A bifunctional lewis acid induced cascade cyclization to the tricyclic core of ent-kaurenoids and its application to the formal synthesis of (±)-platensimycin

Article abstract of DOI:10.1021/ol3033412

A mild and efficient bifunctional Lewis acid induced cascade cyclization reaction has been developed for construction of the tricyclic core of ent-kaurenoids. With ZnBr₂ as the bifunctional Lewis acid, a series of substituted enones and dienes underwent cascade cyclization smoothly at room temperature and provided the tricyclic products in one pot with good yields (75-91%) and high diastereoselectivity. The cyclized product has been successfully employed for the formal synthesis of (±)-platensimycin.

Full text of DOI:10.1021/ol3033412

ORGANIC
LETTERS
2013
Vol. 15, No. 3
524–527
A Bifunctional Lewis Acid Induced
Cascade Cyclization to the Tricyclic Core
of ent-Kaurenoids and Its Application
to the Formal Synthesis of
(()-Platensimycin
Lizhi Zhu, Yejian Han, Guangyan Du, and Chi-Sing Lee*
Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology,
Peking University Shenzhen Graduate School, Shenzhen University Town, Xili,
Shenzhen 518055, China
lizc@pkusz.edu.cn
Received December 6, 2012
ABSTRACT
A mild and efficient bifunctional Lewis acid induced cascade cyclization reaction has been developed for construction of the tricyclic core of
ent-kaurenoids. With ZnBr2 as the bifunctional Lewis acid, a series of substituted enones and dienes underwent cascade cyclization smoothly at
room temperature and provided the tricyclic products in one pot with good yields (75À91%) and high diastereoselectivity. The cyclized product
has been successfully employed for the formal synthesis of (()-platensimycin.
ent-Kaurene, including the 6,7-seco-ent-kaurene (Figure 1),
is one of the major skeletons in diterpenes that was derived
from ent-copalyl pyrophosphate (CPP).1 This class of
natural products exhibited a variety of important biologi-
cal activities such as antibacterial, cytotoxic, anti-inflam-
matory, and immuno-suppressive properties.2 The tricyclic
fused ring system I is an important structural motif of the
ent-kaurenoids (Figure 1).3 It could also be rapidly trans-
formed into the cage structures of platensimycin4 1 and
platencin5 2, which are potent antibiotics against methi-
cillin-resistant Staphylococcus aureus (MRSA) and vanco-
mycin-resistant Enterococcus (VRE) via inhibition of fatty
acid biosynthesis in FASII4À6 and have attracted a tre-
mendous amount of synthetic efforts.7À9 A recent study
suggested that the biosynthesis of 1 involved an ent-
kaurene type intermediate that was also derived from
CPP.10 Due to the structural diversity and the intriguing
biological activities of these ent-kaurene related natural
products, we have decided to develop a bifunctional Lewis
acid induced cascade cyclization reaction for rapid con-
struction of the ent-kaurene framework, which could
(1) Coates, R. M.; Bertram, E. F. J. Org. Chem. 1971, 36, 3722–3729.
(2) Sun, H.-D.; Huang, S.-X.; Han, Q.-B. Nat. Prod. Rep. 2006, 23,
673–698.
(3) (a) Qasseem, M. A.; Rogers, N. A. J.; Othman, A. A. Tetrahedron
1968, 24, 4535–4542. (b) Corey, E. J.; Liu, K. Tetrahedron Lett. 1997, 38,
7491–7494. (c) Toyota, M.; Wada, T.; Fukumoto, K.; Ihara, M. J. Am.
Chem. Soc. 1998, 120, 4916–4925.
(4) Wang, J.; Soisson, S. M.; Young, K.; Shoop, W.; Kodali, S.;
Galgoci, A.; Painter, R.; Parthasarathy, G.; Tang, Y.; Cummings, R.;
Ha, S.; Dorso, K.; Motyl, M.; Jayasuriya, H.; Ondeyka, J.; Herath, K.;
Zhang, C.; Hernandez, L.; Alloco, J.; A’BasilioTormo, J. R.; Genilloud,
O.; Vicente, F.; Pelaez, F.; Colwell, L.; Lee, S. H.; Michael, B.; Felcetto,
T.; Gill, C.; Silver, L. L.; Hermes, J.; Bartizal, K.; Barrett, J.; Schmatz,
D. J.; Becker, W.; Cully, D.; Singh, S. B. Nature 2006, 441, 358–361.
(5) Wang, J.; Kodali, S.; Lee, S. H.; Galgoci, A.; Painter, R.; Dorso, K.;
Racine, F.; Motyl, M.; Hernandez, L.; Tinney, E.; Colletti, S.; Herath,
K.; Cummings, R.; Salazar, O.; Gonzalez, I.; Basilio, A.; Vicente, F.;
Genilloud, O.; Pelaez, F.; Jayasuriya, H.; Young, K.; Cully, D.; Singh,
S. B. Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 7612–7616.
€
(6) (a) Habich, D.; von Nussbaum, F. ChemMedChem 2006, 1, 951–
954. (b) Brown, E. D. Nature 2006, 441, 293–294. (c) Pearson, H. Nature
2006, 441, 260–261. (d) Brinster, S.; Lamberet, G.; Staels, B.; Trieu-Cuot,
P.; Gruss, A.; Poyart, C. Nature 2009, 458, 83–86. (e) Martens, E.; Demain,
A. L. J. Antibiot. 2011, 64, 705–710.
r
10.1021/ol3033412
Published on Web 01/17/2013
2013 American Chemical Society

provide a general and efficient synthetic entry to this class
of natural products.
Bifunctional Lewis acids11 are very useful for developing
cascade cyclization reactions since they could induce cycli-
zation reactions via forming σ- and/or π-complexes with
the substrates as well as the intermediate(s) that were
generated in situ. We are particularly interested in devel-
oping bifunctional Lewis acid induced cascade cyclization
reactions for natural product synthesis since it can usually
construct the core structure of the synthetic target in a
single operation under mild conditions.12 Recently, we
have developed the ZnBr2 catalyzed DielsÀAlder/carbo-
cyclization cascade cyclization reaction for rapid construc-
tion of cis-hydrindanes and demonstrated its utilities in
natural product synthesis.12c As such, we have decided to
employ this strategy for developing new cascade cycliza-
tion reactions that could quickly access the tricyclic core of
ent-kaurene related natural products I. As shown in Figure 2,
Figure 1. Examples of ent-kaurene related natural products.
(7) For reviews on synthetic efforts towards platensimycin and
platencin, see: (a) Tiefenbacher, K.; Mulzer, J. Angew. Chem., Int. Ed.
2008, 47, 2548–2555. (b) Manallack, D. T.; Crosby, I. T.; Khakham, Y.;
Capuano, B. Curr. Med. Chem. 2008, 15, 705–710. (c) Yao, Y.-S.; Yao,
Z.-J. Chin. J. Org. Chem. 2008, 28, 1553–1560. (d) Harsh, P.; O’Doherty,
G. A. Chemtracts 2009, 22, 31–40. (e) Lu, X.; You, Q. Curr. Med. Chem.
2010, 17, 1139–1155. (f) Palanichamy, K.; Kaliappan, K. P. Chem.;
Asian J. 2010, 5, 668–703. Also see: (g) Nicolaou, K. C.; Chen, J. S. D.;
Edmonds, J.; Estrada, A. A. Angew. Chem., Int. Ed. 2009, 48, 660–719.
(g) Nicolaou, K. C.; Chen, J. S.; Dalby, S. M. Bioorg. Med. Chem. 2009,
17, 2290–2303.
our strategy involved a Lewis acid induced DielsÀAlder
(DA) cycloaddition of enone III and IV with diene V. The
resulting silyl enol ether of the DA adducts VI and VII
could undergo intramolecular carbocyclization with the
alkyne to form the bicyclo[3.2.1]octane moiety of I and II
in a one-pot manner. This strategy required a mild
bifunctional Lewis acid that can form σ-complexes
with enone III/IV for inducing DA cycloaddition and
π-complexes with intermediate VI/VII for inducing car-
bocyclization without causing hydrolysis of silyl enol
(8) For synthetic studies on platensimycin and its analogs, see:
(a) Nicolaou, K. C.; Li, A.; Edmonds, D. J. Angew. Chem., Int. Ed.
2006, 45, 7086–7090. (b) Nicolaou, K. C.; Edmonds, D. J.; Li, A.; Tria,
G. S. Angew. Chem., Int. Ed. 2007, 46, 3942–3945. (c) Zou, Y.; Chen,
C.-H.; Taylor, C. D.; Foxman, B. M.; Snider, B. B. Org. Lett. 2007, 9,
1825–1828. (d) Kaliappan, K. P.; Ravikumar, V. Org. Lett. 2007, 9,
2417–2419. (e) Nicolaou, K. C.; Tang, Y.; Wang, J. Chem. Commun.
2007, 1922–1923. (f) Li, P.; Payette, J. N.; Yamamoto, H. J. Am. Chem.
Soc. 2007, 129, 9534–9535. (g) Ghosh, A. K.; Kai, X. Org. Lett. 2007, 9,
4013–4016. (h) Tiefenbacher, K.; Mulzer, J. Angew. Chem., Int. Ed. 2007,
46, 8074–8075. (i) Lalic, G.; Corey, E. J. Org. Lett. 2007, 9, 4921–4923.
(j) Nicolaou, K. C.; Lister, T.; Denton, R. M.; Montero, A.; Edmonds,
D. J. Angew. Chem., Int. Ed. 2007, 46, 4712–4714. (k) Nicolaou, K. C.;
Tang, Y.; Wang, J.; Stepan, A. F.; Li, A.; Montero, A. J. Am. Chem. Soc.
2007, 129, 14850–14851. (l) Nicolaou, K. C.; Pappo, D.; Tsang, K. Y.;
Gibe, R.; Chen, D. Y.-K. Angew. Chem., Int. Ed. 2008, 47, 944–946.
(m) Kim, C. H.; Jang, K.; Choi, P. S.; Chung, Y. Y. K.; Lee, E. Angew.
Chem., Int. Ed. 2008, 47, 4009–4011. (n) Matsuo, J.; Takeuchi, K.;
Ishibashi, H. Org. Lett. 2008, 10, 4049–4052. (o) Yeung, Y.-Y.; Corey,
E. J. Org. Lett. 2008, 10, 3877–3878. (p) Nicolaou, K. C.; Stepan, A. F.;
Lister, T.; Li, A.; Montero, A.; Tria, G. S.; Turner, C. I.; Tang, Y.;
Wang, J. R.; Denton, M.; Edmonds, D. J. J. Am. Chem. Soc. 2008, 130,
13110–13119. (q) Yun, S. Y.; Zheng, J.-C.; Lee, D. J. Am. Chem. Soc.
2009, 131, 8413–8415. (r) Ghosh, A. K.; Xi, K. J. Org. Chem. 2009, 74,
1163–1170. (s) Nicolaou, K. C.; Li, A.; Ellery, S. P.; Edmonds, D. J.
Angew. Chem., Int. Ed. 2009, 48, 6293–6295. (t) McGrath, N. A.;
Bartlett, E. S.; Sittihan, S.; Njardarson, J. T. Angew. Chem., Int. Ed.
2009, 48, 8543–8546. (u) Nicolaou, K. C.; Li, A.; Edmonds, D. J.; Tria,
G. S.; Ellery, S. P. J. Am. Chem. Soc. 2009, 131, 16905–16918. (v) Shen,
H. C.; Ding, F.-X.; Singh, S. B.; Parthasarathy, G.; Soisson, S. M.; Ha,
S. N.; Chen, X.; Kodali, S.; Wang, J.; Dorso, K.; Tata, J. R.; Hammond,
M. L.; MacCoss, M.; Colletti, S. L. Bioorg. Med. Chem. Lett. 2009, 19,
1623–1627. (w) Wang, J.; Lee, V.; Sintim, H. O. Chem.;Eur. J. 2009, 15,
2747–2750. (x) Jang, K. P.; Kim, C. H.; Na, S. W.; Kim, H.; Kang, H.;
Lee, E. Bioorg. Med. Chem. Lett. 2009, 19, 4601–4602. (y) Tiefenbacher,
K.; Trondlin, L.; Mulzer, J.; Pfaltz, A. Tetrahedron 2010, 66, 6508–6513.
(z) Eey, S. T.-C.; Lear, M. J. Org. Lett. 2010, 12, 5510–5513. (aa)
Magnus, P.; Rivera, H.; Lynch, V. Org. Lett. 2010, 12, 5677–5679.
(ab) Oblak, E. Z.; Wright, D. L. Org. Lett. 2011, 13, 2263–2265. (ac)
Wang, J.; Sintim, H. O. Chem.;Eur. J 2011, 17, 3352–3357. For
synthesis of side chain, see: (ad) Heretsch, P.; Giannis, A. Synthesis
2007, 2614–2616. (ae) Maras, N.; Anderluh, P. S.; Urleb, U.; Kocevar,
M. Synlett 2009, 437–440. (af) McNulty, J.; Nair, J. J.; Capretta, A.
Tetrahedron Lett. 2009, 50, 4087–4091.
(9) For synthesis of platencin and its analogs, see: (a) Nicolaou,
K. C.; Tria, G. S.; Edmonds, D. J. Angew. Chem., Int. Ed. 2008, 47, 1780–
1783. (b) Hayashida, J.; Rawal, V. H. Angew. Chem., Int. Ed. 2008, 47,
4373–4376. (c) Tiefenbacher, K.; Mulzer, J. Angew. Chem., Int. Ed. 2008,
47, 2548–2555. (d) Yun, S. Y.; Zheng, J.-C.; Lee, D. Angew. Chem., Int.
Ed. 2008, 47, 6201–6203. (e) Waalboer, D. C. J.; Schaapman, M. C.; van
Delft, F. L.; Rutjes, F. P. J. T. Angew. Chem., Int. Ed. 2008, 47, 6576–
6578. (f) Nicolaou, K. C.; Toh, Q.-Y.; Chen, D. Y.-K. J. Am. Chem. Soc.
2008, 130, 11292–11293. (g) Austin, K. A. B.; Banwell, M. G.; Willis,
A. C. Org. Lett. 2008, 10, 4465–4468. (h) Varseev, G. N.; Maier, M. E.
Angew. Chem., Int. Ed. 2009, 48, 3685–3688. (i) Tiefenbacher, K.;
Mulzer, J. J. Org. Chem. 2009, 74, 2937–2941. (j) Barykina, O. V.; Rossi,
K.; Rybak, L. M. J.; Snider, B. B. Org. Lett. 2009, 11, 5334–5337.
(k) Ghosh, A. K.; Xi, K. Angew. Chem., Int. Ed. 2009, 48, 5372–5375.
(l) Nicolaou, K. C.; Tria, G. S.; Edmonds, D. J.; Kar, M. J. Am. Chem.
Soc. 2009, 131, 15909–15917. (m) Hirai, S.; Nakada, M. Tetrahedron
Lett. 2010, 51, 5076–5079. (n) Singh, V.; Sahu, B. C.; Bansal, V.; Mobin,
S. M. Org. Biomol. Chem. 2010, 8, 4472–4481. (o) Li, P.; Yamamoto, H.
Chem. Commun. 2010, 46, 6294–6295. (p) Waalboer, D. C. J.; Leenders,
S. H. A. M.; Schuelin-Casonato, T.; van Delft, F. L.; Rutjes, F. P. J. T.
Chem.;Eur. J. 2010, 16, 11233–11236. (q) Tiefenbacher, K.; Gollner,
A.; Mulzer, J. Chem.;Eur. J. 2010, 16, 9616–9622. (r) Leung, G. Y. C.;
Li, H.; Toh, Q.-Y.; Ng, A. M.-Y.; Sum, R. J.; Bandow, J. E.; Chen, D.
Y.-K. Eur. J. Org. Chem. 2011, 183–196. (s) Hirai, S.; Nakada, M.
Tetrahedron 2011, 67, 518–530. (t) Yoshimitsu, T.; Nojima, S.; Hashimoto,
M.; Tanaka, T. Org. Lett. 2011, 13, 3698–3701. (u) Palanichamy, K. A.;
Subrahmanyam, V.; Kaliappan, K. P. Org. Biomol. Chem. 2011, 9, 7877–
7886.
(10) (a) Herath, K.; Attygalle, A. B.; Singh, S. B. J. Am. Chem. Soc.
2007, 129, 15422–15423. (b) Smanski, M. J.; Yu, Z.; Casper, J.; Lin, S.;
Peterson, R. M.; Chen, Y.; Wendt-Pienkowski, E.; Rajski, S. R.; Shen,
B. Proc. Natl. Acad. Sci. U.S.A. 2007, 108, 13498–13503.
(11) (a) Yamamoto, Y. J. Org. Chem. 2007, 72, 7817–7831. (b) Itoh,
Y.; Tsuji, H.; Yamagata, K.-i.; Endo, K.; Tanaka, I.; Nakamura, M.;
Nakamura, E. J. Am. Chem. Soc. 2008, 130, 17161–17167.
(12) (a) Peng, W.; Lee, C.-S. Synlett 2008, 142–146. (b) Li, W.; Liu,
X.; Zhou, X.; Lee, C.-S. Org. Lett. 2010, 12, 548–551. (c) Han, Y.; Zhu,
L.; Lee, C.-S. Org. Lett. 2011, 13, 588–591. (d) Huang, S.; Du, G.; Lee,
C.-S. J. Org. Chem. 2011, 76, 6534–6541.
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ether V and VI/VII. We herein reported the development
of a new two-component cascade cyclization reaction for
establishing the 6,6,5-tricyclic fused ring system I in one
pot and its application to the formal synthesis of
(()-platensimycin 1.
Scheme 1. Screening of Bifunctional Lewis Acids
cyclized product 5f in good yield (entry 6). This result
suggested that the sterically demanding substrate IV
(Figure 2) could also be cyclized to provide tetracyclic
fused ring system II (Figure 2) under this cyclization
condition. Introducing an OTBS moiety at C5 afforded
5g also in good yield and diastereoselectivity (entry 7).
These results indicated that these substituted enones and
dienes not only afford comparable results but also provide
a handle for developing asymmetric reactions via substrate
control. Moreover, the seven-membered enone 3h also
gave cyclized product 5h in good yield and diastereoselec-
tivity (entry 8), which could be a useful building block for
the synthesis of grayanane-type diterpenes.15 Diene 4b,
which bears two methyl substituents at the reaction site
(C6), alsosmoothlyunderwent DAcycloadditionand gave
the cyclized product (5i) as a single diastereomer14 (entry 9).
The potential side product that arose from the Michael
addition between 3a and 4b was not observed under this
reaction condition. Diene 4c bears a methyl group at C7
(the reaction site for the carbocyclization) affording the
cyclized product 5j also in very good yield (91%) and
diastereoselectively (entry 10).
To demonstrate the utilities of this cascade cyclization
reaction, diketone 5a was employed as the building block
for the synthesis of platensimycin 1. As shown in Scheme 2,
diketone 5a was first converted to the di-TMS enol ether 6.
Epoxidation using magnesium monoperoxyphthalate
(MMPP) provided R-hydroxy ketone 7 selectively in
65% yield along with 20% of 5a being recovered. Hydroxyl-
directed reduction of the ketone moiety of 7 followed by
elimination of the resulting diol afforded 8 in good
yields.16 Silyl enol formation followed by MMPP epox-
idation of 8 provided R-hydroxyl ketone 9 as a single
diastereomer, which can be equilibrated to the more
stable R-hydroxyl ketone 10 qualitatively upon prolonged
treatment with acid. The R-hydroxylation and equilibration
can be done conveniently in a one-pot manner, and the
diastereomer bearing the trans-decalin was not observed
under these reaction conditions. The resulting alcohol of
10 was then acetylated and deacetoxylated using SmI2.
Finally, reduction of ketone 11 with K-selectride followed
Figure 2. A bifunctional Lewis acid induced cascade cyclization
approach to the skeleton of ent-kaurenoids.
Since we have previously demonstrated that both In(III)
and Zn(II) are useful bifunctional Lewis acids for inducing
cascade cyclization reactions,12 the reaction between enone
3a and diene 4a was studied using a variety of In(III) and
Zn(II) based Lewis acids. As shown in Scheme 1, In(III)
halides or triflates in acetonitrile led to the side product via
hydration ofthe alkyne moietyof3aevenunderanhydrous
conditions. These results indicated that the ketone moiety
could be cyclized with the activated alkyne and form an
unstable cyclic enol ether, which could be hydrolyzed to
form the methyl ketone side product upon workup.
Switching the solvent to dichloromethane resulted in rapid
decomposition of the substrates. No reaction was observed
by using Zn(II) halides in acetonitrile. Finally, we found
that the cascade cyclization went smoothly by using Zn(II)
halides in dichloromethane and afforded the tricyclic
product 5a bearing the cis-declain efficiently and diaster-
eoselectively. The optimal conditions were found to be 1.5
equiv of ZnBr2 in CH2Cl2 at room temperature for 12 h.
These mild conditions afforded the expected cyclized
product 5a in 86% yield as a single diastereomer. The
stereochemistry of the cyclized product 5a was character-
ized unambiguously by NMR experiments13 and X-ray
crystallography.14
With the optimal conditions in hand, the scope of the
substrates was studied with a series of substituted enones
(3aÀh) and dienes (4aÀc). As shown in Table 1, the methyl
substituents at C1 to C4 of the enone are well tolerated and
gave comparable yields and diastereoselectivities of the
cyclized products (5bÀe) (entries 2À5). More importantly,
the geminal dimethyl substituent at C3 also afforded
(13) The NMR data are available in the Supporting Information.
(14) CCDC-909564 (5a) and CCDC-909565 (5i) contain the supple-
mentary crystallographic data for this paper. These data can be obtained
free of charge from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
(15) Chen, S. L.; Zhang, H. P.; Wang, L. Q.; Bao, G. H.; Qin, G. W.
J. Nat. Prod. 2004, 67, 1903–1906.
(16) (a) Garegg, P. J.; Samuelsson, B. Synthesis 1979, 813–814.
(b) Liu, A.; Liu, Z. Z.; Zou, Z. M.; Chen, S. Z.; Xu, L. Z.; Yang, S. L.
Tetrahedron 2004, 60, 3689–3694.
526
Org. Lett., Vol. 15, No. 3, 2013

Table 1. Study on the Scope of Substratesa
Scheme 2. Formal Formal Synthesis of (()-Platensimycin 1
In summary, we have developed a mild bifunctional
Lewis acid induced cascade cyclization reaction for rapid
construction of the tricyclic core of ent-kaurene. With
ZnBr2 (1.5 equiv) in CH2Cl2 at room temperature, a
variety of substituted enones 3aÀh and dienes 4aÀc under-
went cascade cyclization smoothly and afforded the cy-
clized products 5aÀj in one pot with good yields and high
diastereoselectivity. The utilities of this new reaction have
been successfully demonstrated by employing cyclized
product 5a as the precursor for the formal synthesis of
(()-platensimycin 1 (32% overall yields for the Snider
intermediate 12 in 11 steps from cyclized product 5a).
We are currently studying the cascade cyclization for
construction of the tetracyclic system and exploring its
utilities in the synthesis of other bioactive ent-kaurene
related natural products.
Acknowledgment. This work is supported by the Na-
tional Natural Science Foundation of China (Grant No.
21272012), Shenzhen Science and Technology Innovation
Commission of the People’s Government of Shenzhen
Municipality (ZDSY20120614144410389), and the Peking
University Shenzhen Graduate School.
a The general procedures were followed. b Isolated yields. c Single
diastereomer.
Supporting Information Available. Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
by treatment of trifloroacetic acid8m afforded the Snider
intermediate8c 12, which could be converted to 1 accord-
ing to the literature procedures.8a,c
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 3, 2013
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