Biomimetic Syntheses of (±)-Isopalhinine A, (±)-Palhinine A, and (±)-Palhinine D

Article abstract of DOI:10.1002/anie.201809130

The first total synthesis of isopalhinine A, as well as unified syntheses of palhinine A and palhinine D, were successfully accomplished by means of a biomimetic strategy that proceeds through a bioinspired 5/6/6/9 tetracyclic intermediate, which mimics t

Full text of DOI:10.1002/anie.201809130

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Biomimetic Syntheses of (±)-Isopalhinine A, (±)-Palhinine A, and
(±)-Palhinine D
Authors: Chih-Ming Chen, Hui-Yi Shiao, Biing-Jiun Uang, and Hsing-
Pang Hsieh
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201809130
Angew. Chem. 10.1002/ange.201809130
Link to VoR: http://dx.doi.org/10.1002/anie.201809130
http://dx.doi.org/10.1002/ange.201809130

10.1002/anie.201809130
Angewandte Chemie International Edition
COMMUNICATION
Biomimetic Syntheses of (±)-Isopalhinine A, (±)-Palhinine A, and
(±)-Palhinine D
Chih-Ming Chen, Hui-Yi Shiao, Biing-Jiun Uang and Hsing-Pang Hsieh*
Dedicated to Professor Chun-Chen Liao on the occasion of his 75th birthday
Abstract: The first total synthesis of isopalhinine A, as well as
unified syntheses of palhinine A and palhinine D, have been
successfully accomplished by way of a biomimetic strategy that
proceeds through a bio-inspired 5/6/6/9 tetracyclic intermediate,
which mimics the amino ketone form of palhinine D. An early-stage
direct SN2 cyclization to construct the nine-membered azonane ring
minimized the transannular strain which would otherwise be
increased by the twisted nature of the isotwistane skeleton; then, a
diastereoselective Diels-Alder reaction of
benzoquinone using the nine-membered ring as a steric shielding
group furnished functionalized 6/6/9 tricyclic skeleton and
a
masked ortho-
a
established the desired stereochemistry at the C3, C7, C12, and
C15 positions in one step. A thiol-mediated acyl radical cyclization
gave the bio-inspired intermediate bearing three differentiated
oxygen-containing functional groups, from which all three total
syntheses could be completed in either two or three additional steps.
Palhinine is a unique Lycopodium alkaloid, the structure of
which resembles fawcettimine (Scheme 1). Structurally, it differs
from the other Lycopodium alkaloids: a carbon-carbon bond
between C4 and C16 forms an unusual isotwistane skeleton
(tricyclo[4.3.1.03,7]decane, 5/6/6 tricycle). To date, five palhinine
alkaloids, isopalhinine A (1) and palhinines A-D (2-5),[1] have
been isolated from Palhinhaea cernua L. and Lycopodium
japonicum Thunb. by Long,[1a] Zhao,[1b] and Yu.[1c, 1d] Palhinines
Scheme 1. Proposed biosyntheses of the palhinine alkaloids.[1b]
ortho-benzoquinone (MOB) followed by radical cyclization
(She);[2c] and (3) a domino Michael reaction followed by an
intramolecular aldol reaction (Maier).[2d] Recently, Fan et al.
further developed their Diels-Alder chemistry and achieved total
syntheses of palhinines A (2) and D (5) via an elegant auxiliary
construction/deconstruction approach.[3] Herein, we report an
alternative, biomimetic synthetic strategy through a bio-inspired
5/6/6/9 intermediate that constitutes a more efficient approach
for the preparation of palhinines A (2) and D (5), and also
resulted in the first total synthesis of isopalhinine A (1).
The biosynthesis of palhinine D (5) (Scheme 1) is believed to
take place from fawcettimine[1b, 4] by cleavage of the hemiaminal,
six-membered ring formation, and introduction of a hydroxyl
group at the C3 position. Isopalhinine A (1) can be obtained by
oxidation of the aminol ketone form of palhinine D (5) to install a
carbonyl group at the C6 position, followed by hemiaminalization
at the C5 position; and palhinine A (2) can be synthesized by
methylation at the secondary amine of the azonane ring. We
envisioned a bio-inspired 5/6/6/9 tetracyclic intermediate 6
(Scheme 2b) that mimics the aminol ketone form of palhinine D
(5), and from which total syntheses of isopalhinine A (1),
palhinine A (2), and palhinine D (5) should be possible. In
previous syntheses of the fawcettimine alkaloids, direct
construction of the nine-membered azonane ring was
successfully achieved in the hydrindane skeleton, but failed in
the isotwistane skeleton by either N-substitution or ring-closing
metathesis, presumably due to the twisted nature of the
isotwistane skeleton increasing transannular strain.[3] Fan et al.
sought to mitigate transannular interactions through use of an
intramolecular [3+2] cycloaddition to synthesize a hexacyclic
A-C (2-4) possess
a
5/6/6/9 tetracyclic skeleton, and
isopalhinine A (1) and palhinine D (5) contain a more complex
5/6/6/6/7 pentacyclic ring system; this caged architecture is
formed through hemiaminalization of the carbonyl group at either
the C5 or C13 position and the secondary amine of the nine-
membered azonane ring. Although the bioactivities are unclear,
the densely functionalized isotwistane architecture and in
particular the vicinal quaternary carbons atoms (C4 and C12)
have attracted a great deal of attention, and three strategies[2]
have been developed for its construction: (1) a one-step,
intramolecular Diels-Alder (IMDA) reaction of cyclohexadiene
(Fan[2a] and Rychnovsky);[2b] (2) an IMDA reaction of a masked
[*]
C.-M. Chen, Dr. H.-Y. Shiao, Prof. Dr. H.-P. Hsieh
Institute of Biotechnology and Pharmaceutical Research
National Health Research Institutes
Miaoli County 35053, Taiwan
E-mail: hphsieh@nhri.org.tw
C.-M. Chen, Prof. Dr. B.-J. Uang, Prof. Dr. H.-P. Hsieh
Department of Chemistry
National Tsing Hua University
Hsinchu 30013, Taiwan
This article is protected by copyright. All rights reserved.

10.1002/anie.201809130
Angewandte Chemie International Edition
COMMUNICATION
intermediate, which added either five or six additional steps to
the divergent syntheses of palhinines A (2) and D (5) (Scheme
2a). Accordingly, we planned to install the nine-membered ring
before the isotwistane; our retrosynthesis of the 5/6/6/9
tetracyclic intermediate 6 is depicted in Scheme 2b. Intermediate
6 was disconnected through the C4—C5 bond to give the
tricyclic aldehyde 7, where we envisaged the formation of the
isotwistane skeleton through a radical cyclization between the
aldehyde and alkene moieties. Aldehyde 7 was anticipated to be
synthesized by the regio- and stereoselective Diels-Alder
reaction of MOB 8 and acrolein 9,[5] followed by homologation;
TBS protection to afford silyl ether 14.[7] Nucleophilic addition of
acetonitrile gave nitrile 15, reduction of which gave the
corresponding 1,3-hydroxyaminopropane; the primary amine
and benzylic alcohol were protected by Boc and TBS groups,
respectively. Hydroboration-oxidation of the terminal alkene 16
provided the corresponding primary alcohol, which was treated
with mesyl chloride to give the mesylate 17. The direct SN2
cyclization of mesylate 17 was carried out by the addition of
excess sodium hydride in THF under high temperature,[6]
followed by quenching with methanol to achieve a selective
deprotection product, ortho-methoxyphenol 18, in one pot.[8]
With ortho-methoxyphenol 18 in hand, we attempted to
synthesize the radical cyclization precursor aldehyde 20
(Scheme 4) by oxidative dearomatization of ortho-
methoxyphenol 18 using PhI(OAc)2 to generate MOB 21,
followed by Diels-Alder (DA) reaction with 3-butenol to obtain the
DA adduct 19, and oxidation. However, the yield of the desired
DA adduct 19 was only 12%, presumably due to the poor
dienophilicity of 3-butenol. Alternatively, use of the electron-
deficient dienophile acrolein 9 significantly increased the yield of
the desired endo DA adduct 22 (73% isolated yield); the
diastereoselectivity of the reaction was determined by isolation
yield to be 3:1 (22:3-epi-22). The structure of the major
diastereomer 22 was determined by X-ray crystallography,[9]
and MOB
8
by oxidative dearomatization of ortho-
methoxyphenol 10. Closure of the nine-membered azonane ring
of phenol 10 was planned by an efficient SN2 cyclization of
mesylate 11, prepared from isovanillin 12.
The synthesis of protected amine 18 starting from
commercially available isovanillin 12 by direct intramolecular N-
substitution[6] is depicted in Scheme 3. Allylation of isovanillin 12
gave allyl ether 13, which underwent Claisen rearrangement and
Scheme 3. Direct SN2 cyclization to construct 9-membered azonane ring.
Scheme 2. Retrosynthetic analysis of isopalhinine A (1), palhinine A (2), and
palhinine D (5). TBS = tert-butyl(dimethyl)silyl, Bn = benzyl, Boc = tert-
butyloxycarbonyl, Ms = methanesulfonyl.
DMF
= N,N-dimethylformamide, THF = tetrahydrofuran, LAH = lithium
aluminium hydride.
This article is protected by copyright. All rights reserved.

10.1002/anie.201809130
Angewandte Chemie International Edition
COMMUNICATION
Scheme 4. A regio- and stereoselective Diels-Alder reaction for assembly of
the 6/6/9 tricyclic skeleton.
which confirmed that the relative configurations at the C3, C7,
C12 and C15 positions were all consistent with the palhinine
alkaloids. The acrolein dienophile is proposed to approach the
MOB from its less hindered side due to the increased steric bulk
of the azonane ring compared to the TBS protecting group, to
give the requisite DA adduct diastereomer.
Scheme 5. Isotwistane construction by thiol-mediated acyl radical cyclization
to furnish common 5/6/6/9 tetracyclic intermediate 28. AIBN
azobisisobutyronitrile, PTSA = p-toluenesulfonic acid.
=
Wittig olefination and hydrolysis of the DA adduct 22 gave the
radical cyclization precursor aldehyde 20, Scheme 5. Initially, we
attempted to generate the ketyl radical from aldehyde 20 by
treatment with SmI2, followed by radical cyclization with the
alkene moiety and simultaneous reductive demethoxylation of
the geminal dimethoxy groups (also with SmI2) to provide the
tetracyclic intermediate 24 in one step. However, no desired
cyclization product was isolated, even after treatment with
nBu3SnH/AIBN, followed by SmI2. Presumably, either the TBS-
protecting group was too bulky or the twist angle of the alkene
moiety too great (due to the germinal dimethoxy groups) for the
radical cyclization to take place. However, removal of the TBS-
protecting group and geminal dimethoxy groups separately or
together using tetra-n-butylammonium fluoride (TBAF) and/or
SmI2 followed by radical cyclization was still unsuccessful. After
consideration of these results, we hypothesized that the ketone
group in the bicyclo[2.2.2]octenone may have either a mutually
stabilizing effect on the alkene moiety via a through-space -
interaction that disfavors radical cyclization; or a ring strain effect,
wherein cyclization with a sp2 ketone at C13 is associated with a
higher activation energy than cyclization with a sp3 alcohol at
C13. To obviate this problem, the geminal dimethoxy group of
enol ether 23 was first removed by SmI2 to give ketone 25,
which was reduced with NaBH4 to give alcohol 26. Hydrolysis of
enol ether 26 to the desired aldehyde 27 was first investigated
using catalytic HCl in CHCl3, but an intractable mixture of
products was obtained. Use of catalytic PTSA, however, yielded
the desired aldehyde 27 in high yield. With aldehyde 27 in hand,
we started our pursuit of 5/6/6/9 tetracyclic intermediate 28, and
use of a thiol-mediated acyl radical cyclization (Tomioka’s
method)[10] yielded the desired bio-inspired intermediate 28 in
61% yield. The 5/6/6/9 caged structure was further confirmed by
X-ray crystallographic analysis.[11] Most importantly, the thiol-
mediated acyl radical cyclization facilitated the formation of the
desired intermediate 28 bearing three differentiated oxygen-
containing functional groups at the C3, C5, and C13 positions,
which allowed further pursuit of the syntheses of isopalhinine A
(1), palhinine A (2) and palhinine D (5) without the need to
differentiate between oxygen-containing functional groups.
Tetracyclic intermediate 28 was used in the total syntheses of
isopalhinine A (1), palhinine A (2), and palhinine D (5), Scheme
6. Dione 29, precursor of palhinines A (2) and D (5), was
obtained by Dess-Martin periodinane (DMP) oxidation of 28.
One-pot deprotection of both the TBS and Boc groups was
achieved under heterogeneous acidic conditions with sat. HCl in
a mixed solvent (H2O:toluene = 1:5) at high temperature. The
secondary amine of the azonane ring then underwent a
spontaneous intramolecular aza-ketalization at the C13 position
to give palhinine D (5). Consistent with the proposed biomimetic
pathway, we successfully obtained palhinine A (2) from palhinine
D (5) by its reductive amination with formaldehyde – the first
This article is protected by copyright. All rights reserved.

10.1002/anie.201809130
Angewandte Chemie International Edition
COMMUNICATION
diastereoselective Diels-Alder reaction with MOB proceeded
under substrate control to establish the functionalized 6/6/9
tricyclic core with the desired stereochemistry at the C3, C7,
C12, and C15 positions. It is worth mentioning that the thiol-
mediated acyl radical cyclization method not only delivered the
cyclopentanone of the 5/6/6/9 tetracyclic intermediate 28, but
also three different oxygen-containing functional groups (O-TBS
at the C3 position; ketone at the C5 position; secondary alcohol
at the C13 position) of biomimetic intermediate 28, one of which
(the C5 ketone) allowed direct installation of the oxygen atom at
the C6 position by -hydroxylation of the cyclopentanone, and
hence the synthesis of isopalhinine A (1) as well as that of
palhinines A (2) and D (5) in two or three additional steps.
Overall, this study provides a concise method for assembling the
functionalized isotwistane natural product via a Diels-Alder
reaction with MOB and a thiol-mediated acyl radical cyclization
between aldehyde and olefin.
Acknowledgements
The authors acknowledge the financial support by National
Health Research Institutes and Ministry of Science and
Technology, Taiwan (MOST-106-2113-M-400-001). We thank
Prof. Chun-Chen Liao (National Tsing Hua University, Taiwan)
for valuable comments regarding masked ortho-benzoquinones
and their corresponding Diels-Alder adducts, and Dr. Kak-Shan
Shia (National Health Research Institutes, Taiwan) and Dr. Yung
Chang-Hsu (National Health Research Institutes, Taiwan) for
valuable comments regarding radical cyclizations. Special
thanks to Dr. Lun Kelvin Tsou (National Health Research
Institutes, Taiwan) for critical comments and manuscript editing.
We also thank Mr. Ting-Shen Kuo (National Taiwan Normal
University, Taiwan) for assistance with X-ray crystallographic
analysis, and Ms. Ju-Lan Peng (National Tsing Hua University,
Taiwan) for assistance with 600 MHz NMR spectroscopy.
Special thanks to Dr. Richard Guy for English proofreading and
editing.
Scheme 6. Biomimetic syntheses of isopalhinine A (1), palhinine A (2), and
palhinine D (5). DMP = Dess–Martin periodinane, KHMDS = potassium
hexamethyldisilazide.
direct synthesis of palhinine A (2) from palhinine D (5).
The synthesis of isopalhinine
A
(1) from tetracyclic
intermediate 28 required installation of a carbonyl group at the
C6 position, which was accomplished by Davis -
hydroxylation[12] followed by DMP oxidation to afford the trione
32. Isopalhinine A (1) was obtained after the removal of both
protecting groups of trione 32, followed by spontaneous
selective intramolecular aza-ketalization. 1H and 13C NMR
spectral data of our synthetic isopalhinine A (1) were consistent
with that previous isolated; and X-ray crystallography showed
that the secondary amine formed a hemiaminal with carbonyl of
the C5 position to give an architecturally complex 5/6/6/6/7
Keywords: biomimetic synthesis •cyclization •isotwistane
•masked ortho-benzoquinone •radical reaction
[1]
a) F.-W. Zhao, Q.-Y. Sun, F.-M. Yang, G.-W. Hu, J.-F. Luo, G.-H. Tang,
Y.-H. Wang, C.-L. Long, Org. Lett. 2010, 12, 3922-3925; b) L.-B. Dong,
X. Gao, F. Liu, J. He, X.-D. Wu, Y. Li, Q.-S. Zhao, Org. Lett. 2013, 15,
3570-3573; c) X.-J. Wang, L. Li, S.-S. Yu, S.-G. Ma, J. Qu, Y.-B. Liu, Y.
Li, Y. Wang, W. Tang, Fitoterapia 2013, 91, 74-81; d) X.-J. Wang, L. Li,
S.-S. Yu, S.-G. Ma, J. Qu, Y.-B. Liu, Y. Li, Y. Wang, W. Tang,
Fitoterapia 2016, 114, 194.
pentacyclic
structure.[13]
Compared
this
interesting
intramolecular cyclization result with hemiaminalization at C13
position in palhinine D (5), however, in isopalhinine A (1)
intramolecular cyclization result in hemiaminalization at the C5
position due to the thermodynamic instability of the 1,2-diketone
functionality.
In conclusion, the first total synthesis of isopalhinine A (1), as
well as unified syntheses of palhinines A (2) and D (5), have
been achieved by way of a biomimetic strategy and a common
intermediate 28, starting from isovanillin. Early-stage
construction of the nine-membered azonane ring minimized the
transannular strain, which would be increased in the twisted
structure of the isotwistane skeleton; and the subsequent
[2]
[3]
a) G.-B. Zhang, F.-X. Wang, J.-Y. Du, H. Qu, X.-Y. Ma, M.-X. Wei, C.-
T. Wang, Q. Li, C.-A. Fan, Org. Lett. 2012, 14, 3696-3699; b) N.
Sizemore, S. D. Rychnovsky, Org. Lett. 2014, 16, 688-691; c) C. Zhao, H.
Zheng, P. Jing, B. Fang, X. Xie, X. She, Org. Lett. 2012, 14, 2293-2295;
d) D. Gaugele, M. E. Maier, Synlett 2013, 24, 955-958.
F.-X. Wang, J.-Y. Du, H.-B. Wang, P.-L. Zhang, G.-B. Zhang, K.-Y. Yu,
X.-Z. Zhang, X.-T. An, Y.-X. Cao, C.-A. Fan, J. Am. Chem. Soc. 2017,
139, 4282-4285.
[4]
[5]
X. Ma, D. R. Gang, Nat. Prod. Rep. 2004, 21, 752-772.
a) C.-C. Liao, R. K. Peddinti, Acc. Chem. Res. 2002, 35, 856-866; b) H.-
Y. Shiao, H.-P. Hsieh, C.-C. Liao, Org. Lett. 2008, 10, 449-452; c) N. A.
Harry, S. Saranya, K. K. Krishnan, G. Anilkumar, Asian J. Org. Chem.
2017, 6, 945-966.
[6]
P. R. Leger, R. A. Murphy, E. Pushkarskaya, R. Sarpong, Chem. Eur. J.
2015, 21, 4377-4383.
This article is protected by copyright. All rights reserved.

10.1002/anie.201809130
Angewandte Chemie International Edition
COMMUNICATION
[7]
a) S. Chandrasekhar, D. Basu, M. Sailu, S. Kotamraju, Tetrahedron Lett.
2009, 50, 4882-4884; b) B. Dulla, N. D. Tangellamudi, S.
Balasubramanian, S. Yellanki, R. Medishetti, R. Kumar Banote, G. Hari
Chaudhari, P. Kulkarni, J. Iqbal, O. Reiser, M. Pal, Org. Biomol. Chem.
2014, 12, 2552-2558.
It is worth mentioning that when two equivalents of sodium hydride was
used, a low yield of the cyclization product was obtained, and additional
TBAF was added for selective deprotection of the TBS protecting group
on phenol. The optimal reaction conditions were found to entail eight
equivalents of sodium hydride, followed by addition of methanol to give
63% of desired cyclized and selectively deprotected product 18.
CCDC 1859045 (22) contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre.
[10]
[11]
a) K. Yoshikai, T. Hayama, K. Nishimura, K. Yamada, K. Tomioka, J.
Org. Chem. 2005, 70, 681-683; b) D.-S. Hsu, C.-H. Chen, C.-W. Hsu,
Eur. J. Org. Chem. 2016, 2016, 589-598.
CCDC 1859047 (28) contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre.
F. A. Davis, L. C. Vishwakarma, J. G. Billmers, J. Finn, J. Org. Chem.
1984, 49, 3241-3243.
CCDC 1859048 (1) contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre.
[8]
[12]
[13]
[9]
This article is protected by copyright. All rights reserved.

10.1002/anie.201809130
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Layout 1:
COMMUNICATION
Key steps for the synthesis of the core
Author(s), Corresponding Author(s)*
5/6/6/9
tetracyclic
skeleton
for
Page No. – Page No.
palhinine alkaloids include (a) an
early-stage direct SN2 cyclization to
minimized the transannular strain, (b)
Title
a
diastereoselective
Diels-Alder
reaction to furnish 6/6/9 tricyclic
structure, and (c) an acyl radical
cyclization to complete the 5/6/6/9
tetracyclic core architecture.
Layout 2:
COMMUNICATION
Author(s), Corresponding Author(s)*
Page No. – Page No.
Title
Text for Table of Contents
This article is protected by copyright. All rights reserved.