Asymmetric synthesis of ABC tricyclic core in Daphniphyllum alkaloid 21-deoxy-macropodumine D

Article abstract of DOI:10.1016/j.tetlet.2018.04.019

In this paper, we describe our efforts toward the asymmetric synthesis of Daphniphyllum alkaloid 21-deoxymacropodumine D which led to efficient preparation of a ABC tricyclic framework containing five consecutive stereocenters. This synthetic work features (1) utilization of an asymmetric conjugate addition to install the C5 all-carbon quaternary center, (2) an intramolecular aza-Michael addition followed by Pd-catalyzed α-alkenylation to build the bowl-shaped tricyclic core.

Full text of DOI:10.1016/j.tetlet.2018.04.019

Accepted Manuscript
Asymmetric synthesis of ABC tricyclic core in Daphniphyllum alkaloid 21-de-
oxy-macropodumine D
Xiu-Fang Mo, Yun-Fei Li, Ming-Hui Sun, Qiu-Yan Dong, Qin-Xia Xie, Pei
Tang, Fei Xue, Yong Qin
PII:
S0040-4039(18)30462-3
https://doi.org/10.1016/j.tetlet.2018.04.019
TETL 49882
DOI:
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
27 February 2018
7 April 2018
10 April 2018
Please cite this article as: Mo, X-F., Li, Y-F., Sun, M-H., Dong, Q-Y., Xie, Q-X., Tang, P., Xue, F., Qin, Y.,
Asymmetric synthesis of ABC tricyclic core in Daphniphyllum alkaloid 21-deoxy-macropodumine D, Tetrahedron
Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.04.019
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Graphical Abstract
Asymmetric synthesis of ABC tricyclic core
in Daphniphyllum alkaloid 21-deoxy-
macropodumine D
Leave this area blank for abstract info.
a
a
a
a
a
a
Xiu-Fang Mo , Yun-Fei Li , Ming-Hui Sun , Qiu-Yan Dong , Qin-Xia Xie , Pei Tang , Fei Xue and Yong Qin
b, ∗
b, ∗
a
Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, Chongqing
4
b
01331, China
Sichuan Engineering Laboratory for Plant-Sourced Drug and Research Center for Drug Industrial Technology, West China School of Pharmacy,
Sichuan University, Chengdu 610041, China

1
Tetrahedron Letters
journal homepage: www.els evier.com
Asymmetric synthesis of ABC tricyclic core in Daphniphyllum alkaloid 21-deoxy-
macropodumine D
a
a
a
a
a
a
Xiu-Fang Mo , Yun-Fei Li , Ming-Hui Sun , Qiu-Yan Dong , Qin-Xia Xie , Pei Tang , Fei Xue and
b, ∗
b, ∗
Yong Qin
a
Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, Chongqing
4
b
01331, China
Sichuan Engineering Laboratory for Plant-Sourced Drug and Research Center for Drug Industrial Technology, West China School of Pharmacy, Sichuan
University, Chengdu 610041, China
ARTICLE INFO
ABSTRACT
Article history:
Received
In this paper, we describe our efforts toward the asymmetric synthesis of
Daphniphyllum alkaloid 21-deoxymacropodumine D which led to efficient
preparation of a ABC tricyclic framework containing five consecutive
stereocenters. This synthetic work features (1) utilization of an asymmetric
conjugate addition to install the C5 all-carbon quaternary center, (2) an
intramolecular aza-Michael addition followed by Pd-catalyzed α-alkenylation to
build the bowl-shaped tricyclic core.
Received in revised form
Accepted
Available online
Keywords:
Daphniphyllum alkaloid
2
2009 Elsevier Ltd. All rights reserved.
1-deoxymacropodumine D
Asymmetric conjugate addition
Aza-Michael addition
Pd-catalyzed α-alkenylation
CO2Me
MeO2C 14
MeO2C
N
H
Daphniphyllum
Daphniphyllum, are a large group of polycyclic natural products
alkaloids,
isolated
from
the
genus
13
17
19
N
1
8
1
0
18
21
containing over 320 members with more than 20 different
1
skeletal types. Many members of this family have showed a
2
3
5
11
HN
20
7
OAc
HO
HO
wide range of biological activities, including anticancer,
antioxidation, antiviral, vasorelaxation, nerve growth factor-
regulation, anti-HIV and antiplatelet activating factor effects.
methyl homosecodaphniphyllate (1)
daphmanidin E (2)
calyciphylline N (3)
1c,2,3
Calyciphylline A-type subfamily
These significant bioactivities, in combination with intriguing
architectural features of Daphniphyllum alkaloids, have rendered
this family of natural products an alluring target for synthetic
O
H
OH
16
H
1
6
1
5
O
O
16
E
O
13 15
9
17
10
O
N
H
F
8
20
10
12
H
H
1
9
2
1
10 OH
1
,2
18
3
A
4
5
D
6
H
chemists. In the synthesis campaigns toward these alkaloids,
4
B
19
C7
N
H
Heathcock and co-workers reported the inaugural elegant works.
Subsequently, several total syntheses of Daphniphyllum alkaloids
N
H
H
[
6-6-5-7-5-5]
[6-6-5-7-5-5]
[6-6-5-7-5-5]
5
daphnilongeranin B (4)
longeracinphyllin A (5)
himalenine D (6)
were accomplished successively by the groups of Carreira,
10
6
Smith, Li, Yokoshima/Fukuyama, Zhai and Paton/Dixon.
7
8
9
O
13
15
9
MeO2C
H
O
15
E
H
F
E
O
H
H
H
14
9
10
1
8
H
In this family, the calyciphylline A-type alkaloids are among
1
8
D
A
A
21
,7-12
D
OH
the most studied members.
complex scaffold containing
hexacyclic core (4-6, Figure 1). However, daphenylline (8,
Most of this subfamily feature a
highly fused 6-6-5-7-5-5
B
B 3
R
C
H
N
H
N
4
C
N
a
H
1
b
[6-6-5-7-5]
himalensine A (7)
[6-6-5-7-5-6]
[6-5-6-7-5-5]
daphenylline (8)
macropodumine D (9) R = OH
1-deoxymacropodumine D (10) R = H
Figure 1) is a nonrepresentative member possessing a fused 6-6-
7
2
-9,12
5
macropodumine D (9, Figure 1) is another structurally exceptive
-7-5-6 hexacyclic arene-containing skeleton.
Additionally,
Figure 1. Selected Daphniphyllum alkaloids
—
——
∗
Corresponding author.
E-mail addresses: xuefei@scu.edu.cn (F. Xue), yongqin@scu.edu.cn (Y. Qin)

2
Tetrahedron
17
member in this subfamily, which was isolated from the leaves
and barks of Daphniphyllum macropodum Miq. by Guo and co-
workers, we were pleased to observe that the reaction of the
1
known α, β-unsaturated ketone 20 using ligand 21 in the
presence of Me Al and CuTC in Et O at −30 °C smoothly
8
1
workers in 2007. Recently, its deoxidized congener 21-
3
3
2
deoxymacropodumine D (10, Figure 1) was disclosed by the
group of Yue,
afforded the desired adduct 22 in 62% yield and excellent
enantioselectivity up to 95.2% ee. Under the same conditions, the
asymmetric conjugate addition of Bz substrate 23 (see
Supplementary material) was performed more efficiently (87%
yield), delivering 24 in 93.5% ee. Although the enantioselectivity
was slightly decreased, this transformation has proven to be
scalable (17 g scale), and provided enough material supplies for
the subsequent synthetic investigations.
14
the structure of which was confirmed
unambiguously by X-ray diffraction analysis. Structurally,
macropodumine D (9) and 21-deoxymacropodumine D (10)
possess an unprecedented 6-5-6-7-5-5 hexacyclic system, and the
moiety of rings A, B, and C in particular features a unique fusion
of 6-5-6 tricyclic unit, containing the especial N-C3 linkage and a
hydroxyl group at C4, which is unusual in normal calyciphylline
A-type alkaloids (most members have N-C4 linkage). The unique
scaffold of 9 and 10, and seven consecutive stereocenters
including the vicinal all-carbon quaternary centers pose a
challenge for chemical synthesis. Herein, we report our
endeavors that led to the asymmetric synthesis of ABC tricyclic
framework of 21-deoxymacropodumine D (10).
Scheme 2. Preparation of the enantioenriched intermediates 22 and 24.
According to our synthetic plan, the enantioenriched ketone 24
was oxidized to α, β-unsaturated ketone 25 in 76% yield upon
treatment with IBX in DMSO (Scheme 3). Subsequent allylic
1
9
2
0
bromination with NBS/AIBN at 80 °C was found to be the only
effective method for functionalizing the C4 position. The
resulting bromide was smoothly converted into allylic alcohol 26
2
1
3
using CaCO /NaI in 67% overall yield as an inseparable
mixture of two diastereoisomers in a 2:1 ratio. Protection of the
secondary alcohol in 26 occurred smoothly by treating 26 with
TESCl/imidazole/DMAP to generate 27. At this stage, we
envisaged using a silyl enol ether as a masked C1 carbonyl group
to prevent the probable oxo-Michael addition when the primary
alcohol was liberated in the subsequent operations. Thus, enone
Scheme 1. Retrosynthetic analysis of 21-deoxymacropodumine D (10). PG =
2
7 was subjected to silyl enol ether formation employing
TIPSCl/NaHMDS, leading to diene 28 in 88% yield. Subsequent
benzoate hydrolysis with K CO in MeOH delivered the desired
protecting group.
Our retrosynthetic analysis is briefly illustrated in Scheme 1.
Application of a late-stage transannular alkylation to hexacyclic
framework of 21-deoxymacropodumine D (10) led back to
primary iodide 11. We envisioned that the E ring in 11 could be
2
3
alcohol 29 and 4-epi isomer diol 30 in 61% and 29% yield,
respectively. The relative stereochemistry
O
O
O
NBS, AIBN
4
TESCl
Imidazole
readily prepared from 12 via a SmI
2
-promoted ketyl-olefin
IBX, TsOH
CCl , 80 °C
OBz
OBz
OBz
1
5
radical cyclization and subsequent elimination. Formation of
the latter spiro intermediate would rely on an intramolecular
Aldol strategy of 13, which in turn could be simplified as ABC
tricyclic core 14. To provide an efficient access to this key
DMSO, 65 °C
then CaCO3, NaI
dioxane/H2O (5:1)
80 °C, 67%, dr 2:1
4
DMAP, DCM
rt, 95%
7
6%
OH
2
2
4
25
6
O
1
OTIPS
OTIPS
OTIPS
1
6
TIPSCl
NaHMDS
tricyclic structure, we conceived a radical cyclization (when X
OBz
OBz
K CO
3
OH
OH
2
+
4
4
4
=
alkenylation
H, Y = PhSe), or an alternative Pd-catalyzed enolate α-
THF, –78 °C
88%
MeOH, 60 °C
29:61%; 30:29%
1
1a,11l
OTES
OTES
OH
OTES
(when X = Br, Y = H)/hydrogenation sequence
2
7
28
29
30
of 15 to forge C2−C18 bond, in which N-C3 linkage could be
established by an intramolecular aza-Michael addition of enone
OTIPS
1
) Bz2O, DMAP
DCM, rt
1) Dess-Martin periodinane
NaHCO3, DCM, rt
OH
1
6. In turn, introduction of the nitrogen functionality could be
2
) TESCl, Imidazole
DMAP, DCM, rt
2) NaBH4, CeCl3•7H2O
THF, rt
achieved through primary alcohol deprotection of 17, followed
by oxidation/reductive amination or Mitsunobu reaction. 17 was
traced back to an enantioenriched precursor such as 18, a
compound which could arise from readily available enone 19 via
an asymmetric conjugate addition to build the all-carbon
quaternary center at C5.
6
6% in 2 steps
OH
7
5% in 2 steps, dr 2:1
3
1
Scheme 3. Preparation of alcohol intermediate 29.
17
of C4 in 29 was established by the NOE correlation of the
subsequent bicyclic product 34 (red arrow in Scheme 4). Since
our attempts towards a Mitsunobu reaction of 4-epi isomer 30
were unsuccessful, we tried to develop an alternative strategy to
inverse the configuration of secondary alcohol in 30. As
The synthesis commenced with the preparation of
enantioenriched ketone intermediate containing C5 all-carbon
quaternary center (Scheme 2). Following the copper-catalyzed
asymmetric conjugate addition established by Alexakis and co-
2
2
indicated in Scheme 3, we found that Dess-Martin oxidation of
3
diol 30, followed by Luche reduction afforded diol 31 in 75%
2

3
overall yield as a diastereoisomeric mixture in a 2:1 ratio, then
selective benzoylation of the primary alcohol and protection of
the secondary alcohol provided 28 in 66% yield in 2 steps. In the
event, this reaction cycle involving aforementioned four-step
sequence could be conducted smoothly to improve the synthetic
efficiency in the preparation of intermediate 29.
structural feature of the substrate. Finally, catalytic
hydrogenation of the double bond in 41 with PtO in MeOH
afforded the desired product 36 in 33% yield, along with the
epimer 37 in 59% yield. The relative stereochemistry of 36 and
37 was established by the NOE correlations as shown in Scheme
2
5 (red arrow). Other conditions such as Pd/C, Pd(OH) , Raney-Ni,
2
7
Crabtree’s catalyst and [Rh(cod)Cl]
2
/PPh /AgBF
3
4
could not
improve the stereochemical control, either. Thus, the ABC
tricyclic framework of 21-deoxymacropodumine D (10) with five
consecutive stereogenic centers including an all-carbon
quaternary center was successfully synthesized, albeit with a
disappointing 1:1.8 ratio of diastereomers. In this case, we
speculated that the hydrogenation occurred dominantly from
convex face of the alkene substrate, giving the unsatisfied
stereoselectivity.
OTIPS
OTIPS
O
DPPA
OH
PPh3, DIAD
N3
1M HCl
N3
THF, 0 °C to rt
DCM, rt
76%
78%
OTES
OTES
OTES
29
38
39
O
O
OTES
OTES
PPh3
t-BuOK
H
THF/H2O (6:1)
Pd(PPh3)4
2
3
Br
3
18
Br
then
THF, 70°C
4
4
75%
Scheme 4. Explorations into a radical cyclization strategy to achieve the ABC
Br
N
N
tricyclic core.
K CO , THF
2
3
40
41
51%
With alcohol 29 in hand, we turned our attention to construct
the ABC tricyclic core. Dess-Martin oxidation of 29 furnished
aldehyde 32 (Scheme 4), which was subjected to reductive
O
O
OTES
OTES
H
H
2
0
20
2
2
3
PtO2, H2
MeOH, rt
1
8
3
18
amination with allylamine/NaBH
4
in MeOH, delivering the
+
4
4
substrate 33 for the next aza-Michael addition. Pleasingly,
treating 33 with 1M HCl in DCM readily afforded the desired
cyclization product, in which 33 underwent sequential selective
desilylation and aza-Michael addition as planned, to provide
bicyclic ketone 34 with good efficiency (90% yield). Subsequent
regioselective selenation of the kinetic enolate of 34 employing
N
N
3
6:33%; 37:59%
36
37
OTES
H
H
H
H
H
OTES
4
3
2
H
2
O
H
1
6
20
PhSeCl/LDA afforded the desired phenyl selenide 35 in 73%
yield as a single, though unassigned, diastereomer about the
newly formed chiral center. We expected that the radical derived
from 35 could undergo a 5-exo-trig cyclization onto the
allylamine side-chain, concurrently setting the angular methyl
group stereochemistry. Unfortunately, we failed to realize this
potential radical cyclization following several attempts (including
Me 1
Me
H
5
Me
8
O
3
4
N
H
H
6
Me20
N
7
6
7
H
noe
H
36
37
Scheme 5. Preparation of the ABC tricyclic frameworks 36 and 37.
In summary, we have achieved the asymmetric synthesis of
ABC tricyclic framework of Daphniphyllum alkaloid 21-
deoxymacropodumine D (10) in 11 steps from enone 23, which
could be obtained readily in decagram scale. The key steps of our
synthetic efforts include an asymmetric conjugate addition to
install the C5 all-carbon quaternary center, and aza-Michael
addition followed by Pd-catalyzed α-alkenylation to construct the
desired bowl-shaped tricyclic core. Further studies toward the
total synthesis of 21-deoxymacropodumine D are currently
underway in our laboratory.
1
6
24
25
AIBN/n-Bu
3 3 3 2
SnH, V40/n-Bu SnH and Et B/O ) to deliver the
ABC tricyclic structure 36 or 37.
Since the radical cyclization strategy to construct B ring was
1
unsuccessful, inspired by the elegant works of Bonjoch and
1a
1
1l
Liang, our focus turned to the Pd-catalyzed α-alkenylation
protocol defined in our retrosynthetic analysis (vide supra). As
shown in Scheme 5, alcohol 29 was converted into the desired
azido derivative 38 in 78% yield with diphenylphosphoryl azide
2
6
(
DPPA) under Mitsunobu condition. After selective desilylation
with HCl, the resultant azide 39 was subjected to a one-pot three-
step process involving Staudinger reaction (PPh , THF/H O) and
a subsequent cascade N-alkylation/base-promoted aza-Michael
addition sequence (2,3-dibromopropene, K CO ) to deliver the
Acknowledgments
3
2
This work was supported by the National Natural Science
Foundation of China (21502011); the Chongqing Science &
Technology Commission Project (cstc2016jcyjA0168); and the
China Postdoctoral Science Foundation (2017M610608).
2
3
desired azabicyclo[3.3.1]nonane framework 40 in 51% overall
yield. To our delight, when bromide 40 was treated with
Pd(PPh
enolate α-alkenylation,
3 4
) and t-BuOK in the heated THF for Pd-catalyzed
11a,11l
it was smoothly converted to the
References and notes
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stereocenter in 75% yield. It was worth noting that the α-
alkenylation only occurred from one face and neatly installed the
C2-C18 bond in a stereoselective manner due to the intrinsic
1
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1
1
0. For the total synthesis of himalensine A, see: Shi, H. Y.;
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(
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Supplementary material that may be helpful in the review
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submitted along with the manuscript and graphic files to the
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Yang, M.; Wang, L.; He, Z. H.; Wang, S. H.; Zhang, S.Y.; Tu, Y.
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5
Highlights:
ꢀ
Asymmetric synthesis of ABC tricyclic
framework of 21-deoxy-macropodumine D is
achieved.
ꢀ
ꢀ
ꢀ
The construction of five consecutive
stereocenters.
Highly selective asymmetric conjugate addition
in decagram scale.
Highly stereoselective Pd-catalyzed
α-
alkenylation to construct the bowl-shaped
tricyclic core.