Highly efficient synthesis of phenanthroquinolizidine alkaloids via Parham-type cycliacylation

Article abstract of DOI:10.1016/j.tetlet.2009.12.135

A concise and efficient route involving Parham-type cycliacylation as the key step has been used to synthesize phenanthroquinolizidine alkaloids 1a-c and 2a-c. Among the products, 1b-(S), 1b-(R), 2a-(14aS,15S), 2a-(14aR,15R), and 2b were synthesized for the first time.

Full text of DOI:10.1016/j.tetlet.2009.12.135

Tetrahedron Letters 51 (2010) 1377–1379
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Highly efficient synthesis of phenanthroquinolizidine alkaloids
via Parham-type cycliacylation
*
Ziwen Wang, Qingmin Wang
State Key Laboratory of Elemento-Organic Chemistry, Research Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
A concise and efficient route involving Parham-type cycliacylation as the key step has been used to syn-
thesize phenanthroquinolizidine alkaloids 1a–c and 2a–c. Among the products, 1b-(S), 1b-(R), 2a-
(14aS,15S), 2a-(14aR,15R), and 2b were synthesized for the first time.
Received 6 November 2009
Revised 22 December 2009
Accepted 29 December 2009
Available online 7 January 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Phenanthroquinolizidine alkaloids
Synthesis
Parham-type cycliacylation
Phenanthroquinolizidine alkaloids are a small group of alka-
loids existing in the Lauraceae, Vitaceae, and Urticaceae families of
plants. Only five of these alkaloids (À)-cryptopleurine [1c-(R)],
boehmeriasin A [1b-(dl)], boehmeriasin B (Fig. 1), (À)-(15R)-
hydroxycryptopleurine [2c-(14aR,15R)], and cryptopleuridine
(Fig. 1) have been isolated by now.1 It has been reported that these
alkaloids possess unique and interesting biological properties
including vesicant, antimicrobial, antiviral, and anticancer activi-
ties.1a,j–l,2 We have previously reported that these alkaloids possess
excellent antiviral activity against the tobacco mosaic virus
(TMV).3 To extend our research on phenanthroquinolizidine alka-
loids as antiviral agents, we developed an efficient approach to
the preparation of racemic alkaloids.4 Now to further explore the
tion of this structure was the acid-catalyzed cyclization of an ami-
no-acid.5a,b,7 However, in each case, racemic products and low
yields resulted due to the harsh conditions employed for ring
closure.
On the other hand, the intramolecular cyclization reactions that
employ aryllithiums generated by lithium–halogen exchange,
known as Parham cyclization reactions, have become a valuable
protocol for the regiospecific construction of carbocyclic and het-
erocyclic systems.8 Inspired by the methodology of Lete and co-
workers,8g,i this aromatic metalation–cyclization procedure has
been successfully used to prepare the quinolizidine nucleus of
phenanthroquinolizidine alkaloids. In these cases, the unstable ke-
tone intermediates (Fig. 2) were directly reduced to corresponding
alcohols 2a–c to avoid decomposition. In this Letter, we report full
details of this synthetic approach to phenanthroquinolizidine
alkaloids.
effect of the a-C chirality on antiviral activity, a series of enantio-
pure phenanthroquinolizidine alkaloids need to be tested.
So far, only a few members of these alkaloids have been synthe-
sized selectively using the chiron approach or the chiral auxiliary
approach.5 However, these reported approaches are not suitable
for large-scale preparation due to low yields, harsh conditions, or
the many steps required.
The synthetic strategy for the construction of phenanthroquin-
olizidine alkaloids 1a–c and 2a–c is depicted in Figure 2. Firstly, the
Furthermore, the construction of the phenanthrene and quino-
lizidine nuclei always plays a key role in the synthesis of phenan-
throquinolizidine alkaloids. In our previous work, FeCl3 was used
as the oxidative coupling reagent to construct the phenanthrene
nucleus efficiently.6 We then directed our attention toward the
construction of quinolizidine nucleus. In the last five decades, the
most commonly reported synthetic methodology for the construc-
MeO
O
O
N
N
OH
HO
OMe
MeO
Cryptopleuridine
Boehmeriasin B
* Corresponding author. Tel./fax: +86 (0)22 23499842.
E-mail addresses: wangqm@nankai.edu.cn, wang98h@263.net (Q. Wang).
Figure 1. Chemical structures of cryptopleuridine and boehmeriasin B.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.12.135

1378
Z. Wang, Q. Wang / Tetrahedron Letters 51 (2010) 1377–1379
dibromides 5, formed by dibromination reaction of alcohols 4,
underwent a N-alkylation reaction to yield amides 6. Secondly,
the amides 6 proceeded through metalation–cyclization–reduction
sequences to afford alcohols 2. At last, hydride reduction gave the
target products 1.
ium aluminum hydride to give alcohol 4a in 96% yield. It has
been reported that polymethoxylated benzyl alcohols can be con-
verted into the corresponding dibromides in excellent yields in
one step.9 By using this procedure, 4a was successfully converted
into dibromide 5a in 92% yield, thus improving the results previ-
ously reported by Ishibashi and co-workers.10 (S)-N,N-diethylpi-
peridine-2-carboxamide [7-(S)]11 was alkylated with 5a to
The synthetic route to phenanthroquinolizidines 1a–c and 2a–
c is illustrated in Scheme 1. The ester 3a6 was treated with lith-
R2
R2
R2
MeO
MeO
MeO
MeO
MeO
O
OH
H
H
H
reduction
N
N
N
MeO
R1
R1
R1
ketone intermediates
1
2
Parham-type
cycliacylation
R2
R2
R2
MeO
MeO
MeO
MeO
O
Et2N
Br
Dibromination
reaction
N-Alkylation
Br
OH
Br
N
MeO
MeO
R1
4
R1
5
R1
6
Figure 2. Retrosynthetic analysis.
R2
R2
R2
MeO
MeO
MeO
Br
Br2
CHCl3
LiAlH4
THF
OH
Br
COOMe
MeO
MeO
MeO
R1
R1
R1
yield (%)
yield (%)
3a
3b
3c
4a
4b
4c
96
97
95
5a
5b
5c
92
89
90
R2
R2
R2
2
MeO
O
MeO
MeO
3
O
1
OH
Et N
2Br
14
11
15
H
H
N
nBuLi, THF
TMEDA
4
H
13
12
NEt2
Et3SiH
14a
7
N
N
N
5
6
CH3OH,
NaBH4
MeO
CF3COOH
MeO
10
K2CO3, DMF
MeO
9
8
7
R1
R1
R1
yield (%)
93
yield (%)
90
yield (%)
94
er
6a-(S)
6a-(R)
6a-(dl)
6b-(S)
6b-(R)
6b-(dl)
6c-(S)
6c-(R)
6c-(dl)
2a-(14aS, 15S)
2a-(14aR, 15R)
2a-(dl)
2b-(14aS, 15S)
2b-(14aR, 15R)
2b-(dl)
2c-(14aS, 15S)
2c-(14aR, 15R)
2c-(dl)
1a-(S)
91: 9
90:10
--
94
88
1a-(R)
1a-(dl)
1b-(S)
1b-(R)
1b-(dl)
1c-(S)
1c-(R)
1c-(dl)
95
96
91
96
92
92
96
80:20
78: 22
--
81: 19
95: 5
--
93
89
93
91
87
98
90
93
97
94
86
95
91
88
96
a: R1 = R2 = OCH3; b: R1 = OCH3, R2 = H; c: R1 = H, R2 = OCH3
Scheme 1. Synthesis of phenanthroquinolizidine alkaloids 1a–c and 2a–c.

Z. Wang, Q. Wang / Tetrahedron Letters 51 (2010) 1377–1379
OMe
1379
Acknowledgments
MeO
Br
MeO
Br
We gratefully acknowledge the National Key Project for Basic
Research (2010CB126100) and the National Natural Science Foun-
dation of China (20872072).
Br
Br
Br
Br
MeO
MeO
Supplementary data
OMe
5e
5d
Supplementary data (complete experimental procedures and
spectroscopic data for 4a–c, 5a–e, 6a-(S), 6b-(S), 6c-(S), 2a-
(14aS,15S), 2b-(14aS,15S), 2c-(14aS,15S) and 1a–c) associated with
this article can be found, in the online version, at doi:10.1016/
j.tetlet.2009.12.135.
Figure 3. Chemical structures of 5d and 5e.
produce amide 6a-(S) in 93% yield. After metalation–cyclization–
reduction sequences, 6a-(S) was successfully converted into (+)-
7-methoxy-(15S)-hydroxycryptopleurine [2a-(14aS,15S)] in 90%
yield. 2a-(14aS,15S) was reduced using triethylsilane and trifluo-
roacetic acid to give (+)-7-methoxycryptopleurine [1a-(S)] in 94%
yield. When using 7-(R)11 instead of 7-(S), (À)-7-methoxycrypto-
pleurine [1a-(R)] was obtained by the same procedure in 69%
overall yield.
Although a similar approach seemed directly applicable to the
preparation of 1b–c, differences were immediately noted. Reduc-
tion of 3b–c with lithium aluminum hydride afforded the corre-
sponding alcohols 4b–c. When 4b was treated with bromine
under above-mentioned conditions, dibromide 5b was obtained
accompanied by a small percentage of tribromide 5d (Fig. 3). The
1H NMR spectrum of 5d indicated that the additional bromine
was located at the 5-position. To avoid the tribromination, 4b
was treated with bromine below À5 °C for 5 h, then stirred at
10 °C for another 10 h. After this, dibromide 5b was obtained in
89% yield. 7-(S) was alkylated with 5b to produce amide 6b-(S)
in 92% yield. After metalation–cyclization–reduction sequences,
6b-(S) was converted into (+)-(15S)-hydroxyboehmeriasin A [2b-
(14aS,15S)] in 92% yield. 2b-(14aS,15S) was reduced using triethyl-
silane and trifluoroacetic acid to give (+)-boehmeriasin A [1b-(S)]
in 96% yield. By using the same methodology, (À)-boehmeriasin
A [1b-(R)], (+)-cryptopleurine [1c-(S)], and (À)-cryptopleurine
[1c-(R)] were obtained in 66%, 69%, and 66% overall yields,
respectively.
The racemates ( )-7-methoxycryptopleurine [1a-(dl)], ( )-
boehmeriasin A [1b-(dl)], and ( )-cryptopleurine [1c-(dl)] were
also synthesized by using the same synthetic methodology in
74%, 67%, and 66% overall yields, respectively.
It should be noted that the er ratios of alkaloids 1a–c range from
78:22 to 95:5, although the same synthetic methodology and com-
mercially available enantiopure 2-piperidinecarboxylic acid were
used. The partial racemization was most possibly due to the unsta-
ble intermediates 2a–c. Similar results were also reported by Buck-
ley III and Rapoport.5b
In summary, a short and efficient route to phenanthroquinolizi-
dine alkaloids has been accomplished with Parham-type cycliacy-
lation as the key step. This new procedure has distinct
advantages over the previous ones: it is simple and practical,
allowing a series of phenanthroquinolizidine alkaloids to be pre-
pared on a large scale, it involves few steps, and high overall yields.
As a result of the flexibility and robust character of this approach, a
systematic exploration of the pharmacological profile of this prom-
ising class of bioactive natural products may be possible.
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