Total synthesis of (±)-ganocins B and C

Article abstract of DOI:10.1039/c6ob02049f

The first total synthesis of structurally unique polycyclic phenolic meroterpenoids, ganocins B and C is reported. The synthesis features gold-catalyzed intramolecular cascade cyclization to construct the C/D ring bearing an angular methyl group, diastereoselective Michael addition, and acid-mediated one-pot Robinson cyclization/deprotection/isomerization.

Full text of DOI:10.1039/c6ob02049f

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DOI: 10.1039/C6OB02049F
Organic & Biomolecular Chemistry
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Total Synthesis of (±)-Ganocins B and C
a
a
,a,b
,a
Yao Liu, Chu-Jun Zhou, Qingjiang Li,* and Honggen Wang*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
The first total synthesis of structurally unique polycyclic
phenolic meroterpenolids, ganocins B and C is reported. The
synthesis features gold-catalyzed intramolecular cascade
cyclization to construct the C/D ring bearing an angular
methyl group, diastereoselective Michael addition, and acid-
highly strained ring system (A/B/C/D), within two to four
consecutive stereocenters containing a compact quaternary
carbon (C6'). Because of this unusual structure and the
potential for novel biological properties, we sought to explore
their total synthesis. To our knowledge, total synthesis of
these molecules has not been reported thus far. In this study,
we report the first total synthesis of ganocins B and C involving
gold-catalyzed cascade cyclization and Robinson cyclization as
the key steps.
mediated
one-pot
Robinson
cyclization/deprotection/isomerization.
Ganoderma, which has long been used to treat and prevent
various diseases, is one of the most well-known traditional
1
medicines. Its unusual biological activity has fuelled an
Our retrosynthetic analysis of ganocins B (Fig.1-
2) and C (Fig.1-
intensive investigation into the identification of the actual
chemical constituent. In this context, a series of novel phenolic
2
meroterpenolids have been isolated and found to exhibit
3
) is illustrated in Scheme 1. Ganocin C was expected to be
formed from ganocin B upon olefin isomerization. The ring B of
ganocin B would be constructed via a Robinson cyclization of
interesting biological activities including antitumor,
renoprotective, antioxidant, liver-protective, and anti-
structure
diastereoselective alkylation of structure
obtained by a directed Micheal addition to the key
intermediate 2,3-fused chromone , which was envisioned to
be accessible from a gold-catalyzed intramolecular cascade
5
, which could be assembled from the
6
. Alkene might be
6
2
,3
acetylcholinesterase (anti-AChE) activity. In 2014, a new
family of ganocins, possessing four unprecedented polycyclic
phenolic meroterpenoids (Figure 1), were isolated from the
7
5
,6
4
fruiting bodies of Ganoderma cochlear by Qiu and coworkers.
cyclization of phenolic propargyl acetate
8
by using Wong’s
Initial biological evaluation revealed that they exhibit anti-
AChE activity. Structurally, ganocins feature four fused and
O
B
O
O
O
HO
HO
PGO
Aldol
A
D
C
O
O
O
Me
Me
Me
Ganocin C (3)
Ganocin B (2)
5
Alkylation
OH
O
O
O
O
H
HO
Michael
Addition
PGO
[Au]
OH
O
O
Me OAc
Me
Me
8
7
6
Figure 1. The structure of ganocins.
Sonogashira Coupling
a.
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006,
China.
State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing,
O
O
AcO
Br
OH
Me
O
b.
+
OAc
NC
O
1
00191, China.
Email: liqingj3@mail.sysu.edu.cn, wanghg3@mail.sysu.edu.cn.
Electronic Supplementary Information (ESI)
DOI: 10.1039/x0xx00000x
9
10
11
available.
See
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Journal Name
Scheme 1. Retrosynthetic analysis of Ganocins B and C. PG = Table 1. Au-catalyzed cascade cyclization of the propargyl
a
protecting group.
acetate 8.
OH
AuCl(PPh3) (10 mol%)
O
O
O
O
OH
OH
R1
Me
OAc
AgOTf (10 mol%), DCM, 40 C
o
O
O
O
Au(PPh3)Cl
[Ag]
O
O
Me
R1
R1
HO
HO
then pꢀTsOH (1.5 equiv)
O
O
Me
+
B
C
DCM, then PTSA
temperature
O
1,3ꢀacetate
Me
[
Au]
R1
migration
Me OAc
R1
8
7
7a
1
HO
Me
R
SN2 substitution SN2' substitution
[
Au]
OH
Me
HO
Me
O
path a
O
O
ꢀ
OMe
AcO
MeO)
OMe path b
OMe
(
2
HC
OMe
entry [Ag]
temperature
o
40 C
o
25 C
o
25 C
o
25 C
7
7a
38%
A
1
2
3
4
AgOTf
0
Scheme 2. Proposed mechanism for Wong's Au-catalyzed
AgOTf
AgOTf
42% 29%
cascade cyclization.
b
34%
55%
0
0
7
protocol. The precursor, structure
8
could be synthesized by
AgBF
4
Sonogashira coupling from commercially available bromide
9
and propargyl alcohol 10. Commercially available molecule 4,4-
dimethoxybutanenitrile 11 was suggested to be the precursor
a
Au(PPh )Cl (10 mol %), [Ag] (10 mol %), PTSA (1.0 equiv), 3 h,
3
b
isolated yield.
Without addition of PTSA. PTSA = p-
of structure 10
It should be mentioned that in Wong's cyclization reaction, the
2 substitution (last step, Scheme 2) product tricyclic
chromones were predominately formed. However, based on
their mechanistic hypothesis and literature precedent, we
reasoned that the S 2’ substitution, forming the corresponding
tricyclic product bearing an angular methyl group, might be
.
toluenesulfonic acid.
S
N
an in situ generated lithium trimethylsilylacetylide and follow-
up removal of the silyl group, ketone 12 was converted to
B
8
propargyl alcohol 10 in 92% overall yield. The bonding of
9
N
acetylene 10 and commercially available bromide
9
(Scheme 1)
C
1
0
was accomplished by Sonogashira coupling to produce 71%
also possible by a judicious tuning of the electronic properties
of the phenol nucleophile and finding the right reaction
conditions, thus providing an extraordinary simple access to
the core structure (ADC ring) of ganocins A-C.
yield of tertiary alcohol 13, which was then protected with an
acetyl group by treating with Ac O/DMAP. The selective
2
1
1
deprotection of both phenolic acetyl groups with hydrazine
in methanol, furnished the key cyclization substrate
yield.
8 in high
Our total synthesis was begun by construction of the phenolic
Au-catalyzed precursor, propargyl acetate
8 (Scheme 3).
With the intermediate
Au-catalyzed cascade cyclization reaction (Table 1).
Unfortunately, when substrate was subjected to previously
8 in hand, the stage was set for the key
Exposure of nitrile 11 to an ethereal solution of methyllithium
o
at 0 C afforded ketone 12 in 75% yield. Upon treatment with
8
7
reported reaction conditions, S 2 substitution ( Scheme 2)
N
product 7a was formed with a 38% yield without the detection
Trimethylsilylacetylene
of the desired product
previous observation. Interestingly, by lowering the
temperature to 25°C, the desired S 2' substitution product
7 (entry 1), in accordance with a
MeLi, Et
2
O, 0 o
C
nꢀBuLi, THF, 0 o
C
Me
NC
O
O
O
O
O
O
O
HO
75%
2 3
then K CO , MeOH, rt
7
N
92%
1
1
12
10
was obtained in 42% yield accompanied by 29% yield of 7a
(entry 2). We speculate that the tertiary ether might be
OAc
OAc
7
Pd(PPh
CuI, DIPEA, DMF, 60 o
3
)
2
Cl
2
,
O
Ac
O, DMAP, Et
DCM, rt
3
N
2
unstable under acidic conditions and high temperatures due to
its propensity for formation of a stable tertiary carbocation,
C
O
9
+
10
9
8%
71 %
1
2
and thereby being converted to the undesired product, 7a
Indeed, the omission of p-toluenesulfonic acid (PTSA) led to
the exclusive formation of substrate , although in a decreased
.
Me OH
13
OAc
OH
OH
O
NH
2 2
NH —H O
O
7
2
MeOH, rt
O
O
yield of 34% (entry 3). Fortunately, the highest yield was
88%
OAc
obtained by the use of AgBF in place of AgOTf as an additive
4
Me OAc
Me OAc
(
55%, entry 4).
Thereafter, a copper-mediated conjugated addition to α,β-
unsaturated ketone resulted in the formation of cis-fused 15
14
8
Scheme 3. Synthesis of key Au-catalyzed cyclization precursor
DIPEA N,N-diisopropylethylamine, DMAP 4-
7
8.
=
=
13
as a single stereoisomer in 87% yield (Scheme 4). The desired
stereochemistry was presumed to arise from the steric
hindrance from the angular methyl group at C7'. Protection of
dimethylaminopyridine, THF = tetrahydrofuran, DMF = N,N-
dimethylformamide.
2
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a
.
Table 2. Studies of Michael addition of 16
O
OH
O
O
H
O
O
MVK
TBSO
15
+
TBSO
+
conditions
O
Me
Me
OTBS
Me
16
17
18
entry conditions
15
16
17
0
18
0
1
NaOMe in MeOH, 81%
rt
0
2
LHMDS in THF, -60
C
0
84% trace
0
o
3
4
5
DBU in THF, rt
0
0
0
0
16%
53%
22%
0
NaOH in THF, rt
23% 17%
o
NaOH in THF, 0 C
to rt
36% 38% (59%
brsm)
b
6
Sc(OTf) in DCM, rt 75%
3
0
0
0
a
Reaction conditions: 16 (0.1 mmol, 1.0 equiv), MVK (0.15
Scheme 4. Completion of the synthesis of ganocins B and C.
HMPA hexamethylphosphoric triamide, TBS t-
butyldimethylsilyl.
mmol, 1.5 equiv), base (0.05 mmol, 0.5 equiv), solvent (1 mL),
b
=
=
2
3
h, isolated yields. Sc(OTf) (20 mol %) was employed. MVK:
methyl vinyl ketone; DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene;
brsm: based on the recovered starting material.
o
the diketone 17 with BF ·Et O in THF at 30 C, the acid
3
2
mediated Robinson cyclization/deprotection took place in one-
pot, producing ganocin B ( ) in a good yield of 80%. To our
phenol 15 with TBSCl/DMAP produced substrate 16 in 92% surprise, the simple elevation of the temperature to 60 C
2
o
yield.
rendered an in-situ olefin isomerization to give ganocin C (Fig
) in 86% yield. The spectroscopic data of our synthetic
1-3
We then focussed on construction of ring B. Alkylation at this
position proved to be difficult due to the profound steric
hindrance and a retro-oxa-Michael addition side reaction.
After several attempts, we found that Michael addition to
methyl vinyl ketone (MVK) could give the desired diketone
product 17 as a single diastereomer (Scheme 4). Thus, a variety
of reaction parameters (mainly the base/Lewis acid, solvent
and temperature) were examined, and some of the
representative results are summarized in Table 2. Only the
silyl-deprotected product 15 was obtained with 81% yield
under NaOMe/MeOH conditions (entry 1). The use of the
classical lithium bis(trimethylsilyl)amide (LHMDS) as a base
resulted in the recovery of the starting material (entry 2).
1
samples ( H and C NMR) matched well in all respects to those
13
4
reported in the literature.
Conclusions
In summary, we have accomplished the first total synthesis of
ganocins B and C, two phenolic meroterpenolid natural
products possessing a spiro[4,5]decane ring system. The
approach is highly convergent and the linear sequence is 10
steps
starting
from
commercially
available
4,4-
dimethoxybutanenitrile substrate 11. The synthesis features
gold-catalyzed intramolecular cascade cyclization to assemble
the 6-6-5 tricyclic core of ganocins B and C and acid-mediated
successive Robinson cyclization/deprotection/isomerization to
construct ring B. The synthesis of ganocin analogs using our
protocol and their related biological evaluation are ongoing in
our laboratory.
Unexpectedly, DBU gave a 16% yield of the desired product 17
,
along with a considerable amount of retro-oxa-Michael
addition side product 18 (entry 3). The use of NaOH instead of
DBU provided a comparable yield but with much fewer side
reactions (entry 4). The best result was obtained when the
o
reaction was run at lower temperature (0-25 C), with a 59%
yield based on the recovered starting material (entry 5). The
step where Lewis acid promoted Michael addition is known
Acknowledgements
1
4
from the literature. However, from our experience, the use We are grateful for the support of this work by "1000-
of Sc(OTf)
as a catalyst only led to the deprotection of the silyl Youth Talents Plan", a Start-up Grant from Sun Yat-sen
3
group (entry 6).
University, National Natural Science Foundation of China
81402794, 21472250 and 21502242) and the State Key
(
3 2
To finish the total synthesis, it was observed that BF ·Et O was
Laboratory of Natural and Biomimetic Drugs (K20150215).
a good primer for the aldol condensation. Thus, treatment of
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4
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