Toward the total synthesis of palhinine A: Expedient assembly of multifunctionalized isotwistane ring system with contiguous quaternary stereocenters

Article abstract of DOI:10.1021/ol301534r

The stereoselective, expedient assembly of the key functionalized isotwistane (bridged tricyclo[4.3.1.0^3,7]decane) system, 5/6/6 ring, with contiguous quaternary stereocenters in Lycopodium alkaloid palhinine A and its analogues via an intramol

Full text of DOI:10.1021/ol301534r

ORGANIC
LETTERS
2012
Vol. 14, No. 14
3696–3699
Toward the Total Synthesis of Palhinine A:
Expedient Assembly of Multifunctionalized
Isotwistane Ring System with Contiguous
Quaternary Stereocenters
Guo-Biao Zhang, Fang-Xin Wang, Ji-Yuan Du, Hu Qu, Xiao-Yan Ma, Meng-Xue Wei,
Cheng-Tao Wang, Qiong Li,† and Chun-An Fan*
State Key Laboratory of Applied Organic Chemistry, College of Chemistry and
Chemical Engineering, Lanzhou University, 222 Tianshui Nanlu, Lanzhou 730000,
China, and State Key Laboratory of Natural and Biomimetic Drugs, Peking University,
38 Xueyuan Lu, Beijing100191, China
fanchunan@lzu.edu.cn
Received June 4, 2012
ABSTRACT
The stereoselective, expedient assembly of the key functionalized isotwistane (bridged tricyclo[4.3.1.03,7]decane) system, 5/6/6 ring, with contiguous
quaternary stereocenters in Lycopodium alkaloid palhinine A and its analogues via an intramolecular DielsÀAlder strategy is described.
The Lycopodium alkaloids1 are unique heterocyclic mol-
ecules possessing high structural diversity and significant
pharmaceutical potential, and many of them have at-
tracted great interest from biogenetic and synthetic points
of view.2 As a novel C16N-type Lycopodium alkaloid
recently isolated from Palhinhaea cernua L. by Long,
Wang et al.,3 palhinine A (Figure 1) with a structure
† Current address: School of Pharmacy, Lanzhou University, Lanzhou
730000, China.
(1) For some leading reviews, see: (a) Ayer, W. A. Nat. Prod. Rep.
1991, 8, 455. (b) Ayer, W. A.; Trifonov, L. S. Lycopodium Alkaloids. In
The Alkaloids: Chemistry and Pharmacology; Cordell, G. A., Brossi, A.,
Eds.; Academic Press: San Diego, CA, 1994; Vol. 45, Chapter 3, pp
233À266. (c) Kobayashi, J.; Morita, H. The Lycopodium Alkaloids. In
Figure 1. Diverse ring systems in representative major classes of
The Alkaloids: Chemistry and Biology; Cordell, G. A., Ed.; Elsevier: San
Lycopodium alkaloids.
Diego, CA, 2005; Vol. 61, Chapter 1, pp 1À57. (d) Tan, C.-H.; Zhu, D.-Y.
Chin. J. Nat. Med. 2003, 1, 1. (e) Ma, X.; Gang, D. R. Nat. Prod. Rep.
2004, 21, 752. (f) Hirasawa, Y.; Kobayashi, J.; Morita, H. Heterocycles
partially related to the fawcettimine-type alkaloids1e is
featured by a unique 5/6/6/9 tetracyclic ring system con-
2009, 77, 679.
(2) For selected reviews on the synthesis of Lycopodium alkaloids,
see: (a) Blumenkopf, T. A.; Heathcock, C. H. Synthesis of Lycopodium
Alkaloids. In Alkaloids: Chemical and Biological Perspectives; Pelletier,
taining an unusual bridged carbonÀcarbon bond between
S. W., Ed.; Wiley: New York, 1985; Vol. 3, pp 185À240. (b) Kitajima, M.;
C-4 and C-16, which was elucidated by comprehensive
spectroscopic methods and confirmed further by single-
crystal X-ray diffraction analysis. Such a fused-bridged
Takayama, H. Top. Curr. Chem. 2012, 309, 1.
(3) Zhao, F.-W.; Sun, Q.-Y.; Yang, F.-M.; Hu, G.-W.; Luo, J.-F.;
Tang, G.-H.; Wang, Y.-H.; Long, C.-L. Org. Lett. 2010, 12, 3922.
r
10.1021/ol301534r
Published on Web 07/10/2012
2012 American Chemical Society

polycyclic structure of palhinine A is architecturally un-
precedented in Lycopodium alkaloids, and its topological
molecular skeleton having five stereogenic centers, two of
which (C-4 and C-12) are quaternary, is characterized with
a functionalized isotwistane nucleus4À10 (rings B/C/D,
tricyclo[4.3.1.03,7]decane), providing an interesting and
challenging target for the synthetic community.
precursor8À10 is yet to be explored in the synthetic study
of palhinine A. Herein, we report our preliminary efforts
toward the expedient and straightforward access to the
densely functionalized isotwistane framework by using an
intramolecular DielsÀAlder strategy.8,9,13
Very recently, an elegant strategy for the stepwise con-
struction of therelatedisotwistane corehasbeendeveloped
by Xie, She et al.11 on the basis of tandem oxidative
dearomatization/intramolecular DielsÀAlder reaction
(rings C and D)12 and the later-stage 5-exo-trig radical
cyclization4 (ring B). However, the direct assembly of this
kind of functionalized isotwistane ring system with con-
tiguous quaternary stereocenters from a monocyclic
Scheme 1. Retrosynthetic Analysis of Palhinine A
(4) For selected examples on the construction of the isotwistane core
via 5-exo-trig radical cyclization from the bicyclo[2.2.2]octane system,
see: (a) Srikrishna, A.; Reddy, T. J. J. Chem. Soc., Perkin Trans. 1 1997,
3293. (b) Njardarson, J. T.; Wood, J. L. Org. Lett. 2001, 3, 2431. (c)
Matsushita, T.; Ashida, H.; Kimachi, T.; Takemoto, Y. Chem. Commun.
2002, 814. (d) Singh, V.; Pal, S.; Mobin, S. M. J. Org. Chem. 2006, 71,
3014 and ref 11.
(5) For selected examples on the construction of the isotwistane core
via carbenoid CÀH insertion from the bicyclo[2.2.2]octane system, see:
(a) Spiegel, D. A.; Njardarson, J. T.; Wood, J. L. Tetrahedron 2002, 58,
6545. (b) Srikrishna, A.; Satyanarayana, G. Tetrahedron 2005, 61, 8855.
(6) For selected examples on the construction of the isotwistane
core via Pinacol coupling from the bicyclo[2.2.2]octane system, see:
Yoshimitsu, T.; Sasaki, S.; Arano, Y.; Nagaoka, H. J. Org. Chem. 2004,
69, 9262.
(7) For selected examples on the construction of the isotwistane core
via intramolecular alkylation from the bicyclo[4.3.0]nonane system, see:
(a) Corey, E. J.; Behforouz, M.; Ishiguro, M. J. Am. Chem. Soc. 1979,
101, 1608. (b) Hsieh, S.-L.; Chiu, C.-T.; Chang, N.-C. J. Org. Chem.
1989, 54, 3820.
Retrosynthetically, the isotwistane A (Scheme 1)
constitutes the key building block for the synthesis of
palhinine A and its analogues. Logically, its nine-
membered azonane ring could be conceived by a pro-
tocol involving the hydroborationÀoxidation and amina-
tion from the synthon A1 or the chemoselective allylation,
olefinic oxidative cleavage, and amination from the
synthon A2. The crucial tricyclic core in A1 and A2
could be formally envisioned by intramolecular
DielsÀAlder cycloaddition of the rationally designed
B1 and B2, which could be properly derived from
the readily available substituted cyclohexenone C.
It should be noted that the key stereoselective intra-
molecular DielsÀAlder strategy proposed here would
synthetically rationalize the present disconnection,
providing an alternative consideration for the straight-
forward reestablishment of the isotwistane framework
of palhinine A as well as its structurally related mole-
cules. The proposed disconnection approach from the
bridged tricyclic core A2 to triene synthon B2 might be
more synthetically interesting due to the elaborated
installation of oxygen functional groups requisite for
the synthetic study of palhinine A.
(8) For selected examples on the construction of the isotwistane core
via an intramolecular DielsÀAlder reaction from the cyclohexadiene
system, see: (a) Yamamoto, H.; Sham, H. L. J. Am. Chem. Soc. 1979,
101, 1609. (b) Schiehser, G. A.; White, J. D. J. Org. Chem. 1980, 45, 1864.
(c) Magnus, P.; Brown, P. J. Chem. Soc., Chem. Commun. 1985, 184. (d)
Takasu, K.; Mizutani, S.; Ihara, M. J. Org. Chem. 2002, 67, 2881.
(9) For selected examples on the construction of the isotwistane core
via an intramolecular DielsÀAlder reaction from the cyclohexadienone
system, see: (a) Krantz, A.; Lin, C. Y. J. Am. Chem. Soc. 1973, 95, 5662.
ꢀ
(b) Macas, T. S.; Yates, P. Tetrahedron Lett. 1983, 24, 147. (c) Frater, G.;
Wenger, J. Helv. Chim. Acta 1984, 67, 1702. (d) Bhamare, N. K.;
Granger, T.; Macas, T. S.; Yates, P. J. Chem. Soc., Chem. Commun.
1990, 739. (e) Njardarson, J. T.; McDonald, I. M.; Spiegel, D. A.; Inoue,
M.; Wood, J. L. Org. Lett. 2001, 3, 2435. (f) Spangler, J. E.; Sorensen,
E. J. Tetrahedron 2009, 65, 6739. (g) Mitasev, B.; Porco, J. A., Jr. Org.
Lett. 2009, 11, 2285.
(10) For selected examples on the construction of the isotwistane core
via Michael addition/Aldol reaction from the cyclohexenone system,
see: Niwa, H.; Wakamatsu, K.; Hida, T.; Niiyama, K.; Kigoshi, H.;
Yamada, M.; Nagase, H.; Suzuki, M.; Yamada, K. J. Am. Chem. Soc.
1984, 106, 4547.
(11) Zhao, C.; Zheng, H.; Jing, P.; Fang, B.; Xie, X.; She, X. Org.
Lett. 2012, 14, 2293.
(12) For selected reviews on the oxidative dearomatization/intramo-
lecular DielsÀAlder reaction, see: (a) Liao, C.-C.; Peddinti, R. K. Acc.
Chem. Res. 2002, 35, 856. (b) Liao, C.-C. Pure Appl. Chem. 2005, 77,
1221 and references therein.
(13) For some reviews on the intramolecular DielsÀAlder reaction in
organic synthesis, see: (a) Funk, R. L.; Vollhardt, K. P. C. Chem. Soc.
Rev. 1980, 9, 41. (b) Brieger, G.; Bennet, J. N. Chem. Rev. 1980, 80, 63. (c)
Ciganek, E. Org. React. 1984, 32, 1–374. (d) Roush, W. R. Intramole-
cular Diels-Alder Reactions. In Comprehensive Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon Press: New York, 1991; Vol. 5, pp
513À550. (e) Winkler, J. D. Chem. Rev. 1996, 96, 167. (f) Bear, B. R.;
Sparks, S. M.; Shea, K. J. Angew. Chem., Int. Ed. 2001, 40, 820. (g)
Corey, E. J. Angew. Chem., Int. Ed. 2002, 41, 1650. (h) Nicolaou, K. C.;
Snyder, S. A.; Montagnon, T.; Vassilikogiannakis, G. Angew. Chem.,
Int. Ed. 2002, 41, 1668. (i) Takao, K.-i.; Munakata, R.; Tadano, K.-i.
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4381. (k) Juhl, M.; Tanner, D. Chem. Soc. Rev. 2009, 38, 2983.
Initially to address the feasibility of the efficient con-
struction of functionally simplified tricyclic isotwistane
core A1 from C (Scheme 1), we started with known
enone 114 (Scheme 2). Disubstituted cyclohexenone 2 was
(14) (a) Patterson, J. W. Tetrahedron 1993, 49, 4789. (b) Mphahlele,
M. J.; Modro, T. A. J. Org. Chem. 1995, 60, 8236.
Org. Lett., Vol. 14, No. 14, 2012
3697

Based on the above-mentioned positive results for the
simplified cycloaddition model (B1fA1, Scheme 1), a
synthetic pathway for establishing fully functionalized
isotwistane synthon A2 (Scheme 1) was then explored.
The synthesis commenced with Sakurai allylation16 of read-
ily available enone 620 (Scheme 3), and the disubstituted
Scheme 2. Synthesis of Tricyclic Synthon (()-A1
Scheme 3. Synthesis of Tricyclic Synthon (()-A2
accessed in two steps using an alkylation StorkÀDanheiser
approach.15 The olefinic ketone (()-3 bearing the all-
carbon quaternary center was accessed by Sakurai
allylation16 in 68% yield. With (()-3 in hand, the regio-
selective R,β-dehydrogenation of ketone was conducted
by using the combined protocol involving the kinetic
deprotonationÀsilylation of (()-3 and the subsequent
hypervalent iodine-mediated oxidation17 of the resulting
crude silyl enol ether, delivering the desired enone (()-4 in
37% yield over two steps. Treatment of enone (()-4 with
TMSCl in the presence of NEt3 and DMF at 90 °C resulted
in formation of a silyl enol ether. The resulting diene
was directly subjected to a thermally promoted (150 °C)
intramolecular DielsÀAlder reaction. This approach af-
forded the desired isotwistane core (()-A1 in 60% yield
over two steps, proceeding through transition state TS-1
followed by in situ hydrolysis during column chromato-
graphy on silica gel. The relative stereochemistry of tricyc-
lic isotwistane (()-A1 was unambiguously confirmed by
X-ray crystallographic analysis of (()-5 (Figure 2),18
which was obtained in four steps (reduction, silyl protec-
tion, hydroborationÀoxidation, and iodination) from
(()-A1.19
ketone (()-721 was obtained in 82% yield. With (()-7 in
hand, osmium-catalyzed dihydroxylation followed by
NaIO4-mediated oxidative cleavage22 afforded aldehyde
(16) (a) Hosomi, A.; Sakurai, H. J. Am. Chem. Soc. 1977, 99, 1673. (b)
Hosomi, A. Acc. Chem. Res. 1988, 21, 200.
(17) Nicolaou, K. C.; Gray, D. L. F.; Montagnon, T.; Harrison, S. T.
Angew. Chem., Int. Ed. 2002, 41, 996.
(18) CCDC-883176 for (()-5 and CCDC-884247 for (()-13 contain
the supplementary 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.
(19) For details, see the Supporting Information.
(20) For a four-step synthetic protocol to access the enone 6, see the
Supporting Information. Literaturally, the enone 6 was already known:
Taber, D. F.; Sheth, R. B. J. Org. Chem. 2008, 73, 8030.
(21) The chiral 7 could be also accessed by a formal asymmetric
conjugate allylation of enones recently reported by Taber et al. This
synthetically available chiral synthon will alternatively lead the way for
the future study of asymmetric synthesis of palhinine A. Taber, D. F.;
Gerstenhaber, D. A.; Berry, J. F. J. Org. Chem. 2011, 76, 7614.
(22) Pappo, R.; Allen, D. S., Jr.; Lemieux, R. U.; Johnson, W. S.
J. Org. Chem. 1956, 21, 478.
Figure 2. X-ray crystallographic analysis of (()-5.
(15) Stork, G.; Danheiser, R. L. J. Org. Chem. 1973, 38, 1775.
3698
Org. Lett., Vol. 14, No. 14, 2012

one-step derivatization of (()-12b (hydrogenolysis followed
by in situ ketalization).19 Finally, the removal of TBS
protection of (()-12a and (()-12b, followed by Swern
oxidation,26 accomplished the expedient stereoselective
synthesis of (()-A2, which is a synthetically important
building block for the study of the total synthesis of
palhinine A.
In conclusion, a straightforward synthetic strategy
based on the rationally designed intramolecular DielsÀ
Alder reaction has been developed for the efficient assem-
bly of a multifunctionalized isotwistane ring system with
contiguous all-carbon quaternary centers in Lycopodium
alkaloid palhinine A and its deoxy analogue. Of our two
approaches, the 10-step synthetic route involving (()-A2
willbe particularly interestingfor the synthesisof palhinine
A, due to not only the flexibility of installation of func-
tional groups requisite for its total synthesis but also the
feasibility of asymmetric synthesis using the known chiral
synthon.21 Presently, the synthetic study of palhinine A
using this strategy is actively under investigation in our
laboratory.
Figure 3. X-ray crystallographic analysis of (()-13.
(()-8 in 83% yield. Subsequently, the nickel-catalyzed
NozakiÀHiyamaÀKishi reaction23 was used to chemo-
selectively couple (()-8 and tert-butyldimethylsilyl 2-iodo-
allyl ether (CH2dC(I);CH2O;TBS),24 affording the
desired allylic alcohol (()-9 in 76% yield. Following the
TBS protection of (()-9, the enone (()-11 was formed from
(()-10 through the kinetic enolizationÀsilylation and Pd-
(OAc)2-mediated SaegusaÀIto oxidation.25 Upon treat-
ment of (()-11 with the previously optimized conditions
for thermodynamic silyl enol etherification, the resulting
silyl ether diene underwent the key intramolecular DielsÀ
Alder cycloaddition via energetically favorable TS-2 at
180 °C, followed by in situ hydrolysis during column
chromatography on silica gel, giving two separable diaster-
eoisomers (()-12a and (()-12b in a combined yield of 65%.
The stereochemical assignment of the more polar (()-12a
and the less polar (()-12b was further made using X-ray
crystallography of (()-13 (Figure 3).18 This was achieved by
Acknowledgment. We are grateful for financial support
from NSFC (20802030 and 21072082), the Major Inter-
national (Regional) Joint Research Project of NSFC
(20921120404), the 973 Program of MOST (2010C-
B833200), the Fok Ying Tung Education Founda-
tion (121015), the Key Project of Chinese Ministry of
Education (109154), PCSIRT (IRT1138), NCET (NCET-
08-0254), the 111 Project of MOE (111-2-17), the Funda-
mental Research Funds for the Central Universities
(lzujbky-2010-k09 and lzujbky-2012-k39), and Lanzhou
University. We also thank the reviewers for their comments.
(23) (a) Okude, Y.; Hirano, S.; Hiyama, T.; Nozaki, H. J. Am. Chem.
Soc. 1977, 99, 3179. (b) Jin, H.; Uenishi, J.-i.; Christ, W . J.; Kishi, Y.
J. Am. Chem. Soc. 1986, 108, 5644. (c) Takai, K.; Tagashira, M.;
Kuroda, T.; Oshima, K.; Utimoto, K.; Nozaki, H. J. Am. Chem. Soc.
1986, 108, 6048. For selected reviews, see: (d) Kishi, Y. Pure Appl. Chem.
Supporting Information Available. Experimental pro-
cedures, characterization data for all new compounds,
and X-ray crystallographic data in CIF format. This
material is available free of charge via the Internet at
http://pubs.acs.org.
€
1992, 64, 343. (e) Furstner, A. Chem. Rev. 1999, 99, 991. (f) Saccomano,
N. A. Organochromium Reagents. In Comprehensive Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon Press: New York, 1991; Vol. 1, pp
173À209.
(26) Oumra, K.; Sharma, A. K.; Swern, D. J. Org. Chem. 1976, 41, 957.
(24) For the preparation of 2-iodo-allyl alcohol, see: Irifune, S.;
Kibayashi, T.; Ishii, Y.; Ogawa, M. Synthesis 1988, 366.
(25) Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011.
The authors declare no competing financial interest.
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