Rapid biomimetic total synthesis of (±)-rossinone B

Article abstract of DOI:10.1021/ol102438r

A biomimetic total synthesis of (±)-rossinone B has been achieved through a highly efficient strategy featuring a series of rationally designed reactions, including a one-pot allylic rearrangement/oxidation reaction to generate the vinyl quinone 27, an intramolecular vinyl quinone Diels-Alder reaction to construct the linear 6-6-5 tricyclic core of 28, and a double conjugate addition/β-elimination cascade to complete the total synthesis of 1.

Full text of DOI:10.1021/ol102438r

ORGANIC
LETTERS
2
010
Vol. 12, No. 23
554-5557
Rapid Biomimetic Total Synthesis of
()-Rossinone B
5
(
†
†
,†,‡
Ziyang Zhang, Jiahua Chen, Zhen Yang,* and Yefeng Tang*
,‡
Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of
Education and Beijing National Laboratory for Molecular Science (BNLMS), College
of Chemistry, Peking UniVersity, Beijing 100871, China, and The ComprehensiVe AIDS
Research Center, School of Medicine, Tsinghua UniVersity, Beijing 100084, China
zyang@pku.edu.cn; yefengtang@tsinghua.edu.cn
Received October 8, 2010
ABSTRACT
A biomimetic total synthesis of (()-rossinone B has been achieved through a highly efficient strategy featuring a series of rationally designed
reactions, including a one-pot allylic rearrangement/oxidation reaction to generate the vinyl quinone 27, an intramolecular vinyl quinone
Diels-Alder reaction to construct the linear 6-6-5 tricyclic core of 28, and a double conjugate addition/ꢀ-elimination cascade to complete
the total synthesis of 1.
Marine organisms have been proven to be invaluable
resources for discovery of structurally unique and biologically
1
important natural products. As a paradigmatic example,
rossinone B (1, Figure 1) was isolated from an Antarctic
collection of the ascidian Aplidium species by Copp and co-
2
workers in 2009. The preliminary biological investigations
have shown that rossinone B exhibited significant biological
profiles, including potent antiviral, anti-inflammatory and
antileukemic activities. For instance, rossinone B was found
to show prominent antiproliferative activity toward the P388
murine leukemia cell-line with low IC50 value (0.084 µM).
From a structural point of view, rossinone B possesses a
rather novel molecular architecture featured by a linearly
fused 6-6-5 ring core, that so far, has only been found in
†
Peking University.
Tsinghua University.
‡
(
1) (a) Skropeta, D. Nat. Prod. Rep. 2008, 25, 1131–1166. (b) Blunt,
J. W.; Copp, B. R.; Munro, M. H. G.; Northcote, P. T.; Prinsep, M. R. Nat.
Prod. Pep. 2010, 27, 165–237.
Figure 1. Natural products with 6-6-5 ring core structure.
(
2) Appleton, D. R.; Chuen, C. S.; Berridge, M. V.; Webb, V. L.; Copp,
B. R. J. Org. Chem. 2009, 74, 9195–9198.
10.1021/ol102438r  2010 American Chemical Society
Published on Web 11/09/2010

three other natural products, named pycnanthuquinones A
3
3
4
(
2), B (3) and C (4). Biosynthetically, these natural
Scheme 1
.
Proposed Biosynthetic Pathway for Rossinone B and
Bio-inspired Synthetic Strategy
products are most likely to be derived from the corresponding
prenylated hydroquinone derivatives that are usually isolated
concomitantly from the natural source. As such, Altena
et al. proposed that pycnanthuquinones C was biogenetically
produced from a geranyltoluquinol precursor through a
4
cascade cyclization reaction involving a carbocation species.
In contrast, Trauner and coworks recently proposed a
different biosynthetic mechanism, in which a novel vinyl
quinone Diels-Alder (VQDA) reaction was suggested as the
key transformation. Notably, this hypothesis has been
validated by their elegant work on the biomimetic total
5
synthesis of pycnanthuquinones C.
Attracted by its novel chemical structure, promising
biological properties and potentially intriguing biosynthetic
pathway, we initiated a program aiming for developing
an efficient biomimetic route for synthesis of rossinone
B, as well as other members of this family. Herein we
report the first total synthesis of (()-rossinone B by
employing a bioinspired intramolecular VQDA reaction
as the key reaction.
6
The proposed biosynthetic pathway coupled with the
synthetic plan for rossinone B is depicted in Scheme 1.
Rossinone A (5), also isolated from the same resource, is
believed to be the biosynthetic precursor for rossinone B.
Thus, a series of oxidations of 5 leads to vinyl quinone 7.
Then 7 undergoes an intramolecular VQDA reaction to afford
the fleeting isoquinone methide intermediate 9, which
spontaneously advances to rossinone B via an isomerization/
oxidation/conjugate addition/ꢀ-elimination cascade reaction.
Notably, although there were sporadic studies on the VQDA
7
-9
reaction,
its versatile reactivity has been largely unex-
plored. For instance, the vinyl quinone unit was proven to
be an ideal diene partner in the inverse electron-demand
Diels-Alder reaction, as shown in the total synthesis of
benefit the practical synthesis by increasing the HOMO
energy of the diene partner, and thus facilitating the desired
cycloaddition reaction. Moreover, the methoxy group is
expected to serve as a leaving group in the following
conjugate addition/ꢀ-elimination reaction, promoting the
transformation from 10 to 11.
5
9a
pycnanthuquinones C and halenaquinone. However, its
reactivity in the normal electron-demand Diels-Alder reac-
tion, as in the case of rossinone B, remained uncertain,
1
0
considering its extremely electron-deficient properties. To
overcome this challenge, we envisioned that installing a
methoxy group at C-13 (as shown in 8, Scheme 1) would
To test the viability of our strategy, a model study was
first conducted as shown in Scheme 2. Regioselective
(
3) Fort, D. M.; Ubillas, R. P.; Mendez, C. D.; Jolad, S. D.; Inman,
11
metalation of 12 with nBuLi at -78 °C followed by
W. D.; Carney, J. R.; Chen, J. L.; Ianiro, T. T.; Hasbun, C.; Bruening,
R. C.; Luo, J.; Reed, M. J.; Iwu, M.; Carlson, T. J.; King, S. R.; Bierer,
D. E.; Cooper, R. J. Org. Chem. 2000, 65, 6534–6539.
1
2
addition of aldehyde 13 afforded 14 in 50% yield (82%
based on recovered starting material). The synthesis of
VQDA reaction precursor 17 was then achieved in a
streamlined manner: an acid-promoted 1,3-allylic isomer-
(
4) Laird, D. W.; Poole, R.; Wikstrom, M.; van Altena, I. A. J. Nat.
Prod. 2007, 70, 671–674.
5) L o¨ bermann, F.; Mayer, P.; Trauner, D. Angew. Chem., Int. Ed. 2010,
9, 6199–6202.
6) We noticed that a similar proposal about the biosynthetic pathway
of rossinone B was independently disclosed in ref 5.
7) (a) Irngartinger, H.; Stadler, B. Eur. J. Org. Chem. 1998, 605–626.
b) Iwamato, H.; Hamada, T. K.; Fujiwara, R. J. Chem. Soc., Perkin. Trans.
(
4
13
ization converted 14 to the thermodynamically more stable
compound 15, the MOM protection group was then removed
under the acidic conditions, and the resulting phenol was
immediately oxidized to quinone 17. Notably, although the
aforementioned transformations worked well in a stepwise
(
(
(
1
1999, 575–581
8) (a) Noland, W. E.; Kedrowski, B. L. J. Org. Chem. 1999, 64, 596–
03. (b) Kedrowski, B. L.; Noland, W. E. J. Org. Chem. 2002, 67, 8366–
373
9) (a) Kienzler, M. A.; Suseno, S.; Trauner, D. J. Am. Chem. Soc. 2008,
30, 8604–8605. (b) Malerich, J. P.; Trauner, D. J. Am. Chem. Soc. 2003,
25, 9554–9555
10) A normal electron-demand VQDA reaction was reported in ref 9b.
.
(
6
8
.
(
1
1
(11) Katoh, T.; Nakatani, M.; Shikita, S.; Sampe, R.; Ishiwata, A.;
Ohmori, O.; Nakamura, M.; Terashima, S. Org. Lett. 2001, 3, 2701–2704.
(12) For preparation of 13, please see Supporting Information.
(13) Snyder, C. D.; Bondinell, W. E.; Rapoport, H. J. Org. Chem. 1971,
36, 3951–3960.
.
(
However, the vinyl quinone unit was embodied in a pyranonaphthoquinone
system, making it a relatively special case.
Org. Lett., Vol. 12, No. 23, 2010
5555

Encouraged by success of the model study, we commenced
the total synthesis campaign toward rossinone B (1). As
depicted in Scheme 3, synthesis of 25, bearing the fully
Scheme 2. Model Study on VQDA Reaction
Scheme 3. Synthesis of Precursor of VQDA Reaction
14
manner, the best result was obtained in a one-pot procedure
using HNO /AgO combination (6 N HNO for 15 min, then
3
3
AgO for 30 min), providing the desired quinone 17 in 88%
over 2 steps.
With 17 in hand, we next turned our attention to the
intramolecular VQDA reaction. To our delight, the desired
reaction proceeded smoothly under thermal condition (170
°
C, toluene, sealed tube) to give the tricyclic compound 18
as the only isolatable product in 55% yield. Albeit moderate
in yield, the reaction proceeded with high diastereoselectivity,
presumably via the endo transition state Ts-1, to afford 18
with four consecutive stereocenters established in one
operation. The relative stereochemistry of 18 was assigned
based on 1D NOE measurement (Scheme 2) and the coupling
1
7
functionalized side chain, was started with compound 20.
Thus, addition of TMSCN to aldehyde 20 in the presence
1
5
of Et N furnished TMS-protected cyanohydrin 21 in almost
3
constant of the characteristic protons. Furthermore, when
8 was heated in a toluene/water mixture at 70 °C, the
1
8
quantitative yield. Deprotonation of 21 with LiHMDS at
1
-
78 °C, followed by addition of 3-methyl-2-butenal provided
conjugate addition/ꢀ-elimination reaction transpired as ex-
pected, to afford 19 as the sole diastereoisomer in 70% yield,
and the ꢀ-configuration of 6-OH was assigned based on the
the coupled intermediate 22, which spontaneously underwent
a silyl group migration to release the masked ketone, leading
to the formation of 23 in 75% yield. The TMS group was
1
9
16
coupling constant between H-6 and H-7. Notably, 19 shares
the same core structure with pycnanthuquinones A (3), B
(
16) The trans-configuration of H-6 and H-7 could be deduced by the
coupling constant value between them (JH6-H7 ) 9.6 Hz).
17) The aldehyde 20 was prepared according to the following literature
(
4) and C (5).
(
(
14) The allylic isomerization product 15 could be isolated, and its
structure was fully characterized.
15) The trans-configuration of H-7 and H-11 could be deduced by the
coupling constant value between them (JH7-H11 ) 12.3 Hz).
except that TBDPSCl was used instead of TBSCl: Labadie, G. R.;
Viswanathan, R.; Poulter, C. D. J. Org. Chem. 2007, 72, 9291–9297.
(18) Jacobson, R. M.; Lahm, G. P.; Clader, J. W. J. Org. Chem. 1980,
45, 395–405.
(
5556
Org. Lett., Vol. 12, No. 23, 2010

then removed upon treatment with 1 N HCl, and the resulting
alcohol was acetylated with Ac O/Py. Removal of the
2
Scheme 4. Completion of Total Synthesis of Rossinone B
TBDPS group with aqueous HF, followed by oxidation with
Dess-Martin periodinane gave aldehyde 24 in 51% overall
yield from 23. The next task was to assemble the two
fragments 12 and 24, following the procedure established
in our model study. As such, metalation of the MOM-
protected phenol 12 with nBuLi at -78 °C followed by
addition of aldehyde 24 afforded 25 as a 1:1 mixture of
inseparable diastereoisomers in 67% yield (88% based on
recovered starting material). The acetate was then removed
by K
2
CO
3
/CH
3
OH, and the resulting benzylic alcohol 26 was
, and then AgO, to furnish vinyl
treated with 6 N HNO
3
quinone 27 in 71% overall yield.
With 27 in hand, the stage was set to test the key step of
our synthesis, the biomimetic intramolecular VQDA reaction.
Thus, 27 was heated in toluene (sealed tube, 150 °C) until
the characteristic deep brown color of quinone disappeared.
However, this reaction, unlike that in the model study,
seemed to be somewhat complicated. Preliminary analysis
of the crude NMR data showed that two components of the
mixture bear very similar NMR spectrum with that of
rossinone B, and thus their structures were tentatively
assigned as 28, which represented a mixture of epimers at
C-15. Further efforts to obtain pure single isomer for fully
structural characterization proved to be fruitless, mainly
because of a possible thermodynamic equilibrium observed
between the two epimers. In reality, the ratio of epimers at
C-15 varied extensively from 12:1 to 1:1 depending on the
conditions used (see Supporting Information for details).
These interesting phenomena led us to believe that both of
the two epimers could be converted to rossinone B in next
transformation through the existing equilibrium. This hy-
pothesis was quickly validated by the following experiments.
In summary, the first total synthesis of (()-rossinone B
was achieved through a highly efficient biomimetic strategy.
It strongly supports the proposal that a novel vinyl quinone
Diels-Alder reaction might be involved in the biosynthetic
pathway of rossinone B. Further studies on the asymmetric
synthesis of 1 and its application to the synthesis of other
members of this family as well as their analogs for biological
evaluations are undergoing in our laboratory, and will be
reported in due course.
Acknowledgment. We gratefully acknowledge the finan-
cial support from the National Natural Science of Foundation
of China (20832003) to Z.Y., the China’s 985 project
When the mixture of epimeric 28 was heated in CH
3
OH/
(411307141) and the Support Fund for Key Personnel from
H
2
O in presence of TsOH at 80 °C for 12 h, rossinone B
2
0
Tsinghua University (563107002) to Y.T. We also thank Mr.
Luo Tuoping (Harvard University), Dr. Zhang Yandong
was obtained in 31% isolated yield over two steps.
Although intermediate 29 was not observed, the transforma-
tion from 28 to 1 was believed to proceed through a double
conjugate addition/ꢀ-elimination cascade reaction (as shown
in Scheme 4). The spectroscopic data of synthetic rossinone
(Columbia University), Dr. Huang Zhihong (Genomics
Institute of Novartis Research Foundation, San Diago, CA)
and Dr. Christine Fang Gelin (Novartis Institutes for
Biomedical Research at Boston, MA) for their helpful
discussions in manuscript preparation.
1
13
B ( H and C NMR, IR, HRMS) were fully identical with
those reported for the naturally occurring product.
Supporting Information Available: Experimental pro-
cedure and characterization data for all of new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(
19) (a) Deuchert, K.; Hertenstein, U.; H u¨ nig, S. Synthesis 1973, 777–
7
79. (b) H u¨ nig, S.; Wehner, G. Synthesis 1975, 180. (c) H u¨ nig, S.; Wehner,
¨
G. Synthesis 1975, 391–392. (d) Hertenstein, U.; H u¨ nig, S.; Oller, M.
Synthesis 1976, 416–417.
(
20) The double conjugate addition/ꢀ-elimination reaction was first run
under the condition used in our model study (H
only epimerization at C-15 was observed.
2
O/toluene, 80 °C); however,
OL102438R
Org. Lett., Vol. 12, No. 23, 2010
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