Enantioselective total synthesis of (+)-methoxystemofoline and (+)-isomethoxystemofoline

Article abstract of DOI:10.1039/c4cc09598g

The first enantioselective total synthesis of (+)-methoxystemofoline (2) and (+)-isomethoxystemofoline (3) has been reported. The synthesis employed the halide-assisted bromotropanonation method that we developed recently to construct the core structure, and Overman's strategy for the implementation of the butenolide moiety. Through this work, the structure of methoxystemofoline was revised as 2 with an E-alkene, and its absolute configuration was established. This journal is

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DOI: 10.1039/C4CC09598G
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ARTICLE TYPE
Enantioselective Total Synthesis of (+)-Methoxystemofoline and (+)-
Isomethoxystemofoline
Pei-Qiang Huang,a,b,* Su-Yu Huang,a Long-Hui Gao,a Zhong-Yi Mao,a Zong Chang,a and Ai-E Wanga
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
The first enantioselective total synthesis of (+)-
O
OMe
O
methoxystemofoline (2) and (+)-isomethoxystemofoline (3) is
reported. The synthesis employed the halide-assisted
bromotropanonation method that we developed recently to
O
O
16
17
8
O
11
N
9
13
9a
N
R
O 10
OMe
7
(CH2)4OMe
3
10 construct the core structure, and Overman’s strategy for the
implementation of the butenolide moiety. Through this work,
the structure of methoxystemofoline was revised as 2 with an
E-alkene, and its absolute configuration was established.
O
2
O
stemofoline (1, R = n-Bu)
methoxystemofoline (2)
(revised structure)
isomethoxystemofoline (3, R = 4-MeO-n-Bu)
(proposed structure for methoxystemofoline)
50
Figure 1. Structures of selected stemofoline alkaloids
Stemofoline alkaloids1-2 (Figure 1) is
a subclass of
Our retrosynthetic analysis of methoxystemofoline (2/ 3) is
delineated in Scheme 1. The retro-vinylogous aldol
disconnection,6,7 resulted in vinylogous lithium enolate 4 and
the core structure 5. The latter could be synthesized from 6 by
15 structurally complex Stemona alkaloids.3,4 Since the isolation
of stemofoline (1), the first member of this subclass in 1970,1
considerable efforts have been devoted to their chemical
synthesis.5-9 The three seminal total syntheses are Kende’s
total synthesis of (±)-isostemofoline in 1999,6 Overman’s
20 total syntheses of (±)-didehydrostemofoline and (±)-
55
a
cross-metathesis (CM) reaction.12 The tropan-3-one
derivative 6 could be prepared from keto-lactam 7 by the
method that we developed recently.11
isodidehydrostemofoline
in
2003,7
total
and
Martin’s
enantioselective formal
syntheses
of
didehydrostemofoline and isodidehydrostemofoline in 2012.8
Methoxystemofoline (2) was isolated in 1991 by Xu and co-
25 workers from the roots of S. parviflora Wright, C. H.2 The
structure of methoxystemofoline (2) was elucidated by MS and
spectroscopic analyses,2 while its absolute configuration remains
unknown. Recently, Pyne and co-workers disclosed the
semisyntheses of several stemofoline alkaloids9 including
30 isomethoxystemofoline (3)9a starting from (11Z)-1’2’-
didehydrostemofoline. The achievement allowed them ready
access to several stemofoline alkaloids and analogues, and to
reveal acetylcholinesterase inhibitory activity of those alkaloids.
Herein, in continuation of our work in the synthesis of
35 alkaloids,4i,10,11 we report the first enantioselective total synthesis
of methoxystemofoline (2) and isomethoxystemofoline (3).
Scheme 1. Retrosynthetic analysis of methoxystemofoline.
60 The synthesis started with (S)-α-hydroxy-γ-lactone 8. O-
benzylation and aminolysis gave hydroxy amide 9 in 81%
overall yield (Scheme 2). Oxidation of 9 with Dess-Martin
periodinane13 afforded a tautomeric mixture of aldehyde-
amide and hemiaminal. The mixture was refluxed in MeOH in
65 the presence of silica gel to convert the former to the latter
that was acetylation to yield acetate 10 as
a 1.3: 1
a Department of Chemistry and Fujian Provincial Key Laboratory of
Chemical Biology, and Collaborative Innovation Centre of Chemistry for
40 Energy Materials, College of Chemistry and Chemical Engineering,
Xiamen University, Xiamen, Fujian 361005, P.R. China.
b State Key Laboratory of Applied Organic Chemistry Lanzhou
University, Lanzhou 730000, P.R. China.
† In memory of Professor Dr. Ernest Wenkert
diastereomeric mixture in 74% yield over three steps.
Treatment of 10 with silyl enol ether of acetone and TMSOTf
in CH2Cl2 yielded the α-amidoalkylation14 products. The tert-
70 butyldimethylsilyl (TBDMS) group did not survive in these
conditions and resilylation of the primary alcohol was
required to afford the desired cis-lactam 7 in 72% yield, along
with a small amount of the trans isomer. The stereochemistry
of the minor diastereomer of 7 was determined by NOESY
75 experiments. Formation of the requisite tropanone structure
11 was accomplished smoothly using the method that we
45 Tel: 86-592-2182240; E-mail: pqhuang@xmu.edu.cn
† Electronic Supplementary Information (ESI) available: characterization
data and 1H and 13C NMR spectra of methoxystemofoline (2) and
isomethoxystemofoline (3). See DOI: 10.1039/b000000x/
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DOI: 10.1039/C4CC09598G
developed recently.11 Hence, cis-7 was treated with TMSOTf
in the presence of Et3N to get silyl enol ether.
O
OH
a
OTBDMS
MeO
a
N
Intramolecular addition of the silyl enol ether onto the in situ
activated lactam afforded 1-bromotropan-3-one 11 in 78%
C3 aldol addition
6
+
product 13 (16%)
O
BnO
5
yield.
Heating
a
mixture
of
11,
1,1'-
and
12 (62%)
azobis(cyclohexanecarbonitrile)
allyltributylstannane16 in toluene at 85 ºC for 18 h led to the
(ACCN),15
b
desired cross-coupling product 6 in 78% yield.
O
O
OMe
OTBDMS
+
BnO
BnO
OTBDMS
MeO
HO
N
N
a, b
c, d, e
74%
OAc
O
O
O
OH
N
NH
O
O
BnO
(Z)-14 (60%)
O
81%
BnO
(E)-14 (16%)
(S)-8
OTBDMS
OTBDMS
BnO
10
9
BnO
O
c,d
88%
O
O
h, i
f, g
+
O
O
O
N
N
78%
from cis-7
X
e
MeO
MeO
N
N
9
9
OTBDMS
OTBDMS
7
7
O
O
7 (20%)
trans-
7
cis- (72%)
BnO
BnO
N
N
15 (X = OH)
16 (X = Br)
j
OTBDMS
OTBDMS
(Z)-17 (68%)
Br
45
O
O
78%
BnO
BnO
Scheme 3. Construction of the functionalized tricyclic core (Z)-17.
Reagents and conditions: (a) LDA, methyl pyruvate, THF, −78 °C; (b)
POCl3, pyridine, 0 °C ~ rt; (c) p-TsOH, acetone, 50 °C; (d) Ph3P, CBr4,
CH2Cl2, 0 °C; (e) NaOMe, THF, 0 °C.
11
6
10 Scheme 2. Synthesis of tropan-3-one derivative 6. Reagents and
conditions: (a) Ag2O, BnBr, rt; (b) TBDMSOCH2CH2NH2, MeOH, rt; (c)
Dess-Martin periodinane, CH2Cl2, rt; (d) MeOH, silica gel, reflux; (e)
Ac2O, Et3N, DMAP, CH2Cl2, rt; (f) silyl enol ether of acetone, TMSOTf,
CH2Cl2, −78 °C ~ rt; (g) imidazole, TBDMSCl, rt; (h) TMSOTf, Et3N,
15 CH2Cl2, 0 °C; (i) Tf2O, DTBMP, ZnBr2, CH2Cl2, −78 °C ~ rt; (j) ACCN,
allyl(n-Bu)3Sn, toluene, 85 °C.
We next investigated the regioselective C-C bond
formations at α and α’ positions of the ketone of tropanone 6
(Scheme 3). Successive treatment of 6 with LDA and methyl
20 pyruvate yielded the desired product 12 in 62% along with a
small amount of undesired regioisomer 13 (16%) and some
recovered starting material (17%). Dehydration of 12 with
POCl3 in the presence of pyridine produced the desired Z-
isomer (Z)-14 as a major product in 60% yield. Desilylation
25 of (Z)-14 under acidic conditions (p-TsOH, acetone, 50 ºC)
followed by bromination with Ph3P and CBr4 afforded
bromide 16. 16 cyclized easily when treated with NaOMe in
THF at 0°C to give the tricyclic product (Z)-17 in 68% yield.
For the side chain elongation, the hydrochloride salt of (Z)-
30 17 was heated with (Z)-1,4-dimethoxybut-2-ene in the
presence of Grubbs’ 2nd generation catalyst12 in toluene at 60
ºC (Scheme 4) to afford the desired cross-coupling product 18
in 56% yield (E/Z = 6.5:1). Isomerization of tetrasubstituted
double bond occurred under the reaction conditions and a
35 small amount of 19 (14%) was also obtained. Hydrogenation
of 18 proceeded smoothly to give compound 20 in 85% yield.
The structure of 20 was confirmed by single crystal X-ray
analysis.17 Silylation of 20 with TMS-imid. at 130 ºC7 led to
ester 21 in 83% yield. DIBAL-H reduction of the ester group
40 of 21 followed by Swern oxidation produced aldehyde 22 in
83% yield. The stereochemistry α to the aldehyde group is
wrong for the natural product. Hence, aldehyde 22 was
epimerized by treating it with DBU in toluene7 at 100 ºC to
afford the desired diastereomer 5 (5/ 22 = 12:1).
50
Scheme 4. Synthesis of the advanced tetracyclic core 5. Reagents and
conditions: (a) 2 N HCl, MeOH; then (Z)-1,4-dimethoxybut-2-ene,
Grubbs catalyst, 2nd generation, toluene, 60 °C; (b) Pd/C, H2, MeOH, rt,
24 h; then 2 N HCl, 48 h; (c) TMS-imid., 130 °C; (d) DIBAL-H, CH2Cl2,
55 −78 °C; (e) (COCl)2, DMSO, CH2Cl2, Et3N, −78 °C; (f) DBU, toluene,
100 °C.
With compound 5 in hand, Overman’s strategy7 was
adopted for the installation of the butenolide moiety.18 Thus,
2
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DOI: 10.1039/C4CC09598G
40
45
50
55
60
65
70
75
80
85
90
95
100
3
4
For reviews on the chemistry and biological activities of Stemona
alkaloids, see: (a) H. Greger, Planta Med., 2006, 72, 99; (b) R. A.
Pilli, G. B. Rosso and M. C. F. De Oliveira, Nat. Prod. Rep., 2010,
27, 1908.
aldehydes 5 was reacted with vinylogous lithium enolate 4 at
−78 ºC and the resulting adducts were treated with HCl in
MeOH/CHCl3 to give the vinylogous aldol adduct 23 as a
mixture of stereoisomers (Scheme 5). Oxidation of 23 with
IBX in DMSO7,19 at rt yielded a diastereomeric mixture 24,
which was treated with thiophosgene in the presence of
DMAP7,20 to afford 25 in 65% yield. Finally, heating 25 and
P(OMe)3 at 120 ºC provided methoxystemofoline (2) in 30%
For a review, see: (a) R. Alibés and M. Figueredo, Eur. J. Org.
Chem., 2009, 2421; For recent enantioselective total synthesis of
Stemona alkaloids, see: (b) Z.-H. Chen, Y.-Q. Tu, S.-Y. Zhang and
F.-M. Zhang, Org. Lett., 2011, 13, 724; (c) Z.-H. Chen, Y.-Q.
Zhang, Z.-M. Chen, Y.-Q. Tu and F.-M. Zhang, Chem. Commun.,
2011, 47, 1836; (d) A. T. Hoye and P. Wipf, Org. Lett., 2011, 13,
2634; (e) Y. Wang, L.-L. Zhu, Y.-Y. Zhang and R. Hong, Angew.
Chem. Int. Ed., 2011, 50, 2787; (f) J. B. Chen, J. C. Chen, Y. Xie
and H. B. Zhang, Angew. Chem. Int. Ed., 2012, 51, 1024; (g) Z.-H.
Chen, J.-M. Tian, Z.-M. Chen and Y.-Q. Tu, Chem.- Asian J., 2012,
7, 2199; (h) N. Bardají, F. Sánchez-Izquierdo, R. Alibés, J. Font, F.
Busqué and M. Figueredo, Org. Lett., 2012, 14, 4854; (i) X.-K. Liu,
J.-L. Ye, Y.-P. Ruan, Y.-X. Li and P.-Q. Huang, J. Org. Chem.,
2013, 78, 35.
5
yield, along with isomethoxystemofoline (3) in 30% yield.
10 The specific rotation {2: [α]D +71~85 (c 0.1, CH3OH); lit.2
20
21.6
20
[α]D
+75.6 (c 0.037, CH3OH); 3: [α]D +220~226 (c 0.1,
25
CH3OH); lit.9a [α]D +249 (c 0.29, CH3OH)} and spectral
data of our synthetic compounds 2 and 3 are consistent with
those reported by Xu2 and Pyne,9a respectively. Since Pyne
15 and co-workers employed (11Z)-1’2’-didehydrostemofoline as
the sarting material for the semisynthesis, their product
should have a 11Z stereochemistry (3). Accordingly, the
structure of the natural methoxystemofoline suggested by Xu
should be revised as 2, with a 11E stereochemistry, and
20 Pyne’s product be named as isomethoxystemofoline (3).
In summary, we have accomplished the first
enantioselective total synthesis of (+)-methoxystemofoline (2)
5
For recent synthetic studies on stemofoline alkaloids, see: (a) A. M.
Baylis, M. P. H. Davies and E. J. Thomas, Org. Biomol. Chem.,
2007, 5, 3139; (b) A. M. Baylis and E. J. Thomas, Tetrahedron,
2007, 63, 11666; (c) R. J. Carra, M. T. Epperson and D. Y. Gin,
Tetrahedron, 2008, 64, 3629; (d) E. J. Thomas and C. F. Vickers,
Tetrahedron: Asymmetry, 2009, 20, 970; (e) T. Sastraruji, S. G.
Pyne and A. T. Ung, Tetrahedron, 2012, 68, 598; (f) K. Sastraruji,
T. Sastraruji, A. T. Ung, R. Griffith, A. Jatisatienr and S. G. Pyne,
Tetrahedron, 2012, 68, 7103; (g) T. Burns, M. Helliwell and E. J.
Thomas, Tetrahedron Lett., 2013, 54, 2120.
and
(+)-isomethoxystemofoline
(3).
The
absolute
configuration of the natural methoxystemofoline (2) was
25 established as (11E,13E,2S,3S,7R,8S,9R,9aS,10S).
6
7
8
A. S. Kende, T. L. Smalley Jr and H. Huang, J. Am. Chem. Soc.,
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9
(a) K. Sastraruji, T. Sastraruji, S. G. Pyne, A. T. Ung, A. Jatisatienr
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Luo, L.-D. Guo, L.-H. Gao, S. Li and P.-Q. Huang, Chem. Eur. J.,
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12
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14 For recent reviews on -amidoalkylation via N-acyliminium ions,
see: (a) A. Yazici and S. G. Pyne, Synthesis, 2009, 339; (b) A.
Scheme 5. Completion of the total synthesis of methoxystemofoline (2)
and isomethoxystemofoline (3). Reagents and conditions: (a) 4, THF,
−78 °C; (b) HCl, MeOH/ CHCl3; (c) IBX, DMSO, rt; (d) CSCl2, DMAP,
30 CH2Cl2, −50 °C; (e) P(OMe)3, 120 °C.
α
Yazici and S. G. Pyne, Synthesis, 2009, 513.
15 T. Taniguchi, A. Ishita, M. Uchiyama, O. Tamura, O. Muraoka, G.
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44, 546.
Financial support provided by the Natural Science
Foundation (NSF) of China (21472153 and 21332007) and the
Program for Changjiang Scholars and Innovative Research
Team in University of the Ministry of Education. The authors
35 are grateful for Professor S. Pyne for valuable discussion.
17 Crystallographic data for this compound have been deposited at the
Cambridge Crystallographic Data Centre: CCDC 960240.
105 18 D. W. Knight and G. Pattenden, J. Chem. Soc., Perkin Trans. 1,
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Notes and references
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2
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