Cascade cyclization triggered by imine formation. Formal synthesis of the alkaloid (±)-stemoamide and its 9a-epimer

Article abstract of DOI:10.1016/j.tetlet.2015.10.017

A concise formal synthesis of stemoamide (1) and its 9a-epimer 14 in 5 steps is described featuring a cascade cyclization triggered by imine formation. A good selectivity for either epimer is readily accomplished by variation of the ester (9b or 9a, respectively) and the reaction conditions.

Full text of DOI:10.1016/j.tetlet.2015.10.017

Tetrahedron Letters 56 (2015) 6664–6668
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Cascade cyclization triggered by imine formation. Formal synthesis
of the alkaloid ( )-stemoamide and its 9a-epimer
Gilmar A. Brito a, Ariel M. Sarotti b, Peter Wipf c, Ronaldo A. Pilli a,
⇑
a Institute of Chemistry, University of Campinas (UNICAMP), C.P. 6154, CEP 13084-971 Campinas, São Paulo, Brazil
b Instituto de Química Rosario (CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 531, Rosario 2000, Argentina
c Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A concise formal synthesis of stemoamide (1) and its 9a-epimer 14 in 5 steps is described featuring a cas-
cade cyclization triggered by imine formation. A good selectivity for either epimer is readily accom-
plished by variation of the ester (9b or 9a, respectively) and the reaction conditions.
Ó 2015 Elsevier Ltd. All rights reserved.
Received 7 August 2015
Revised 2 October 2015
Accepted 5 October 2015
Available online 14 October 2015
Keywords:
Stemoamide
Formal synthesis
Cascade cyclization
Imine formation
Mukaiyama-Michael reductive
carbamoylation
Michael/Nef reaction
O
O
O
O
Extracts from plants belonging to the Stemonacea family have
been used in Southeast Asia’s folk medicine for a long time. In
particular, extracts from the roots of Stemona tuberosa, Stemona
sessilifolia, and Stemona japonica have been prescribed in China
and Japan for therapeutic purposes and also used as domestic
insecticides, and they are still readily available at local markets.1
Stemona alkaloids comprise a group of approximately 170 poly-
cyclic compounds2 with most of them displaying a characteristic
pyrrolo[1,2-a]azepine, pyrido[1,2-a]azepine or, as recently found,
a pyrido[1,3-a]azepine core. Additionally, some other structural
H
H
H
H
H
H
O
Me
H
H
9a N
H
H
H
H
O
N
N
H
O
H
O
H
O
1
2
3
Tuberostemonine ( )
Stemoamide ( )
Stenine ( )
Figure 1. Structures of representative Stemona alkaloids.
features such as the presence of
a
pyrido[1,2-a]azonine3 or
precedented diastereoselective methylation. Imine B was assumed
to form after amine deprotection in C which, in turn, would be
prepared via a stereoselective Michael addition of nitroester E to
furanone D (Scheme 1).
Intermediates 9a,b were prepared via
Mukaiyama-Michael addition of commercially
2-(trimethylsilyloxy)furan (4) to acrolein, catalyzed by pyrrolidine
in the presence of 2,5-dinitrobenzoic acid, to provide aldehyde 5 in
96% yield.7 While our work was in progress, Qiu and co-workers
indolizidine4 have recently been described.
Stemoamide (1, Fig. 1) was first identified by Xu and co-workers
in 1992 as a secondary metabolite from S. tuberosa.5 Due to its
novel architecture and its stature as one of the simplest represen-
tative members of this class of alkaloids, it attracted the attention
of synthetic chemists and it has been prepared several times in the
past, with most approaches focusing on the construction of the ring
junction at C9a, followed by diastereoselective transformations to
set in place the remaining stereogenic carbons.6
a
straightforward
available
reported the addition of 2-methyl-c-butenolide to acrolein
catalyzed by dimethylamine hydrochloride in 67% yield.6m
The nitrogen atom present in the desired alkaloid was inserted
via reductive carbamoylation to provide carbamate 6 in 85% yield
according to the procedure by Dubé and co-workers.8 DBU-
mediated Michael addition of nitroesters 7a,b to 6, followed by a
Our retrosynthetic analysis of stemoamide (1) relies on a
stereoselective reduction/lactamization of imine B, followed by a
⇑
Corresponding author.
E-mail address: pilli@iqm.unicamp.br (R.A. Pilli).
http://dx.doi.org/10.1016/j.tetlet.2015.10.017
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

G. A. Brito et al. / Tetrahedron Letters 56 (2015) 6664–6668
6665
RO2C
Imine reduction
and lactamization
O
Me
Imine
formation
H
H
H
N
N
H
O
O
O
O
H
(-)-Stemoamide (1)
B
O
Michael addition
and Nef reaction
H
CO2R
O2N
O
NHPG
O
O
CO2R
NHPG
H
O
H
C
D
E
Scheme 1. Retrosynthetic analysis.
Nef reaction, furnished compounds 9a,b in good overall yields
(Scheme 2). The trans-stereochemistry was assigned based on
our previously published results9 and for highest yields in the
Nef reaction the mild reaction conditions described by Burés and
Villarasa were required.10
Entries 1–3 (Table 2) provide the results for reactions carried
out in different solvents using Pd(OH)2/C as the catalyst and
10 atm of H2. Under these conditions, the best ratio in favor of iso-
mer 11 was achieved when trifluoroethanol was employed as sol-
vent (entry 3, dr = 1:10). In contrast, the use of PtO2/C, Crabtree’s
catalyst12 or Ru/C was not effective in promoting the cascade of
events leading to the formation of the stemoamide core. In the
presence of platinum(IV) oxide, the secondary alcohol 13 was the
only isolated product (80% yield). Therefore, the best experimental
conditions (entry 3) afforded tricyclic lactam 11 in 27% overall
yield (four steps) as a 1:10 diastereomeric mixture, together with
31% of aminoacid 12.
The influence of the nature of the remote ester in the diastereos-
electivity of the imine reduction was also investigated via a compu-
tational analysis at the PCM/M062X/6-311+G⁄⁄//M062X/6-31G⁄
level of theory either in ethyl acetate or trifluoroethanol (TFE) as sol-
vents. Figure 2 shows the most stable conformationslocated for each
system, all displaying a half-chair topology in the 7-membered ring.
In the case of imine B-a (Scheme 1, R = Me), the side chain in two
of the most populated conformations (B-a_c1 and B-a_c3) is direc-
Esters 9a and 9b were subjected to hydrogenolysis in the pres-
ence of Pd(OH)2/C as catalyst and 2 or 4.5 atm of hydrogen pres-
sure in ethyl acetate in order to set the stage for a tandem
nitrogen deprotection, imine formation followed by a stereoselec-
tive hydrogenation which was expected to deliver the hydrogen
from the less encumbered Re-face of the imine intermediate to pro-
vide the stemoamide core. To our surprise, when methyl ester 9a
was subjected to the hydrogenolysis conditions mentioned above,
a 5:1 mixture of tricyclic lactams 10 and 11 (epimers at C-9a) was
obtained in 45% overall yield (after four transformations). Since
both products were already described in the literature.6i,11 the
diastereomeric ratio was easily determined by 1H NMR analysis
(see Supporting information).
In contrast, when benzyl ester 9b was submitted to the same
reaction conditions (4.5 atm of H2), lactam 11 was obtained as
the major isomer, albeit in a low diastereomeric ratio (1:1.4)
(Scheme 3). Fortunately, when the reaction was carried out at
10 atm of hydrogen pressure under otherwise identical experimen-
tal conditions, the preference of ester 9b to afford tricyclic lactam
11 increased (dr = 1:3, Table 1).
ted toward the
a face of the molecule, facilitating the Si face hydro-
genation that leads to the tricyclic core of 9a-epi-stemoamide (14).
The preference was much more straightforward upon inspection of
the hydrogenation of the imine derived from benzyl ester 9b: the
energy differences between the two most stable conformations
B-b_c1 and B-b_c2 (Fig. 2) were 0.9 kcal molÀ1 in ethyl acetate
and 1.1 kcal molÀ1 in trifluoroethanol, respectively, with the benzyl
group in both conformations directing the hydrogenation from the
Intrigued by these results, we explored a small series of ester
analogs in the hydrogenolysis/cyclization/reduction manifold
(Table 1). The bulky 2,6-dimethylphenyl ester 9c (entry 2) led to
a slight decrease in the formation of the desired isomer while
Re face probably due to CH/
p
interactions,13 thus leading to the
a
- and b-branched alkyl esters 9d and 9e provided either no selec-
stemoamide core. It should be noted that the computationally
obtained energy difference is fully consistent with the 1:10
diastereoisomeric ratio favoring the tricyclic stemoamide core that
was observed experimentally in trifluoroethanol at 10 atm of
hydrogen pressure. Methylation of lactone 11 to give the natural
tivity (entry 3) or tricyclic lactam 10 as the main product (entry 4).
Based on these results, we decided to investigate the nature of the
solvent and the catalyst on the diastereoselectivity of this reaction
sequence using benzylic ester 9b as the substrate (Table 2).
O
N
O
DNBA
H
O
O
TFA, Et3SiH
NHCbz
O
O
OSiMe3
5 h, -50 ºC, 96 %
H
H2NCbz, CH3CN
12 h, 85 %
H
O
4
5
6
NO2
O
O2N
CO2R
H
H
H
CO2R
PMe3, (pTolS)2
CO2R
NHCbz
7a,b
O
O
THF, 48 h
DBU, CH2Cl2
12 h
NHCbz
O
O
H
R = Me, 70 % 8a
8b
R = Me, 81 % 9a
9b
R = Bn, 84 %
R = Bn, 78 %
Scheme 2. Preparation of 1,4-dicarbonyl compounds by nitro-Michael and Nef reactions.

6666
G. A. Brito et al. / Tetrahedron Letters 56 (2015) 6664–6668
O
O
O
H
9aN
H
H
H
conditions a) or b)
CO2R
N
H
O
O
O
NHCbz
O
O
O
H
H
H
10
5
11
1
9a,b
R = Me
R = Bn
:
:
1
1.4
Scheme 3. Cascade cyclization reactions. Reagents and conditions: (a) R = Me (9a), Pd(OH)2/C (40% wt/wt), H2 (2 or 4.5 atm), EtOAc, 48 h, 45%; (b) R = Bn (9b), Pd(OH)2/C (40%
wt/wt), H2 (4.5 atm), EtOAc, 60 h, 42%.
Table 1
Diastereomeric ratio of ring epimers as a function of ester group
O
H
H
H
O
O
Pd(OH)2, H2 (10 atm)
N
CO2R
O
N
O
O
H
H
EtOAc
48-60 h
O
O
O
NHCbz
H
H
H
9b-e
10
11
Entry
1
R
Substrate
Ratio (10:11)
9b
1:3
2
9c
1:2
3
4
9d
9e
1:1
3:1
Table 2
Diastereomeric ratio of ring isomers as a function of reaction solvent and catalyst
O
H
H
H
O
O
conditions
48-60 h
N
CO2Bn
O
N
O
O
H
H
O
O
O
NHCbz 10 atm H2
H
H
H
9b
10
Catalyst
11
Entry
Solvent
Ratio (10:11)
1
2
3
4
5
6
EtOAc
HOAc
CF3CH2OH
EtOAc
EtOAc
Pd(OH)2/C
Pd(OH)2/C
Pd(OH)2/C
PtO2/C
Crabtree’s
Ru/C
1:3
1:1.4
1:10a
b
c
c
EtOAc
a
b
c
Aminoacid 12 was also isolated.
Only product 13 from carbonyl reduction was observed.
Only starting material was recovered.
HO
O
H
H
CO2Bn
NHCbz
CO2
NH3
O
O
PCy3
O
O
Ir
H
H
N
12
13
Crabtree's catalyst

G. A. Brito et al. / Tetrahedron Letters 56 (2015) 6664–6668
6667
B-a_c1
Erel = 0.0 kcal/mol (EtOAc)
rel = 0.0 kcal/mol (TFE)
B-a_c2
B-a_c3
Erel = 0.1 kcal/mol (EtOAc)
Erel = 0.6 kcal/mol (EtOAc)
E
E
rel = 0.3 kcal/mol (TFE)
E
rel = 0.4 kcal/mol (TFE)
2.7 Å
2.8 Å
B-b_c1
B-b_c2
B-b_c3
Erel = 0.0 kcal/mol (EtOAc)
Erel = 0.0 kcal/mol (TFE)
Erel = 0.9 kcal/mol (EtOAc)
Erel = 1.1 kcal/mol (TFE)
Erel = 1.2 kcal/mol (EtOAc)
Erel = 1.0 kcal/mol (TFE)
Figure 2. Relative energies of imines derived from esters 9a and 9b.
H
H
9aN
O
Pd(OH)2/C
O
O
ref 6i
O
N
H
H
H2 (10 atm)
CF3CH2OH
27 %
O
O
9b
O
H
H
OSiMe3
O
(+/-)-Stemoamide (1)
11 (10:1)
4
O
H
CO2R
4 steps
O
O
NHCbz
H
O2N
CO2R
7a,b
H2NCbz
R = Me, 9a, 46 %
R = Bn, 9b, 53 %
H
N
O
H
O
9aN
ref 11
9a
Pd(OH)2/C
O
O
H
H
O
H
H2 (2 atm)
EtOAc
45 %
O
H
(+/-)-9a-epi-Stemoamide (14)
10 (5:1)
Scheme 4. Overview of the formal total syntheses of epimeric stemoamides.
product
1 has previously been described in the literature
Supplementary data
(Scheme 4).6i,11
In summary, we have developed a reaction sequence that
enables a concise formal synthesis of stemoamide (1) and its 9a-
epimer 14 in 5 steps from commercially available building blocks
(Scheme 4). A good selectivity for either epimer is readily accom-
plished by variation of the ester (9b or 9a, respectively) and the
reaction conditions.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.10.017.
References and notes
1. Greger, H. Planta Med. 2006, 72, 99.
2. For reviews on Stemona alkaloids, see: (a) Pilli, R. A.; Oliveira, M. da C. F. de.
Nat. Prod. Rep. 2000, 17, 117; (b) Pilli, R. A.; Rosso, G. B.; De Oliveira, M. D. C. F.
In The Alkaloids: Chemistry and Biology; Cordell, G. A., Ed.; Academic Press, 2005;
Vol. 62, pp 77–173; (c) Pilli, R. A.; Rosso, G. B.; Oliveira, M. da C. F. de. Nat. Prod.
Rep. 1908, 2010, 27.
3. Hitotsuyanagi, Y.; Uemura, G.; Takeya, K. Tetrahederon Lett. 2010, 51, 5694.
4. Hitotsuyanagi, Y.; Takeda, E.; Fukuya, H.; Takeya, K. Tetrahedron Lett. 2008, 49,
7376.
Acknowledgments
G.A.B. and R.A.P. are grateful to FAPESP (2009/51602-5,
2010/00219-4 and 2012/23569-3). P.W. acknowledges Boehringer
Ingelheim for support.

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G. A. Brito et al. / Tetrahedron Letters 56 (2015) 6664–6668
5. Lin, W.-H.; Ye, Y.; Xu, R.-S. J. Nat. Prod. 1992, 55, 571.
Gawade, R. L. Tetrahedron Lett. 2012, 53, 2647; (m) Li, Z.; Zhang, L.; Qiu, F. Asian
J. Org. Chem 2014, 3, 52; (n) Mi, X.; Wang, Y.; Zhu, L.; Wang, R.; Hong, R.
Synthesis 2012, 44, 3432; (o) Hoye, A. T.; Wipf, P. Org. Lett. 2011, 13, 2634.
7. Brown, S. P.; Goodwin, N. C.; MacMillan, D. W. C. J. Am. Chem. Soc. 2003, 125,
1192.
8. Dubé, D.; Scholte, A. A. Tetrahedron Lett. 1999, 40, 2295.
9. Rosso, G. B.; Pilli, R. A. Tetrahedron Lett. 2006, 47, 185.
10. Burés, J.; Vilarrasa, J. Tetrahedron Lett. 2008, 49, 441.
11. Gao, P.; Tong, Z.; Hu, H.; Xu, P.-F.; Liu, W.; Sun, C.; Zhai, H. Synlett 2009, 2188.
12. Crabtree, R. Acc. Chem. Res. 1979, 12, 331.
6. (a) Williams, D. R.; Reddy, J. P.; Amato, G. S. Tetrahedron Lett. 1994, 35, 6417; (b)
Kinoshita, A.; Mori, M. J. Org. Chem. 1996, 61, 8356; (c) Kohno, Y.; Narasaka, K.
Bull. Chem. Soc. Jpn. 1996, 69, 2063; (d) Jacobi, P. A.; Lee, K. J. Am. Chem. Soc.
1997, 119, 3409; (e) Jacobi, P. A.; Lee, K. J. Am. Chem. Soc. 2000, 122, 4295; (f)
Gurjar, M. K.; Reddy, D. S. Tetrahedron Lett. 2002, 43, 295; (g) Sibi, M. P.;
Subramanian, T. Synlett 2004, 1211; (h) Olivo, H. F.; Tovar-Miranda, R.;
Barragán, E. J. Org. Chem. 2006, 71, 3287; (i) Torssell, S.; Wanngren, E.; Somfai,
P. J. Org. Chem. 2007, 72, 4246; (j) Honda, T.; Matsukawa, T.; Takahashi, K. Org.
Biomol. Chem. 2011, 9, 673; (k) Wang, Y.; Zhu, L.; Zhang, Y.; Hong, R. Angew.
Chem., Int. Ed. 2011, 50, 2787; (l) Chavan, S. P.; Harale, K. R.; Puranic, V. G.;
13. Tsuzuki, S.; Fujii, A. Phys. Chem. Chem. Phys. 2008, 10, 2584.