First Total Synthesis of Dermocanarin 2

Article abstract of DOI:10.1055/s-0035-1561417

The first total synthesis of dermocanarin 2 is described. The synthesis features the construction of the anthraquinone and naphthoquinone frameworks through annulation reactions onto an axially chiral biphenyl intermediate, obtained by an enzyme-catalyzed enantioselective desymmetrization of a σ-symmetric precursor, followed by a stereoselective aldol reaction to construct the stereogenic center in the side chain.

Full text of DOI:10.1055/s-0035-1561417

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–G
letter
A
S. Yamaguchi et al.
Letter
Synlett
First Total Synthesis of Dermocanarin 2
OMe
Satoru Yamaguchia
Diels–Alder
reaction
OMe
Nobuyuki Takahashia
OMe
Bn
O
Daisuke Yuyamab
Kayo Sakamotob
Keisuke Suzuki*a
Takashi Matsumoto*b
RO
Cl
O
O
Cl
OMe
O
HO
O
Me
HO Me
O
RO
O
OMe
Me
OMe
OR
O
OMe
HO
AcO
lactonization
HO
O
O
MOMO
a Department of Chemistry, Tokyo Institute of Technology,
2- 12-1 O-okayama, Meguro-ku, Tokyo, 152-8551, Japan
ksuzuki@chem.titech.ac.jp
b School of Pharmacy, Tokyo University of Pharmacy and
Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo,
192-0392, Japan
HO
R = Ac
R = H
O
electrocyclic
reaction
O
Me
enantioselective
desymmetrization
Me
dermocanarin 2
tmatsumo@toyaku.ac.jp
Received: 23.01.2016
Accepted after revision: 11.02.2016
Published online: 24.03.2016
OMe
OMe
O
DOI: 10.1055/s-0035-1561417; Art ID: st-2016-u0043-l
HO Me
O
OMe
Abstract The first total synthesis of dermocanarin 2 is described. The
synthesis features the construction of the anthraquinone and naphtho-
quinone frameworks through annulation reactions onto an axially chiral
biphenyl intermediate, obtained by an enzyme-catalyzed enantioselec-
tive desymmetrization of a σ-symmetric precursor, followed by a stere-
oselective aldol reaction to construct the stereogenic center in the side
chain.
O
O
O
HO
O
Me
dermocanarin 2 (1)
Key words axial chirality, biphenyls, enzymes, desymmetrizations, an-
nulations, total synthesis
Figure 1 Structure of dermocanarin 2 (1)
We previously reported a simple and highly enantiose-
lective synthesis of axially chiral biaryls through an en-
zyme-catalyzed desymmetrization (Scheme 1).4 A feature
of this method is that the operation responsible for enantio-
selection is executed by using an achiral biaryl precursor.
This leads to a reduction in the difficulties associated with
synthesis of sterically congested biaryl derivatives. Further-
more, the enzymatic process is compatible with a broad
range of biaryls I. We expected that the monoacetate II
would permit multidirectional elaboration through ex-
ploitation of well-discriminated functionalities to give a bi-
aryl structure composed of the highly oxygen-functionalized
polycyclic chromophores present in dermocanarin 2 (1).5
Axially chiral biaryls are structural motifs abundant in
natural products.1 Such structures arise from diverse aro-
matic precursors produced by various biosynthetic routes,
including polyketide and shikimate pathways, primarily
through oxidative coupling. Consequently, many natural bi-
aryls are composed of multiply functionalized polyaromatic
derivatives, rather than simple monocyclic aromatic deriva-
tives, and they are exceedingly congested around the biaryl
axis; as a result, they present formidable challenges as tar-
get compounds in organic synthesis.2
In this communication, we describe the first total syn-
thesis of dermocanarin 2 (1; Figure 1),3a,b a pigment isolated
from an Australian toadstool, Dermocybe canaria, and one
of ten analogues isolated from the related species.3 The
structure features anthraquinone and naphthoquinone
moieties interconnected by a σ-bond and bridged by a nine-
membered lactone structure. Hindered rotation of the
C(sp2)–C(sp2) bond between the quinone moieties imparts
axial chirality, and a stereogenic center is present in the lac-
tone portion.
Z
Z
Z
enzyme
X
HO
Y
OAc
X
AcO
Y
OAc
X
AcO
Y
OH
or
I
II
ent-II
Scheme 1 Desymmetrization approach to axially chiral biaryls by en-
zyme-catalyzed hydrolysis
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–G

B
S. Yamaguchi et al.
Letter
Synlett
Our retrosynthetic analysis of dermocanarin 2 (1) is
shown in Scheme 2.6 On the assumption that the lactone
bridge could be formed in the final stage of the synthesis,
dermocanarin 2 (1) was traced back to the stereodefined bi-
phenyl VI with a β-hydroxybutenoic acid side chain, as a
key intermediate. We surmised that the anthraquinone
moiety might be constructed through sequential electrocy-
clic reactions using benzocyclobutene V as the building
block corresponding to the C1–C4, C4a, C9a, C9, C10, and
C3-Me atoms (shown in red in Scheme 2).5,7 The naphtho-
quinone moiety should be accessible through selective oxi-
dation of one of the aromatic rings (the upper portion of VI)
followed by a Diels–Alder reaction with siloxydiene IV,
with the chloro substituent controlling the regiochemical
course of the reaction.8 Disconnection of the C2′–C3′ link-
age leads to the ketone VII and an acetate-derived enolate
as the precursors. We hoped that the axial chirality of the
biphenyl would induce diastereodifferentiation of the π-
faces of the carbonyl group in an aldol reaction with a suit-
able choice of the phenol-protecting groups P1 and P2. Bi-
phenyl ketone VII, in which the two phenolic groups are
differentiated by protection, should be accessible enantio-
selectively from the corresponding diacetate VIII through
the enzyme-catalyzed desymmetrization described above.
The synthesis began with the preparation of the biphe-
nyl diacetate 7, the substrate for the enzymatic desymme-
trization (Scheme 3). We selected a benzyl protecting group
for the C10′ phenol, as this should have been capable of se-
lective detachment at a later stage to permit selective oxi-
dation of the aromatic ring (Scheme 2, VI→III). Suzuki–Mi-
yaura coupling of aryl bromide 29,10 with boronic acid 84a
proceeded in high yield under the standard conditions [10
mol% Pd(PPh3)4, K3PO4, DME, H2O, reflux].11 The resulting
biphenyl 3 was selectively chlorinated at the ortho position
of the free phenol by treatment with NCS and NaH (THF,
–10 °C),12 to give chloride 4. After methylation of the hy-
droxy group (MeI, K2CO3, DMF), aldehyde 5 was converted
into the methyl ketone 6 by alkoxyethylenation with the
phosphine oxide 9.13 Finally, cleavage of the methoxymeth-
yl groups (6 M aq HCl, phloroglucinol, THF),14 followed by
acetylation, gave the desired σ-symmetric biphenyl diace-
tate 7.
BnO
BnO
a
b
OHC
OH
MOMO
OMOM
OHC
OH
Br
2
3
6
Bn
O
BnO
Cl
Cl
O
c–f
g, h
OHC
OR
OMOM
Me
MOMO
OMe
MOMO
OMOM
4: R = H
5: R = Me
OMe
Bn
O
IV
10'
OMe
Cl
O
Diels–Alder
5'
reaction
OMe
R3SiO
Cl
Me
OMe
OAc
B(OH)2
OMOM
8'
10'
O
O
PPh2
MeO
O
OMe
AcO
MOMO
HO Me
O
HO
9'
Me
Me
O
OMe
3'
4'
2'
RO
O
OMe
O
7
8
9
HO
O
5
O
HO
Scheme 3 Synthesis of diacetate 7. Reaction conditions: (a) 8, Pd(PPh3)4
(10 mol%), K3PO4, DME, H2O, reflux, 20 h (84%); (b) NCS, NaH, THF,
–10 °C, 10 min; (c) MeI, K2CO3, DMF, r.t., 2 h (5: 92% from 3); (d) 9, LDA,
THF, –78 °C, 15 min; (e) NaH, THF, r.t., 12 h; (f) TsOH, acetone, H2O,
0 °C, 5 h (82% from 5); (g) 6 M aq HCl, phloroglucinol, THF, r.t., 15 h; (h)
Ac2O, DMAP, py, 0 °C, 2.5 h (92% from 6).
RO
Me
III
9
9a
10
4a
HO
O
O
1
4
electrocyclic
reaction
Me
dermocanarin 2 (1)
O–
R
10'
O
Cl
OMe
RO
O
HO
Me
2'
We screened various enzymes for the enantioselective
desymmetrization by treating diacetate 7 with a fixed
weight of the appropriate enzyme in pH 7 phosphate buffer
(0.1 M) at 35 °C (Table 1). Among the commercially avail-
able enzymes that we tested,15 porcine pancreas lipase
(PPL; Sigma, Type II) and Rhizopus oryzae lipase (ROL; Ama-
no, lipase F-AP15) brought about the desired reaction (en-
tries 1 and 2). Although the yields of monoacetate 10 were
far from satisfactory due to competing overhydrolysis of 10
to the diol 11, the product 10 obtained by the reaction with
PPL was enantiomeric with that obtained by the reaction
with ROL, and their enantiomeric purities were both fairly
high. Fortunately, the use of an organic cosolvent in the re-
action with ROL effected an improvement in enantioselec-
3'
RO
P1
O
O
P2
O
RO
OMe
OMe
VI
Me
V
R
R
O
O
Cl
Cl
O
O
Me
OMe
P2
Me
OMe
OAc
P1
O
O
AcO
VII
VIII
Scheme 2 Retrosynthetic analysis of dermocanarin 2
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–G

C
S. Yamaguchi et al.
Letter
Synlett
tivity, as well as suppressing the overhydrolysis (entries 5–
8).16 (i-Pr)2O was the best cosolvent, and gave (R)-(+)-10 in
83% yield and in an enantiomerically pure form (entry 6).
Further optimization proved that the catalyst load could be
reduced to 30 wt% on the substrate in a gram-scale reaction
(entry 9). The absolute stereochemistry of 10 was deter-
mined by X-ray crystal structure analysis.17
properties of the protecting groups would permit effective
diastereofacial differentiation in enolate addition. However,
the results proved disappointing, and the stereoselectivities
were very low in all four cases. We then attempted to exe-
cute the reaction without protecting one of the phenol
groups (P1 = H; entries 5–7). To our delight, the reactions of
racemic 12e–g proceeded in very high selectivities, regard-
less of the nature of the phenol-protecting group P2, to give
tert-alcohols (R*,aS*)-13e–g as the major isomers.
Table 1 Optimization of Conditions of the Desymmetrization of 7a
Bn
O
Table 2 Diastereoselective Aldol Reaction
Cl
O
Bn
enzyme
Me
OMe
OAc
OLi
O
O
Cl
AcO
O
pH 7.0 phosphate buffer, 35 °C
(+ cosolvent)
EtO
(6 equiv)
Me
P1
OMe
O P2
THF
–78 ºC, 30 min
7
Bn
O
Bn
O
Bn
O
Bn
Bn
12a–g
Cl
Cl
Cl
O
O
O
O
Cl
O
Cl
O
O
HO Me
Me OH
Me
OMe Me
OH
OMe Me
OH HO
OMe
OH
EtO
OMe EtO
O P2
OMe
O P2
AcO
AcO
P1
O
P1
O
(R)-10
Enzyme Cosolvent
(S)-10
11
13a–g
14a–g
Entry
Time (d) Yield (%)
Entry
Substrate
P1
P2
Yield (%)
dra (13/14)
7
10 (eeb)
11
1
2
3
4
5
6
7
12a
12b
12c
12d
12e
12f
MOM
MOM
MOM
MOM
H
Me
95
96
96
99
94
98
92
56:44
68:32
65:35
67:33
97:3
1
2
3
4
5
6
7
8
9c
PPL
ROL
PPL
PPL
ROL
ROL
ROL
ROL
ROL
–
3
3
3
3
1
1
3
3
1
69
47
90
81
6
13 (92, S)
30 (96, R)
3 (70, S)
9 (62, S)
11
18
1
TBDMS
–
TBDPS
TIPS
heptane
(i-Pr)2O
heptane
(i-Pr)2O
Et2O
2
Me
67 (>99, R)
83 (>99, R)
66 (>99, R)
39 (N.D.)
19
11
15
2
H
MOM
TBDPS
97:3
5
12g
H
97:3
17
59
5
a Determined by 1H NMR (400 MHz).
CH2Cl2
(i-Pr)2O
84 (>99, R)
11
The proposed stereochemical course of the reaction is
shown in Figure 2. As a result of restricted rotation about
the biphenyl linkage and the presence of the five sp2 carbon
atoms, the nine-membered lithium chelate adopts the con-
formation shown.18 The enolate preferentially attacks the
bottom face of the carbonyl, because the trajectory to the
upper face is hindered by the C10′ benzyloxy substituent.
Results for the comparative reactions of biphenyl ketones
a The reaction was performed in a test tube (ϕ = 24 nm) by using 7 (20 mg),
enzyme (20 mg), solvent (4.2 mL of phosphate buffer for entries 1 and 2;
2.8 mL of phosphate buffer + 1.4 mL of organic cosolvent for entries 3–8).
b Determined by chiral HPLC analyses [CHIRALPAK® IA (Daicel), 0.46 × 25
cm, 85:15 hexane–i-PrOH (1.0 mL/min), 20 °C, λ = 254 nm]; tR = 11.5 min
for (R)-10, 7.2 min for (S)-10.
c The reaction was performed in a 1 L round-bottomed flask by using 7 (4.34
g), ROL (1.29 g, 30 wt%), phosphate buffer (290 mL), and (i-Pr)2O (145 mL)
at r.t. (24–26 °C).
With axially chiral biphenyl (R)-10 in hand, our next
task was the stereocontrolled construction of the stereo-
genic center at C3′. To this end, we first examined the addi-
tion of ethyl acetate-derived lithium enolate to the racemic
biphenyl ketones 12a–d (Table 2, entries 1–4), in which one
of the enantiotopic phenol groups was protected as a me-
thoxymethyl ether (P1), which has potent metal-ion coordi-
nating ability, and the other phenol was protected as a
methyl ether or as one of a series of silyl ethers with various
steric demands (P2). We expected that the difference in
R 10'
Bn
O
H
O
Me
OMe
OMOM
Me
HO
O
H
MeO
Li
P2-O
15: R = H
O
99%, (R*,aS*):(S*,aS*) = 66:34
16: R = OMe
99%, (R*,aS*):(S*,aS*) = 94:6
Figure 2 Proposed stereochemical course of the aldol addition
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–G

D
S. Yamaguchi et al.
Letter
Synlett
15 and 16 under similar conditions supported this hypothe-
sis. The reaction of 15 showed a significant decrease in se-
lectivity [(R*,aS*)/(S*,aS*) = 66:34], whereas a high selectiv-
ity was observed in the reaction of 16, with a methoxy
group in the relevant position [(R*,aS*)/(S*,aS*) = 94:6].
We then prepared (R,aS)-13e, the planned key interme-
diate, in an enantiomerically pure form (>99% ee)19 starting
from (R)-10 in three steps: methyl etherification of the
phenol, deacetylation, and aldol addition (Scheme 4).
The total synthesis of dermocanarin 2 (1) was complet-
ed by construction of the anthraquinone and the naphtho-
quinone moieties, with a final lactonization, as shown in
Scheme 5.
Bn
1) MeI, K2CO3, DMF, 0 °C
O
Cl
O
HO Me
2) K2CO3, MeOH, 0 °C
(quant, 2 steps)
R
EtO
OMe
OMe
S
(R)-10
HO
3)
OLi
THF, –78 ºC
EtO
(R,aS)-13e:(S,aS)-14e
= 98:2
Scheme 4 Synthesis of (R,aS)-13e
Bn
Bn
Bn
O
Cl
O
Me
Cl
O
Me
Cl
O
O
O
O
O
HO Me
f, g
a–d
e
EtO
OMe
OMe
OMe
OMe
OMe
OMe
HO
R
MOMO
I
MOMO
HO
MOMO
(R,aS)-13e: R = H
17: R = I
18
R
O
MOMO
OMe
OMe
Me
20: R = (OMe)2
21: R = O
19
Me
Cl
Bn
R
O
Cl
O
Cl
O
O
O
O
O
O
O
Me
Me
Me
h, i
(from 22)
j, k
(from 23)
l, m
n, o
OMe
OMe
O
OMe
OMe
OMe
RO
PivO
O
PivO
O
O
MOMO
PivO
PivO
O
O
O
22: R = MOM
23: R = H
24: R = Bn
25: R = H
Me
Me
26
Me
OMe
OMe
OMe
OMe
OMe
8'
O
Me
O
O
O
O
OR
OMe
HO Me
HO Me
Me3SiO
32
OMe
R
t–v
p–s
O
OMe
O
OMe
O
OMe
PivO
O
HO
O
O
O
O
NO2
CO O
PivO
HO
HO
O
O
O
Me
33
2
29: R = CH2OH
30: R = CHO
31: R = CO2H
27: R = H
28: R = Me
dermocanarin 2 (1)
Me
Me
Me
Scheme 5 Completion of the total synthesis of 1. Reagents and conditions: (a) I2, AgO2CCF3, CHCl3, –20 °C, 5 min (17: 88%); (b) LiAlH4, Et2O, –20 to 0 °C,
50 min (85%); (c) (MeO)2CH2, (±)-CSA, CH2Cl2, reflux, 3.5 h; (d) MOMCl, DIPEA, CH2Cl2, 0 °C, 1.5 h (88%, 2 steps); (e) i-PrMgCl·LiCl, THF, –40 °C, then 19,
–40 to 0 °C, 28 h (85%, dr = 1.4:1); (f) pyridinium p-toluenesulfonate, acetone, H2O, r.t., 30 h (21: 87%, dr = 1.4:1); (g) BHT, 1,2-dichlorobenzene,
165 °C, 1 h, then air, 3 h (22: 70%, 23: 11%); (h) 6 M aq HCl, r.t., 5 h; (i) PivCl, DMAP, Et3N, CH2Cl2, 0 °C, 1 h (89%, 2 steps); (j) 6 M aq HCl, r.t., 2.5 h; (k)
PivCl, DMAP, Et3N, CH2Cl2, 0 °C, 1 h (85%, 2 steps); (l) H2, Pd/C, EtOAc, r.t., 40 min (25: 88%); (m) CAN/SiO2, CH2Cl2, H2O, 0 °C, 10 min; (n) 32, toluene,
r.t., 1.5 h, then SiO2, r.t., 12 h; (o) K2CO3, EtOH, 0 °C, 1.5 h (72%, 3 steps); (p) MeI, K2CO3, DMF, 0 °C, 5 h (28: 82%); (q) 1 M aq NaOH, MeOH, 0 °C, 34 h
(94%); (r) (F3CCO)2O, AcOH, r.t., 2 h (82%); (s) K2CO3, MeOH, 0 °C, 5 h (99%); (t) IBX, DMSO, r.t., 2.5 h (30: 93%); (u) NaClO2, NaH2PO4, 2-methylbut-2-
ene, t-BuOH, H2O, r.t., 15 min; (v) 33, DMAP, CH2Cl2, 0 °C, 15 min (70%, 2 steps). BHT = 2,6-di-tert-butyl-4-methylphenol; IBX = 2-iodoxybenzoic acid.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–G

E
S. Yamaguchi et al.
Letter
Synlett
To construct the anthraquinone, the biphenyl ester
(R,aS)-13e was first converted into the iodide 18 (Scheme
5). Selective iodination at the position ortho to the unpro-
tected phenol was effected by the treatment with I2 and
AgO2CCF3 (CHCl3, –20 °C).20 Reduction of the ester moiety
with LiAlH4 (Et2O, –20 to 0 °C) proceeded cleanly without
affecting the iodine substituent. The resulting 1,3-diol moi-
ety was protected as the methylene acetal [(MeO)2CH2, CSA,
CH2Cl2, reflux], and the phenol was protected as the me-
thoxymethyl ether (MOMCl, DIPEA, CH2Cl2, 0 °C) to give io-
dide 18 in 88% yield. Treatment of iodide 18 with i-PrMg-
Cl·LiCl21 in THF at –40 °C, followed by addition of the benzo-
cyclobutenone 1922 gave the adduct 20 as a mixture of
diastereomers (dr = 1.4:1) which was then converted into
ketone 21 by acid hydrolysis of the dimethyl acetal moiety
(pyridinium p-toluenesulfonate, acetone, H2O).
In summary, we have accomplished the first total syn-
thesis of dermocanarin 2. The present approach using an
axially chiral biphenyl obtained by enzyme-catalyzed de-
symmetrization of a σ-symmetric precursor as a versatile
platform for multidirectional elaboration should find wide-
spread application in syntheses of axially chiral natural
products composed of multiply functionalized polyaromat-
ic derivatives that are sterically congested around the axial
linkage.
Acknowledgment
This work was supported by JSPS KAKENHI Grant Numbers 2300006
and 25460024, and in part by the Platform for Drug Discovery, Infor-
matics, and Structural Life Science of MEXT, Japan.
On heating at 165 °C in 1,2-dichlorobenzene in the pres-
ence of 2,6-di-tert-butyl-4-methylphenol,23 ketone 21 un-
derwent a sequential electroreversion/electrocyclization to
give a dihydroanthraquinone, which, on exposure to air,
gave anthraquinone 22 in 70% yield, along with the byprod-
uct 23 (11%), formed by detachment of one of the MOM
groups. Anthraquinones 22 and 23 were individually con-
verted into pivaloate 24. Importantly, this procedure for
construction of the anthraquinone, despite requiring a high
temperature, preserved the stereochemical integrity of
(R,aS)-13e.
After removal of the benzyl group from 24 (H2, Pd/C,
EtOAc), the resulting phenol was cleanly oxidized by ceric
ammonium nitrate impregnated silica gel (CH2Cl2, H2O,
0 °C) to give the benzoquinone 26.24,25 Diels–Alder reaction
of 26 with the siloxy diene 328 proceeded smoothly at room
temperature in toluene to give the naphthoquinone 27 in
72% yield after conversion of the silyl acetal moiety into a
carbonyl group during workup on silica gel, followed by
aromatization with K2CO3 in ethanol. Subsequent methyla-
tion of the C8′ phenol (MeI, K2CO3, DMF, 0 °C) led to the
completion of the naphthoquinone structure of dermoca-
narin 2.
We then proceeded to the final lactonization stage.
Cleavage of the two pivaloyl groups by alkaline hydrolysis
(1 M aq NaOH, MeOH, 0 °C) and liberation of the 1,3-diol in
the side chain in high yield by sequential treatment with
(F3CCO)2O in AcOH and with K2CO3 and MeOH (0 °C)26 gave
the tetraol 29. This was oxidized with 2-iodoxybenzoic acid
in DMSO27 to give the corresponding aldehyde 30, which
was further oxidized with NaClO2 (NaH2PO4, 2-methylbut-
2-ene, t-BuOH, H2O)28 to give the trihydroxy acid 31. Lac-
tonization of 31 was cleanly promoted by the Shiina meth-
od using 2-methyl-6-nitrobenzoic anhydride (33; DMAP,
CH2Cl2, 0 °C)29 to give dermocanarin 2 (1) in 70% yield from
aldehyde 30.30 The spectroscopic data, including the 1H
NMR, 13C NMR, IR, and CD spectra, were in accordance with
those reported for natural dermocanarin 2.30
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561417.
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References and Notes
(1) Bringmann, G.; Günther, C.; Ochse, M.; Schupp, O.; Tasler, S.
Prog. Chem. Org. Nat. Prod. 2001, 82, 1.
(2) For recent reviews, see: (a) Bringmann, G.; Gulder, T.; Gulder, T.
A. M.; Breuning, M. Chem. Rev. 2011, 111, 563. (b) Zhang, D.;
Wang, Q. Coord. Chem. Rev. 2015, 286, 1. (c) Wencel-Delord, J.;
Panossian, A.; Leroux, F. R.; Colobert, F. Chem. Soc. Rev. 2015, 44,
3418. (d) Ma, G.; Sibi, M. P. Chem. Eur. J. 2015, 21, 11644.
(e) Smith, J. E.; Butler, N. M.; Keller, P. A. Nat. Prod. Rep. 2015, 32,
1562. (f) Loxq, P.; Manoury, E.; Poli, R.; Deydier, E.; Labande, A.
Coord. Chem. Rev. 2016, 308, 131.
(3) (a) Gill, M.; Giménez, A. Tetrahedron Lett. 1990, 31, 3505.
(b) Gill, M.; Giménez, A. J. Chem. Soc., Perkin Trans. 1 1995, 645.
(c) Gill, M.; Giménez, A.; Jhingran, A. G.; Milanovic, N. M.;
Palfreyman, A. R. J. Chem. Soc., Perkin Trans. 1 1998, 3431.
(d) Elsworth, C.; Gill, M.; Milanovic, N. M. Aust. J. Chem. 1999, 52,
867. (e) Buchanan, M. S.; Gill, M.; Phonh-Axa, S.; Yu, J. Aust. J.
Chem. 1999, 52, 875. (f) Gill, M.; Millar, P. M.; Phonh-Axa, S.;
Raudies, E.; White, J. M.; Yu, J. Aust. J. Chem. 1999, 52, 881.
(4) (a) Matsumoto, T.; Konegawa, T.; Nakamura, T.; Suzuki, K.
Synlett 2002, 122. (b) Okuyama, K.; Shingubara, K.; Tsujiyama,
S.; Suzuki, K.; Matsumoto, T. Synlett 2009, 941.
(5) For our related work, see: Takahashi, N.; Kanayama, T.;
Okuyama, K.; Kataoka, H.; Fukaya, H.; Suzuki, K.; Matsumoto, T.
Chem. Asian J. 2011, 6, 1752.
(6) The numbering system used in this paper corresponds to that of
dermocanarin 2.
(7) (a) Liebeskind, L. S.; Iyer, S.; Jewell, C. F. Jr. J. Org. Chem. 1986, 51,
3065. (b) Moore, H. W.; Yerxa, B. R. Chemtracts 1992, 5, 273.
(c) Suzuki, T.; Hamura, T.; Suzuki, K. Angew. Chem. Int. Ed. 2008,
47, 2248. For a review, see: (d) Flores-Gaspar, A.; Martion, R.
Synthesis 2013, 563.
(8) Savard, J.; Brassard, P. Tetrahedron 1984, 40, 3455.
(9) Aryl bromide 2 was prepared from the known phenol 34 (see
ref. 10), as shown in Scheme 6:
(10) Hu, Y.; Li, C.; Kulkarni, B. A.; Strobel, G.; Lobkovsky, E.;
Torczynski, R. M.; Porco, J. A. Jr. Org. Lett. 2001, 3, 1649.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–G

F
S. Yamaguchi et al.
Letter
Synlett
1) BnBr, K2CO3
BnO
Bn
O
Me OH
Bn
O
HO Me
HO
EtOH (72%)
Cl
Cl
1) 6 M HCl aq.
2) LiOH
OHC
OTBDMS
2) 6 M HCl aq.
THF (97%)
OHC
OH
(R,aS)-13e 98
OMe
OMe
OMe
OMe
Br
Br
+
O
O
3) 33, DMAP
(S,aS)-14e
2
34
2
O
O
Scheme 6 Synthesis of aryl bromide 2
(R,aR)-35
96%
(S,aR)-36
1.3%
(11) (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457. (b) Suzuki,
A. J. Organomet. Chem. 1999, 576, 147.
98%
K2CO3, EtOH
(12) Appendino, G.; Daddaro, N.; Minassi, A.; Moriello, A. S.; De Pet-
rocellis, L.; Di Marzo, V. J. Med. Chem. 2005, 48, 4663.
(13) Earnshaw, C.; Wallis, C. J.; Warren, S. J. Chem. Soc., Perkin Trans.
1 1979, 3099.
(R,aS)-13e
Scheme 7 Separation of (R,aS)-13e
(14) Stadlbauer, S.; Ohmori, K.; Hattori, F.; Suzuki, K. Chem. Commun.
2012, 48, 8425.
suitable for X-ray crystal structure analysis, on crystallization
from hexane–CH2Cl2, whereas optically pure 35 and 13e did
not.
(15) In addition to ROL and PPL, we tested Pseudomonas fluorescence
lipase (Amano, lipase AK), pig liver esterase (Sigma), Pseudomo-
nas cepacia lipase (Amano, lipase PS), Candida rugosa lipase
(Amano, lipase AY), Aspergillus niger lipase (Amano, lipase AS),
Candida antarctica lipase (Roche Diagnostics, Chirazyme L-2),
Mucor javanicus lipase (Amano, Lipase M), Burkholderia cepacia
lipase (Amano, Lipase PS), Penicillium camembertii lipase
(Amano, Lipase G), and a lipase from Alcaligenes sp. (Meito).
(16) Heptane, (i-Pr)2O, Et2O, CH2Cl2, toluene, acetone, DMSO, THF,
1,4-dioxane, MeCN, and t-BuOH were tested.
(17) CCDC 1445353 (10), 1445412 [(R*,aR*)-35], 1445413 [(S*,aR*)-
36], 1445869 (17), and 1445886 (18) contain the supplemen-
tary crystallographic data for this paper. The data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/getstructures. Two of
these structures are shown in Figure 3.
(20) Janssen, D. E.; Wilson, C. V. Org. Synth. Coll. Vol. IV 1963, 547.
(21) Krasovskiy, A.; Knochel, P. Angew. Chem. Int. Ed. 2004, 43, 3333.
(22) For the synthesis of ketone 19, see the Supporting Information;
see also: (a) Hamura, T.; Hosoya, T.; Yamaguchi, H.; Kuriyama,
Y.; Tanabe, M.; Miyamoto, M.; Yasui, Y.; Matsumoto, T.; Suzuki,
K. Helv. Chim. Acta 2002, 85, 3589. (b) Tsujiyama, S.; Suzuki, K.
Org. Synth. 2007, 84, 272.
(23) The reaction in the absence of BHT was less successful, giving
anthraquinone 22 and 23 in 54% and 5% yields, respectively,
together with many unidentified byproducts.
(24) Ali, M. H.; Niedbalski, M.; Bohnert, G.; Bryant, D. Synth.
Commun. 2006, 36, 1751.
(25) Attempts to oxidize of 24 and model compounds 37a–c (Figure
4) under various conditions led to intractable mixtures of prod-
ucts, whereas the reaction of 38 with CAN/SiO2 in wet CH2Cl2
gave the corresponding benzoquinone in 99% yield.
MeO
RO
MeO
Cl
HO
MeO
MeO
Cl
OMe
OMe
OMe
OMe
37a: R = H
37b: R = Me
37c: R = Ac
38
Figure 4 Structures of model compounds for oxidation
(26) Gras, J.-L.; Pellissier, H.; Nouguier, R. J. Org. Chem. 1989, 54,
5675.
(27) (a) Frigerio, M.; Santagostino, M. Tetrahedron Lett. 1994, 35,
8019. (b) Frigerio, M.; Santagostino, M.; Sputore, S. J. Org. Chem.
1999, 64, 4537.
Figure 3 X-ray crystal structures of (R)-10 and (R*,aR*)-35
(28) (a) Lindgren, B. O.; Nilsson, T. Acta Chem. Scand. 1973, 27, 888.
(b) Kraus, G. A.; Taschner, M. J. J. Org. Chem. 1980, 45, 1175.
(c) Kraus, G. A.; Roth, B. J. Org. Chem. 1980, 45, 4825.
(29) (a) Shiina, I. Chem. Rev. 2007, 107, 239. (b) Shiina, I. Bull. Chem.
Soc. Jpn. 2014, 87, 196.
(18) The lithium chelate in Figure 2 was drawn on the basis of the
DFT-optimized geometries of the model compounds. See the
Supporting Information.
(19) Although direct separation of diastereomers (R,aS)-13e and
(S,aS)-14e was difficult, conversion into the corresponding lac-
tones 35 and 36, accomplished quantitatively by Shiina lacton-
ization (Scheme 7), permitted easy separation by silica-gel
chromatography. Transesterification of lactone 35 with EtOH
and K2CO3 regenerated (R,aS)-13e in a diastereomerically pure
form. Furthermore, the stereochemistry at C3′ could be deter-
mined by means of an X-ray crystal structure analysis of (±)-35.
A racemic sample of 35 gave a single crystal (colorless plate),
(30) Dermocanarin 2 (1); Experimental Procedure for the Final
Synthetic Step
NaH2PO4·2H2O (32.7 mg, 210 μmol) and NaClO2 (13.0 mg, 175
μmol) were added to a solution of aldehyde 30 (23.7 mg, 39.4
μmol) and 2-methylbut-2-ene (167 mg, 2.38 mmol) in t-BuOH
(4.0 mL) and H2O (1.0 mL) at r.t., and the mixture was stirred for
15 min. The mixture was then poured into brine at 0 °C, and the
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–G

G
S. Yamaguchi et al.
Letter
Synlett
products were extracted with CH2Cl2. The combined organic
extracts were washed with brine, dried (Na2SO4), filtered, and
concentrated. The crude product was dissolved in CH2Cl2 (6.0
mL) and added to a solution of 2-methyl-6-nitrobenzoic anhy-
dride (33; 29.1 mg, 84.6 μmol) and DMAP (19.8 mg, 162 μmol)
in CH2Cl2 (1.0 mL) at 0 °C. The mixture was then stirred for 15
min before the reaction was stopped by adding 0.1 M phosphate
buffer (pH 7). The products were extracted with CH2Cl2, and the
combined organic extracts were washed sequentially with 1 M
aq HCl, brine, sat. aq NaHCO3, and brine, then dried (Na2SO4),
filtered and concentrated in vacuo. The residue was purified by
preparative TLC [CHCl3–MeOH (95:5)] to give dermocanarin 2
(1) as a yellow solid; yield: 16.6 mg (70%, 2 steps). Reprecipita-
tion from hexane–CH2Cl2 followed by crystallization (EtOH,
–20 °C) gave a yellow powder; mp 227–230 °C (dec.); Rf = 0.63
(CHCl3–MeOH, 95:5); [α]D22 +2.1 × 102 (c 0.50, CHCl3); IR (ATR):
3505, 1774, 1657, 1632, 1582 cm–1; HRMS (ESI-TOF): m/z calcd
[M + H]+ for C33H27O11: 599.1553; found: 599.1563.
Table 4 13C NMR (100 MHz, CDCl3) of Dermocanarin 2 (1)
Synthetic Reported3b Synthetic Reported3b
C-1
162.6
125.1
148.2
120.8
132.2
107.0
161.7
125.5
151.1
118.1
186.4
114.1
181.6
137.2
22.1
162.6
125.1
148.2
120.9
132.2
107.0
161.7
125.5
151.2
118.1
186.4
114.1
181.6
137.2
22.1
C-2′
44.1
71.3
44.1
71.3
C-2
C-3′
C-3
C-4′
40.6
40.6
C-4
C-4a′
C-5′
143.3
104.2
162.1
104.5
164.8
114.2
178.8
142.9
185.7
135.8
33.9
143.3
104.2
162.2
104.6
164.8
114.3
178.8
142.9
185.7
135.8
33.9
C-4a
C-5
C-6′
C-6
C-7′
C-7
C-8′
C-8
C-8a′
C-9′
C-8a
C-9
C-9a′
C-10′
C-10a′
3′-Me
6′-OMe
8′-OMe
1
The H NMR (Table 3) and 13C NMR data (Table 4) for synthetic
C-9a
C-10
C-10a
3-Me
6-OMe
C-1′
and natural dermocanarin 2 (1) are listed.
Table 3 1H NMR (400 MHz, CDCl3) of Dermocanarin 2 (1)
56.4
56.5
Synthetic
Reported3b
57.0
57.0
56.0
56.0
2-H
7.12 (s)
7.12 (br s)
166.6
166.6
4-H
7.64 (s)
7.64 (br s)
5-H
7.83 (s)
7.83 (s)
3-Me
6-OMe
1-OH
2′-HA
2′-HB
4′-HA
4′-HB
5′-H
2.47 (s)
2.47 (s)
3.99 (s)
3.98 (s)
12.39 (s)
12.38 (s)
2.51 (d, J = 13.2 Hz)
2.72 (d, J = 13.2 Hz)
1.98 (d, J = 13.5 Hz)
3.36 (d, J = 13.5 Hz)
7.32 (d, J = 2.4 Hz)
6.75 (d, J = 2.4 Hz)
1.40 (s)
2.47 (d, J = 13.2 Hz)
2.71 (d, J = 13.2 Hz)
1.97 (d, J = 13.9 Hz)
3.36 (br d, J = 13.9 Hz)
7.32 (d, J = 2.4 Hz)
6.75 (d, J = 2.4 Hz)
1.39 (s)
7′-H
3′-Me
3′-OH
6′-OMe
8′-OMe
3.05 (s)
3.03 (s)
3.97 (s)
3.96 (s)
3.92 (s)
3.92 (s)
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–G