Divergent total syntheses of five illudalane sesquiterpenes and assignment of the absolute configuration

Article abstract of DOI:10.1039/c9cc00933g

Concise, divergent total syntheses of five bioactive illudalane sesquiterpenes have been achieved. Our synthesis features an intermolecular [2+2+2] cycloaddition, and a lactone-directed aromatic C-H oxygenation to generate a temporary phenolic hydroxyl group which enables regioselective methylation. Furthermore, the absolute configuration of radulactone was assigned by chemical synthesis.

Full text of DOI:10.1039/c9cc00933g

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc
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3
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3
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DOI: 10.1039/C9CC00933G
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Divergent Total Syntheses of Five Illudalane Sesquiterpenes and
Assignment of the Absolute Configuration
Zhixiong Zeng, Yifan Zhao and Yandong Zhang*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Concise, divergent total syntheses of five bioactive illudalane
sesquiterpenes have been achieved. Our synthesis features an
intermolecular [2+2+2] cycloaddition, a lactone-directed aromatic
C–H oxygenation to generate a temporary phenolic hydroxyl group
which enables a regioselective methylation. Furthermore, the
absolute configuration of radulactone was assigned by chemical
synthesis.
O
O
O
HO 1 8
7
O
1
Me
5
10
1
O
Me
Me
O
Me
Me
O
6
5
Me
1
2
12
9
3
3
4
4
11
HO
13 Me
Me
Me
radulactone (1)
echinolactone A (2)
calomelanolactone (
3)
O
OH
O
1
Me
OH
Me
Me
O
Me
Me
OH Me
Me
Illudalane sesquiterpenes are a group of secondary metabolites
1
which have been majorly discovered in ferns and fungi, and
2
recently were also isolated from the Antarctic and sub-
Me
Me
Me
alcyopterosin N (6)
3
4
riparol B ( )
5
Antarctic marine soft corals. Structurally, these sesquiterpenes
granulolactone ( )
share a multisubstituted indane core which usually comprises a Fig.1 Selected examples of illudalane sesquiterpenes.
pentasubstituted phenyl ring, but differ in the oxygenation
types. The illudalane skeletons are biosynthetically derived [2+2+2] cycloaddition and a Ru-catalyzed aromatic C–H
7
8
from the protoilludane skeletons probably through specific oxygenation.
4
bond cleavage and aromatization. To date, over a hundred
At the outset of our synthetic studies, the structural
illudalane sesquiterpenes have been identified (Fig. 1), many of relevance of these sesquiterpenes inspired us that this natural
them displays interesting biological activities, such as product family could be rapidly accessed from a less
5
5e
antimicrobial, pesticidal, and anticancer activities. Notably, functionalized natural precursor granulolactone (4) through a
9
echinolactone A (2) significantly promotes radicle elongation at late-stage divergent functionalization strategy. As outlined in
1
00 ppm in lettuce seedling assay, which suggests it might be Scheme 1, radulactone (1), echinolactone
A
(2) and
5
c
5d
5a
involved in reproduction process. Riparol B (5) exhibits calomelanolactone (3) could be obtained from 4 by specific
5
e
potent pesticidal activity against thrips. Their fascinating oxygenation. We anticipated that the key intermediate 4
structure features and promising applications in the bearing a pentasubstituted phenyl ring could be accessed from
pharmaceutical or agrochemical industry have attracted tetrasubstituted benzene derivative 8 by a regioselective
6
considerable synthetic interest, and several strategies have methylation. However, due to the low reactivity and poor
been developed for the construction of multisubstituted indane regioselectivity of the congested tetrasubstituted phenyl ring in
skeletons.
8 towards methylation, a more reactive phenol intermediate 7
Herein, we report the first asymmetric synthesis of was employed. We expected that the temporary introduction
radulactone (1)5 and concise divergent syntheses of the other of the C7 phenolic hydroxyl group can facilitate the desired
b
four illudalane sesquiterpenes 2-5, featuring a Rh-catalyzed
methylation by increasing the electron density of the aromatic
ring and meanwhile blocking a competing reaction site (C7). We
envisioned that C7 hydroxyl group could be introduced by a
lactone carbonyl directed aromatic C–H oxygenation in the
presence of transition metals. Through this C–H activation
manipulation, two competitive sites (C4 and C7) could be
Department of Chemistry and Key Laboratory of Chemical Biology of Fujian
Province, iChEM, College of Chemistry and Chemical Engineering, Xiamen
University, Xiamen, Fujian 361005, China
E-mail: ydzhang@xmu.edu.cn
†
Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any supplementary differentiated while the extra phenolic hydroxyl group could be
information available should be included here]. See DOI: 10.1039/x0xx00000x
easily removed afterwards. Then the tetrasubstituted phenyl
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Journal Name
fruitless, presumably for reasons of high steric hindrance. To
enhance the reactivity of the phenyl ring and control the
View Article Online
DOI: 10.1039/C9CC00933G
O
O
HO
1
[
O]
Methylation
Me
Me
1
O
Me
Me
O
regioselectivity of the methylation, a hydroxyl group was
introduced to C7 through lactone carbonyl group directed
8
i
Me
radulactone (1)
13 Me
granulolactone (4)
oxygenation. By using Hong’s Ru (II) catalysis methodology,
phenol 7 was obtained in 74% yield. Subsequent two-step
methylation involving C4 bromination and Suzuki coupling
smoothly provided compound 11 in 81% overall yield. Finally,
the extra phenolic hydroxyl group was removed by palladium
catalyzed hydrogenation of its triflate derivative to deliver
granulolactone (4) in 6 overall steps.
Starting from the key intermediate granulolactone (4), four
illudalane sesquiterpenes were synthesized through simple
reduction or C–H oxygenation and reduction sequence.
Specifically, Dibal-H reduction of the lactone afforded riparol B
(5), a potent pesticide against thrips, in 97% yield. Treatment of
OH
O
C–H
H
7
O
7
oxygenation
[2+2+2]
Me
Me
O
O
Me
Me
O
4
4
H
H
7
8
OEt
Me
Me
+
OH
9
symmetrical
10
3
4 with CrO in acetic acid afforded echinolactone A (2) in 37%
yield together with its constitutional isomer 13. Notably, no
oxygenation products at benzylic C11 or C13 positions were
observed, probably due to the less electron density of those C–
Scheme 1 Retrosynthetic analysis of illudalane sesquiterpenes.
ring could be constructed by a transition metal catalyzed
intermolecular [2+2+2] cycloaddition of diyne 9 and ethyl 5-
hydroxypent-2-ynoate 10.
As depicted in Scheme 1, our synthesis commenced with the
known diyne 9,10 which can be readily prepared in four steps
from commercially available isophorone oxide. Rh-catalyzed
4
H bonds. Reduction of the former ketone with NaBH delivered
racemic radulactone (1) in 99% yield while the reduction of the
later one produced calomelanolactone (3) in 98% yield. At this
stage, we have achieved concise total syntheses of five
illudalane sesquiterpenes.
1
1
[
2+2+2] cycloaddition of 9 and 10 with Wilkinson’s catalyst
followed by treatment with NaH afforded indane lactone 8 in
0% yield. Actually, the initial attempts of [2+2+2] cycloaddition
O
1
Dibal-H
Me
Me
O
Me
Me
OH
OH
6
CH Cl , –78 °C
2
2
3
11
between unsymmetrical diyne S6 and 10 only produced the
desired product 4 as a minor product in very low yield (see the
Supporting Information (SI)), together with the undesired
regioisomer.12 With 8 in hand, the initial attempts of
97%
13Me
Me
riparol B (5)
granulolactone (4)
O
O
O
O
HO
CrO3
AcOH
H2O
0 °C
1
1
1
3
methylation at C4 through halogenation or borylation were all
Me
Me
NaBH4
Me
Me
O
O
O
OEt
MeOH
99%
Rh(PPh3)3Cl
EtOH, reflux
6
ref. 10
Me
Me
Me
Me
O
+
Me
then
echinolactone A (2) (37%)
(±)-radulactone (1)
Me
Me
OH THF, NaH
6
0%
O
O
isophorone
oxide
9
10
NaBH4
MeOH
Me
Me
O
Me
Me
O
H
7
O
O
OH
O
3
3
98%
[RuCl2(p-cymene)]2
PhI(CF3CO2)2
7
O
Me
HO
(±)-calomelanolactone (3)
Me
Me
Me
Me
O
1
3 (25%)
Ag2CO3
TFAA/TFA, 80 °C
74%
4
H
8
4
H
7
Scheme 3 Divergent total syntheses of riparol B, echinolactone A, (±)-radulactone,
and (±)-calomelanolactone.
OH
7
O
1
) NBS, MeCN, rt
Tf2O, DMAP
py, rt
Me
Me
O
-
+
2) MeBF3 K
Pd(dppf)Cl2
Although the optical rotation of radulactone was reported by
Anke and coworkers, its absolute configuration is still unknown
to date. An asymmetric synthesis of a natural product can serve
as a reliable way for the determination of its absolute
4
94%
81%, 2 steps
Me
1
1
OTf
O
O
1
4
Pd(OAc)2, dppf
Et3SiH
stereochemistry. After a brief screening of reductants and
catalysts (see SI), we found that, reduction of the ketone group
Me
Me
O
Me
Me
O
DMF, 60 °C
1
5
3 2
with (S)-Corey-Bakshi-Shibata (CBS) catalyst and BH •SMe
9
3%
1
6
Me
Me
granulolactone (4)
afforded (+)-radulactone (1) in 38% yield and 87.2% ee. The
12
low yield was probably for reasons of high steric hindrance
1
7
around the ketone group and overreduction of lactone group.
Scheme 2 Total synthesis of granulolactone (4).
The optical rotation matched well with that of naturally
2
| J. Name., 2012, 00, 1-3
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Journal Name
occurring radulactone. Furthermore, the single crystal x-ray
COMMUNICATION
In summary, we have developed a divergent strVaietwegAryticfloe rOntlhinee
crystallography of its p-bromobenzoate derivative 14 syntheses of five illudalane sesquiterpenDeOsI:in106.10to398/Cs9tCeCp0s0f9r3o3mG
unambiguously defined the absolute configuration of 1 as (1S) known diyne 9, and four of them [radulactone (1),
(Scheme 4). At this point, we have achieved the first asymmetric echinolactone A (2), granulolactone (4) and riparol B (5)] were
total synthesis of radulactone (1) in 8 overall steps.
obtained by chemical synthesis in laboratory for the first time.
The key transformations include a Rh-catalyzed [2+2+2]
cycloaddition to generate a tetrasubstituted phenyl ring, a Ru-
catalyzed aromatic C–H bond oxygenation to form reactive
phenol intermediate and late-stage divergent oxygenations.
The well-orchestrated transition metal catalysis secured the
high efficiency of the synthesis. Moreover, the absolute
configuration of naturally occurring (+)-radulactone (1) was
assigned as (1S) on the basis of our total synthesis. The success
of the C–H activation strategy also enables efficient syntheses
of four illudalane analogues which bear a synthetically
challenging hexasubstituted phenyl ring. The reported strategy
and technologies are clearly applicable for the syntheses of
other illudalane sesquiterpenes and their derivatives.
O
O
O
HO
BH3SMe2
(S)-CBS
1
(S)
Me
Me
O
Me
Me
O
1
THF, 0 °C
3
8%
Me
echinolactone A (2)
Me
+)-radulactone (1)
(
p-BrBzCl
Et3N, 94%
]D25 = +15.5, (c 0.5, CHCl3)
[
ee = 87.2%
Reported:
[
]D25 = +24, (c 0.5, CHCl3)
14 [x-ray]
Scheme 4 Asymmetric synthesis of (+)-radulactone and assignment of absolute
We gratefully acknowledge Natural Science Foundation of
China for financial support of this work by grants (21772164 and
configuration.
2
1572187). We thank the FRFCU (20720160025), NFFTBS
(J1310024), NCETFJ and PCSIRT for support.
Finally, to further demonstrate the synthetic value of the
temporary phenol intermediate 11 which was prepared through
the aromatic C–H bond activation, four illudalane analogues
were prepared (Scheme 5). By palladium catalyzed Suzuki
coupling (method a) or Negishi coupling (method b) over its
triflate derivative 12, the analogues bearing benzodioxole (15a),
thiophene (15b), vinyl (15c) and ethyl (15d) groups at C7
position were obtained in high yields. Overall, we not only
developed an efficient way to make illudalane analogues, but
also provided a useful strategy for the synthesis of challenging
Conflicts of interest
There are no conflicts to declare.
Notes and references
1
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1
8
hexasubstituted phenyl ring.
a. Pd(PPh3)2Cl2, Na2CO3
RB(OH)2 or RBF3 K
OTf
7
O
R
7
O
-
+
Me
Me
O
dioxane/H2O, reflux
Me
Me
O
2
3
4
5
b. Pd(dppf)Cl2, ZnR2
dioxane, reflux
Me
Me
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15
O
P. Siengalewicz, J. Mulzer and U. Rinner, Eur. J. Org. Chem.,
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S
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O
O
Me
O
Me
Me
O
Me
1
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Me
(
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6
7
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1
O
9, 813; (b) S. J. Neeson and P. J. Stevenson, Tetrahedron,
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Me
O
Me
Me
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Me
5c (85%), method a
Me
1
15d (99%), method b
Scheme 5 Synthesis of illudalane analogues through a late-stage functionalization.
2
016, 18, 3470.
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J. Name., 2013, 00, 1-3 | 3
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Journal Name
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4
| J. Name., 2012, 00, 1-3
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O
+
OEt
O
HO
O
DOI: 10.1039/C9CC00933G
Me
Me
Me
Me
O
Me
Me
O
OH
Me
(+)-radulactone
Total Synthesis & Configuration Assignment
Transition metal catalyzed [2+2+2] cycloaddition and aromatic C–H oxygenation enables concise,
divergent total syntheses of five bioactive illudalane sesquiterpenes.