Total synthesis of cyanthiwigins A, C, G, and H

Article abstract of DOI:10.1021/ol4019425

The first total synthesis of cyanthiwigins A, C, H and concise synthesis of cyanthiwigin G was achieved from a common intermediate. A modified formal [4 + 2] cycloaddition was developed to construct the key cis-hydrindanone (A-B). Stereospecific 1,4-addition, alkylation, and ring-closing metathesis were used to build the tricarbocyclic ring system (A-B-C). Various site-selective oxidations were applied to create the desired oxidation states of the different cyanthiwigins.

Full text of DOI:10.1021/ol4019425

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Total Synthesis of Cyanthiwigins A, C, G,
and H
Cheng Wang,† Dan Wang,† and Shuanhu Gao*,‡
Shanghai Key Laboratory of Green Chemistry and Chemical Processes, Department of
Chemistry, East China Normal University, 3663N Zhongshan Road, Shanghai 200062,
China, and State Key Laboratory of Bioorganic and Natural Products Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
345 Lingling Road, Shanghai 200032, China
shgao@chem.ecnu.edu.cn
Received July 10, 2013
ABSTRACT
The first total synthesis of cyanthiwigins A, C, H and concise synthesis of cyanthiwigin G was achieved from a common intermediate. A modified
formal [4 þ 2] cycloaddition was developed to construct the key cis-hydrindanone (AꢀB). Stereospecific 1,4-addition, alkylation, and ring-closing
metathesis were used to build the tricarbocyclic ring system (AꢀBꢀC). Various site-selective oxidations were applied to create the desired
oxidation states of the different cyanthiwigins.
Cyanthiwigin diterpenoids belong to a large family of
cyathane natural products.1 In 1992, Green and co-workers
reported the first isolation and structural characterization
of cyanthiwigin A (2), B (3), C (4), and D.2 To date, over
30 members of this class of natural products have been
isolated from both the marine sponge Epipolasis reiswigi
and Mermekioderma styx.3,4 As shown in Figure 1, the
basic skeleton of cyanthiwigin diterpenoids typically con-
tains a 5ꢀ6ꢀ7 [AꢀBꢀC] fused tricarbocyclic ring, where
the B ring has four contiguous stereocenters, including
two all-carbon quaternary centers at C-6 and C-9. The
relative cis-configuration of C-6 and C-9 in cyanthiwigin
diterpenoids is opposite to that of other cyathane natural
products, which normally have two anti-oriented methyl
groups. The diversity of oxidations possible on the carbo-
cyclic ring (as shown in 1) is the major source of structural
differences among cyanthiwigin diterpenoids. Cyanthiwigin
C (4) exhibits cytotoxicity against A549 human lung cancer
cells (IC50 = 4.0 mg/mL),4 and cyanthiwigin F (5) is cyto-
toxic against human primary tumor cells (IC50 = 3.1 mg/mL).3
However, scarcity of these compounds has prevented
researchers from examining the full spectrum of cyanthiwigin
bioactivity.3b
One solution may be total chemical synthesisofthis class
of diterpenoids, but few synthetic studies have been pub-
lished about them, despite their appealing structures and
promising biological activities. In 2005, Phillips and co-
workers reported the first total synthesis for a member of
this class of natural products, cyanthiwigin U (8). They
used an elegant ROM-RCM cascade to construct the core
tricyclic skeleton.5 Stoltz and co-workers developed a
unique double asymmetric catalytic alkylation and applied
† East China Normal University
‡ Shanghai Institute of Organic Chemistry
(1) For a review of cyathane type natural products, see: (a) Wright,
D. L. C.; Whitehead, R. Org. Prep. Proced. Int. 2000, 32, 309–330. (b)
Enquist, J. A., Jr.; Stoltz, B. M. Nat. Prod. Rep. 2009, 26, 661–680.
(2) Green, D.; Goldberg, I.; Stein, Z.; Ilan, M.; Kashman, Y. Nat.
Prod. Lett. 1992, 4, 193–199.
(3) (a) Peng, J.; Walsh, K.; Weedman, V.; Bergthold, J. D.; Lynch, J.;
Lieu, K. L.; Braude, I. A.; Kelly, M.; Hamann, M. T. Tetrahedron 2002,
58, 7809–7819. (b) Peng, J.; Avery, M. A.; Hamann, M. T. Org. Lett.
2003, 5, 4575–4578. (c) Peng, J.; Kasanah, N.; Stanley, C. E.; Chadwick,
J.; Fronczek, M.; Hamann, M. T. J. Nat. Prod. 2006, 69, 727–730.
(4) Sennett, S. H.; Pomponi, S. A.; Wright, A. E. J. Nat. Prod. 1992,
55, 1421–1429.
(5) (a) Pfeiffer, M. W. B.; Phillips, A. J. J. Am. Chem. Soc. 2005, 127,
5334–5335. (b) Pfeiffer, M. W. B.; Phillips, A. J. Tetrahedron Lett. 2008,
49, 6860–6861.
r
10.1021/ol4019425
XXXX American Chemical Society

Scheme 1. Retrosynthetic Analysis of Cynthawigins
Scheme 2. Construction of the Core 5ꢀ6 Ring (AꢀB Ring)
System
Figure 1. Structure of cyanthiwigins.
it to the asymmetric synthesis of cyanthiwigins B (3), F (5)
and G (6).6 Reddy and co-workers reported the synthesis
of (þ)-cyanthiwigin AC (9), a rearranged spiro-molecule,
using a spiro-bis-alkylation strategy.7 Because of our inter-
est in the structureꢀactivity relationships of cyanthiwigins,
we wished to develop a more general and flexible approach
to constructing the core tricarbocyclic skeleton, which
could be used as a common intermediate to synthesize
the variety of cyanthiwigin diterpenoids and their deriva-
tives. As the first step in this project, we describe here our
approach allowing the total synthesis of cyanthiwigins A
(2), C (4), G (6), and H (7).
Our retrosynthetic analysis is outlined in Scheme 1. We
envisioned that cyanthiwigin diterpenoids could be synthe-
sized from a common intermediate 10, which has the basic
tricarbocyclic skeleton. cis-Hydrindanone (AꢀB ring) 11
could be constructed using a formal [4 þ 2] cycloaddition,
and this compound could provide the cycloheptene ring
(C ring) and the stereocenters of 10 through a series of
carbocycle-forming reactions, including stereospecific 1,4-
addition, alkylation, and ring-closing metathesis.
mixture and adding Lewis acids. A literature search re-
vealed that Fringuelli et al.,9 Baker et al.,10 and Danishefs-
ky et al.11 encountered the same puzzling problem. To get
around it, Danishefsky and co-workers11 used an ap-
proach of “two sequential Michael additions” involving
lithium enolate of 12b and “actived dienophile” 14, which
gave the desired cis-hydrindanone 16b as a single diaster-
eomer in 73% yield. Following Danishefsky’s protocol,11
we successfully prepared 16a and 17 in moderate yield by
reacting the lithium enolate of 12a with 14 and 15.
The synthesis started with preparation of cis-hydrinda-
none 11 (Scheme 2). Structural considerations suggested
that it should be easy to construct 11 using a DielsꢀAlder
reaction8 of Danishefsky’s diene 12a and dienophile 13.
However, after extensively surveying reaction conditions,
we were unable to react 12a with 13 or 14 to yield the
desired cycloaddition product 11 or 16a, after heating the
To synthesize 11, we modified this formal [4 þ 2]
reaction by incorporating a sequential Michael addition
followed by oxonium ion-promoted cyclization (Scheme 3).
Direct deprotonation of ketone 18 with LDA generated
the corresponding lithium enolate, which reacted smoothly
with 15 and yielded the Michael addition product 19.
Adding PTSA to compound 19 without purification gave
the oxonium intermediate 20. Then oxonium ion-promoted
(6) (a) Enquist, J. A., Jr.; Stoltz, B. M. Nature 2008, 453, 1228–1230.
(b) Enquist, J. A., Jr.; Virgil, S. C.; Stoltz, B. M. Chem.;Eur. J. 2011, 17,
9957–9969.
(7) Reddy, T. J.; Bordeau, G.; Trimble, L. Org. Lett. 2006, 8, 5585–
5588.
(8) For reviews of the DielsꢀAlder reaction in total synthesis, see:
Nicolaou, K. C.; Snyder, S. A.; Montagnon, T.; Vassilikogiannakis, G.
Angew. Chem., Int. Ed. 2002, 41, 1668–1698.
(9) Fringuelli, F.; Pizzo, F.; Taticchi, A.; Wenkert, E. J. Org. Chem.
1983, 48, 2802–2808.
(10) Baker, R.; Selwood, D. L.; Swain, C. J.; Webster, N. M. H.
J. Chem. Soc., Perkin Trans. I 1988, 471–480.
(11) Zhang, Y.; Danishefsky, S. J. J. Am. Chem. Soc. 2010, 132, 9567–
9569.
B
Org. Lett., Vol. XX, No. XX, XXXX

cylization occurred, followed by elimination, generating
enone 17 in 75% yield. The fact that the starting material
was an easily available ketone instead of silyl enol ether not
only simplified this process but also improved the total yield.
Decarboxylation of 16a or 17 was proved to be challenging
with these specific substrates. We first tried the Krapcho’s
decarboxylation conditions12 by heating a solution of 16a in
the presence of different salts (LiCl, NaCl, etc.). We ob-
served the decomposition of material occurred under these
harsh thermal conditions. Ultimately, we found that dec-
arboxylation of 17 with Raney Nickel gave cis-hydrinda-
none 11 in an acceptable yield.13 The cis relative configuration
of 11 was unambiguously confirmed by X-ray analysis. We
consider that 11 is a homologue of “HajosꢀParrish ketone”14
and promises to be a useful building block in natural product
synthesis.
Scheme 4. Construction of the Core 5ꢀ6ꢀ7 Ring (AꢀBꢀC)
System
(RCM)17 of 26 using Grubbs II catalyst in reflux CH2Cl2
gave 10 in 97% yield.6
Scheme 3. Modified Formal [4 þ 2] Cycloaddition
Compound 10 has the basic tricarbocyclic skeleton
(AꢀBꢀC ring) of cyanthiwigins, potentially allowing it
to serve as an intermediate from which diverse members of
this class of diterpenoids can be prepared. To demonstrate
this, we first regulated the oxidation state of the B ring by
modulating the C-7 carbonyl group (Scheme 5). Reducing
10 with NaBH4 gave 27, which was deoxygenated using
Barton’s protocol18 to afford 28. Removing the ketal
group yielded ketone 29, which contains a saturated B
ring that can serve as a precursor of cyanthiwigin A (2).
After a sequential SaegusaꢀIto oxidation,19 29 was oxi-
dized to enone 30. Treating 30 with i-propyllithium gave
1,2-addition tertiary alcohol as a mixture of two
diastereomers.20 PCC-mediated rearrangement21 of this
mixture without purification produced cyanthiwigin A (2)
in 62% yield over 2 steps.5 Spectroscopic data of synthetic 2
(1H and 13C NMR spectra, HRMS) were fully consistent
with the corresponding data for the natural product.3a We
believe that cyanthiwigin A (2) is the biogenetic precursor of
related cyanthiwigins (C, H, I, K, L, M, P, Q, U, W, Y, Z)
that contain a saturated B ring and different oxidation states
at the A and C rings. Consistent with this hypothesis, we
converted 2 into cyanthiwigin C (4) and cyanthiwigin H (7).
Luche reduction of 2 gave cyanthiwigin C (4) (dr = 7:1) as
major product in 90% yield. Selectively oxidizing the cyclo-
heptene ring of 2 using m-CPBA gave cyanthiwigin H (7)
and its diastereomer in a 6:1 ratio in 98% combined yield.
With 11 in hand,15 we began to construct the cyclohep-
tene ring (C ring) (Scheme 4). Selective protection of the
C-3 carbonyl group as ketal with ethylene glycol gave
compound 22. Stereospecific 1,4-addition of enone 22 with
Grignard reagent 23 in the presence of CuI and TMSCl
yielded silyl enol ether 24.16 Treating 24 with methyl
lithium gave the corresponding lithium enolate, which
after being trapped by allylic iodide yielded a mixture of
oxygen and carbon alkylation products 25 and 26 in an
approximately 1:2 ratio. A thermal 3,3-sigmatropic rear-
rangement then converted 25to 26. Ring-closingmetathesis
(17) For a review of metathesis in natural product synthesis, see: (a)
Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18–29. (b)
Grubbs, R. H. Tetrahedron 2004, 60, 7117–7140. (c) Diver, S. T.;
Giessert, A. J. Chem. Rev. 2004, 104, 1317–1382. (d) Nicolaou, K. C.;
Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4490–4527. (e)
Villar, H.; Fringsa, M.; Bolm, C. Chem. Soc. Rev. 2007, 36, 55–66.
(18) (a) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin
Trans. 1 1975, 1574–1585. (b) Hartwig, W. Tetrahedron 1983, 39, 2609–
2645.
(19) Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011–
1013.
(20) We also found the 1,4-addition product in this reaction. The
ratio of 1,2-addition to 1,4-addition products was 2:1.
(21) Dauben, W. G.; Michno, D. M. J. Org. Chem. 1977, 42, 682–685.
(12) (a) McMurry, J. Org. React. 1976, 24, 187–224. (b) Krapcho,
A. P. Synthesis 1982, 893–914. (c) Krapcho, A. P. Synthesis 1982, 805–
822.
(13) (a) Hashimoto, S.; Shinoda, T.; lkegami, S. J. Chem. Soc., Chem.
Commun. 1988, 1137–1139. (b) Hashimoto, S.; Miyazaki, Y.; Shinoda,
T.; Ikegami, S. Tetrahedron Lett. 1989, 30, 7195–7198.
(14) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615–1621.
(15) cis-Hydrindanone 11 is unstable at room temperature under air.
We found this compound to be stable at the low temperature under N2
and can be stored in the ꢀ20 °C for several weeks without
decomposition.
(16) Snider, B. B.; Vo, N. H.; O’Neil, S. V.; Foxman, B. M. J. Am.
Chem. Soc. 1996, 118, 7644–7645.
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C

Scheme 5. Total Synthesis of Cyanthiwigins
We were also able to dehydrate 10 to create the C7ꢀC8
double bond that exists in the B ring of cyanthiwigin G (6).
We transformed ketone 10 to vinyl triflate 31, which was
then reduced to 32 through a Pd-catalyzed reduction with
Et3SiH in 96% yield over two steps.22 The relative stereo-
chemistry of the tricarbocyclic skeleton was confirmed by
X-ray analysis of the deprotection product 33. Using the
same strategy we used to prepare 2 (Scheme 5), we
converted 33, which contains an unsaturated B ring, into
cyanthiwigin G (6)5 in four steps involving a sequence of
SaegusaꢀIto oxidation and 1,2-addition, followed by
PCC-mediated oxidative rearrangement.21
In summary, we have achieved the first total synthesis of
cyanthiwigins A, C, H and concise synthesis of cyanthiwi-
gin G from a common intermediate 10. We used a series of
highly stereospecific carbocycle-forming reactions to con-
struct the basic tricarbocyclic ring system (AꢀBꢀC);
reactions included a modified formal [4 þ 2] cycloaddition,
1,4-addition, alkylation, and ring-closing metathesis.
Various site-selective oxidations allowed us to create the
different oxidation states of cyanthiwigins. This flexible
approach should enable the synthesis of diverse cyanthi-
wigins and their derivatives, thereby facilitating the biolo-
gical study of these promising natural products. We are
currently studying the divergent and asymmetric synthesis
of cyanthiwigin diterpenoids.
Acknowledgment. Financial support was provided by
the NSFC (21102045, 21272076), the Shanghai “Pujiang
Program” (11PJ1402800), RFDP (No. 20110076120022)
of Higher Education of China and the program for
professor of special appointment (Eastern Scholar) at
Shanghai institutions of higher learning. We also thank
Prof. Xiaoli Zhao (Department of Chemistry, East China
Normal University) for X-ray analysis.
Supporting Information Available. Experimental pro-
cedures, characterization data and crystallographic data
(CIF). This material is available free of charge via the
Internet at http://pubs.acs.org.
(22) Scott, W. J.; Stille, J. K. J. Am. Chem. Soc. 1986, 108, 3033–3040.
The authors declare no competing financial interest.
D
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