Concise total synthesis of (±)-dasyscyphin D

Article abstract of DOI:10.1021/ol201047m

The first and efficient total synthesis of (±)-dasyscyphin D was achieved in 9 steps with 22.6% overall yield. The key steps involved a PtCl ₂-catalyzed pentannulation reaction and acid-catalyzed double Robinson annulations.

Full text of DOI:10.1021/ol201047m

ORGANIC
LETTERS
2011
Vol. 13, No. 11
2956–2958
Concise Total Synthesis of (()-
Dasyscyphin D
Ling Zhang,† Xingang Xie,† Jian Liu,† Jing Qi,† Donghui Ma,† and Xuegong She*,†,‡
State Key Laboratory of Applied Organic Chemistry, Department of Chemistry,
Lanzhou University, Lanzhou 730000, People’s Republic of China, and State Key
Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical
Physics, Chinese Academy of Sciences, Lanzhou 730000, People’s Republic of China
shexg@lzu.edu.cn
Received April 20, 2011
ABSTRACT
The first and efficient total synthesis of (()-dasyscyphin D was achieved in 9 steps with 22.6% overall yield. The key steps involved a
PtCl2-catalyzed pentannulation reaction and acid-catalyzed double Robinson annulations.
Dasyscyphins (AÀE) bear a unique [6À5À6À6] fused
tetracyclic skeleton and are a family of tetracyclic terpe-
noid natural products possessing potent cytotoxic and mod-
erate antimocrobial activities (Figure 1).1 Among them,
dasyscyphin D, isolated from Dasyscyphus niveus by Till
Opatz and co-workers in 2008, inhibits the germination of
conidia of Magnaporthe grisea at 20 μg/mL and imbeds
five stereogenic centers, which contain two quaternary
stereocenters.2 These intriguing structural features, along
with low availability from natural sources, have attracted
our attention to define this compound as a synthetic target.
Herein, we report a concise and efficient total synthesis of
(()-dasyscyphin D via a PtCl2-catalyzed pentannulation
reaction and acid-catalyzed Robinson annulation as
key steps.
Our retrosynthetic analysis was outlined in Scheme 1.
Figure 1. Structures of dasyscyphin AÀE.
(()-Dasyscyphin D (1) was envisionedtobe obtainedfrom
tetracyclic precursor 2 through a simple functional group
interconversion, which could be preparedfrom 2-indanone
3 by acid-catalyzed Robinson annulations. In the case of 3,
it could be obtained from 4 by a PtCl2-catalyzed pentan-
nulation reaction developed by Ohe’s group previously.3,4
Toward this end, ester 4 could be readily prepared by
acetophenone 5 by a simple transformation.
† Lanzhou University.
‡ Lanzhou Institute of Chemical Physics.
(1) (a) Rojas de la Parra, V.; Mierau, V.; Anke, T.; Sterner, O.
Tetrahedron 2006, 62, 1828–1832. (b) Mierau, V.; Rojas de la Parra,
V.; Sterner, O.; Anke, T. J. Antibiot. 2006, 59, 53–56.
(2) Liermann, J. C.; Kolshorn, H.; Anke, H.; Thines, E.; Opatz, T.
J. Nat. Prod. 2008, 71, 1654–1656.
Our synthesis began with readily available acetophenone
5, which was protected by MeI, followed by nucleophilic
r
10.1021/ol201047m
Published on Web 05/11/2011
2011 American Chemical Society

Withthe key intermediate3 in hand, the C and D rings of
1 were then constructed via Robinson annulation, which was
widely used in the synthesis of complex natural products.5À7
However, to the best of our knowledge, Robinson annula-
tion has not been utilized in the construction of the
[6À5À6] skeleton, because of the similar acidity of the
two benzylic positions of 3. Initially, construction of the C
ring was proceeded by treatment of 3 with ethyl vinyl ketone
or 10 under base conditions (K2CO3/MeOH, NaH or
EtONa, etc.); however, only a complex mixture was ob-
tained, owing to the similar acidity of H-8 and H-11. After
many trials, attention was then turned to acidic conditions.
We were pleased to find that when exposing 3 and 10 (1.5
equiv) to p-toluenesulfonic acid in refluxing toluene, the
desired tricycle 6 was obtained in 87% yield, together with
a small amount (<1%) of tetracycle 7, which could be
generated by the second Robinson annulation from com-
pound 6, and found that the percentage of tetracycle 7
increased with prolongation of the reaction time (Scheme 3).
Scheme 1. Retrosynthetic Analysis of (()-Dasyscyphin D
Scheme 2. Synthesis of Indanone 3
Scheme 3. Robinson Annulation of 3
addition of ethynylmagnesium bromide and afforded the
corresponding alcohol, which was further protected by
acetyl to obtain 4 in 95% yield (Scheme 2). Treatment of
ester 4 with 5 mol % PtCl2 intoluene underwent the desired
PtCl2-catalyzed pentannulation reaction and then acidic
hydrolysis to give the desired 2-indanone 3 in 72% yield.
(3) (a) Ohe, K.; Nakanishi, Y.; Miki, K. Tetrahedron 2007, 63, 12138–
12148. (b) Miki, K.; Ohe, K.; Uemura, S. J. Org. Chem. 2003, 68, 8505–
8513 and reference cited therein.
(4) For selected pentannulation examples, see: (a) Bhanu Prasad,
B. A.; Yoshimoto, F. K.; Sarpong, R. J. Am. Chem. Soc. 2005, 127,
12468–12469. (b) Brian, G. P.; Bhanu Prasad, B. A.; Sarpong, R. J. Am.
Chem. Soc. 2006, 128, 6786–6787. (c) Marco-Contelles, J.; Soriano, E.
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Wang, T.-Z.; Sivik, M. R. J. Am. Chem. Soc. 1994, 116, 11323–11334.
(e) Shi, B.; Hawryluk, N. A.; Snider, B. B. J. Org. Chem. 2003, 68,
1030–1042.
(6) For construction of [6.6.6] core, see: (a) Buckbinder, L.; Haugeto,
A. I.; McNiff, P. A.; Millham, M. L.; Robinson, R. P. J. Med. Chem.
2009, 52, 1731–1743. (b) Gan, Y.; Spencer, T. A. J. Org. Chem. 2006, 71,
5870–5875. (c) Howell, F. H.; Taylor, D. A. H. J. Chem. Soc. 1958, 1248–
1254. (d) Howell, F. H.; Taylor, D. A. H. J. Chem. Soc. 1959, 1607–1613.
(e) Paquette, L. A.; Belmont, D. T.; Hsu, Y.-L. J. Org. Chem. 1985, 50,
4667–4672. (f) Banerjee, A. K.; Azοcar, J. A. Synth. Commun. 1999, 29,
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902–921.
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J. Org. Chem. 1984, 49, 3264–3274. (b) Kerwin, S. M.; Paul, A. G.;
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Branchaud, B.; Maestrone, T. Tetrahedron Lett. 1975, 16, 527–528.
Even 7 could be obtained as the major product in 76% yield
by annulation of 3 with 2.5 equiv of 10 over 12 h in refluxing
toluene. Hydrogenation of 7 readily provided 9 in quantita-
tive yield. The structure of 9 was confirmed by single crystal
X-ray analysis. This finding featured construction of the C
and D ring in one step; although effective, the relative
configuration of CH3-18 and CH3-21 of 9 was cis, which
was not consistent with the natural Dasyscyphins’ skeleton.
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relative configration of tetracycle 2 was consistent with the
skeleton of the natural product as expected. The sequential
Birch reductionÀalkylation reaction of 2 proceeded and
was quenched by excessive CH3I,10 followed by removal of
the methyl protecting group, and ketone 12 was obtained
in 68% yield. Finally, with reduction of ketone 12 with
NaBH4 inMeOH, the total synthesisof (()-dasyscyphin D
(1) was accomplished. Our synthetic sample was in good
Scheme 4. Chem 3D of the Intermediate I and II
1
agreement with the natural sample on the basis of H
NMR, 13C NMR, HRMS, and IR.
Scheme 5. Completion of Total Synthesis of (()-Dasyscyphin D
Constructing the D ringwasthe nexttaskfor completion
of the total synthesis. Upon treatment of tricycle 6 with
ketone 10 (1.1 equiv) under basic conditions, a mixture of 8
and 7 was obtained in 72% combined yield.8 After analysis
of the sterechemistry of dasyscyphin D, we think that it is
favorable if the CdC bond of tricycle 6 was reduced to a
saturated one. This was clearly illustrated in Scheme 4.
Electrophilic 10 could be approached from the convex face
of the intermediate II with higher selectivity than the
intermediate I.
With this idea in mind, the stage was then set for the
reduction of the R,β-enone of tricycle 6 (Scheme 5). Birch
reduction of enone 6 was performed in Li/NH3(l)/t-BuOH
to provide tricycle ketone 11 (R:β = 1:6) in 88% yield. In a
similar fashion to the first Robinson annulation, ketone
11 was treated with ketone 10 catalyzed by p-TSA in
refluxing benzene. The second Robinson annulation took
place, and the tetracycle 2 was obtained in 55% yield
(∼20% recovery of starting material, 69% BRSM).9 The
In conclusion, a concise and efficient total synthesis of
(()-dasyscyphin D was acomplished in 9 steps with 22.6%
overall yield. Our sythesis features two points: (1) prepar-
ing the 2-indanone 3 by a PtCl2-catalyzed pentannulation
reaction; (2) constructing the fused cyclic system by a
double acid-catalytic Robinson annulation, which trans-
formed 2-indanone into a tetracyclic [6À5À6À6] skeleton
and installed C(8) and C(10), two all-carbon quaternary
stereocenters. We believe that the synthetic efforts will
pave the way for the syntheses of other members of the
dasyscyphins family.
(8) Favaloro, F. G., Jr.; Honda, T.; Honda, Y .; Gribble, G. W.; Suh,
N.; Risingsong, R.; Sporn, M. B.; Gribble, G. W. Org. Biomol. Chem.
2003, 1, 4384–4391.
Acknowledgment. We are grateful for the generous
financial support by the MOST (2010CB833200) and the
NSFC (21072086, 20872054, 20732002) and Program 111.
(9) (a) Paquette, L. A.; Wang, T. Z.; Sivik, M. R. J. Am. Chem. Soc.
1994, 116, 2665–2666. (b) Paquette, L. A.; Wang, T. Z.; Sivik, M. R.
J. Am. Chem. Soc. 1994, 116, 11323–11334.
(10) (a) Stork, G.; Rosen, P.; Goldman, N. L. J. Am. Chem. Soc.
1961, 83, 2965–2966. (b) Stork, G.; Rosen, P.; Goldman, N.; Coombs,
R. V.; Tsuji, J. J. Am. Chem. Soc. 1965, 87, 275–286. (c) Hiroya, K.;
Ichihashi, Y.; Furutono, A.; Inamoto, K.; Sakamoto, T.; Doi, T. J. Org.
Chem. 2009, 74, 6623–6630 and references cited therein.
Supporting Information Available. Detailed experi-
mental procedures, characterizations, and copies of
1H and 13C NMR spectra of all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
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