Tandem oxidative dearomatization/intramolecular Diels-Alder reaction for construction of the tricyclic core of palhinine A

Article abstract of DOI:10.1021/ol3007138

A concise construction of the 6/6/5 tricyclic core of Lycopodium alkaloid palhinine A (1) has been accomplished. The developed synthetic strategy featured a tandem oxidative dearomatization/intramolecular Diels-Alder reaction to construct C/D rings and an

Full text of DOI:10.1021/ol3007138

ORGANIC
LETTERS
2012
Vol. 14, No. 9
2293–2295
Tandem Oxidative Dearomatization/
Intramolecular DielsÀAlder Reaction
for Construction of the Tricyclic Core
of Palhinine A
Changgui Zhao,† Huaiji Zheng,† Peng Jing,† Bowen Fang,† Xingang Xie,*,† 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
xiexg@lzu.edu.cn; shexg@lzu.edu.cn
Received March 21, 2012
ABSTRACT
A concise construction of the 6/6/5 tricyclic core of Lycopodium alkaloid palhinine A (1) has been accomplished. The developed synthetic strategy
featured a tandem oxidative dearomatization/intramolecular DielsÀAlder reaction to construct C/D rings and an intramolecular 5-exo-trig radical
cyclization to install the B ring of palhinine A (1). The developed approach paves the way for the total synthesis of palhinine A (1).
The Lycopodium alkaloids are a group of diverse and
structurally related secondary metabolites. Most of them
possess unique and fascinating skeletal characteristics and a
variety of biological activities.1À3 Palhinine A (1) (Figure 1),
a novel C16N-type Lycopodium alkaloid, was isolated from
the whole plant of Palhinhaea cernua L. by Long et al. in
2010.4 The structure of 1 was disclosed to contain a unique
5/6/6/9 tetracyclic ring system by comprehensive NMR
spectroscopic analysis and a single-crystal X-ray study.
Figure 1. Structure of palhinine A (1).
Different from the fawcettimine-type Lycopodium alkaloid,
palhinine A represents the first example of a Lycopodium
alkaloid in which a new carbonÀcarbon bond formed
between C-16 and C-4.4 The highly compact arrangement
of the fused polycyclic structure of palhinine A and two
contiguous quaternary carbons (C-4 and C-12) served to be
a great challenge to the science of chemical synthesis and
attracted our research interest. Herein we report a concise
approach for the construction of the tricyclic core of
palhinine A (1) via a tandem oxidative dearomatization/
intramolecular DielsÀAlder(IMDA) reaction5 and 5-exo-
trig radical cyclization as key steps. The developed approach
paves the way for the total synthesis of target 1.
† Lanzhou University.
‡ Chinese Academy of Sciences.
(1) For recent reviews of the Lycopodium alkaloids, see: (a) Ayer,
W. A.; Trifonov, L. S. In The Alkaloids, Vol. 45; Cordell, G. A., Brossi,
A., Eds.; Academic Press: New York, 1994; p 233. (b) Ma, X.; Gang,
D. R. Nat. Prod. Rep. 2004, 21, 752. (c) Kobayashi, J.; Morita, H. In The
Alkaloids, Vol. 61; Cordell, G. A, Ed.; Academic Press: New York, 2005;
p 1. (d) Hirasawa, Y.; Kobayashi, J.; Morita, H. Heterocycles 2009, 77,
679. (e) Kitajima, M.; Takayama, H. Lycopodium Alkaloids: Isolation
€
and Asymmetric Synthesis in Topics in Current Chemistry; Knolker, H.-J.,
Ed.; Springer: Berlin, 2012; Vol. 309/2012, pp 1À31.
r
10.1021/ol3007138
2012 American Chemical Society
Published on Web 04/12/2012

Retrosynthetically, 1 was envisioned to be obtained
from 2 by an intramolecular Mitsunobu reaction or N-
alkylationreaction, and ketone 2 couldbeestablishedfrom
the tricyclic core 3 through several chemical transforma-
tions. As for tricyclic core 3, we expected that its five-
membered B ring could be constructed via radical cycliza-
tion from bromo ketal 4. Bicyclic bromo ketal 4 could be
realized via functional group transformation of ester 5
which in turn could be derived from phenol 6 via a tandem
oxidative dearomatization/IMDA reaction. Phenol 6
could easily be prepared from benzaldehyde 7 by a Wittig
reaction and further transformations (Scheme 1).
With compound 6 in hand, we then explored the key
tandem oxidative dearomatization/IMDA reaction for
construction of the bridged C/D rings. When phenol 6
and hydroxymethylacrylate were treated with PhI(OAc)2
in CH2Cl2, only the oxidative dearomatization product
acetate ketal 17was obtained. Wethen changed the oxidant
to PhI(OCOCF3)2 and performed the reaction at 0 °C. To our
delight, the tandem oxidative dearomatization/IMDA reac-
tion occurred smoothly to give the desired bicyclic intermedi-
ate 5 in 46% yield. The yield could be increased to 60% when
this reaction was performed at À78 °C and slowly warmed
to À50 °C for 2 h. Using this approach the bicyclic core and
two contiguous quaternary carbon atoms have been estab-
lished in a single step (Scheme 2).
Scheme 1. Retrosynthetic Analysis
Scheme 2. Synthesis of 5
Our synthesis started from the known benzaldehyde 7.6
Sequential transformations including the Wittig reaction
with carboethoxytriphenylphosphorane, hydrogenation,
and condensation with methylamine successfully provided
amide 9 in good yield (Scheme 2). Reduction of 9 with
lithium aluminum hydride, then protection of the resulting
amine, and subsequent removal of the MOM group with
6 N HCl afforded phenol 6in 72% overall yield in three steps.
Having succeeded in the preparation of the bridged ring
intermediate 5, we then turned our attention to construc-
tion of the B ring of palhinine A (Scheme 3). Initially, the
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Org. Lett., Vol. 14, No. 9, 2012

five-membered ring was proposed to be installed via an
R-carbonyl radical cyclization7 with the double bond.
Reduction of ketone 5 with NaBH4 followed by protection
of alcohol gave exclusively β-OMe ester 12. Subsquent treat-
ment of ester 12 with bromoiodomethane and n-BuLi
afforded bromo ketone 13. However, when ketone 13
was treated with tributyltin hydride and AIBN in toluene
at 120 °C for 3 h, the radical cyclization reaction did not occur
but debromination product 14 was obtained in high yield.
Maybe this was due to the carbonyl-substituted radicals
being more stable than their alkyl-substituted counterparts.8
ether 15 by treatment withLDA/Me2SO4.11 Inthis manner
the overall yield increased to 49% from ester 12. Methoxy
bromination of 15 with NBS/MeOH12 gave bromo ketal 4
which smoothly underwent an intramolecular 5-exo-trig
radical cyclization to afford tetracyclic ketal 16 in 72%
overall yield in two steps. This strategy for the construction
of the B ring using a radical cyclization reaction may
provide a new access to establish other fawcettimine-type
Lycopodium alkaloids. Finally, removal of the ketal pro-
tecting group gave tricyclic core 3in 96% yield. The structural
validity of the tetracyclic product 16 was confirmed by X-ray
single crystallographic analysis as shown in Scheme 4.
Scheme 3. Radical Cyclization Reaction
Scheme 4. Synthesis of Tricyclic Core 3
With this idea in mind, it was desirable to synthesize
bromo ketal 4. Treatment of ester 12 with Tebbe’s
reagents9 afforded the methyl enol ether 15. However this
transformation did not occur at 0 °C or room temperature;
when it was heated to reflux, the reaction mixture became
complex and only 30% of product 15 was isolated. Thus, a
two-step sequence was applied to prepare 15. Treatment of
12 with TMSCH2Li and quenching with MeOH gave
methyl ketone 1410 which was converted to methyl enol
Inconclusion, a conciseapproach for construction of the
tricyclic core of palhinine A (1) has been demonstrated.
The developed synthetic sequence features a tandem oxi-
dative dearomatization/IMDA reaction to stereoselec-
tively construct the bridged ring and two contiguous all-
carbon quarternary centers followed by a radical cycliza-
tion reaction to form the B ring. Application of this
strategy to the synthesis of palhinine A is ongoing in our
laboratory.
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Acknowledgment. We are grateful for the generous
financial support by the MOST (2010CB833200), the
NSFC (21125207, 21072086, 21102062), and program 111.
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Supporting Information Available. Experimental pro-
cedures and characterization data for all compounds.
This material is available free of charge via the Internet
at http://pubs.acs.org.
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The authors declare no competing financial interest.
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