Reductive cyclization strategy for construction of the highly oxygenated CD ring system of aconitine

Article abstract of DOI:10.1016/j.tetlet.2016.08.096

The synthesis of a CD ring analogue of aconitine is described. The SmI₂-mediated reductive cyclization of an α,β-epoxyketone with a pendant formyl group allowed for stereocontrolled construction of the bicyclo[3.2.1]octane framework. Further ox

Full text of DOI:10.1016/j.tetlet.2016.08.096

Tetrahedron Letters 57 (2016) 4585–4587
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Tetrahedron Letters
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Reductive cyclization strategy for construction of the highly
oxygenated CD ring system of aconitine
⇑
Akinobu Matsuzawa, Akihiko Kasamatsu, Kazuyuki Sugita
Department of Synthetic Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of a CD ring analogue of aconitine is described. The SmI -mediated reductive cyclization of
2
Received 22 July 2016
Revised 26 August 2016
Accepted 30 August 2016
Available online 1 September 2016
an
3.2.1]octane framework. Further oxidative manipulation installed oxygen functionalities with the
desired stereochemistry, thus completing the synthesis of the CD ring fragment of aconitine.
Ó 2016 Elsevier Ltd. All rights reserved.
a,b-epoxyketone with a pendant formyl group allowed for stereocontrolled construction of the bicyclo
[
Keywords:
Aconitine
Diterpenoid alkaloids
Total synthesis
Samarium(II) iodide
Reductive cyclization
Introduction
Results and discussion
C
19-Diterpenoid alkaloids, mainly isolated from the genera
Our retrosynthetic analysis of aconitine (1) is depicted in
Scheme 1. We selected bicyclic ketone 7 as a suitable building
block for the synthesis of aconitine (1). The two oxygen functional-
ities at C15 and C16 would be installed by oxidation of ketone 8,
and we envisioned that the requisite bicyclo[3.2.1]octane frame-
Aconitum and Delphinium, possess a wide range of bioactivities
Fig. 1). For example, aconitine (1) is a representative C19-diter-
penoid alkaloid that is well known for its extremely high toxicity.
The toxicity is attributed to the activation of voltage-dependent
sodium ion channels, which, in turn, causes persistent depolariza-
tion of the cell membrane potential. In addition to the bioactivities,
1
(
2
work could be constructed by SmI -mediated reductive cyclization
of epoxyketone 9. Birch reduction of commercially available alco-
hol 10 and subsequent oxidation would furnish 9 in a diastereose-
lective manner.
C
19-diterpenoid alkaloids have unique structures featuring a com-
plex hexacyclic skeleton bearing varying numbers of oxygen func-
tionalities. These structural and biological properties have
attracted significant attention from synthetic chemists over the
Our synthesis commenced with the Birch reduction of alcohol
1
1
10 (Scheme 2). The resultant enol ether 11 was hydrolyzed under
acidic conditions, and the resulting primary alcohol was protected
with a TBS group to form cyclohexenone derivative 12. Epoxidation
2
,3
past decades, which has resulted in the successful total synthe-
ses of talatisamine (2), chasmanine (3),5 13-deoxydelphonine
4
5
(
C
4), liljestrandinine (5),6 and cardiopetaline (6).7 However, these
of 12 and subsequent treatment with Et
13. The hydroxy group-directed nucleophilic epoxidation of 13
afforded ,b-epoxyketone 14 as a single diastereomer. After pro-
3
N afforded allylic alcohol
19-diterpenoid alkaloids have a relatively simple D ring, and
chemical syntheses of natural products that have a more oxy-
genated D ring, such as aconitine (1), remain a great challenge. In
our program toward the total synthesis of 1, we decided to explore
an efficient methodology for constructing the D ring with all the
oxygen functionalities installed stereoselectively. Herein, we
a
tection of the tertiary alcohol with a TES group, the TBS group
was selectively removed under acidic conditions, and the resulting
primary alcohol was oxidized to deliver aldehyde 9.
2
With aldehyde 9 in hand, we turned our attention to the SmI -
report the synthesis of the CD ring system of aconitine (1) utilizing
mediated reductive cyclization to form bicyclic ketone 8
-mediated reductive cyclization.8
–10
(Scheme 3). We envisioned that samarium enolate 15, generated
SmI
2
1
2
from 9 and SmI
2
,
would readily undergo intramolecular aldol
reaction to form samarium alkoxide 17, which, upon protonation,
would be converted into 8. High diastereoselectivity at C10 was
expected because the intramolecular aldol reaction would most
⇑
Corresponding author. Tel./fax: +81 3 5498 5791.
E-mail address: k-sugita@hoshi.ac.jp (K. Sugita).
http://dx.doi.org/10.1016/j.tetlet.2016.08.096
040-4039/Ó 2016 Elsevier Ltd. All rights reserved.
0

4
586
A. Matsuzawa et al. / Tetrahedron Letters 57 (2016) 4585–4587
OH
‡
AcO
O
O
I
OH
O
OH
SmI
2
O
O
O
O
Sm
O
O
I
N
O
N
H
D
N
O
O
2 × SmI2
O
O
O
OH
O
HO
C
O
I2SmO
OHC
O
OHC
OTES
OH
OH
OTES
OTES
I2SmO
9
Ph
15
16
aconitine (1)
talatisamine (2)
3
chasmanine ( )
OSmI2
O
OH
1
0
OH
OH
N
OH
N
H
3
O+
O
O
N
O
O
O
OTES
OTES
O
O
O
I2SmO
HO
1
7
8
OH
OH
OH
H
13-deoxydelphonine (4)
liljestrandinine (5)
cardiopetaline (6)
2
Scheme 3. Proposed reaction mechanism for SmI -mediated reductive cyclization.
Figure 1. Structures of representative C19-diterpenoid alkaloids.
proceeded from intermediary alkoxide 17, we decided to add a
proton source to suppress the migration. As expected, addition of
six equivalents of either MeOH or EtOH almost completely shut
down the migration; however, these alcohols also protonated
intermediary enolate 15, generating lactol 18 as an equilibrium
OH
O
OTBS
AcO
O
OMOM
OTBS
O
O
O
N
O
O
O
≡
15
OH
O
O
mixture with the corresponding c-hydroxy aldehyde (entries 2
HO
16
and 3). Use of PivOH as a proton source slightly improved the yield
of 8, but the TES group migration was not suppressed efficiently
(entries 3 and 4). We then investigated the addition of sterically
less hindered carboxylic acids, expecting more rapid protonation
of alkoxide 17. Addition of either isobutyric acid or AcOH to the
reaction mixture, however, did not improve the yield of 8 (entries
O
MOMO
OMOM
MOMO
O
Ph
aconitine (1)
7
oxidation
OMe
O
OH
SmI
2
-mediated
reductive cyclization
O
O
6
and 7). Interestingly, when the reaction was run without HMPA,
the TES group migration was almost absent, although the unsatis-
factory yield and poor diastereoselectivity of 8 led us to seek better
reaction conditions (entry 8). After several investigations, we were
HO
OHC
OTES
OTES
OH
10
9
8
pleased to find that the use of 6 equiv of SmI
HMPA in the presence of PivOH produced 8 selectively in 71% yield
entry 9).
The remaining task was installation of two oxygen functionali-
2
and 24 equiv of
Scheme 1. Retrosynthetic analysis of the CD ring of aconitine (1).
(
ties at C15 and C16 (Scheme 4). After MOM protection of the diol,
ketone 19 was oxidized to enone 20 under conventional condi-
tions. Epoxidation of 20 was then attempted under various condi-
tions; however, none of these experiments were successful. Given
that the bulky TES group seemed to be the reason for the unsuc-
cessful epoxidation, the TES group was removed by the action of
TBAF. As expected, epoxidation of the resulting allylic alcohol 21
OMe
O
OMe
b. 1 M HCl
c. TBSCl
a. Li, NH3
HO
TBSO
HO
10
11
12
proceeded smoothly, affording a,b-epoxyketone 22 quantitatively.
We then investigated epoxide-opening reaction with various oxy-
gen nucleophiles to install an oxygen functionality at C15, but none
O
O
d. mCPBA
then Et
f. TESOTf
g. TsOH
h. IBX
3
N
e. TBHP
O
TBSO
9
2
of the attempts were successful. Thus, 22 was treated with SmI to
TBSO
1
2
reductively open the epoxide, and the resulting vic-diol was pro-
tected to produce acetonide 23. Fortunately, the structure of 23
could be unambiguously determined by single-crystal X-ray anal-
OH
OH
14
13
1
3
14
Scheme 2. Synthesis of aldehyde 9. Reagents and conditions: (a) Li, liq. NH
Et
O, ꢀ78 °C, 25 min; (b) 1 M aq HCl, THF, ꢀ20 °C, 10 min; (c) TBSCl, imidazole,
DMF, 0 °C, 30 min; (d) mCPBA, NaHCO , CH Cl , 0 °C, 1 h; then Et N, 0 °C, 1 h, 38%
from 10); (e) TBHP, Triton B, THF, ꢀ20 °C, 1.5 h, 92%; (f) TESOTf, 2,6-lutidine,
CH Cl O, H O, THF, 0 °C, 7 h, 61%; (h) IBX, DMSO,
3
, EtOH,
ysis. Finally, subjecting 23 to Rubottom oxidation conditions
provided -oxygenated ketone 7 as a 1.2:1 mixture of diastere-
omers, which could be easily separated by silica gel column
2
a
3
2
2
3
(
1
5
chromatography.
2
2
, ꢀ78 °C, 40 min, 98%; (g) TsOHꢁH
2
2
rt, 4 h, 95%. TBS = tert-butyldimethylsilyl; mCPBA = 3-chloroperbenzoic acid;
TBHP = tert-butyl hydroperoxide, Triton B = benzyltrimethylammonium hydroxide;
TES = triethylsilyl; TsOH = 4-toluenesulfonic acid; IBX = 2-iodoxybenzoic acid.
Conclusion
We have completed the synthesis of the CD ring of aconitine in
8 steps. The SmI -mediated reductive cyclization of ,b-epoxyke-
1
2
a
likely proceed via cyclic transition state 16. Initial trials were made
tone 8 was the key to diastereoselective construction of the highly
oxygenated bicyclo[3.2.1]octane skeleton. To the best of our
knowledge, this is the first example of the synthesis of the CD ring
system of aconitine with all the requisite oxygen functionalities.
Further studies toward the total synthesis of aconitine are ongoing
in our laboratory and will be reported in due course.
by treating 9 with SmI
2
(3 equiv) and HMPA (12 equiv) in THF at
ꢀ
78 °C (Table 1). Under these reaction conditions, the desired
cyclized product 8 was obtained in only 8% yield, with concomitant
0
formation of TES-migrated compound 8 and other unidentified
byproducts (entry 1). Given that TES group migration most likely

A. Matsuzawa et al. / Tetrahedron Letters 57 (2016) 4585–4587
4587
Table 1
Optimization of reaction conditions
O
SmI2
x eq
y eq
3 eq
OH
OH
O
HMPA
10
O
O
proton source
O
+
+
THF, —78 °C
O
OTES
OTES
OH
OHC
OTES
HO
TESO
HO
9
8
8'
18
Entry
x [equiv]
y [equiv]
Proton source
None
Timea [min]
Yieldb [%]
0
8
8
18
1
2
3
4
5
6
7
8
9
3
3
3
3
3
3
3
3
6
12
6
6
12
12
12
12
0
20
100
75
100
90
55
35
85
70
8
22
Trace
42
6
Trace
Trace
Trace
Trace
Trace
Trace
c
MeOH
32
30
29
30
32
27
40
71
Trace
Trace
22
10
18
9
3
18
c
EtOH
PivOH
PivOHd
2
iPrCO H
AcOH
PivOH
PivOH
e
24
a
b
c
Reactions were run until complete consumption of 9 was observed on TLC.
Isolated yield. Diastereoselectivity was >15/1 unless otherwise noted.
Proton source (6 equiv) was added.
d
e
PivOH (10 equiv) was added.
8
was obtained as a 2.5:1 mixture of diastereomers at C10.
References and notes
OH
OMOM
O
OMOM
O
O 15
b. LHMDS;
PhSeBr
1. (a) Ameri, A. Prog. Neurobiol. 1998, 56, 211; (b) Wang, F.-P.; Chen, Q.-H.; Liu, X.-
Y. Nat. Prod. Rep. 2010, 27, 529.
2. For synthetic studies on C19-diterpenoid alkaloids, see: (a) Baillie, L. C.;
a. MOMCl
MOMO
2 2
e. H O
1
6
c. H
2
O
2
OTES
OTES
OR
Batsanov, A.; Bearder, J. R.; Whiting, D. A. J. Chem. Soc., Perkin Trans. 1 1998,
3471; (b) Barker, D.; Brimble, M. A.; McLeod, M. D.; Savage, G. P. Org. Biomol.
Chem. 2004, 2, 1659; (c) Kraus, G. A.; Kesavan, S. Tetrahedron Lett. 2005, 46,
HO
MOMO
d. TBAF
8
19
20
:
R = TES
2
1: R = H
1111; (d) Conrad, R. M.; Bois, J. D. Org. Lett. 2007, 9, 5465; (e) Liu, Z.-G.; Xu, L.;
OMOM
O
OMOM
O
OMOM
Chen, Q.-H.; Wang, F.-P. Tetrahedron 2012, 68, 159; (f) Cheng, H.; Xu, L.; Chen,
D.-L.; Chen, Q.-H.; Wang, F.-P. Tetrahedron 2012, 68, 1171; (g) Liu, Z.-G.; Cheng,
H.; Ge, M.-J.; Xu, L.; Wang, F.-P. Tetrahedron 2013, 69, 5431; (h) Cheng, H.; Zeng,
F.-H.; Ma, D.; Jiang, M.-L.; Xu, L.; Wang, F.-P. Org. Lett. 2014, 16, 2299; (i)
Fujioka, K.; Miyamoto, N.; Toya, H.; Okano, K.; Tokuyama, H. Synlett 2016, 621.
3. For a review, see: Goodall, K. J.; Barker, D.; Brimble, M. A. Synlett 2005, 1809.
OTBS
h. LHMDS
TBSOTf
O
f. SmI
2
g. 2,2-DMP
i. mCPBA
O
OH
O
O
O
O
MOMO
MOMO
MOMO
4.
5.
6.
(a) Wiesner, K.; Tsai, T. Y. R.; Huber, K.; Bolton, S. E.; Vlahov, R. J. Am. Chem. Soc.
974, 96, 4990; (b) Wiesner, K. Pure Appl. Chem. 1975, 41, 93.
(a) Wiesner, K.; Tsai, T. Y. R.; Nambiar, K. P. Can. J. Chem. 1978, 56, 1451; (b)
Wiesner, K. Pure Appl. Chem. 1979, 51, 689.
Marth, C. J.; Gallego, G. M.; Lee, J. C.; Lebold, T. P.; Kulyk, S.; Kou, K. G. M.; Qin, J.;
Lilien, R.; Sarpong, R. Nature 2015, 528, 493.
1
22
23
7
Scheme 4. Oxidation of the bicyclo[3.2.1]octane skeleton. Reagents and conditions:
a) MOMCl, iPr NEt, CH Cl
, rt, 37 h, 86%; (b) LHMDS, THF, ꢀ78 to 0 °C, 1 h; then
PhSeBr, ꢀ78 °C, 20 min; (c) H , pyridine, CH Cl , 0 °C, 20 min, 70% (from 19); (d)
TBAF, THF, 0 °C, 25 min, 95%; (e) H , NaOH, MeOH, 0 °C, 25 min, quant.; (f) SmI
MeOH, THF, ꢀ78 °C, 15 min, 70%; (g) 2,2-DMP, PPTS, CH Cl , 0 °C to rt, 4 h, 79%; (h)
LHMDS, THF, ꢀ78 °C, 5 min; then TBSOTf, 40 min, ꢀ78 to ꢀ20 °C, quant. (i) mCPBA,
toluene, NaHCO = 1.2:1. MOM = methoxymethyl;
aq, ꢀ78 to 0 °C, 85 min, 50%, b/
LHMDS = lithium bis(trimethylsilyl)amide; TBAF = tetrabutylammonium fluoride;
,2-DMP = 2,2-dimethoxypropane; PPTS = pyridinium 4-toluenesulfonate.
(
2
2
2
2
O
2
2
2
7
8
.
.
Nishiyama, Y.; Yokoshima, S.; Fukuyama, T. Org. Lett. 2016, 18, 2359.
(a) Sono, M.; Nakashiba, Y.; Nakashima, K.; Takaoka, S.; Tori, M. Heterocycles
2001, 54, 101; (b) Pudhom, K.; Arai, H.; Yamane, K.; Mukaiyama, T. Chem. Lett.
2002, 31, 82; For intermolecular variants, see: (c) Mukaiyama, T.; Arai, H.;
Shiina, I. Chem. Lett. 2000, 29, 580; (d) Mukaiyama, T.; Pudhom, K.; Yamane, K.;
Arai, H. Bull. Chem. Soc. Jpn. 2003, 76, 413.
2
O
2
2
,
2
2
3
a
2
2
9. For selected reviews on the use of SmI in organic synthesis, see: (a) Nicolaou,
K. C.; Ellery, S. P.; Chen, J. S. Angew. Chem., Int. Ed. 2009, 48, 7140; (b) Szostak,
M.; Spain, M.; Procter, D. J. Chem. Soc. Rev. 2013, 42, 9155; (c) Szostak, M.;
Fazakerley, N. J.; Parmar, D.; Procter, D. J. Chem. Rev. 2014, 114, 5959.
2
10. For detailed preparation and storage methods of SmI , see: Szostak, M.; Spain,
M.; Procter, D. J. J. Org. Chem. 2012, 77, 3049.
1. Fassnacht, J. H.; Nelson, N. A. J. Org. Chem. 1962, 27, 1885.
2. Molander, G. A.; Hahn, G. J. Org. Chem. 1986, 51, 2596.
Acknowledgment
1
1
This work was financially supported by JSPS KAKENHI Grant
Numbers JP24590136 and JP16K08180.
13. CCDC 1494908 (23) contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
A
summary of crystallographic analysis and the crystal structure is provided in
the Supporting information.
Supplementary data
1
4. (a) Brook, A. G.; Macrae, D. M. J. Organomet. Chem. 1974, 77, C19; (b) Rubottom,
G. M.; Vazquez, M. A.; Pelegrina, D. R. Tetrahedron Lett. 1974, 15, 4319; (c)
Hassner, A.; Reuss, R. H.; Pinnick, H. W. J. Org. Chem. 1975, 40, 3427.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2016.08.
15. The stereochemistry at C15 was determined based on 1H NMR and NOESY
spectroscopic analysis. See the Supporting information for details.
0
96.