Rapid construction of [5-6-7] tricyclic ring skeleton of calyciphylline alkaloid daphnilongeranin B

Article abstract of DOI:10.1021/ol200312q

A concise photochemical [2 + 2] cycloaddition-Grob fragmentation sequence sets the common tricyclic ring skeletons of the Calyciphylline A-type alkaloids, particularly those in daphnilongeranins, daphniyunnines, and daphniglaucins.

Full text of DOI:10.1021/ol200312q

ORGANIC
LETTERS
2011
Vol. 13, No. 7
1812–1815
Rapid Construction of [5-6-7] Tricyclic
Ring Skeleton of Calyciphylline Alkaloid
Daphnilongeranin B
Chen Xu,† Zheng Liu,† Huifei Wang,† Bo Zhang,† Zheng Xiang,†,§ Xiaojiang Hao,*,‡ and
David Zhigang Wang*,†
Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology,
Shenzhen Graduate School of Peking University, Shenzhen University Town, Nanshan
District, Shenzhen, China 518055, and Kunming Institute of Botany, Chinese Academy
of Sciences, Kunming, China 650204
dzw@szpku.edu.cn haoxj@mail.kib.ac.cn
Received February 3, 2011
ABSTRACT
A concise photochemical [2 þ 2] cycloaddition-Grob fragmentation sequence sets the common tricyclic ring skeletons of the Calyciphylline
A-type alkaloids, particularly those in daphnilongeranins, daphniyunnines, and daphniglaucins.
Of the many fascinating natural products uncovered in
recent years, the Daphniphyllum class of alkaloids stood
out for their highly impressive structural diversities, stereo-
chemical complexities, and skeletal novelties. More than
200 members have been isolated from 13 species of the
genus Daphniphyllum.1 The biological functions and phar-
macological activities of these compounds have been
poorly studied so far due to their extremely limited natural
supply. These, however, wouldinvitefurtherinvestigations
since the relevant plant species themselves have long been
used in acclaimed traditional herbal medical formulations,
and several members had already been shown to have
meaningful cytotoxic2 and antioxidation3 properties and
enhancement effects on neurotrophic factor biosynthesis.4
Attracted by the synthetic challenges posed by these
structures, particularly those of the Daphniphyllum sub-
class Calyciphylline-type alkaloids5 including calyciphyl-
line A, daphnihlaucins, daphnilongeranins, and daphniyu-
nnines (Figure 1), we initiated a program aiming at total
syntheses of some members of this series of compounds.
Within this context, remarkably, as visualized by the
(4) (a) Saito, S.; Yahata, H.; Kubota, T.; Obara, Y.; Nakahata, N.;
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Y. T.; Wang, Y.; Wang, Y. H.; Zhang, Z.; Lu, Y.; Zhang, L.; Hao, X. J.
† Shenzhen Graduate School of Peking University.
‡ Kunming Institute of Botany.
€
§ Current address: The Jack H. Skirball Center for Chemistry & Proteo-
mics, the Salk Institute for Biological Studies, 10010 N. Torrey Pines Road,
La Jolla, CA 92037-1099.
J. Nat. Prod. 2007, 70, 1628–1631. (c) Chen, X.; Zhan, Z. J.; Yue, J. M.
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C. R.; Cheng, H. D.; Yue, J. M. J. Nat. Prod. 2006, 69, 79–82. (e) Zhang,
H.; Yang, S. P.; Fan, C. Q.; Ding, J.; Yue, J. M. J. Nat. Prod. 2006, 69,
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Yue, J. M. Org. Lett. 2009, 11, 4692–2695. (g) Morita, H.; Kobayashi, J.
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T.; Kobayashi, J. J. Nat. Prod. 2009, 72, 148–151. (j) Luo, D. Q.; Zhu,
W. L.; Yang, X. L.; Liang, S. J.; Cao, Z. R. Helv. Chim. Acta 2010, 93,
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(1) For a comprehensive overview, see: Kobayashi, J.; Kubota, T.
Nat. Prod. Rep. 2009, 26, 936–962.
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r
10.1021/ol200312q
Published on Web 03/09/2011
2011 American Chemical Society

structural inner connections highlighted in Figure 1, the
three types of alkaloids share the same [5-6-7] tricyclic
core skeleton 1. The importance of exploring a general
and efficient approach toward the rapid assembly of 1 is
controlling strategy in the facile construction of the tricyclic
core structure 1.
With daphnilongeranin B as a specific target, our syn-
thetic plan is briefly outlined in Scheme 1. We envisioned
that the southwestern piperidine ring could be constructed
through a relativelyroutine carbonyl-directedR-alkylation
protocol, and the northeastern [5-5] bicyclic cyclopente-
none unit could be installed with a tandem Pauson-K-
hand annulation-double bond shift sequence. These steps
would efficiently degrade the target into the neatly tricyclic
intermediate A. With the C-5 chirality (star-labeled below)
as a critical stereochemical control element, the seven-
membered ring in A could be accessed with a [2 þ 2] photo-
chemical cycloaddition event on allylic amine C, followed
by a ring-strain-driven Grob-type fragmentation8 collap-
sed through a trajectory illustrated in B. C itself would be
prepared by a Mannich-type9 condensation between an
appropriately functionalized iminium ion D and cyclopen-
tanedione. Finally, the required 1,3-transposition of amine
Scheme 1. Retrosynthetic Disconnections
Figure 1. Structural diversities of Calyciphylline alkaloids.
therefore immediately recognizable, as this motif potentially
may constitute the central platform on which the structure
and functionality complexities of these alkaloids might have
evolved. Up to this point, no total synthesis of any member
of these new alkaloid structures has been reported.6
Of several stereogenic centers present in these molecules,
up to seven (six carbon atom-centered, i.e., 1-2-3-4-5-7,
and one nitrogen atom-centered, i.e., 6) were found to be
densely and contiguously distributed on the bowl-shaped
framework of 1. Further inspection on 10s stereochemical
architecture revealed two interesting features: one, the ring
junctions within the tricyclic skeleton adopt cis-geometry;
and two, relative to the tricyclic plane, these stereogenic
centers were well differentiated into two contiguous “up”
and “down” sets (Figure 1) where such orientations flip at the
key C-5 chirality. These observations in turn inspired a
photochemical cycloaddition event7 as a key stereochemically
and alcohol functions could be achieved by an Overman
rearrangement10 on the carboximidate precursor E.
To examine the feasibility of the above strategies, a
synthesis in the forward direction was then pursued with
(S)-(þ)-carvone as an appropriate starting point. We
report herein our success in implementing these reaction
sequences for the construction of Calyciphylline [5-6-7]
tricyclic core structure 24 and its close analog 31 with two
vicinally positioned angular methyl groups (vide infra).
As summarized in Scheme 2, (S)-(þ)-carvone was con-
verted into allylic alcohol 13 with a known PtO2/H2 alkene
hydrogenation-LiAlH4 carbonyl reduction procedure.11
(8) (a) Prantz, K.; Mulzer, J. Chem. Rev. 2010, 110, 3741–3766.
(b) Weyerstahl, P.; Marschall, H. Comprehensive Organic Synthesis;
Trost, B. M., Ed.; Pergamon Press: Oxford, 1991; Vol. 6, pp 1044-1065.
(9) For a review on Mannich reactions, see: Arend, M.; Westermann,
B.; Risch, N. Angew. Chem., Int. Ed. 1998, 37, 1045–1070.
(10) (a) Overman, L. E. J. Am. Chem. Soc. 1976, 98, 2901–2910.
(b) Overman, L. E. Acc. Chem. Res. 1980, 13, 218–224. (c) Overman,
L. E. Angew. Chem., Int. Ed. 1984, 23, 579–586.
(6) For recent studies directed toward the total synthesis of new
Daphniphyllum alkaloids, see: (a) Ikeda, S.; Shibuya, M.; Kanoh, N.;
Iwabuchi, Y. Org. Lett. 2009, 11, 1833–1836. (b) Dunn, T. B.; Ellis,
J. M.; Kofink, C. C.; Manning, J. R.; Overman, L. E. Org. Lett. 2009, 11,
ꢀ
5658–5661. (c) Sole, D.; Urbaneja, X.; Bonjoch, J. Org. Lett. 2006, 7,
5461–5464. (d) Coldham, I.; Burrell, A. J. M.; Guerrand, H. D. S.;
Oram, N. Org. Lett. 2011, ASAP (DOI: 10.1021/ol102961x).
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J. D.; Bowen, C. M.; Liotta, F. Chem. Rev. 1995, 95, 2002–2020.
(c) Oppolzer, W. Acc. Chem. Res. 1982, 15, 135–141. (d) Crimmins,
M. T. Chem. Rev. 1988, 88, 1453–1473.
(11) (a) Sorensen, E. J.; Shipe, W. D. J. Am. Chem. Soc. 2006, 128,
7025–7035. (b) Bourque, L. E.; Cleary, P. A.; Woerpel, K. A. J. Am.
Chem. Soc. 2007, 129, 12602–12603.
Org. Lett., Vol. 13, No. 7, 2011
1813

Scheme 2. Synthesis of [5-6-7] Tricyclic Core 24
Scheme 3. Synthesis of [5-6-7] Tricyclic Core 31
single crystal X-ray analysis. Just as anticipated, the allylic
chirality in 19 (i.e., the C-5 chirality in 1) was capable of
directing anintramolecular [2 þ 2] cycloaddition through a
highly organized exo-alkene-enone transition state assem-
bly, thereby leading to 20 with essentially complete stereo-
chemical control over the four contiguous chiral centers on
its cyclobutane ring. It should be emphasized that the
success of this photochemical cycloaddition seemed to
depend sensitively on the electronic property of the N-
protecting group; MeOC(O) was found to be optimal in a
variety of substituents examined. The ketone carbonyl in 20
was reduced with NaBH4 to generate alcohol 21. 21 was
subsequently mesylated with MsCl/pyridine and subjected
to K2CO3-promoted Grob fragmentation (structured as
23); the tetracyclic rings collapsed rapidly to give the desired
tricyclic [5-6-7] core 24 in 77% yield over these two steps.
Execution of these reaction sequences in pursuit of
analogous structure 31 with the vicinally positioned angu-
lar methyl groups, however, had proven to be nontrivial
(Scheme 3). Although (S)-(þ)-carvone can be converted
to allylic carbamate 26 smoothly with the aid of a room-
temperature (i.e., no xylene refluxing was required herein)
Overman rearrangement driven presumably by the release
of quaternary steric congestion in the corresponding
imidate intermediate, 26 failed completely to react in a
similar manner as that defined in procedures from
16-18 of Scheme 2. It was only after extensive screening
had we eventually been able to identify Sn(NTf2)4 as a
viable Lewis acid14 that promoted the desired Mannich
13 Reacted with CCl3CN to yield an imidate which upon
heating in xylene rearrangedto16after methanolysis of the
resultant allylic trichloroacetamide 1512 intermediate, with
a total yield of 64% over the three-step sequence. 16 was
next transformed to 17 with MOMCl, which, under the
action of TBSOTf, underwent direct Mannich condensa-
tion with cyclopentanedione to give enone 18.13 It merits a
note here thatthe choice ofTBSOTfiscritical, as a range of
other Lewis acid promoters screened, such as TMSOTf,
TIPSOTf, TiCl4, BF3, all lead to significantly lower yields
or complicated mixtures. Direct photochemical irradiation
of 18 failed to give the desired cycloaddition product but
cleanly yielded the de Mayo-type diketone structure, so its
hydroxyl group was acylated first; the resultant 19 was
then subjected to photochemical irradiation with light of
a primary 254 nm (via medium-pressure Hg lamp) wave-
length in CH3CN to yield the expected [2 þ 2] cycloaddi-
tion product 20 in 49% yield. 20 Possesses a highly
congested [6-4-5-5] tetracyclic skeleton, and its absolute
stereochemistry was unambiguously established through
(12) For an important improvement on Overman rearrangement,
see: (a) Nishikawa, T.; Asai, M.; Ohyabu, N.; Isobe, M. J. Org. Chem.
1998, 63, 188–192. (b) Nishikawa, T.; Urabe, D.; Tomita, M.; Tsujimo-
to, T.; Iwabuchi, T.; Isobe, M. Org. Lett. 2006, 8, 3263–3266.
(13) Othman, R. B.; Bousquet, T.; Fousse, A.; Othman, M.; Dalla, V.
Org. Lett. 2005, 7, 2825–2828.
(14) Othman, R. B.; Affani, R.; Tranchant, M. J.; Antoniotti, S.;
~
Dalla, V.; Dunach, E. Angew. Chem., Int. Ed. 2010, 49, 776–780.
1814
Org. Lett., Vol. 13, No. 7, 2011

condensation between an iminium ion generated from
hydroxymethylated 26 (i.e., structure 27) and cyclopenta-
nedione, leading to enone 28 in 56% isolated yield. 28 was
next photocyclized to give tetracyclic ketone 29 with
comparable efficiency and stereoselectivity found pre-
viously in the transformation of 19 to 20. Upon ketone
reduction in 29, the stereostructure of 30 was again deter-
mined by single crystal X-ray analysis. Finally, Grob
fragmentation on mesylated 30 was triggered by K2CO3
in methanol to yield tricyclic [5-6-7] core 31 in 88%
overall yield.
In summary, with Overman rearrangement, Mannich
reaction, [2 þ 2] photochemical cycloaddition, and Grob
fragmentation as key steps, we have defined a concise and
highly stereoselective synthetic approach for the construc-
tion of [5-6-7] tricyclic core skeletons commonly found
in a range of the Daphniphyllum subclass Calyciphylline
A-type alkaloids, particularly those in calyciphylline A,
daphnihlaucins, daphnilongeranins, and daphniyunnines.
Central to the success reported here is the recognition that
C-5 allylic chirality plays a pivotal role in directing the
entire stereochemical course involved in the outlined se-
quences, thus significantly facilitating chirality control in a
highly congested polycyclic setting. Continued efforts to-
ward a total synthesis of daphnilongeranin B are currently
underway.
Acknowledgment. We thank the National Science
Foundation of China (Grants 20872004 and 20972008 to
D.Z.W. and 20672120 to X.J.H.), the National “973
Project” from the State Ministry of Science and Technol-
ogy, the Shenzhen Bureau of Science, Technology and
Information, and the Shenzhen “Shuang Bai Project” for
generous financial support.
Supporting Information Available. Experimental details
and procedures, compound characterization data, copies
1
of H, 13C, and 2D-NMR spectra for new compounds,
and X-ray crystallographic data. This material is available
free of charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 7, 2011
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