Asymmetric synthesis of common aza-tricyclic core of various alkaloids

Article abstract of DOI:10.1016/j.tetlet.2015.08.017

The asymmetric synthesis of common aza-tricyclic core of different types of natural alkaloids had been accomplished from commercially available l-Cbz-tyrosine. This practical approach was capable of generating scale-up aza-tricyclic skeleton. Meanwhile, i

Full text of DOI:10.1016/j.tetlet.2015.08.017

Tetrahedron Letters 56 (2015) 5460–5464
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Tetrahedron Letters
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Asymmetric synthesis of common aza-tricyclic core of various
alkaloids
Ming Ding a,b, Xiaogang Tong , Dashan Li a,b, Kangjiang Liang a,b, Ankun Zhou , Zhili Zuo ,
Chengfeng Xia
a
a
a
a
a,
⇑
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China
University of Chinese Academy of Sciences, Beijing 100049, China
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 17 June 2015
Revised 24 July 2015
Accepted 10 August 2015
Available online 12 August 2015
The asymmetric synthesis of common aza-tricyclic core of different types of natural alkaloids had been
accomplished from commercially available L-Cbz-tyrosine. This practical approach was capable of gener-
ating scale-up aza-tricyclic skeleton. Meanwhile, it will facilitate the manipulating functionalities on the
aza-tricyclic framework further, for the purpose of target-oriented synthesis of a large number of differ-
ent natural alkaloids containing this versatile aza-tricyclic structure.
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Alkaloid
Asymmetric
Cyclization
Natural product
Synthesis
Introduction
Results and discussion
Multi-functionalized aza-[6,5,6]-tricyclic skeleton (1) (Fig. 1) is
an important structural core that is found in many different types
of natural products, such as daphnilongeranin B (2) (Calyciphylline
To embark on the synthetic approach for aza-[6,5,6]-tricyclic
skeleton (1), a general retrosynthetic scheme was designed and
further experimentally explored as illustrated in Scheme 1. We
envisioned that the enantioselective synthesis of aza-[6,5,6]-tri-
cyclic ring could be directly achieved from the chiral functionalized
tricyclic motif 8 with all the stereogenic carbon centers located
densely. The transannular C ring, conjunction with two rings of
compound 8, could be constructed straight forward from
[4,3,0]-bicyclic framework 9 by means of several different power-
ful methods which were well documented in literatures, such as
Michael addition-type palladium-catalyzed reductive Heck reac-
1
2
3
A-type), nominine (3) (Hetisine-type alkaloids), strychnine (4),
4
5
minfiensine (5, akuammicine (6), dehydrotubifoline (7) (Strych-
6
nos-type), etc. These natural products, which possess impressive
structural complexities along with diverse biological activities,
have stimulated many synthetic efforts by plenty of different
research groups for decades.7 The successes of these synthetic
strategies, which generally and primarily circumvented the con-
struction of the umbrella-like ABC tricyclic skeleton, brought about
scientific milestones in the history of total synthesis. However,
there are still considerable challenges, but also opportunities to
establish this kind of umbrella-like polycyclic ring system in a
more convenient and practical way. Herein, we reported a unique
and scalable synthesis of this tricyclic framework, which held great
potential for the total synthesis of many different types of natural
alkaloids and their derivatives.
8
9
10
tion, nickel(0)-mediated addition, or radical cyclization. The
aliphatic amine 9 could be generated from the asymmetric enone
intermediate 10, which was facilely prepared from the
commercially available
global stereochemistry.
L-tyrosine as the chiral pool to induce the
As shown in Scheme 2, our synthesis was commenced with the
scalable synthesis of carbamate 11. Carbamate 11 was readily and
practically prepared on multiple grams from L-Cbz-tyrosine with
1
1
known procedures developed by Peter Wipf et al. The four-step
preparation sequences involved an intramolecular oxidative cou-
pling, ring-opening with spontaneously concomitant intramolecu-
lar aza-Michael addition, protecting the hydroxyl group generated
in situ, and ring configuration inversion, in overall yield of 20%.
⇑
Corresponding author. Tel.: +86 871 6522 3354.
E-mail address: xiachengfeng@mail.kib.ac.cn (C. Xia).
http://dx.doi.org/10.1016/j.tetlet.2015.08.017
040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
0

M. Ding et al. / Tetrahedron Letters 56 (2015) 5460–5464
5461
H
N
cyclization transformation was problematic, after exploring a ser-
ies of representative cyclization conditions (as depicted in
O
H
H
H
H
O
H
OH
H
8,9
8a
Table 1),
such as Pd(OAc)
2
/K
2
CO
3
/HCO
2
Na, PdCl
2 3 2
(CH CN) /
H/DIPEA,8b AIBN/Bu
/Et SiH/Et N, etc.
9a,d
N
HCO
3
SnH, Ni(cod)
H
2
2
3
3
H
N
Except the N-allylic side chain removal compound 17 or the
H
O
O
N
H
16
H
de-iodide product 20, no desired cyclization product 19 was
daphnilongeranin B (2)
nominine (3)
strychine (4)
observed. We also tried to convert the allyl alcohol moiety of
N
compound 18 to a,b-unsaturated ketone by removal of the TBS
N
H
B
C
protecting group and oxidation of the alcohol. However, the related
compound could not undergo the designed transannular cycliza-
tion too. We inferred that the conformation of tertiary amine 18
might be critical to the cyclization (Fig. 2). It was possible that
steric interactive effects between the N-side chain and ester group
dominated the favored conformation. The iodide-substituted side
chain was pushed toward the exo-face of [4,3,0]-bicyclic frame-
work, leading to the two reactive sites (N-side chain and cyclohex-
ene) far away from each other. We supposed that removal of the
methyl ester will facilitate the N-side chain approach the
cyclohexene.
H
H
A
H
H
aza-[6,5,6]-tricyclic skeleton (1)
N
H
H
N
H
H
OH
N
N
H
H
N
N
H
CO Me
2
minfiensine (5)
akuammicine (6)
dehydrotubifoline (7)
As shown in Scheme 3, the removal of the hindered methyl
ester group was conducted through three-step sequences, involv-
ing basic hydrolysis of the ester group, oxidative decarboxyla-
Figure 1. Selected natural alkaloids with tricyclic core.
1
7
tion, and reduction. The bicyclic unit 23 was smoothly obtained
via merely one flash column chromatography isolation in 92% total
yield over three-step. Then the N-Cbz group was removed under
the same conditions as in Scheme 2 to deliver the amine 24. We
noticed that little amount of the olefin over-reducing by-product
was generated during the hydrogenation, and it was difficult to
be removed by column chromatography. However, we found that
the by-product was inert to the following TBAF-mediated desilica-
tion and thus could be easily separated in the following step. After
N-alkylation and removal of the TBS group, the alcohol 26 was
obtained as pure product in 59% yield. Finally, alcohol 26 was trea-
ted with Dess–Martin periodinane in the presence of excessive
N
N
H
B
C
H
N
H
I
H
A
H
O
H
O
H
H
1
8
9
MeO C
2
CO H
NPG
H
2
NHPG
L-tyrosine
HO
H
O
1
0
3
NaHCO to afford a,b-unsaturated ketone 27.
All of the three compounds 25, 26, and 27 could be served as
cyclization substrates. However, none of the cyclization products
were detected when compounds 25 and 26 were conducted. When
compound 27 was treated with Pd(OAc) /HCO Na/TBAC in heated
Scheme 1. Retrosynthetic analysis of aza-[6,5,6]-tricyclic core.
Inspired by the synthetic protocol developed by Tokuyama and co-
2
2
workers, we started to prepare alcohol 15.12 Carbamate 11 was
anhydrous DMF, a single product was obtained in good yields
(Table 2, entry 1). This compound was identified as compound
28 where the transannular cyclization occurred. It’s interesting
that the double-bond shifted from the exocyclic position (as the
structure of compound 8) to the intracyclic position.18 Although
this compound possessed the desired [6,5,6]-tricyclic skeletons,
we wanted to figure out the reason why the double-bond shifted
and whether it could be inhibited. According to the representative
mechanism of reductive Heck reaction as well as the nature of Pd
catalyst, we supposed that the isomerization raised from readdi-
tion–elimination of [HPdX] species toward the exo double-bond.19
We inferred that this kind of undesired double-bond isomerization
could be prohibited when the hydrohalic acid generated in situ was
treated with large excessive zinc dust to give b,c-unsaturated
ketone 12 in 93% yield. Then the ketone 12 was stereoselectively
isomerized the unconjugated double-bond to the conjugated dou-
ble-bond by treatment with catalytic amounts of DBU (0.15 equiv)
to afford
a,b-unsaturated ketone 13 in excellent yields on one-
gram scale. When this reaction was conducted on multi-gram
scale, the starting material ketone 12 was not consumed thor-
oughly no matter how long the reaction duration was. Then, an
enantioselective epoxidation occurred with excess H
presence of catalytic aqueous NaOH (4 N) to give the
2
O
2
in the
a,b-epoxy
ketone 14 as a single diastereomer in almost quantitative yields
without further purification. The resultant slurry was immediately
subjected under Wharton transposition conditions to afford the
desired alcohol 15 smoothly in 64% moderate yield over two-step
operation on three-gram scale.13 In order to enhance the reaction
yield, further optimization was also performed, such as screening
the solvents, but no improvement was achieved. After protection
of the alcohol with TBSCl, the N-Cbz group was removed via Pd
trapped under basic conditions. However, when excessive Et N
3
was added to the reaction system, this unexpected double-bond
isomerization process still occurred. If inorganic base such as
K2CO3 was used as an alternative, the starting material decom-
posed very quickly under these conditions. There were several
examples that olefin isomerization could be extensively restrained
by utilizing AgNO , Ag CO either as base or as additive under Heck
(
1
OAc)
2
-catalyzed hydrogenation to give the secondary basic amine
3
2
3
1
4
20
7 in 92% yield. This hydrogenation was highly chemo-selective
conditions. Guided by the literature, substantial experimenta-
tions were explored but failed too. Olefin isomerization compound
28 was still obtained as a single product.
and none of olefin over-reducing byproduct was observed. After
alkylation of secondary amine 17 with (Z)-1-bromo-2-iodo-2-
1
5
butene, we could linearly synthesize allylic tertiary amine 18
on multi-gram scale in one batch.
To investigate the reason why only the double-bond shifted
compound 28 was generated, both of the two isomers 8 and 28
were calculated for their potential energies. Their geometries were
fully optimized without imposing any symmetry constraints. The
Having the key intermediate 18 in hand, we turned our atten-
tion to the studies of cyclization transformation. However, the

5
462
M. Ding et al. / Tetrahedron Letters 56 (2015) 5460–5464
OBz
CO H
2
4 steps
Zn dust
THF/HOAc = 2/1
reflux, 93%
2
CO Me
NHCbz
N
HO
O
O
H Cbz
L
-Cbz-tyrosine
11
H
CO Me
DBU
CO Me H O , NaOH (4N)
2
2 2
2
N
N
CH Cl , 81%
O
MeOH, 0 o
2
2
C
H
Cbz
H Cbz
1
2
13
OH
H
O
H
TBSCl , imidazole
2
H
4.
H
2
O
HOAc, N
CO Me
2
CO Me
2
CH Cl , 0 oC ~ rt
N
DMAP, DMF
99 %
O
2
2
N
H
Cbz
H Cbz
1
6
5 % yield
14
5
over 2 steps
OTBS
H
OTBS
H
I
Pd(OAc)
2
Br
TEA, Et SiH
CO Me
3
2
CO Me
2
N
CH Cl , 92%
2 2
K
2
CO
3
, CH
3
CN
N
H Cbz
H H
8
9 %
16
17
OTBS
H
CO Me
2
N
H
I
18
Scheme 2. Synthesis of the intermediate 18.
Table 1
Initial attempts to the cyclization
OTBS
H
OTBS
H
OTBS
H
CO Me
2
CO Me
CO Me
2
2
N
H
N
N
H
H
H
I
H
18
19
20
Entry
1
Conditions
Solventa
DMF
Temp (°C)
Product
Pd(OAc)
2
, K
2
CO
3
, TBAC, HCO
2
Na
60
17 (14%)
20 (<5%)
2
3
4
5
6
7
8
Pd(OAc)
2
, PPh
, DIPEA, HCO
, HCO Na
CN) , HCO
B, air, Bu SnH
AIBN, Bu SnH or TMSSH
Ni(cod) , Et SiH, Et
3
, TBAC, HCO
2
Na
DMF
DMF
80
120/MW
80
80
rt
Reflux
rt
20 (78%)
20 (8%)
20 (60%)
NR
20 (<5%)
20 (<5%)
Decomposed
Pd
Pd(PPh
PdCl (CH
Et
2
(dba)
3
2
Na
3
)
4
2
CH
3
CN
2
3
2
2
H, DIPEA
DMF/CH
Toluene
Toluene
3
CN
3
3
3
2
3
3
N
3
CH CN
a
Extra dry solvents were used unless otherwise noted.
O
H
energies of the stationary points on the potential energy surface
were calculated using the DFT (X3LYP) and into (MP2) methods
in conjunction with the 6-311++G(d,p) basis sets. The calculated
relative energies suggest the compound 28 is lower than that of
H
N
Si
O
H
H
Si
O
O
OMe
N
OMe
H
H
I
À1
I
8. The value is about À7.20 kcalÁmol at MP2/6-311++G(2d,2p)
disfavoured
favoured
level as shown in Table 3. These results indicated that exo dou-
ble-bond of compound 8 was catalyzed by palladium species again
to afford the more stable analogue 28.
Figure 2. Plausible conformational interconversion of [4,3,0]-bicyclic framework
8.
1

M. Ding et al. / Tetrahedron Letters 56 (2015) 5460–5464
5463
OTBS
H
OTBS
OTBS
H
H
Cu(OAc)2
Pb(OAc)
LiOH
4
CO Me
CO H
OR
2
2
N
N
Pyridine, THF
N
Cbz
Cbz
21
H
Cbz
R = OH, 22a
R = OAc, 22b
H
H
16
I
OTBS
H
OTBS
H
Et SiH
3
.
Br K CO
2 3
BF3 Et O
Pd(OAc) , Et N
2
2
3
CH Cl , -78 oC
2
2
Et SiH, 92%
CH CN, reflux, 4 h
3
3
N
N
9
2 % yield
H
Cbz
H
H
over 3 steps
24
23
O
OTBS
H
OH
H
H
H
TBAF, THF
DMP, NaHCO
3
N
N
59 % yield
over 2 steps
N
CH Cl , 77%
2
2
H
H
I
I
I
25
26
27
Scheme 3. Preparation of the decarboxylation substrates.
synthetic steps could be conducted on multi-gram scale and in
good yields. Meanwhile, the double-bond and carbonyl group pro-
vide the chance for further functionalities and chemical transfor-
mations to synthesize many different types of natural alkaloids.
The reported protocols would also allow for the preparation of
their derivatives for biological studies.
Table 2
Study on the reductive heck cyclization
O
H
N
H
H
conditions
H
O
N
H
I
Acknowledgments
2
8
2
7
This work was financially supported by National Natural
Science Foundation of China (21272242), Yunnan High-End
Technology Professionals Introduction Program (2010CI117), and
National Basic Research Program of China (2011CB915500).
Entry
Catalyst
Base
—
Additive
Yielda (%)
1
3
4
5
6
7
8
9
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd (dba)
2 3
Pd(PPh
Pd(PPh
2
2
2
2
TBAC
TBAB
TBAC
52
33
Et
3
N
K
2
CO
3
Decomposed
Complex
25
Decomposed
Decomposedb
45
—
—
—
—
—
—
PPh
—
3
Supplementary data
3
)
)
4
—
—
Supplementary data (experimental and characterization data)
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2015.08.017.
3
4
Pd(OAc)
Pd(OAc)
2
AgNO
Ag CO
3
1
0
2
2
3
29
a
All reactions were conducted in extra dry DMF at 60 °C, using HCO
2
Na as
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b
1
2
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