Tandem aza-Michael/spiro-ring closure sequence: Access to a versatile scaffold and total synthesis of (±)-coerulescine

Article abstract of DOI:10.1016/j.tetlet.2013.02.047

The total synthesis of the alkaloid (±)-coerulescine is presented. The key step of this approach is an efficient tandem aza-Michael initiated ring closure (aza-MIRC) process between ethoxymethylene-oxindole and benzyl(2-bromoethyl)carbamate. The potency of the aza-MIRC reaction was first tested onto less challenging Michael acceptors and led in good yields to the corresponding N-Cbz α-alkoxy-β-gem-disubstituted pyrrolidines. The resulting N-acyliminium precursor obtained from ethoxymethylidene-oxindole was efficiently converted in four steps, including 2 deprotections, into the targeted (±)-coerulescine.

Full text of DOI:10.1016/j.tetlet.2013.02.047

Tetrahedron Letters 54 (2013) 2174–2176
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Tandem aza-Michael/spiro-ring closure sequence: access to a versatile
scaffold and total synthesis of ( )-coerulescine
⇑
Meral Görmen, Ronan Le Goff, Ata Martin Lawson, Adam Daïch, Sébastien Comesse
URCOM, EA 3221, INC3M, FR-CNRS 3038, UFR des Sciences & Techniques de l’Université du Havre, BP: 540, 25 rue Philippe Lebon, F-76058 Le Havre Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The total synthesis of the alkaloid ( )-coerulescine is presented. The key step of this approach is an effi-
cient tandem aza-Michael initiated ring closure (aza-MIRC) process between ethoxymethylene-oxindole
and benzyl(2-bromoethyl)carbamate. The potency of the aza-MIRC reaction was first tested onto less
Received 24 December 2012
Revised 12 February 2013
Accepted 15 February 2013
Available online 24 February 2013
challenging Michael acceptors and led in good yields to the corresponding N-Cbz a-alkoxy-b-gem-disub-
stituted pyrrolidines. The resulting N-acyliminium precursor obtained from ethoxymethylidene-oxindole
was efficiently converted in four steps, including 2 deprotections, into the targeted ( )-coerulescine.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Tandem reaction
Total synthesis
Spirooxindoles
Coerulescine
Alkaloids
The simplest members of the spirooxindole family are coerules-
cine (1) and horsfiline (2) isolated respectively from the blue can-
ary grass Phalaris coerulescens, and the roots of the Malaysian tree
Horsfieldia superba (Fig. 1).1 Another tricyclic member elacomine
(3),2 substituted in the 40 position, exhibits anti-tumor activity.
Moreover, tetra- and pentacyclic spirooxindole alkaloids such as
rhynchophylline (5)3 and spirotryprostatins A (6) and B (7)4 are
well known for their interest as a neuroprotective agent or anti-
cancer agents, respectively. In fact, the spiro[oxindole-3,30-pyrroli-
dine] ring system is among the most interesting scaffold since it is
found in many relevant biologically active compounds. For exam-
ple, synthetic MI-219 (4) is a highly selective inhibitor of the
MDM2–P53 interactions making it an efficient anti-cancer agent.5
Furthermore, the formation of the spiro junction remains a
stimulating synthetic challenge for chemists. These observations
explain why numerous approaches were developed over the years6
including our own results for the access to unprecedented spiroox-
indole cores.7 We wish to report herein our recent findings regard-
ing the total synthesis of ( )-coerulescine (1). The key step for this
sequence is an efficient aza-MIRC (Michael initiated ring closure)
process between 3-ethoxymethylene-oxindole 89 and benzyl(2-
bromoethyl)carbamate 9 developed by our group.8
H
N
OH
O
Me
HO
N
O
NH
OH
Cl
F
R
2
NH
N
H
N
H
O
Cl
N
O
1
R = H, coerulescine ( )
H
3
elacomine ( )
4
MI-219 ( )
R = OMe, horsfiline (2)
N
Et
H
O
OMe
N
H
O
N
H
CO2Me
HO
N
H
O
R
N
H
O
6
5
R = OMe, spirotryprostatin A (
R = H, spirotryprostatin B (7)
)
rhynchophylline ( )
Figure 1. Representative spirooxindoles.
8. Starting from compound ( )-10, selective reduction, via N-acyli-
minium ion chemistry, deprotections, and methylation of the
resulting amine should lead to the desired ( )-coerulescine (1).
This retrosynthetic pathway implied to use benzyl(2-bromoeth-
yl)carbamate 9 as a partner for the spiro-ring closure.
Indeed, the key step of the synthesis was the tandem reaction
between benzyl(2-bromoethyl)carbamate 9 and an oxindole de-
rived Michael acceptor. As mentioned above, this reaction is
The retrosynthetic pathway envisioned for this total synthesis is
presented in Scheme 1. The requisite original key substrate ( )-
1010 bearing orthogonally protected nitrogen atoms would be ob-
tained by an aza-MIRC sequence between 9 and Michael acceptor
known with a-bromoacetamides but investigated for the first time
using compound 9 as the starting material.7,8 The challenge of this
step was the possible competitive formation of N-Cbz aziridine
⇑
Corresponding author. Tel.: +33 (0)2 32 74 44 03; fax: +33 (0)2 32 74 43 91.
E-mail address: sebastien.comesse@univ-lehavre.fr (S. Comesse).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.02.047

M. Görmen et al. / Tetrahedron Letters 54 (2013) 2174–2176
2175
deprotection
then methylation
Cbz
EtO
Cbz
Br
Cbz
N
N
H
Br
Cbz
2 steps
9
Me
EtO
N
H
N
OEt
N
O
9
29%
NaH, THF, rt
83%
N
H
O
N
O
N
Ac
O
OEt
reduction
( )-10
Ac
8
oxindole (13)
N
H
O
N
O
N
Ac
( )-
TFA
deprotection
Ac
CH2Cl2, rt
8
10
( )-coerulescine (1)
Cbz
N
Cbz
Cbz
N
N
Scheme 1. Retrosynthetic analysis.
Et3SiH
+
N
Ac
O
N
Ac
+ EtOH
O
N
H
O
resulting from the intramolecular cyclization of N-protected 2-bro-
moethanamine 9.11 For this reason, the first attempts of the tan-
dem reaction were performed with more conventional Michael
acceptors 11 in Table 1.12 Thankfully, the process proved to be
highly efficient leading in moderate to good yield to the expected
( )-15, 20%
( )-14, 66%
( )-I
Na2CO3, MeOH, 0°C, 99%
Scheme 2. Access to N-Cbz spiro[oxindole-3,30-pyrrolidine] ring system ( )-15.
N-Cbz
a-alkoxypyrrolidines 12. For instance, commercially avail-
able Michael acceptors 11a–d led to the formation of the corre-
sponding pyrrolidine systems 12a and d in good yields ranking
from 64% to 84% (Table 1, entries 1–4). Diphenylketone derived Mi-
chael acceptor 11e furnished the desired cyclic compound in an
acceptable 57% yield (Table 1, entry 5). The reaction was also effi-
cient with the acceptor 11f bearing a bulky phenylsulfone moiety,
giving a high 98% yield (Table 1, entry 6).
was first converted into the Michael acceptor 8 by using classical
procedures (Scheme 2).13 The tandem reaction furnished in 83%
yield the desired tricyclic spiro-product ( )-10. Reduction of the
resulting
a-ethoxy-pyrrolidine was performed via N-acyliminium
ion ( )-I generated in situ upon acidic treatment (e.g., excess of
TFA in DCM at rt) using triethylsilane as the reducing agent. We
obtained a 3:1 mixture of ( )-14 together with the deacylated com-
pound ( )-15 in an overall 86% yield. This deprotection can be
rationalized by the addition of EtOH produced during the process
onto the acyl group. Product ( )-14 was easily and quantitatively
converted into ( )-15 in the presence of sodium carbonate in
methanol.14
Next we turned our attention to the application of this tandem
process to the total synthesis of ( )-coerulescine (1). Oxindole (13)
Table 1
Tandem reaction between benzyl(2-bromoethyl)carbamate 9 and Michael acceptors
11a
Interestingly, the N-Cbz-spiro-system ( )-15 was afterward iso-
lated in three steps and 71% yield starting from 8 without any
intermediate purification (Scheme 3). The carboxybenzyl group
was then quantitatively removed by hydrogenation in the presence
of a catalytic amount of Pd/C in methanol. The resulting tricyclic
product ( )-1615 was converted in 38% yield to ( )-coerulescine
(1) by methylation of the secondary amine with dimethyl sulfate
in acetonitrile. The 1H NMR spectral data are in accordance with
those reported in the literature.16 It is important to note that the
conversion of coerulescine (1) into horsfiline (2) was previously
published.17
Br
EWG'
EWG
RO
EWG'
NaH, THF, rt
EWG
RO
+
N
HN
9
Cbz
11
Cbz
12
Entry
1
11
12
Yieldb (%)
MeO2C
MeO
CO2Me
CO2Me
MeO2C
11a
84
80
MeO
N
12a
Cbz
EtO2C
EtO
CO2Et
CO2Et
In summary, we have demonstrated the efficiency of benzyl(2-
EtO2C
bromoethyl)carbamate to access N-Cbz
a-ethoxy-pyrrolidines 12
11b
2
3
4
5
6
EtO
(Table 1). For the total synthesis of coerulescine (1), the key precur-
sor ( )-10, bearing orthogonally protected nitrogen atoms, was
readily obtained in good yield employing an aza-MIRC methodol-
ogy. An application to the straightforward total synthesis of ( )-
coerulescine (1) in seven steps and 8% overall yield starting from
N
Cbz
12b
NC
CO2Et
11c
CO2Et
NC
64c
81
57
98c
EtO
EtO
N
Cbz
oxindole (13) has been achieved. The reactivity of N-Cbz
a-eth-
12c
oxy-pyrrolidines 12 thus obtained by our tandem process in the
N-acyliminium ion chemistry is currently studied. Moreover, the
promising spiro-template ( )-10 is a key intermediate for the syn-
thesis of a wide library of spirooxindole derivatives by the way of
nucleophilic addition onto the N-acyliminium ion ( )-I. This reac-
tivity is also already under investigation and will be published in
due course.
NC
CN
11d
CN
NC
EtO
EtO
N
Cbz
COPh
12d
PhOC
EtO
COPh
11e
PhOC
EtO
N
Cbz
12e
NC
SO2Ph
11f
SO2Ph
NC
EtO
NH
EtO
Pd/C, H2
MeOH, rt
(MeO)2SO2, K2CO3
CH3CN, rt
N
Cbz
3 steps
71%
12f
8
15
1
( )-
( )-
99%
38%
N
H
O
a
Reaction conditions: benzyl(2-bromoethyl)carbamate 9 (0.5 mmol), Michael
acceptors 11 (0.5 mmol), NaH (0.6 mmol), THF (2.5 mL).
( )-16
b
Isolated yields.
dr >95:5 determined by 1H NMR analysis of the crude mixture.
c
Scheme 3. Synthesis of ( )-coerulescine (1).

2176
M. Görmen et al. / Tetrahedron Letters 54 (2013) 2174–2176
11. A solution of benzyl(2-bromoethyl)carbamate 9 (129 mg, 0.5 mmol) and NaH
Acknowledgments
(60% in mineral oil, 24 mg, 0.6 mmol) in THF (2.5 mL) was stirred at rt for 7 h.
1H NMR of the crude mixture showed the presence of 9 together with N-Cbz
aziridine in a ratio of 45:55. The 1H NMR spectral data of N-Cbz aziridine is in
accordance with the literature: Moore, E. G.; Xu, J.; Jocher, C. J.; Corneillie, T.
M.; Raymond, K. N. Inorg. Chem. 2010, 49, 9928–9939; Access to N-Cbz
We thank the ‘Fédération de Chimie’: FR CNRS 3038 (INC3 M),
the ‘réseau CRUNCH’, the ‘Région Haute-Normandie’ (Marie Curie
Postdoctoral Fellowship for M.G.), the French ‘Ministère de l’Ens-
eignement Supérieur et de la Recherche’ (Graduate Fellowship
attributed to R.L.G.), ERDF funding (A-I chem channel – Interreg
IV4 program) and the URCOM laboratory for their financial
support.
ˇ
´
ˇ ´
´
aziridine starting from tosylate derivative, see: Zinic, M.; Alihodzic, S.; Škaric,
V. J. Chem. Soc., Perkin Trans. 1 1993, 21–26; For the use of N-substituted
aziridines in the alkylative cyclization of 1,3-dimethylindole catalyzed by
Sc(OTf)3 and TMSCl for the formation of eserine-like alkaloids, see: Nakagawa,
M.; Kawahara, M. Org. Lett. 2000, 2, 953–955.
12. General procedure: To a solution of benzyl(2-bromoethyl)carbamate 9 (129 mg,
0.5 mmol) and the corresponding Michael acceptor 11 (0.5 mmol) in THF
(2.5 mL) at 0 °C, was added NaH (60% in mineral oil, 24 mg, 0.6 mmol) portion
by portion. The ice bath was removed and the reaction mixture was stirred for
3 h to 3 days (monitored by TLC), was then poured into a saturated NH4Cl
solution, and extracted with ethyl acetate (2 ꢀ 25 mL). The organic phase was
washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The
crude mixture was purified by flash chromatography (cyclohexane/EtOAc: 20/
80). 1-Benzyl 3,3-dimethyl 2-methoxypyrrolidine-1,3,3-tricarboxylate (12a):
84% as a white solid. mp 67–69 °C. IR (neat) 1737, 1705, 1396, 1275, 1246,
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.
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