ClNO7: C, 69.64; H, 5.05; N, 2.20. Found: C,
69.52; H, 5.19; N, 2.05.
1H NMR (400 MHz, CDCl3): δ = 1.61 (d, J = 6.4 Hz, 3 H), 1.90 (s, 3 H),
2.60 (d, J = 10.1 Hz, 1 H), 3.93 (s, 3 H), 4.52 (dq, J = 10.1, 6.4 Hz, 1 H),
6.12 (s, 1 H), 7.00 (d, J = 8.3 Hz, 1 H), 7.10 (s, 1 H), 7.38 (d, J = 7.8 Hz, 1
H), 7.51 (dd, J = 8.3, 7.8 Hz, 1 H), 7.59 (d, J = 7.8 Hz, 1 H), 7.76 (d, J = 7.8
Hz, 1 H), 8.15 (br d, J = 5.7 Hz, 1 H), 11.55 (br d, J = 5.7 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 21.0, 23.5, 55.7, 56.4, 59.0, 85.1, 88.4,
113.3, 114.8, 115.4, 120.8, 120.9, 121.0, 128.2, 129.8, 132.3, 133.4,
135.1, 137.0, 143.7, 144.6, 146.8, 154.8, 156.1, 158.3, 175.5, 182.1,
184.9.
Enone 33
Rf 0.56 (hexane/EtOAc 2:3); mp 278–279 °C (CHCl3/Et2O, yellow
prisms).
IR (ATR): 3006, 2978, 2932, 2837, 1698, 1607, 1579, 1452, 1437, 1296,
1267, 1255, 1040, 799, 710 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.63 (d, J = 6.7 Hz, 3 H), 1.97 (d, J = 1.2
Hz, 3 H), 2.86 (d, J = 10.4 Hz, 1 H), 3.57 (s, 3 H), 3.89 (s, 3 H), 4.00 (s, 3
H), 4.53 (dq, J = 10.4, 6.7 Hz, 1 H), 6.19–6.23 (m, 1 H), 6.66 (s, 1 H),
6.78 (d, J = 7.9 Hz, 1 H), 7.12 (d, J = 8.5 Hz, 1 H), 7.39 (dd, J = 8.0, 7.9 Hz,
1 H), 7.46–7.60 (m, 3 H), 7.66 (d, J = 8.5 Hz, 1 H), 7.72 (dd, J = 8.0, 1.2
Hz, 1 H), 7.98–8.05 (m, 2 H), 12.50 (s, 1 H).
HRMS (ESI): m/z [M + H]+ calcd for C28H21ClNO6: 502.1054; found:
502.1052.
Synthesis of Anthraquinone 35
To a solution of naphthoquinone 34 (17.8 mg, 0.035 mmol) in ben-
zene (2.0 mL) and THF (0.5 mL) was added a solution of diene 8 (33.0
mg, 0.18 mmol) in benzene (0.5 mL) at 0 °C. After stirring for 11 h at
r.t., silica gel (4.0 g) and CH2Cl2 (5.0 mL) were added, and stirring was
continued for an additional 24 h. After removal of the solvent under
reduced pressure, the silica gel was filtered off and rinsed with
CHCl3/MeOH (10:1). The filtrate was concentrated in vacuo to afford
the crude product. The residue was purified by PTLC (CHCl3/MeOH
20:1), then small amounts of impurities were removed by PTLC (CH2-
Cl2/ MeOH 50:1) to afford anthraquinone 35 (15.9 mg, 87%) as a yel-
low solid; Rf 0.29 (hexane/EtOAc 1:3); mp 191–192 °C.
13C NMR (100 MHz, CDCl3): δ = 21.5, 24.2, 55.8, 55.9, 58.8, 61.4, 62.2,
83.8, 105.8, 108.8, 112.0, 115.5, 117.1, 117.5, 119.1, 119.4, 119.8,
123.7, 127.5, 127.9, 128.7, 129.0, 129.8, 132.2, 132.4, 134.3, 136.0,
143.1, 144.4, 149.6, 152.0, 153.2, 157.4, 166.5, 188.6.
Anal. Calcd for C37H30ClNO7: C, 69.86; H, 4.75; N, 2.20. Found: C,
69.73; H, 5.04; N, 2.01.
Synthesis of Enaminone 34
To a solution of naphthalene 33 (257 mg, 0.404 mmol) in MeCN (12
mL) and CH2Cl2 (6 mL) was added a solution of CAN (399 mg, 0.928
mmol) in water (3 mL) at r.t. After stirring for 20 min, the mixture was
diluted with water. The mixture was extracted with CH2Cl2 (3 ×), and
the combined organic extracts were washed with brine, dried
(Na2SO4), and concentrated in vacuo. The residue was purified by
PTLC (hexane/EtOAc/CH2Cl2 1:1:1) to afford naphthoquinone S-2 (166
mg, 68%) as a yellow solid.
IR (ATR): 3445, 2973, 2935, 1669, 1634, 1606, 1567, 1484, 1431, 1301,
1265, 1235, 1205, 936, 817, 799, 751 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.63 (d, J = 6.0 Hz, 3 H), 1.91 (s, 3 H),
2.42 (s, 3 H), 2.67 (d, J = 9.6 Hz, 1 H), 3.92 (s, 3 H), 4.54 (dq, J = 9.6, 6.0
Hz, 1 H), 6.14 (s, 1 H), 7.00 (d, J = 8.4 Hz, 1 H), 7.06 (s, 1 H), 7.41 (d, J =
7.8 Hz, 1 H), 7.50–7.58 (m, 2 H), 7.76–7.83 (m, 2 H), 8.15 (d, J = 6.0 Hz,
1 H), 11.55 (d, J = 6.0 Hz, 1 H), 12.86 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 21.1, 22.1, 23.5, 55.6, 56.4, 59.0, 85.1,
88.6, 113.3, 114.5, 115.5, 117.0, 120.3, 120.7, 120.8, 121.6, 124.1,
128.3, 129.8, 132.9, 133.4, 134.0, 137.2, 143.6, 144.8, 147.9, 154.8,
156.0, 158.4, 162.5, 182.2, 185.0, 187.2.
A solution of S-2 (23.0 mg, 0.038 mmol) in 10.0 M aq H2SO4 (3.0 mL)
was heated at 60 °C for 25 min. The reaction was quenched by the
careful addition of sat. aq NaHCO3 at 0 °C. The products were extract-
ed with EtOAc (3 ×), and the combined organic extracts were washed
with brine, dried (Na2SO4), and concentrated in vacuo. The residue
was purified by PTLC (CHCl3/MeOH 30:1) to afford enaminone 34
(17.4 mg, 91%) as an orange solid.
HRMS (ESI): m/z [M + H]+ calcd for C33H26NO7: 548.1703; found:
548.1704.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–Z

T
Y. Yamashita et al.
Feature
Synthesis
Synthesis of Diketone 6
13C NMR (150 MHz, CDCl3): δ = 20.5, 21.2, 31.3, 39.4, 53.6, 56.0, 56.2,
62.0, 63.0, 104.6, 106.3, 111.5, 112.3, 113.6, 116.5, 117.5, 120.1,
121.41, 121.42, 124.0, 127.3, 128.6, 131.8, 136.5, 144.4, 150.6, 152.0,
154.0, 156.4, 169.7, 170.9.
To a solution of enaminone 35 (93.8 mg, 0.171 mmol) and t-BuONO
(41 μL, 0.34 mmol) in DMSO (2.5 mL) was added TfOH (152 μL, 1.71
mmol) at r.t. After stirring for 80 min, the reaction was quenched by
the addition of sat. aq NaHCO3 at 0 °C. The mixture was extracted
with EtOAc (3 ×), and the combined organic extracts were washed
with water and brine, dried (Na2SO4), and concentrated in vacuo. The
residue was purified by PTLC (CHCl3/MeOH 40:1) to afford diketone 6
(50.5 mg, 54%) as a yellow solid; Rf 0.29 (hexane/EtOAc 1:3); mp 361
°C (dec., CHCl3/Et2O, yellow solid).
Anal. Calcd for C31H26ClNO8: C, 64.64; H, 4.55; N, 2.43. Found: C,
64.42; H, 4.44; N, 2.13.
α-Acetate α-41
Rf 0.35 (hexane/EtOAc 2:3); mp 258–261 °C (CHCl3/hexane, white sol-
id).
IR (ATR): 2975, 1632, 1586, 1432, 1301, 1265, 1235, 1059, 1021, 941,
IR (ATR): 3009, 2967, 2943, 2840, 1751, 1584, 1413, 1359, 1333, 1277,
866, 821, 802, 748 cm–1
.
1210, 1047, 997, 949, 926, 906, 799 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 1.66 (d, J = 6.1 Hz, 3 H), 2.00 (d, J = 1.2
Hz, 3 H), 2.43 (s, 3 H), 2.74 (d, J = 10.0 Hz, 1 H), 3.90 (s, 3 H), 4.52 (dq,
J = 9.8, 6.1 Hz, 1 H), 6.21 (d, J = 1.2 Hz, 1 H), 7.00 (d, J = 8.3 Hz, 1 H),
7.07 (s, 1 H), 7.37 (d, J = 7.6 Hz, 1 H), 7.56 (s, 1 H), 7.59 (dd, J = 8.2, 8.0
Hz, 1 H), 7.70 (d, J = 8.0 Hz, 1 H), 7.83 (d, J = 7.6 Hz, 1 H), 12.80 (s, 1 H),
16.56 (s, 1 H).
13C NMR (150 MHz, CDCl3): δ = 21.3, 22.2, 24.2, 55.1, 56.4, 59.0, 85.5,
95.2, 113.7, 114.5, 117.4, 117.5, 119.7, 120.5, 120.9, 121.7, 124.2,
124.3, 128.1, 132.8, 134.6, 135.3, 139.0, 141.5, 148.0, 149.9, 155.9,
159.8, 162.7, 179.3, 179.7, 182.2, 187.1.
1H NMR (600 MHz, CDCl3): δ = 1.33 (d, J = 7.2 Hz, 3 H), 1.78 (s, 3 H),
2.42–2.50 (m, 1 H), 2.84 (dd, J = 17.4, 4.2 Hz, 1 H), 2.95 (dd, J = 5.4, 1.2
Hz, 1 H), 3.26 (dd, J = 17.4, 9.0 Hz, 1 H), 3.90 (s, 3 H), 3.97 (s, 3 H), 4.03
(s, 3 H), 6.55 (d, J = 5.4 Hz, 1 H), 6.70 (s, 1 H), 7.00 (d, J = 8.4 Hz, 1 H),
7.18 (d, J = 8.7 Hz, 1 H), 7.46 (dd, J = 8.4, 7.8 Hz, 1 H), 7.73 (d, J = 8.7 Hz,
1 H), 7.80 (d, J = 7.8 Hz, 1 H).
13C NMR (150 MHz, CDCl3): δ = 20.8, 24.5, 28.7, 29.5, 51.7, 55.9, 56.1,
56.3, 62.2, 99.8, 106.2, 109.5, 112.0, 113.8, 116.1, 117.4, 120.6, 120.7,
120.9, 124.1, 127.1, 127.3, 131.7, 137.3, 144.1, 151.0, 151.9, 154.1,
156.2, 169.3, 170.1.
HRMS (ESI): m/z [M + H]+ calcd for C33H25O8: 549.1542; found:
549.1544.
Anal. Calcd for C31H26ClNO8; C, 64.64; H, 4.55; N, 2.43. Found: C,
64.36; H, 4.26; N, 2.30.
Synthesis of β-Acetate β-41 and α-Acetate α-41
Synthesis of Isoxazole 42
The preparation of racemic sample is representative: To a solution of
lactone 11 (5.00 g, 9.40 mmol) in CH2Cl2 (157 mL) was added slowly a
solution of 1.00 M DIBAL-H in CH2Cl2 (11.3 mL, 11.3 mmol) over 5
min at –100 °C. After stirring for 15 min, the reaction was quenched
by the addition of sat. aq NH4Cl and Rochelle’s salt, which was diluted
with CH2Cl2 and water. After stirring overnight at r.t., the mixture was
extracted with CH2Cl2 (7 ×). The combined organic extracts were
washed with brine, dried (Na2SO4), and concentrated in vacuo. To a
solution of this crude material in CH2Cl2 (94 mL) were added Ac2O
(3.55 mL, 37.6 mmol), pyridine (3.80 mL, 47.0 mmol), and DMAP (115
mg, 0.940 mmol) at 0 °C. After stirring for 3 h at r.t., the reaction was
quenched by the addition of sat. aq NH4Cl, and the mixture was ex-
tracted with CH2Cl2 (3 ×). The combined organic extracts were
washed with brine, dried (Na2SO4), and concentrated in vacuo. Tritu-
ration (Et2O) gave β-acetate β-41 (2.87 g, 53%) as a white solid. The
mother liquor was concentrated in vacuo, and the residue was puri-
fied by Smart Flash EPCLC W-Prep 2XY system [Hi-FlashTM column,
silica gel, size 3L, hexane/EtOAc 3:2 → 2:3 (gradient), flow rate; 60
mL/min] to give additional β-acetate β-41 (1.31 g, 24%; total yield =
77%) and α-acetate α-41 (0.40 g, 7%) both as a white solid.
The preparation of racemic sample is representative: To a solution of
β-acetate β-41 (399 mg, 0.693 mmol) in CH2Cl2 (35 mL) were added
1.30 M Me3Al in hexane (3.99 mL, 5.19 mmol), H2O (56.1 μL, 3.11
mmol), and TMSOTf (1.25 mL, 6.93 mmol) at –78 °C. The reaction was
allowed to warm up gradually to r.t. over 12 h. The reaction was
quenched by the addition of sat. aq NaHCO3 and Rochelle’s salt, which
was diluted with CH2Cl2 and water. After stirring for 30 min at r.t., the
mixture was extracted with CH2Cl2 (3 ×), and the combined organic
extracts were washed with brine, dried (Na2SO4), and concentrated in
vacuo. Trituration (Et2O) gave isoxazole 42 (300 mg, 82%) as a white
solid. The mother liquor was concentrated in vacuo, and the residue
was purified by PTLC (hexane/EtOAc 1:1) to afford additional 42 as a
white solid (38.2 mg, 10%; total yield = 92%); Rf 0.39 (hexane/EtOAc
1:1); rac-42: mp 259 °C (dec., CHCl3/hexane, white solid); (+)-42 (op-
tically pure): mp 205–207 °C (EtOAc/hexane, white solid), [α]D20 +246
(c 1.02, CHCl3).32
IR (ATR): 2959, 2929, 1579, 1410, 1332, 1281, 1043, 817, 799 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 1.26 (d, J = 7.2 Hz, 3 H), 1.50 (d, J = 6.6
Hz, 3 H), 1.85–1.93 (m, 1 H), 2.32 (dd, J = 6.0, 6.0 Hz, 1 H), 2.82 (dd, J =
16.2, 7.8 Hz, 1 H), 3.13 (dd, J = 16.2, 6.0 Hz, 1 H), 3.91 (s, 3 H), 3.97 (s,
3 H), 3.99–4.05 (m, 1 H), 4.00 (s, 3 H), 6.69 (s, 1 H), 6.98 (d, J = 8.4 Hz,
1 H), 7.11 (d, J = 8.4 Hz, 1 H), 7.47 (dd, J = 8.4, 7.8 Hz, 1 H), 7.71 (d, J =
8.4 Hz, 1 H), 7.80 (d, J = 7.8 Hz, 1 H).
13C NMR (150 MHz, CDCl3): δ = 22.2, 22.7, 30.2, 36.2, 54.2, 55.9, 56.1,
62.2, 62.3, 86.3, 106.0, 111.1, 111.8, 113.6, 115.8, 117.6, 120.70,
120.74, 120.9, 123.9, 127.1, 129.0, 131.8, 138.4, 144.4, 150.6, 152.0,
154.4, 156.3, 169.8.
β-Acetate β-41
Rf 0.35 (hexane/EtOAc 1:1); rac-β-41: mp 167–170 °C (CHCl3/hexane,
white solid); (+)-β-41 (optically pure): mp 157–160 °C (EtOAc/hex-
ane, white solid), [α]D20 +151 (c 1.03, CHCl3).
IR (ATR): 2957, 2931, 2837, 1753, 1585, 1414, 1363, 1333, 1292, 1222,
1040, 998, 969, 932, 912, 819, 804 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 1.26 (d, J = 6.6 Hz, 3 H), 1.62–1.71 (m, 1
H), 2.01 (s, 3 H), 2.66 (d, J = 9.6 Hz, 1 H), 2.80 (dd, J = 15.6, 11.4 Hz, 1
H), 3.13 (dd, J = 15.6, 3.6 Hz, 1 H), 3.92 (s, 3 H), 3.97 (s, 3 H), 3.99 (s, 3
H), 6.25 (s, 1 H), 6.71 (s, 1 H), 7.00 (d, J = 8.1 Hz, 1 H), 7.09 (d, J = 8.4
Hz, 1 H), 7.49 (dd, J = 8.1, 8.1 Hz, 1 H), 7.73–7.82 (m, 2 H).
Anal. Calcd for C30H26ClNO6: C, 67.73; H, 4.93; N, 2.63. Found: C,
67.49; H, 5.21; N, 2.53.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–Z

U
Y. Yamashita et al.
Feature
Synthesis
Synthesis of α-Selenide α-43 and β-Selenide β-43
×), and the combined organic extracts were washed with brine, dried
(Na2SO4), and concentrated in vacuo. Trituration (Et2O) gave olefin 44
(172 mg, quant.) as a white solid.
The preparation of racemic sample is representative: To a solution of
isoxazole 42 (511 mg, 0.961 mmol) in a mixed solvent of THF (31 mL)
and DMPU (6 mL) was added a solution of 1.65 M n-BuLi in hexane
(0.85 mL, 1.4 mmol) at –100 °C. After stirring for 30 min at –90 °C, a
solution of PhSeBr (567 mg, 2.40 mmol) in THF (1.0 mL) was added to
the mixture, and the stirring was continued for 10 min at this tem-
perature. The reaction was quenched by the addition of sat. aq NH4Cl,
and the mixture was extracted with EtOAc (3 ×). The combined or-
ganic extracts were washed with brine, dried (Na2SO4), and concen-
trated in vacuo. The residue was purified by flash column chromatog-
raphy (silica gel, hexane/EtOAc/CH2Cl2 4:1:1) to afford α-selenide α-
43 (253 mg, 38%) and β-selenide β-43 (250 mg, 38%) both as a white
solid.
Synthesis of Olefin 44 from β-Selenide β-43
The preparation of racemic sample is representative: To a solution of
β-selenide β-43 (232 mg, 0.338 mmol) and NaHCO3 (283 mg, 3.37
mmol) in a mixed solvent of THF (28 mL) and H2O (14 mL) was added
30% aq H2O2 (0.68 mL, 6.76 mmol) at 0 °C, and the reaction was al-
lowed to warm up to r.t. After stirring for 14 h, the reaction was
stopped by the addition of 10% aq Na2S2O3. The mixture was extracted
with CH2Cl2 (3 ×), and the combined organic extracts were washed
with brine, dried (Na2SO4), and concentrated in vacuo. Trituration
(Et2O) gave olefin 44 (125 mg, 70%) as a white solid. The mother li-
quor was concentrated in vacuo, and the residue was purified by PTLC
(CH2Cl2) to afford additional 44 as a white solid (27.0 mg, 15%; total
yield = 85%); Rf 0.43 (hexane/EtOAc 1:1); rac-44: mp 316 °C (dec.,
CH2Cl2/hexane, white solid); (+)-44 (optically pure): mp 176–178 °C
(CH2Cl2/hexane, white solid), [α]D20 +121 (c 1.01, CHCl3).
α-Selenide α-43
Rf 0.53 (hexane/EtOAc 1:1); mp 207–209 °C (CHCl3/hexane, white sol-
id).
IR (ATR): 2998, 2935, 2903, 2839, 1579, 1411, 1273, 1047, 1024, 740
cm–1
.
IR (ATR): 2975, 2934, 2832, 1575, 1408, 1358, 1331, 1281, 1270, 1058,
1030, 930, 909, 837 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 1.29 (d, J = 6.6 Hz, 3 H), 1.34 (d, J = 7.2
Hz, 3 H), 2.19–2.25 (m, 1 H), 2.37 (dd, J = 9.0, 1.8 Hz, 1 H), 3.73 (dq, J =
9.0, 6.6 Hz, 1 H), 3.89 (s, 3 H), 3.96 (s, 3 H), 4.01 (s, 3 H), 4.35 (d, J = 4.2
Hz, 1 H), 6.68 (s, 1 H), 6.96 (d, J = 8.4 Hz, 1 H), 7.05 (d, J = 8.4 Hz, 1 H),
7.28–7.36 (m, 3 H), 7.43 (dd, J = 8.4, 7.8 Hz, 1 H), 7.67 (d, J = 8.4 Hz, 1
H), 7.71–7.78 (m, 3 H).
1H NMR (600 MHz, CDCl3): δ = 1.54 (d, J = 6.0 Hz, 3 H), 2.01 (d, J = 1.8
Hz, 3 H), 2.68 (d, J = 9.6 Hz, 1 H), 3.91 (s, 3 H), 3.97 (s, 3 H), 4.02 (s, 3
H), 4.05 (dq, J = 9.6, 6.0 Hz, 1 H), 6.61 (q, J = 1.8 Hz, 1 H), 6.70 (s, 1 H),
6.98 (dd, J = 8.3, 0.8 Hz, 1 H), 7.13 (d, J = 8.4 Hz, 1 H), 7.46 (dd, J = 8.3,
7.9 Hz, 1 H), 7.71 (d, J = 8.4 Hz, 1 H), 7.83 (dd, J = 7.9, 0.8 Hz, 1 H).
13C NMR (150 MHz, CDCl3): δ = 21.5, 24.0, 52.5, 55.9, 56.2, 61.0, 62.2,
86.5, 106.2, 106.4, 111.9, 113.1, 114.0, 116.0, 117.8, 120.3, 120.7 (2 C),
123.9, 127.1, 127.6, 131.8, 139.2, 143.7, 144.6, 149.7, 152.0, 154.6,
156.5, 166.4.
13C NMR (150 MHz, CDCl3): δ = 20.2, 23.3, 39.3, 39.4, 53.5, 55.9, 56.1,
60.9, 62.2, 85.1, 106.2, 110.1, 111.9, 113.9, 115.6, 117.7, 120.3, 120.4,
120.9, 123.9, 127.3, 127.6, 127.7, 128.9, 129.4 (2 C), 131.9, 136.1 (2 C),
138.6, 144.4, 151.1, 152.0, 155.0, 156.5, 167.7.
HRMS (APCI): m/z [M + H]+ calcd for C36H31ClNO6Se: 688.1000; found:
688.1005.
Anal. Calcd for C30H24ClNO6: C, 67.99; H, 4.56; N, 2.64. Found: C,
67.95; H, 4.51; N, 2.44.
Synthesis of Naphthoquinone 45
β-Selenide β-43
The preparation of racemic sample is representative: To the flask con-
taining silica gel (1.43 g) was added dropwise a solution of CAN (219
mg, 0.400 mmol) in water (1.0 mL) with vigorous stirring at r.t. After
stirring for 5 min, the resulting orange powder was suspended in
CH2Cl2 (2.5 mL). A solution of naphthalene 44 (103 mg, 0.195 mmol)
in CH2Cl2 (3.0 mL) was added to the suspension at r.t. After stirring for
10 min, the mixture was filtered through a glass filter (washed with
EtOAc). Water was added to the filtrate, and the mixture was extract-
ed with EtOAc (3 ×). The combined organic extracts were washed
with brine, dried (Na2SO4), and concentrated in vacuo. The residue
was purified by PTLC (CH2Cl2/MeOH 60:1) to give naphthoquinone 45
(85.3 mg, 88%) as a yellow solid; Rf 0.40 (hexane/EtOAc 2:3); rac-45:
mp 203–206 °C (CHCl3/hexane, yellow solid); (+)-45 (optically pure):
Rf 0.48 (hexane/EtOAc 1:1); mp 237–240 °C (dec., CHCl3/hexane,
white solid).
IR (ATR): 3672, 2971, 2934, 2902, 1580, 1453, 1411, 1334, 1274, 1044,
1026, 740 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 1.29 (d, J = 6.6 Hz, 3 H), 1.61 (d, J = 6.6
Hz, 3 H), 1.89–1.96 (m, 1 H), 2.42 (dd, J = 9.6, 3.0 Hz, 1 H), 3.91 (s, 3 H),
3.94 (s, 3 H), 3.96 (s, 3 H), 4.25 (dq, J = 3.0, 6.6 Hz, 1 H), 4.64 (d, J = 4.2
Hz, 1 H), 6.69 (s, 1 H), 6.96 (d, J = 8.1 Hz, 1 H), 7.33–7.38 (m, 3 H), 7.47
(dd, J = 8.1, 8.1 Hz, 1 H), 7.73–7.79 (m, 4 H), 7.86 (d, J = 9.0 Hz, 1 H).
13C NMR (150 MHz, CDCl3): δ = 19.2, 25.0, 41.1, 45.6, 54.3, 56.0, 56.1,
60.6, 62.1, 87.7, 106.2, 111.9, 112.0, 113.6, 115.7, 117.3, 121.3, 121.9,
122.3, 123.7, 127.3, 128.4, 128.6, 129.6 (2 C), 129.7, 131.8, 134.5 (2 C),
137.7, 144.5, 150.5, 152.1, 154.6, 156.2, 172.8.
20
mp 220–222 °C (CH2Cl2/hexane, yellow solid), [α]D +253 (c 1.00,
CHCl3).
HRMS (APCI): m/z [M + H]+ calcd for C36H31ClNO6Se: 688.1000; found:
IR (ATR): 2970, 2933, 2845, 1677, 1663, 1587, 1578, 1431, 1279, 1228,
688.0996.
1045, 927, 796 cm–1
.
Synthesis of Olefin 44 from α-Selenide α-43
1H NMR (600 MHz, CDCl3): δ = 1.56 (d, J = 6.0 Hz, 3 H), 2.04 (d, J = 0.9
Hz, 3 H), 2.69 (d, J = 9.6 Hz, 1 H), 3.98 (s, 3 H), 4.10 (dq, J = 9.6, 6.0 Hz,
1 H), 6.63 (q, J = 0.9 Hz, 1 H), 7.02 (d, J = 8.4 Hz, 1 H), 7.15 (s, 1 H), 7.37
(d, J = 7.8 Hz, 1 H), 7.49 (dd, J = 8.4, 7.8 Hz, 1 H), 7.63 (d, J = 7.8 Hz, 1
H), 7.78 (d, J = 7.8 Hz, 1 H).
13C NMR (150 MHz, CDCl3): δ = 21.3, 24.0, 51.7, 56.2, 59.6, 87.6, 105.0,
112.5, 113.43, 113.49, 115.4, 120.6, 121.1, 122.5, 128.7, 132.3, 133.0,
135.1, 137.7, 138.3, 143.4, 146.9, 154.2, 156.46, 156.53, 166.7, 175.3,
181.9.
The preparation of racemic sample is representative: To a solution of
α-selenide α-43 (223 mg, 0.325 mmol) and NaHCO3 (69.0 mg, 0.817
mmol) in a mixed solvent of THF (13.5 mL) and H2O (5.4 mL) was add-
ed NaIO4 (437 mg, 2.04 mmol) at 0 °C, and the reaction was allowed to
warm up to r.t. After stirring for 14 h, the reaction was stopped by the
addition of 10% aq Na2S2O3. The mixture was extracted with CH2Cl2 (3
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–Z

V
Y. Yamashita et al.
Feature
Synthesis
Anal. Calcd for C28H18ClNO6: C, 67.27; H, 3.63; N, 2.80. Found: C,
67.27; H, 3.61; N, 2.50.
1H NMR (600 MHz, CDCl3): δ = 1.55 (d, J = 6.1 Hz, 3 H), 1.58 (s, 9 H),
1.73 (s, 9 H), 2.04 (br d, J = 1.3 Hz, 3 H), 2.49 (s, 3 H), 2.69 (d, J = 9.4 Hz,
1 H), 4.09 (dq, J = 9.4, 6.1 Hz, 1 H), 6.61 (br d, J = 1.3 Hz, 1 H), 7.26 (dd,
J = 8.1, 1.1 Hz, 1 H), 7.30 (s, 1 H), 7.35 (d, J = 7.6 Hz, 1 H), 7.45 (dd, J =
8.1, 8.0 Hz, 1 H), 7.83 (d, J = 7.6 Hz, 1 H), 8.01 (br s, 1 H), 8.08 (dd, J =
8.0, 1.1 Hz, 1 H).
13C NMR (150 MHz, CDCl3): δ = 21.4, 21.6, 24.0, 27.65 (3 C), 27.73 (3
C), 51.8, 59.8, 84.1 (2 C), 87.3, 105.5, 113.1, 118.4, 118.8, 121.2, 121.5,
123.2, 124.1, 125.9, 126.5, 127.8, 130.1, 131.6, 134.2, 134.4, 138.0,
138.2, 143.9, 146.0, 147.1, 150.3, 151.1, 151.3, 153.3, 156.1, 167.2,
179.6, 182.2.
Synthesis of Anthraquinone 46
The preparation of racemic sample is representative: To a solution of
naphthoquinone 45 (201 mg, 0.403 mmol) in a mixed solvent of ben-
zene (1.0 mL) and CH2Cl2 (2.0 mL) was added a solution of diene 8
(225 mg, 1.21 mmol) in benzene (1.0 mL) at 0 °C. After stirring for 3.5
h at r.t., CH2Cl2 (4.0 mL) and silica gel (3.57 g) were added to the mix-
ture at 0 °C. The suspension was further stirred for 2 h at r.t. After re-
moving the solvent under reduced pressure, the silica gel was filtered
off and rinsed with EtOAc and CH2Cl2, and the filtrate was concentrat-
ed in vacuo. To a solution of the crude mixture in a mixed solvent of
MeOH (20 mL) and CH2Cl2 (8.0 mL) was added K2CO3 (111 mg, 0.803
mmol) at 0 °C. After stirring for 20 min at this temperature, the reac-
tion was quenched by the addition of sat. aq NH4Cl. The mixture was
extracted with CH2Cl2 (3 ×), and the combined organic extracts were
washed with brine, dried (Na2SO4), and concentrated in vacuo. Tritu-
ration (Et2O) gave anthraquinone 46 (190 mg, 86%) as a yellow solid.
The mother liquor was concentrated in vacuo, and the residue was
purified by PTLC (CH2Cl2) to afford additional 46 as a yellow solid
(17.9 mg, 8%; total yield = 94%); Rf 0.53 (hexane/EtOAc 2:3); rac-46:
mp 359 °C (dec., CHCl3/hexane, yellow solid); (+)-46 (optically pure):
mp 305 °C (dec., CH2Cl2/hexane, yellow solid), [α]D20 +358 (c 1.00, CH-
Cl3).
Anal. Calcd for C42H37NO11: C, 68.94; H, 5.10; N, 1.91. Found: C, 68.77;
H, 5.40; N, 1.85.
Synthesis of Epoxide 62
The preparation of racemic sample is representative: To a solution of
olefin 59 (499 mg, 0.682 mmol) in a mixed solvent of HCOOH (18.0
mL) and CH2Cl2 (3.6 mL) was added N-bromosaccharin (49; 197 mg,
0.752 mmol) at 0 °C. After stirring for 20 min at this temperature, the
reaction was stopped by the addition of 10% Na2S2O3 solution. The
mixture was extracted with EtOAc (3 ×), and the combined organic
extracts were successively washed with water (3 ×), NaHCO3 (3 ×),
brine, and then dried (Na2SO4) and concentrated in vacuo. To a solu-
tion of this crude material, including bromo-formates 60 and 61
(60/61 1.8:1, estimated by 1H NMR), in MeOH (68 mL) was added Na2-
CO3 (145 mg, 1.37 mmol) at 0 °C. After stirring for 1.5 h at r.t., the re-
action was stopped by the addition of aq NH4Cl, and the mixture was
extracted with EtOAc (3 ×). The combined organic extracts were
washed with brine, dried (Na2SO4), and concentrated in vacuo. The
residue was purified by flash column chromatography (hexane/
EtOAc/CH2Cl2 4:1:1) to afford epoxide 62 (425 mg, 83%) as a yellow
amorphous solid; Rf 0.40 (hexane/EtOAc 2:1); (+)-62 (optically pure):
IR (ATR): 2977, 2934, 2844, 1634, 1587, 1578, 1432, 1266, 1241, 1029,
1021, 931, 819, 795 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 1.58 (d, J = 6.0 Hz, 3 H), 2.05 (s, 3 H),
2.43 (s, 3 H), 2.73 (d, J = 9.6 Hz, 1 H), 3.98 (s, 3 H), 4.11 (dq, J = 9.6, 6.0
Hz, 1 H), 6.65 (br s, 1 H), 7.03 (d, J = 8.4 Hz, 1 H), 7.09 (s, 1 H), 7.39 (d,
J = 7.5 Hz, 1 H), 7.52 (dd, J = 8.4, 7.8 Hz, 1 H), 7.57 (s, 1 H), 7.81 (d, J =
7.8 Hz, 1 H), 7.84 (d, J = 7.5 Hz, 1 H), 12.82 (s, 1 H).
13C NMR (150 MHz, CDCl3): δ = 21.4, 22.1, 24.0, 51.7, 56.2, 59.8, 87.6,
105.3, 112.5, 113.5, 113.7, 114.5, 117.7, 120.49, 120.52, 121.8, 122.4,
124.3, 128.7, 132.3, 132.7, 134.9, 137.9, 138.1, 143.5, 148.1, 154.3,
156.4, 156.6, 162.7, 166.8, 182.0, 186.9.
20
mp 219–222 °C (EtOAc/hexane, yellow solid), [α]D +319 (c 1.00,
CHCl3).
IR (ATR): 2981, 2932, 1760, 1676, 1233, 1144, 1131, 817 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 1.52 (d, J = 6.1 Hz, 3 H), 1.58 (s, 9 H),
1.60 (s, 3 H), 1.72 (s, 9 H), 2.50 (s, 3 H), 2.71 (d, J = 9.5 Hz, 1 H), 4.04 (s,
1 H), 4.15 (dq, J = 9.5, 6.1 Hz, 1 H), 7.27 (d, J = 8.0 Hz, 1 H), 7.31 (br s, 1
H), 7.38 (d, J = 7.7 Hz, 1 H), 7.48 (dd, J = 8.0, 8.0 Hz, 1 H), 7.88 (d, J = 7.7
Hz, 1 H), 8.01 (br s, 1 H), 8.06 (d, J = 8.0 Hz, 1 H).
Anal. Calcd for C33H23NO7: C, 72.65; H, 4.25; N, 2.57. Found: C, 72.44;
H, 4.55; N, 2.36.
Synthesis of Carbonate 59
13C NMR (150 MHz, CDCl3): δ = 20.5, 21.7, 25.6, 27.7 (3 C), 27.8 (3 C),
49.3, 53.8, 58.6, 59.3, 83.0, 84.3, 84.4, 112.0, 117.6, 118.8, 120.7,
121.4, 123.1, 124.4, 126.1, 126.5, 126.8, 130.3, 132.1, 134.28, 134.33,
137.88, 137.95, 146.2, 147.1, 150.3, 151.1, 151.4, 153.7, 156.5, 165.7,
179.7, 182.1.
The preparation of racemic sample is representative: To a solution of
methyl ether 46 (100 mg, 0.183 mmol) in CH2Cl2 (8.0 mL) was added a
solution of BBr3 (165 mg, 0.659 mmol) in CH2Cl2 (1.0 mL) at –78 °C.
After gradual warming to –10 °C over 2 h, the mixture was further
stirred for 1 h at this temperature. The reaction was quenched by the
addition of water, and the mixture was extracted with CH2Cl2 (3 ×).
The combined organic extracts were washed with brine, dried
(Na2SO4), and concentrated in vacuo. To a solution of this crude mate-
rial in CH2Cl2 (5.0 mL) were added Boc2O (126 μL, 0.549 mmol) and
DMAP (22.4 mg, 0.183 mmol) at –20 °C. After stirring for 20 min at
this temperature, the reaction was quenched by the addition of sat. aq
NH4Cl, and the mixture was extracted with CH2Cl2 (3 ×). The com-
bined organic extracts were washed with brine, dried (Na2SO4), and
concentrated in vacuo. The residue was purified by PTLC (hex-
ane/EtOAc/CH2Cl2 3:1:1) to afford carbonate 59 (110 mg, 82%) as a
yellow amorphous solid; Rf 0.49 (hexane/EtOAc 2:1); (+)-59 (optically
pure): mp 212–215 °C (dec., EtOAc/hexane, yellow solid), [α]D20 +209
(c 0.963, CHCl3).
Anal. Calcd for C42H37NO12: C, 67.46; H, 4.99; N, 1.87. Found: C, 67.23;
H, 5.27; N, 1.75.
Synthesis of Enaminone 63
The preparation of racemic sample is representative: To a solution of
epoxide 62 (131 mg, 0.175 mmol) in CH2Cl2 (5.0 mL) was added TFA
(0.5 mL) at 0 °C. After stirring for 2 h at r.t., the reaction was stopped
by the addition of sat. aq NaHCO3. The mixture was extracted with
CH2Cl2 (3 ×), and the combined organic extracts were washed with
brine, dried (Na2SO4), and concentrated in vacuo. To a solution of this
crude material in a mixed solvent of MeCN (6.0 mL) and H2O (1.2 mL)
was added Mo(CO)6 (185 mg, 0.701 mmol) at r.t. After stirring for 30
min at 85 °C, an additional portion of Mo(CO)6 (40.0 mg, 0.152 mmol)
was added. After stirring for 10 min at 85 °C, the mixture was allowed
to cool to r.t. The mixture was diluted with water, and the resulting
IR (ATR): 2980, 2932, 1760, 1675, 1231, 1146, 1131, 941, 816, 749 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–Z

W
Y. Yamashita et al.
Feature
Synthesis
suspension was filtered through a Celite pad (washed with EtOAc).
The filtrate was washed with brine, dried (Na2SO4), and concentrated
in vacuo. The residue was purified by PTLC (CH2Cl2/MeOH 15:1) to af-
ford enaminone 63 (93.1 mg, 97%) as a yellow solid; Rf 0.29 (hex-
ane/EtOAc 1:4); (+)-63 (optically pure): mp 304 °C (dec., acetone/hex-
ane, yellow solid), [α]D20 +470 (c 0.50, CHCl3).
HRMS (APCI): m/z [M + H]+ calcd for C39H30NO8: 640.1966; found:
640.1951.
Diketone 64
Rf 0.52 (hexane/EtOAc 2:1); rac-64: mp 176–180 °C; (+)-64 (optically
20
pure): mp 222–224 °C (EtOAc/hexane, yellow solid), [α]D +580 (c
IR (ATR): 3384, 2930, 1635, 1605, 1589, 1456, 1433, 1370, 1299, 1265,
0.59, CHCl3).
1234, 1203, 953, 818, 801, 749 cm–1
.
IR (ATR): 2972, 2927, 1634, 1591, 1302, 1265, 1234, 1205, 818, 804,
1H NMR (600 MHz, DMSO-d6): δ = 1.29 (s, 3 H), 1.51 (d, J = 6.1 Hz, 3
H), 2.38 (s, 3 H), 2.57 (d, J = 10.0 Hz, 1 H), 3.33 (s, 1 H), 4.44 (dq, J =
10.0, 6.1 Hz, 1 H), 6.99 (d, J = 8.4 Hz, 1 H), 7.13 (s, 1 H), 7.36–7.43 (m, 2
H), 7.48 (dd, J = 8.2, 7.6 Hz, 1 H), 7.49 (d, J = 7.6 Hz, 1 H), 7.60 (d, J = 7.6
Hz, 1 H), 7.74 (d, J = 7.6 Hz, 1 H), 9.15 (br s, 1 H), 11.47 (br s, 1 H),
12.67 (s, 1 H).
13C NMR (150 MHz, DMSO-d6): δ = 20.5, 21.7, 24.4, 55.8, 56.2, 56.9,
58.3, 81.6, 87.4, 112.2, 114.3, 116.4, 118.5 (2 C), 119.9, 120.4, 121.6,
123.9, 128.2, 132.7, 133.5, 133.9, 136.9, 144.5, 148.2, 155.5, 157.3,
157.6, 161.7, 181.5, 186.8, 188.2.
738 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 1.43 (s, 3 H), 1.64 (d, J = 6.0 Hz, 3 H),
2.43 (s, 3 H), 2.58 (d, J = 10.2 Hz, 1 H), 3.46 (s, 1 H), 4.68 (dq, J = 10.2,
6.0 Hz, 1 H), 5.12 (d, J = 12.3 Hz, 1 H), 5.22 (d, J = 12.3 Hz, 1 H), 7.03 (d,
J = 7.8 Hz, 1 H), 7.08 (s, 1 H), 7.30 (dd, J = 8.4, 8.4 Hz, 1 H), 7.35–7.39
(m, 2 H), 7.40 (d, J = 7.8 Hz, 1 H), 7.46–7.50 (m, 2 H), 7.57 (s, 1 H), 7.59
(dd, J = 7.8, 7.8 Hz, 1 H), 7.69 (d, J = 7.8 Hz, 1 H), 7.89 (d, J = 7.8 Hz, 1
H), 12.75 (s, 1 H), 16.32 (s, 1 H).
13C NMR (150 MHz, CDCl3): δ = 20.5, 22.2, 24.8, 55.2, 56.0, 56.4, 57.1,
71.0, 82.4, 98.2, 114.5, 115.1, 117.45, 117.53, 120.0, 120.1, 120.5,
121.8, 124.3, 126.8 (2 C), 127.3, 128.0, 128.6 (2 C), 132.8, 134.7, 136.0,
136.1, 139.8, 141.9, 148.1, 155.8, 159.2, 162.6, 180.4, 182.1, 183.1,
187.0.
HRMS (APCI): m/z [M + H]+ calcd for C32H24NO8: 550.1496; found:
550.1486.
HRMS (APCI): m/z [M + H]+ calcd for C39H29O9: 641.1806; found:
Synthesis of Diketone 64
The preparation of racemic sample is representative: To a solution of
phenol 63 (29.9 mg, 0.0544 mmol) and BnBr (67.9 μL, 0.572 mmol) in
DMF (1.0 mL) was added Ag2O (12.6 mg, 0.0544 mmol) at 0 °C. After
stirring for 1 h at r.t., the resulting suspension was filtered through a
Celite pad (washed with EtOAc). The filtrate was diluted with water,
and the mixture was extracted with EtOAc (3 ×). The combined or-
ganic extracts were washed with brine, dried (Na2SO4), and concen-
trated in vacuo. The residue was purified by PTLC (hexane/EtOAc 1:2)
to afford enaminone S-3 (32.3 mg, 93%) as a yellow solid.
641.1795.
Synthesis of 2
The preparation of racemic sample is representative: To a solution of
PhSeSePh (234 mg, 0.750 mmol) in EtOH (4.0 mL) was added NaBH4
(57.0 mg, 1.51 mmol) at 0 °C. After stirring for 3 min, to the mixture
was added AcOH (15.0 μL, 0.262 mmol) at r.t. (PhSeH solution). To a
solution of epoxide 64 (17.6 mg, 0.0275 mmol) in a mixed solvent of
THF (1.0 mL) and EtOH (1.0 mL) was added the PhSeH solution (0.73
mL, 0.27 mmol) at 0 °C. The resulting mixture was stirred at the same
temperature for 20 min. The mixture was diluted with EtOAc and
brine into which oxygen was passed for 5 min. The mixture was ex-
tracted with EtOAc (3 ×), and the combined organic extracts were
washed with brine, dried (Na2SO4), and concentrated in vacuo. The
residue was purified by Smart Flash EPCLC W-Prep 2XY system (UL-
TRA PACK, DIOL-40A, hexane/EtOAc/CH2Cl2 3.5:1:1) to afford alcohol
S-4 (14.4 mg, 82%) as a yellow solid.
To a solution of S-3 (24.7 mg, 0.0386 mmol) and t-BuONO (9.2 μL,
0.077 mmol) in DMSO (0.5 mL) was added TfOH (34.2 μL, 0.386
mmol) at r.t. After stirring for 40 min, the reaction was quenched by
the addition of sat. aq NaHCO3 at 0 °C. The mixture was extracted
with EtOAc (3 ×), and the combined organic extracts were washed
with brine, dried (Na2SO4), and concentrated in vacuo. The residue
was purified by flash column chromatography (silica gel coated with
oxalic acid,11d hexane/EtOAc/CH2Cl2 5:1:1) to give diketone 64 (15.1
mg, 61%) as a yellow solid.
To a solution of S-4 (25.7 mg, 40.0 μmol) in CH2Cl2 (4.7 mL) was added
a solution of BBr3 (51.5 mg, 0.205 mmol) in CH2Cl2 (0.4 mL) at –78 °C.
After gradual warming to –55 °C over 30 min, the mixture was further
stirred for 30 min at this temperature. The reaction was quenched by
the addition of sat. aq NaHCO3, and the mixture was extracted with
CH2Cl2 (3 ×). The combined organic extracts were washed with brine,
dried (Na2SO4), and concentrated in vacuo. The residue was purified
by RP-HPLC [Mightysil® RP-18 GP II 2.0 cmφ × 25 cm (5 μm),
MeCN/H2O 85:15 (0.1% HCOOH), flow rate 6.0 mL/min] to afford (±)-
BE-43472B (rac-2) (16.8 mg, 76%) as a yellow solid. Recrystallization
of rac-2 from CDCl3 gave a yellow plate, which was analyzed by X-ray
diffraction.32
Enaminone S-3
Rf 0.53 (hexane/EtOAc 1:1); rac-S-3: mp 325 °C (racemic, dec., CHCl3/
Et2O); (+)-S-3 (optically pure): mp 169–170 °C (acetone/hexane, yel-
low solid), [α]D20 +518 (c 1.04, CHCl3).
IR (ATR): 3425, 3064, 3036, 2970, 2929, 1733, 1671, 1610, 1588, 1482,
1302, 1264, 1236, 1204, 817, 798, 750 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 1.38 (s, 3 H), 1.63 (d, J = 6.2 Hz, 3 H),
2.43 (s, 3 H), 2.55 (d, J = 10.1 Hz, 1 H), 3.29 (s, 1 H), 4.69 (dq, J = 10.1,
6.2 Hz, 1 H), 5.09 (d, J = 10.9 Hz, 1 H), 5.17 (d, J = 10.9 Hz, 1 H), 7.06 (br
s, 1 H), 7.09 (d, J = 8.5 Hz, 1 H), 7.36–7.44 (m, 6 H), 7.54–7.59 (m, 2 H),
7.81 (d, J = 7.8 Hz, 1 H), 7.87 (d, J = 7.6 Hz, 1 H), 8.68 (br d, J = 5.1 Hz, 1
H), 11.72 (br s, 1 H), 12.81 (s, 1 H).
Alcohol S-4
Rf 0.30 (hexane/EtOAc 1:1); rac-S-4: mp 251–254 °C (CHCl3, yellow
solid); (+)-S-4 (optically pure): mp 198–201 °C (EtOAc/hexane, yellow
solid), [α]D20 +560 (c 0.50, CHCl3).
13C NMR (150 MHz, CDCl3) δ = 20.5, 22.2, 24.8, 56.0, 56.7, 57.1, 58.5,
72.2, 82.3, 88.7, 114.4, 114.6, 114.7, 117.2, 120.4 (2 C), 121.2, 121.8,
124.2, 127.5, 127.8, 127.9, 129.0, 129.1 (2 C), 132.8, 134.0, 134.1,
134.6, 138.0, 144.3, 148.0, 155.8, 157.4, 157.8, 162.6, 182.2, 187.1,
188.8.
IR (ATR): 3528, 2970, 2919, 2872, 1634, 1591, 1371, 1303, 1265, 1234,
1207, 1014, 821, 802, 746 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–Z

X
Y. Yamashita et al.
Feature
Synthesis
1H NMR (600 MHz, CDCl3): δ = 1.38 (s, 3 H), 1.68 (d, J = 9.4 Hz, 3 H),
1.71 (s, 1 H), 2.42 (s, 3 H), 2.47 (d, J = 6.5 Hz, 1 H), 2.75 (d, J = 19.2 Hz,
1 H), 2.91 (d, J = 19.2 Hz, 1 H), 5.02 (dq, J = 9.4, 6.5 Hz, 1 H), 5.12 (d, J =
12.6 Hz, 1 H), 5.20 (d, J = 12.6 Hz, 1 H), 7.03 (d, J = 9.7 Hz, 1 H), 7.06 (s,
1 H), 7.26–7.38 (m, 4 H), 7.45–7.50 (m, 2 H), 7.54–7.59 (m, 2 H), 7.71
(d, J = 9.2 Hz, 1 H), 7.84 (d, J = 9.3 Hz, 1 H), 12.75 (s, 1 H), 16.35 (s, 1 H).
13C NMR (150 MHz, CDCl3): δ = 22.1, 24.8, 30.1, 48.1, 55.6, 65.4, 71.06,
71.08, 80.9, 101.2, 114.5, 115.4, 116.8, 117.3, 120.42, 120.45, 121.5,
122.3, 124.3, 126.8 (2 C), 127.9, 128.0, 128.6 (2 C), 132.7, 134.1, 135.4,
136.2, 138.2, 144.7, 147.9, 156.1, 158.9, 162.5, 177.1, 182.1, 187.0,
190.4.
HRMS (ESI): m/z [M + H]+ calcd for C19H21NO5: 344.1493; found:
344.1502.
Synthesis of Keto-aldehyde (+)-21
To a solution of 65 (1.07 g, 3.13 mmol) in THF (16 mL) were add NaH
(63% dispersion in mineral oil, 250 mg, 6.57 mmol) and diethyl car-
bonate (754 μL, 6.26 mmol) at 0 °C. After the mixture was heated un-
der reflux for 2 h, the reaction was stopped by the addition of sat. aq
NH4Cl and extracted with EtOAc (3 ×). The combined extracts were
washed with brine, dried (Na2SO4), and concentrated in vacuo. This
material was employed in the next experiment without further puri-
fication. To a solution of crude material in acetone (19 mL) was added
2 M HCl (13 mL) at 0 °C. After stirring for 11 h at r.t., the reaction was
stopped by the addition of sat. aq NaHCO3 and extracted with EtOAc
(3 ×). The combined extracts were washed with brine, dried (Na2SO4),
and concentrated in vacuo. The residue was purified by flash column
chromatography (silica gel, hexane/EtOAc 2:1 to 1:1) to afford keto-
aldehyde (+)-21 [976 mg, 87% (2 steps)] as a pale yellow solid.
HRMS (APCI): m/z [M + H]+ calcd for C39H31O9: 643.1963; found:
643.1951.
BE-43472B (2)
Rf 0.38 (CH2Cl2/MeOH 9:1); rac-2: mp 211–213 °C (CDCl3, yellow
plates); (+)-2 (optically pure): mp 285 °C (dec., CHCl3/hexane, yellow
solid), [α]D20 +550 (c 0.85, CHCl3).
IR (ATR): 3501, 2974, 2930, 1613, 1580, 1453, 1434, 1267, 1236, 1206,
1180, 1126, 816, 801, 747 cm–1
.
Funding Information
1H NMR (600 MHz, CDCl3): δ = 1.41 (s, 3 H), 1.66 (d, J = 6.6 Hz, 3 H),
2.38 (br s, 1 H), 2.43 (s, 3 H), 2.44 (d, J = 5.5 Hz, 1 H), 2.75 (d, J = 16.4
Hz, 1 H), 2.86 (d, J = 16.4 Hz, 1 H), 5.02 (dq, J = 5.5, 6.6 Hz, 1 H), 6.94
(dd, J = 7.7, 1.7 Hz, 1 H), 7.08 (s, 1 H), 7.34 (d, J = 7.7 Hz, 1 H), 7.55–
7.62 (m, 3 H), 7.87 (d, J = 7.7 Hz, 1 H), 11.96 (s, 1 H), 12.72 (s, 1 H),
14.39 (s, 1 H).
This work was supported by a Grant-in-Aid for Specially Promoted
Research (No. 23000006) and Grant-in-Aid for Scientific Research (S)
(No. 16H06351) from Japan Society for the Promotion of Science
(JSPS) (Japan). Y.Y. thanks the JSPS for a Research Fellowship for Young
Scientists.
)(
13C NMR (150 MHz, CDCl3): δ = 22.2, 24.8, 29.8, 44.5, 56.4, 65.2, 71.3,
81.0, 102.1, 113.1, 114.5, 117.4, 118.9, 119.2, 120.5, 121.5, 121.6,
124.4, 127.8, 132.7, 134.5, 137.1, 137.6, 143.6, 148.1, 156.1, 161.9,
162.6, 178.1, 182.2, 186.9, 189.5.
HRMS (APCI): m/z [M + H]+ calcd for C32H25O9: 553.1493; found:
553.1484.
Acknowledgment
We are grateful to Banyu Pharmaceutical Co., Ltd. for kindly providing
an authentic sample of BE-43472B (2). We thank Sachiyo Kubo for X-
ray analysis, and Prof. Shang-Cheng Hung for providing the Origami
model of 2.
Synthesis of Isoxazole 65
A mixture of nitrile oxide 18 (13.4 g, 57.1 mmol) and enone 6645 (9.43
g, 85.6 mmol) in toluene (57 mL) was stirred at r.t. for 53 h. To the
mixture was added activated MnO2 (58.4 g, 85%, 571 mmol) and heat-
ed for 20 min at 80 °C. After filtration through a Celite pad, the filtrate
was concentrated under reduced pressure. The residue was purified
by flash column chromatography (silica gel, hexane/EtOAc 2:1 to 1:1)
to afford isoxazole 65 (14.6 g, 75%) as a white amorphous solid;
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610136.
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References
20
Rf 0.40 (hexane/EtOAc 1:1); (–)-65 (optically pure): [α]D –12.4
(c 1.00, CHCl3).
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1H NMR (600 MHz, CDCl3): δ = (without distinction of the two rotam-
ers) 1.21 (d, J = 6.5 Hz, 1.5 H), 1.23 (d, J = 6.4 Hz, 1.5 H), 1.31 (br d, J =
13.1 Hz, 1 H), 2.06–2.19 (m, 1 H), 2.20–2.35 (m, 1 H), 2.44–2.64 (m, 2
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1.5 H), 3.73 (s, 1.5 H), 3.85 (br d, J = 11.9 Hz, 1 H), 3.95–4.06 (m, 1 H),
4.19 (br dd, J = 11.3, 4.6 Hz, 1 H), 5.46 (s, 1 H), 6.96 (d, J = 8.1 Hz, 0.5
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Hz, 0.5 H), 7.46 (dd, J = 8.1, 8.0 Hz, 1 H).
13C NMR (150 MHz, CDCl3) δ = without distinction of the two rotam-
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56.0, 67.10, 67.12, 67.2, 99.16, 99.17, 111.2, 111.3, 115.2, 116.1, 116.2,
118.3, 118.4, 130.99, 131.01, 138.8, 155.68, 155.73, 157.7, 157.8,
179.8, 179.9, 190.3, 190.5.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–Z

Y
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Feature
Synthesis
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MeO
NH2
O
OMe
NH2
Me
O
O
H
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O
O
Me
MeO
Cl
Me
H
O
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H
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δ
H 4.32
δH 1.87
NOE
32
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–Z

Z
Y. Yamashita et al.
Feature
Synthesis
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AcO
N
O
OAc
Br
Me
K2CO3
O
O
H
Me
O
MeOH, 0 °C
25 min
AcO
Me
OH
N
O
16%
O
O
Me
51
(41) Epoxide formation from bromo-acetates 51 and 52 was unsuc-
cessful (Scheme 20): Upon treatment of bromo-acetate 51 with
K2CO3 in MeOH, epoxide 56 was obtained in only 16% yield
along with many byproducts. Worse still, the reaction of regio-
isomeric bromo-acetate 52 under the same conditions did not
afford epoxide 56, giving only a complex mixture. These results
could be ascribed to the slow solvolysis of acetates, especially
for sterically congested acetate 52.
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group, see: Bode, J. W.; Uekusa, H.; Suzuki, K. Org. Lett. 2003, 5,
395.
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50, 1569. (b) Tsuchiya, T.; Ohmuro, S. Tetrahedron Lett. 2002, 43,
611. (c) Adachi, S.; Watanabe, K.; Iwata, Y.; Kameda, S.;
Miyaoka, Y.; Onozuka, M.; Mitsui, R.; Saikawa, Y.; Nakata, M.
Angew. Chem. Int. Ed. 2013, 52, 2087.
O
O
H
Me
O
HO
AcO
N
O
Br
O
56
OAc
Me
Me
K2CO3
O
O
H
Me
O
AcO
Me
MeOH, 0 °C
0%
O
52
Scheme 20
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to prepare crystals suitable for X-ray analysis were unsuccess-
ful’.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–Z