Formal synthesis of (+)-tashiromine and study toward the total synthesis of (+)-stemoamide

Article abstract of DOI:10.1016/j.cclet.2013.07.015

An efficient formal synthesis of (+)-tashiromine was achieved by employing an intermolecular asymmetric Mannich-type reaction as the key step. Concurrently, a novel approach toward the total synthesis of (+)-stemoamide through dyotropic rearrangement of 3,4-cis-β-lactone was also explored.

Full text of DOI:10.1016/j.cclet.2013.07.015

Chinese Chemical Letters 24 (2013) 953–956
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Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Original article
Formal synthesis of (+)-tashiromine and study toward the total
synthesis of (+)-stemoamide
Yue-Jie Chen, Rui-Yang Bao, Xiao-Dong Zhang, Ye-Feng Tang *
The Comprehensive AIDS Research Center, Department of Pharmacology & Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing 100084,
China
A R T I C L E I N F O
A B S T R A C T
Article history:
An efficient formal synthesis of (+)-tashiromine was achieved by employing an intermolecular
asymmetric Mannich-type reaction as the key step. Concurrently, a novel approach toward the total
Received 26 April 2013
Received in revised form 9 June 2013
Accepted 24 June 2013
synthesis of (+)-stemoamide through dyotropic rearrangement of 3,4-cis-b-lactone was also explored.
ß 2013 Ye-Feng Tang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights
Available online 14 September 2013
reserved.
Keywords:
Stemoamide
Tashiromine
Dyotropic rearrangement
b
-Lactone
Total synthesis
1
. Introduction
stemoamide feature a characteristic trisubstituted g-butyrolac-
tone moiety that is trans-fused with a seven-membered ring. Such
The Stemona alkaloids represent a group of natural products
structural similarity led us to assume that the 5-7-5 tricyclic core
isolated from the plants named Stemonaceae. Over 120 structurally
diverse compounds have been identified so far, and many of them
display unique molecular architectures and biological profiles
of stemoamide could also be made from the chiral b-lactone 2
through a dyotropic rearrangement, as depicted in Scheme 1B. We
envisioned that the concerted nature of dyotropic rearrangement
in conjunction with the rationally arranged stereochemistry of 2
(the migrating C4–C8 bond and C9–O2 bond positioned in the anti-
periplanar relationship) could ensure the proposed transformation
to occur in the desired manner. To validate the assumption, the
[
1,2]. As one representative member of Stemona alkaloids,
stemoamide (1, Scheme 1) was isolated from Stemona tuberosa
Lour, a Chinese traditional medicine that has been used for the
treatment of respiratory diseases, such as asthma, bronchitis, and
tuberculosis [3]. Owing to its novel chemical structure and
prominent biological activities, stemoamide has stimulated
extensive synthetic efforts [4]. However, although much progress
has been achieved in this field, most of the synthetic routes toward
stemoamide take long linear sequences and result in racemic
synthesis. Therefore, the development of more efficient and
asymmetric approach for the synthesis of stemoamide remains
a considerable synthetic challenge.
asymmetric synthesis of
b-lactone 2 is required, which might be
achieved through an asymmetric ketene-aldehyde [2+2] cycload-
dition from the aldehyde 3. In turn, 3 could be derived from the
alcohol 4 via oxidation.
2. Experimental
The procedure for preparation of all the intermediates in
Recently, we have developed a novel approach for the syntheses
Scheme
2 and Scheme 3 are included in the Supporting
of enantiopure, trisubstituted
rearrangement of 3,4-cis- -lactones [5]. As the proof-of-concept
case, the total syntheses of a number of xanthanolides natural
products (e.g., 11 ,13-dihydroxanthatin) were achieved (Scheme
A). From the structural point of view, both xanthanolides and
g-butyrolactones via the dyotropic
information, and some selected examples (for compounds 9, 4
and 2) are listed as below:
b
Synthesis of compound 9: To a solution of compound 7 (50 mg,
a
0
(
.14 mmol, 1.0 equiv.) in DCM (2.5 mL) at 0 8C was added TiCl
0.03 mL, 0.27 mmol, 2.0 equiv.), and the reaction mixture was
stirred for 5 min. After cooling to À30 8C, the reaction mixture was
treated with solution of diisopropylethylamine (DIPEA)
(0.026 mL, 0.15 mmol, 1.2 eq.) in CH Cl (1 mL), and then stirred
for 40 min. The reaction mixture was further cooled to À78 8C, and
4
1
a
*
Corresponding author.
2
2
E-mail address: yefengtang@tsinghua.edu.cn (Y.-F. Tang).
1
001-8417/$ – see front matter ß 2013 Ye-Feng Tang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2013.07.015

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Y.-J. Chen et al. / Chinese Chemical Letters 24 (2013) 953–956
Scheme 1. Dyotropic rearrangement of 3,4-cis-b-lactone and synthetic strategy toward stemoamide.
a solution of compound 8 in CH
0 min, the reaction mixture was allowed to warm to 0 8C and kept
stirring for 6 h before it was quenched with saturated NH Cl. The
aqueous layer was extracted with CH Cl
(3 Â 10 mL), and the
combined organic layers were washed with brine, dried over
Na SO , filtered, and concentrated. The residue was purified by
flash chromatography (DCM/EtOAc, 3:1) to afford compound 9 as
2
Cl
2
(0.5 mL) was added. After
0.1 equiv.) in methanol (4 mL) was stirred at room temperature for
3 h. The solvent was evaporated in vacuo, and the residue was
purified by flash chromatography (DCM/EtOAc, 1:1) to afford
1
4
2
5
2
2
compound 4 as colorless oil (150 mg, 90%). [
a
]
D
+85.0 (c 1.3,
À1
acetone); R
f
= 0.33 (silica gel, DCM/MeOH, 20:1); IR (film, cm ):
1
2
4
nmax 3386, 2920, 1661, 1460, 1369, 1050, 731; H NMR (400 MHz,
CDCl ): 4.13 (dd, 1H, J = 12.8, 4.4 Hz), 3.57–3.69 (m, 2H), 3.24–
3
d
25
yellow oil (60 mg, 91%). [
a
]
D
À216.1 (c 1.4, CH
3
Cl); R
f
= 0.62
3.28 (m, 1H), 2.53–2.60 (m, 1H), 2.28–2.39 (m, 3H), 1,92–1.96 (m,
À1
13
(
silica gel, DCM/E EtOAc, 3:2); IR (film, cm ):
n
max 2121, 1691,
): 7.26–7.34 (m,
H), 6.18 (s, 1H), 5.36–5.41 (m, 1H), 4.93 (m, 1H), 4.05 (dd, 1H,
1H), 1.67–1.76 (m, 4H), 1.29–1.43 (m, 3H); C NMR (100 MHz,
1
1
5
502, 1257, 1165, 829; H NMR (400 MHz, CDCl
3
d
CDCl
3
): d 173.9, 59.2, 46.1, 40.0, 30.6, 27.1, 24.6, 24.1; HRMS (ESI)
+
m/z [M+ H] calcd. for C
9 2
H15NO : 170.1176, found: 170.1177.
J = 12.0, 6.4 Hz), 3.34–3.38 (m, 3H), 3.20 (d, 1H, J = 12.8 Hz), 3.02–
.07 (m, 1H), 2.95 (d, 1H, J = 12.0 Hz), 2.24–2.38 (m, 3H), 1.98–2.06
Synthesis of compound 2: A suspension of compound 16
(20 mg, 0.09 mmol, 1.0 equiv.) in DCM (2 mL) was treated with
3
13
(m, 1H), 1.67–1.90 (m, 5H); C NMR (100 MHz, CDCl
3
):
d
202.6,
3
Et N (0.04 mL, 0.27 mmol, 3 equiv) and BOP-Cl (33 mg, 0.13 mmol,
1
3
C
77.9, 175.3, 136.1, 129.5, 129.0, 127.5, 68.8, 55.2, 46.1, 37.1, 32.8,
1.5 equiv.) at 23 8C. After stirring for 2 h, the resulting reaction
mixture was diluted with water (10 mL) and extracted with EtOAc
(3 Â 10 mL). The combined organic phases were dried and
concentrated in vacuo. The residue was submitted to chromato-
graph (DCM/MeOH, 20:1) to afford the pure product 2 as white
+
2.5, 30.3, 29.8, 26.9, 24.3; HRMS (ESI) m/z [M+H] calcd. for
25BrN : 457.0437, found: 457.0437.
Synthesis of compound 4: A solution of compound 12 (253 mg,
mmol, 1.0 equiv.) and p-toluenesulfonic acid (25 mg, 0.1 mmol,
20
H
2 2 2
O S
1
Scheme 2. Reagents and conditions: (a) (COCl)
dihydro-2-pyran, p-toluenesulfonic acid pyridine salt, DCM, r.t.; (e) NaH, THF, r.t., 89% for two steps; (f) p-toluenesulfonic acid, MeOH, r.t., 90%; (g) 4-nitrobenzoyl chloride,
Et N, DCM, r.t., 80%.
2 3 4 4
, DMF, DCM, r.t., then 6, Et N, r.t., 80%; (b) TiCl , DIPEA, then 8, DCM -78 8C; (c) NaBH , MeOH, r.t., 60% for two steps; (d) 3,4-
3

Y.-J. Chen et al. / Chinese Chemical Letters 24 (2013) 953–956
955
Scheme 3. Reagents and conditions: (a) DMP, DCM, r.t., 80%; (b) TMSQ, LiClO
DCM, 60%; (e) H , Pd/C, MeOH, r.t.; (f) BOP-Cl, Et N, DCM, r.t., 50%.
4
, propionyl chloride, DCM, À40 8C; (c) TiCl
4
, DIPEA, NMP, 15, DCM, À78 8C, 35%; (d) BnOH, DMAP,
2
3
2
5
solid (10 mg, 50%). [
a
]
D
+22.1 (c 0.6, CH
3
Cl); R
f
= 0.30 (silica gel,
formed the 3,4-cis-b-lactone 2 in 50% yield. With the precursor 2 in
À1
DCM/MeOH, 20:1); IR (film, cm ):
n
max 2958, 1821, 1764, 1677,
): 4.48 (dd,
H, J = 6.4, 4.4 Hz), 4.08–4.17 (m, 1H), 3.85–3.88 (m, 1H), 3.30–3.36
hand, we next turned to examine the ambitious dyotropic
rearrangement to synthesize the tricyclic compound 19, which
in principle, could be further converted into (+)-1 by inversion of
the stereochemistry of 12-Me. However, to our disappointment,
we failed to observe the desired transformation using the standard
1
1
1
(
2
(
3
442, 1270, 1144, 1114, 759; H NMR (400 MHz, CDCl d
m, 1H), 2.58–2.64 (m, 1H), 2.36–2.40 (m, 1H), 2.22–2.33 (m, 1H),
.00–2.04 (m, 1H), 1.83–1.86 (m, 1H), 1.56–1.66 (m, 5H), 1.42–1.49
m, 2H), 1.38 (d, 3H, J = 7.6 Hz); C NMR (100 MHz, CDCl
73.7, 171.6, 74.8, 59.4, 47.9, 42.8, 40.0, 30.3, 29.8, 25.5, 24.8, 23.6;
13
3
):
d
conditions (Et
reaction by employing different Lewis acids (e.g. EtAlCl
MgBr ) also turned out to be fruitless. Comparing this result with
2
AlCl, DCM, r.t.) [5]. Further efforts to improve the
1
2
, TiCl and
4
+
HRMS (ESI) m/z [M+Na] calcd. for C12
H
17NO
3
: 224.1281, found:
2
2
24.1280.
the previous one [5], we assumed that the failure of the dyotropic
rearrangements of 2 could be attributed to the presence of the
lactam ring which may coordinate to the Lewis acid and preclude
the rearrangement from occurring.
3
. Results and discussion
We initiated our study by preparing the enantiopure compound
4
. Although several racemic syntheses of 4 were documented [6,7],
4
. Conclusion
to date only one asymmetric synthesis of (+)-4 has been achieved,
which required 11 linear steps and resulted in 18% overall yield [8].
To keep our synthesis as concise as possible, we developed a new
approach to access (+)-4, as described in Scheme 2. Thus, treatment
of the acid 5 with oxalyl chloride provided the corresponding acid
chloride, which was coupled with thiazolidinethione 6 in the
presence of Et3N to give compound 7 in 80% yield. The Lewis acid-
promoted Mannich-type reaction between
pyrrolidine 8 proceeded with high diastereoselectivity to afford
compound 9 [9], which after treatment with NaBH /MeOH, gave
In summary, we have completed a highly efficient asymmetric
formal synthesis of (+)-tashiromine. Furthermore, the total
synthesis (+)-stemoamide (1) via a novel dyotropic rearrangement
of 3,4-cis-b-lactone was also explored. Albeit this route failed to
attain the intended objective, the experimental results shed light
on the substrate limitation of the dyotropic rearrangement of 3,4-
cis-b-lactone, which prompted us to devise an alternative strategy
to achieve the compounds. The relevant work is in progress and
will be reported in due course.
7 and ethoxy-2-
4
the alcohol 10 in 60% yield for two steps. Protection of the hydroxyl
group with THP followed by treatment of the resulting product 11
with NaH furnished the bicyclic compound 12 in good yield.
Removal of the THP group of 12 with TsOH/MeOH led to the
formation of (+)-4 in an excellent yield (90%). The relative
stereochemistry of 4 was unambiguously confirmed by the X-
ray crystallographic study of its derivative 13, while its absolute
configuration was verified in the following experiments (see the X-
ray of 16). Compound (+)-4 could be converted into (+)-
tashiromine (14) in a single step according to the literature
method [8], thus our work represents a formal synthesis of (+)-14
via 7 linear steps in 30% overall yield.
Acknowledgments
We gratefully acknowledge the financial supports from Beijing
Natural Science Foundation (No. 2132037), NSFC (Nos. 21102081,
21272133), New Teachers’ Fund for Doctor Stations Ministry of
Education (No. 20110002120011) and Scientific Research Founda-
tion for the Returned Overseas Chinese Scholars, Ministry of
Education (No. 20121027968).
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[