Studies toward the total synthesis of (+)-gelsemine and synthesis of spirocyclopentaneoxindole through intramolecular Michael cyclization

Article abstract of DOI:10.1016/j.tetlet.2012.08.048

During the approach to the total synthesis of (+)-gelsemine, two novel spirocyclopentaneoxindole compounds 2 and 3 were obtained. Starting from compound 9, spirocyclopentaneoxindole 3 was efficiently and unexpectedly obtained through a Boc migration-intramolecular Michael cyclization cascade procedure. This intramolecular Michael addition strategy allows conveniently access to complex spirooxindole and spirocyclopentaneoxindole derivatives.

Full text of DOI:10.1016/j.tetlet.2012.08.048

Tetrahedron Letters 53 (2012) 5684–5687
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Studies toward the total synthesis of (+)-gelsemine and synthesis of
spirocyclopentaneoxindole through intramolecular Michael cyclization
⇑
Shiyi Zhou, Tao Xiao, Hao Song, Xuan Zhou
Department of Chemistry of Medicinal Natural Products, Key Laboratory of Drug Targeting and Novel Delivery System of Ministry of Education,
West China School of Pharmacy, Sichuan University, Chengdu 610041, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 June 2012
Revised 26 July 2012
Accepted 10 August 2012
Available online 17 August 2012
During the approach to the total synthesis of (+)-gelsemine, two novel spirocyclopentaneoxindole com-
pounds 2 and 3 were obtained. Starting from compound 9, spirocyclopentaneoxindole 3 was efficiently
and unexpectedly obtained through a Boc migration–intramolecular Michael cyclization cascade proce-
dure. This intramolecular Michael addition strategy allows conveniently access to complex spirooxindole
and spirocyclopentaneoxindole derivatives.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Gelsemine
Michael addition
Synthesis
Spirocyclopentaneoxindole
Heterocyclic compounds play important roles in the drug dis-
covery process. Polycyclic spirooxindoles are commonly occurring
heterocyclic ring systems found in a range of natural products
and pharmaceuticals.1–5 Among them, spirocyclopentaneoxindole
scaffolds are widely embodied in natural alkaloids such as paraher-
quamide A, notoamide B, and sclerotiamide (Fig. 1).6,7 Spirocycl-
opentaneoxindole, bearing a critical quaternary carbon at the
joint point, remains a challenging motif for synthetic chemists.
Because of the intriguing structure and potential biological activity,
the synthetic methodologies of spirocyclopentaneoxindole frame-
work have received significant attention around the world. To date,
many elegant strategies concerning the synthesis of spirocyclopen-
taneoxindole framework have been reported.8–11 Recently, two
new spirocyclopentaneoxindole derivatives compounds 2 and 3
were efficiently constructed through an intramolecular Michael
addition and an unexpected Boc migration–intramolecular Michael
cyclization cascade procedure, respectively.
As shown in the retrosynthetic analysis of (+)-gelsemine
(Scheme 1), we envisioned that (+)-gelsemine could be synthesized
O
O
NH
NH
O
H
H
OH
O
H
N
O
Me
N
O
O
N
N
O
(-)-Paraherquamide A
(-)-Notoamide B
O
NH
O
NH
H
O
H
N
O
OH
(-)-Sclerotiamide
N
O
Spirocyclopentaneoxindole
(+)-Gelsemine 1 was first isolated in 1876 and its elusive struc-
ture was elucidated in 1959 by NMR spectroscopy and X-ray
crystallographic analysis,12–14 which has attracted numerous syn-
thetic efforts in the chemical community.15 During our research
on asymmetric total synthesis of (+)-gelsemine,16 to our surprise,
two new spirocyclopentaneoxindole derivatives 2 and 3 were
achieved (Fig. 2). In this Letter, we will have a further discussion
on studies toward the total synthesis of (+)-gelsemine and forma-
tion of the spirocyclopentaneoxindole skeleton.
Figure 1. Natural products containing the spirocyclopentaneoxindole scaffold.
Me
N
H
N
O
18
Me
N
1
8
19
O
2
12
OMOM
O
7
20
O
6
OMOM
O
NC
NC
15
14
3
21
10
5
N
O
O
O
4
16
N
Me
17
N
H
Bn
1
(+)-gelsemine
2
3
⇑
Corresponding author.
E-mail address: zhouxuan526@gmail.com (X. Zhou).
Figure 2. Structures of (+)-gelsemine and compounds 2 and 3.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.08.048

S. Zhou et al. / Tetrahedron Letters 53 (2012) 5684–5687
5685
Bn
N
O
Bn
N
H
N
O
O
CHO
CHO
D
C
CHO
N
N
N
Me
O
O
Me
Me
OMOM
4
1
5
(+)-gelsemine
NMe
O
NMe
NC
OHC
H
OMOM
OEt
OEt
H
OMOM
CHO
O
O
N
N
N
Bn
Bn
Bn
8
7
6
+
NC
TBDMSO
NMe
NC
NMe
O
OH
ref.16
OMOM
OEt
OHC
OMOM
OEt
OEt
EtO
12 steps
OH
D-diethyl tarate 11
Scheme 1. Retrosynthetic analysis of (+)-gelsemine.
O
EtO
OEt
9
10
D
-diethyl tartrate in 12 steps according to our reported synthetic
route.16
According to the retrosynthetic analysis, our total synthesis of
from the intermediate 5 through an acid-catalyzed enol-oxonium
cyclization. We reasoned that the C-ring and D-ring of compound
5 could be constructed by two continuous intramolecular Michael
(+)-gelsemine commenced with converting 10 to 12 (Scheme 2).
Removal of t-butyldimethylsilyl (TBDMS) with tetrabutylammo-
nium fluoride in 10 provided alcohol 12 in 93% yield, which fol-
lowed by the partial hydrogenation of triple bond in 12 with
Lindlar catalyst (Pd/CaCO3) at 1 atm of hydrogen pressure in MeOH
for 3 h gave the expected Z-conformation alkene 13 in excellent
additions due to the nucleophilicity of
a position of aldehyde
group in 6. Compound 6 could be achieved through cyano reduc-
tion and deprotection of acetal from compound 7. Compound 7
was synthesized by intermolecular aldol condensation of N-benzy-
loxindole 8 and aldehyde 9. Cis alkene 9 could be conveniently
generated from compound 10, which was easily prepared from
NMe
NMe
NC
NMe
NMe
CN
CN
HO
OMOM
OMOM
CN
i
ii
iii
H
OMOM
OEt
OEt
O
TBDMSO
OMOM
OEt
OEt
+
N
OH
O
Bn
EtO
OEt
EtO
OEt
8
10
12
13
9
NMe
NMe
NMe
NMe
20
D
NC
NC
NC
OHC
HO
OMOM
OEt
H
OMOM
OEt
OMOM
OEt
6
H
OMOM
CHO
6
iv
v
vii
H
OEt
OEt
OEt
O
O
O
O
N
N
N
N
Bn
Bn
Bn
Bn
14
7
6
15
vi
Bn
H
N
O
CHO
O
NMe
N
OHC 20
H
20
OMOM
O
6
D
C
15
CHO
NMe
N
N
O
O
NC 20
Me
Me
(+)-gelsemine
N
OMOM
OMOM
Bn
17
H
1
5
7
15
O
O
N
Me
N
Bn
16
OMOM
O
NC
7
O
N
Bn
2
Scheme 2. The first route toward (+)-gelsemine. Reagents and conditions: (i) Bu4N+FÀ, THF, rt, 93%; (ii) Lindlar Cat., H2, CH3OH, rt, 95%; (iii) Swern oxidation, 95%; (iv) LDA,
THF, À78 °C, 70%; (v) SOCl2/pyridine, 0 °C, 85%, E/Z = 3:5; (vi) LDA, THF, À78 °C, 70%; (vii) PPTS, acetone–H2O, rt., 80%.

5686
S. Zhou et al. / Tetrahedron Letters 53 (2012) 5684–5687
NMe
NMe
O
NMe
NC
NMe
NC
HO
NC
NC
OMOM
OEt
H
OMOM
OEt
OMOM
OEt
H
i
ii
iii
H
O
+
OMOM
OEt
OEt
N
H
OEt
OEt
OEt
O
O
O
N
H
N
H
N
H
9
18
19
20
21
H
N
BocO
CN
20
H
O
N
CHO
NMe
NMe
N
NC
NC 20
Me
(+)-gelsemine
N
Me
O
OMOM
OEt
OMOM
O
OMOM
24
iv
v
1
15
OBoc
OEt
OBoc
22
N
H
N
H
Me
O
N
23
O
OMOM
vi
NC
O
O
N
H
3
Scheme 3. The second route toward (+)-gelsemine. Reagents and conditions: (i) LDA, THF, À78 °C, 70%; (ii) SOCl2/pyridine, 0 °C, 85%; (iii) LDA, THF, À78 °C, 70%; (iv) (Boc)2O,
Et3N, CH2Cl2, rt, 40%; (v) PPTS, acetone–H2O, rt, 80%; (vi) LiHMDS, THF, À78 °C ? À40 °C.
yield. Oxidation of the hydroxy group in 13 provided aldehyde 9.
Aldol condensation of the resulting aldehyde 9 with N-benzyloxin-
dole 8 in the presence of LDA at À78 °C, followed by dehydration
with SOCl2/pyridine delivered compound 7 (E/Z = 3:5). With 7 in
hand, we began to synthesize the key compound 6. Perhaps, due
to the instability of 6, numerous efforts for converting compound
7 to 6 failed, which declared the failure of our initial plan to assem-
ble the C/D rings, and C20 quaternary stereocenter of gelsemine via
two continuous intramolecular Michael additions. Based on the
above results, we have to construct the C/D rings of gelsemine,
respectively. Starting from compound 7, the pyrrolidine ring (D
ring) was easily prepared through the first intramolecular Michael
addition of C20 to C6 in the presence of LDA at À78 °C to provide
15 in 70% yield. However, our attempt to construct the C-ring via
a second intramolecular Michael addition of C20 to C15 in com-
electrophilic C15 under acidic condition.17,18 However, the C-ring
of gelsemine was more difficult to form, as a strong base was usu-
ally needed to active the
a position of cyano. Based on the above
analysis, in order to construct C-ring smoothly, the nucleophilicity
of C7 should be weakened at first. Therefore, we designed com-
pound 23 to avoid the cyclization of C7 to C15. Adopting the above
procedure, compound 21 was obtained successfully in three steps
from
9 including Aldol condensation, Lindlar reduction, and
Michael addition. Protection of 21 with ditertbutyl-dicarbonate
in the presence of Et3N gave the O-protected indole 22 in 40% yield.
Removal of acetal in 22 provided the stable a,b-unsaturated alde-
hyde 23 in 80% yield. It is anticipated that the key precursor 24
of (+)-gelsemine could be synthesized by intramolecular Michael
addition between C20 and C15. Surprisedly, treatment of
a
,b-unsaturated aldehyde 23 with LiHMDS yielded an enantiome-
pound 17 was failed. Although the anticipated
a,b-unsaturated
rically pure spirocyclopentaneoxindole compound 319 rather than
the desired 24 (Scheme 3).
aldehyde 16 was achieved after the deprotection of the acetal,
compound 17 was unable to be prepared from compound 16 be-
cause 16 was directly converted into an enantiomerically pure spi-
rocyclopentaneoxindole derivative 219 via an intramolecular
Michael addition of C7 to C15 (Scheme 2).
The data of 1H and 13C NMR spectra, together with further
1H–1H, direct 1H–13C, and long range 1H–13C scalar connectivities
as measured from 2D experiments, allowed the determination of
the structure of 3 as shown in Figure 2.
a
,b-Unsaturated aldehyde 16 was easily converted into spiroox-
The unexpected novel spirocyclopentaneoxindole derivative
compound 3 was assumed to be obtained through a tandem
indole 2 via the spontaneous attack of oxindole enolate on the
O
Me
NMe
H
N
O
N
O
20
H
N
NC
CN
O
O
O
OMOM
O
OMOM
O
20
NC
Boc
15
NC
7
20
OBoc
23
CHO
O
N
N
H
CHO
Me
N
N
H
3
Me
OMOM
OMOM
i
O
O
O
H
N
H
N
O
O
O
NC
NC
7
15
CHO
CHO
N
N
Me
Me
OMOM
OMOM
25
Scheme 4. Plausible mechanism for the formation of 3. Reagents and conditions: (i) LiHMDS, THF, À78 °C ? À40 °C.

S. Zhou et al. / Tetrahedron Letters 53 (2012) 5684–5687
5687
procedure of Boc migration–intramolecular Michael cyclization.
References and notes
The plausible mechanism for the unexpected cascade reaction is
proposed in Scheme 4. After deprotonation of C20, the formed an-
1. Galliford, C. V.; Scheidt, K. A. Angew. Chem., Int. Ed. 2007, 46, 8748–8758.
2. Williams, R. M.; Cox, R. J. Acc. Chem. Res. 2003, 36, 127–139.
3. Marti, C.; Carreira, E. M. Eur. J. Org. Chem. 2003, 2209–2219.
4. Shangary, S.; Wang, S. Annu. Rev. Pharmacol. Toxicol. 2009, 49, 223–241.
5. Ding, K.; Lu, Y.; Nikolovska-Coleska, Z.; Wang, G. P.; Qiu, S.; Shangary, S.; Gao,
W.; Qiu, D. G.; Stuckey, J.; Krajewski, K.; Roller, P. P.; Wang, S. M. J. Med. Chem.
2006, 49, 3432–3435.
6. Williams, R. M.; Stocking, E. M.; Sanz-Cevera, J. F. Top. Curr. Chem. 2000, 209,
97–173.
7. Williams, R. M. Chem. Pharm. Bull. 2002, 50, 711–740.
8. Tan, B.; Candeias, N. R.; Barbas, C. F. J. Am. Chem. Soc. 2011, 133, 4672–4675.
9. Miller, K. A.; Tsukamoto, S.; Williams, R. M. Nat. Chem. 2009, 1, 63–68.
10. Voituriez, A.; Pinto, N.; Neel, M.; Retailleau, P.; Marietti, A. Chem. Eur. J. 2010,
16, 12541–12544.
11. Bin, T.; Nuno, R. C.; Carlos, F. B. Nat. Chem. 2011, 3, 473–477.
12. Sonnenschein, F. L. Ber. Dtsch. Chem. Ges. 1876, 9, 1182–1186.
13. Conroy, H.; Chakrabarti, J. K. Tetrahedron Lett. 1959, 1, 6–13.
14. Lovell, F. M.; Pepinsky, R.; Wilson, A. J. C. Tetrahedron Lett. 1959, 1, 1–5.
15. Lin, H.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2003, 42, 36–51.
16. Zhou, X.; Xiao, T.; Yusuke Iwama; Qin, Y. Angew. Chem., Int. Ed. 2012, 51, 4909–
4912.
ion is unreactive toward the
a,b-unsaturated aldehyde, probably
because of the strong steric exclusion involved in the formation
of C20 quaternary stereocenter and cage-like structure. However,
the C20 anion is enough to attack the adjacent enol-Boc group to
form compound 25. After Boc migrated to C20, the spirocyclopen-
taneoxindole skeleton was immediately formed via a spontaneous
intramolecular Michael addition of C7 to C15.
In conclusion, the synthetic strategy using two continuous
intramolecular Michael additions to construct C/D-ring and C20
quaternary stereocenter of (+)-gelsemine was studied. Although
the key skeleton of (+)-gelsemine failed to be synthesized, interest-
ing chemistry ensued from our exploration. Two novel enantiome-
rically pure spirocyclopentaneoxindole derivatives 2 and 3 were
achieved, and the research of their possible bioactivities is now
in progress. The spirocyclopentaneoxindole skeleton of 3 was effi-
ciently and unexpectedly prepared through a Boc migration–intra-
molecular Michael cyclization cascade procedure. This work
demonstrates the intramolecular Michael addition strategy which
will be useful for the synthesis of complex spirooxindole and spiro-
cyclopentaneoxindole derivatives.
17. Zhang, S. L.; Xie, H. X.; Zhu, J.; Li, H.; Zhang, X. S.; Li, J.; Wang, W. Nat. Commun.
2011, 2, 1214/1–1214/7.
18. Cai, Q.; Zheng, C.; Zhang, J. W.; You, S. L. Angew.Chem., Int. Ed. 2011, 50, 8665–8669.
19. Analytical data
Compound 2: 1H NMR (400 MHz, CDCl3) d 9.58 (s, 1H), 7.36 (d, J = 7.6 Hz, 1H),
7.34–7.24 (m, 5H), 7.22 (t, J = 7.6 Hz, 1H), 7.08 (t, J = 7.6 Hz, 1H), 6.72 (d,
J = 7.6 Hz, 1H), 4.98 (d, J = 15.6 Hz, 1H), 4.75 (d, J = 15.6 Hz, 1H), 4.65(s, 2H),
3.78–3.63 (m, 4H), 3.38 (s, 3H), 3.28 (t, J = 11.6 Hz, 1H), 3.20 (dt, J = 12.0, 3.2 Hz,
1H), 3.04 (t, J = 11.6 Hz, 1H), 2.96 (d, J = 10.8 Hz, 1H), 2.78 (dd, J = 16.0, 3.2 Hz,
1H), 2.45 (s, 3H), 2.29–2.22 (m, 1H), 2.05–1.98 (m, 1H); 13C NMR (100 MHz,
CDCl3) d 200.9, 177.3, 142.7, 135.5, 131.1, 128.7, 128.6, 128.5, 127.6, 127.5,
127.3, 123.1, 122.6, 119.3, 109.8, 96.7, 72.5, 66.9, 65.3, 61.9, 55.6, 50.8, 50.6,
46.4, 45.5, 44.1, 41.9, 23.5; IR (KBr) 2960, 2933, 2896, 2247, 1720, 1705, 1638,
1486, 1379, 1191, 1168, 1120, 1097, 923, 768, 701 cmÀ1; HRMS (M+Na+) calcd
for C28H31N3NaO4 496.2207, found 496.2211.
Acknowledgments
This work was supported by grants from NSFC (20825207,
21021001, and 21132006), the State Key Laboratory of Bioorganic
and Natural Products Chemistry, Shanghai Institute of Organic
Chemistry.
Compound 3: 1H NMR (400 MHz, CDCl3) d 9.13 (s, 1H), 7.86 (s, 1H), 7.18 (t,
J = 7.6 Hz, 1H), 7.04 (d, J = 7.6 Hz, 1H), 6.96 (t, J = 7.6 Hz, 1H), 6.85 (d, J = 7.6 Hz,
1H), 4.62 (s, 2H), 3.97 (d, J = 11.2 Hz, 1H), 3.87–3.84 (m, 1H), 3.70–3.65 (m, 2H),
3.44–3.32 (m, 1H), 3.35 (s, 3H), 3.29 (d, J = 12.4 Hz, 1H), 3.22 (d, J = 11.2 Hz,
1H), 2.92 (dd, J = 18.8, 10.8 Hz, 1H), 2.79 (dd, J = 18.8, 4.0 Hz, 1H), 2.51 (s, 3H),
2.04–2.01 (m, 1H), 1.11 (s, 9H); 13C NMR (100 MHz, CDCl3) d 199.1, 178.1,
166.2, 141.7, 128.7, 128.2, 124.6, 121.8, 116.5, 110.0, 96.5, 84.4, 72.6, 71.3,
69.3, 63.0, 55.5, 50.8, 46.8, 46.2, 44.2, 41.8, 27.7, 27.4, 27.2; IR (KBr) 3002, 2985,
2876, 2246, 1718, 1707, 1624, 1485, 1374, 1205, 1145, 1107, 1072, 923, 720,
697 cmÀ1; HRMS (M+Na+) calcd for C26H33N3NaO6 506.2267, found 506.2272.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.08.
048. These data include MOL files and InChiKeys of the most
important compounds described in this article.