First stereospecific total synthesis of (-)-affinisine oxindole as well as facile entry into the C(7)-diastereomeric chitosenine stereochemistry

Article abstract of DOI:10.1016/j.tetlet.2014.11.036

The first synthesis of (-)-affinisine oxindole was completed in an enantiospecific fashion from commercially available d-(+)-tryptophan in 10% overall yield. The asymmetric Pictet-Spengler reaction, diastereospecific oxidative-rearrangement of a tetrahydr

Full text of DOI:10.1016/j.tetlet.2014.11.036

Tetrahedron Letters xxx (2014) xxx–xxx
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Tetrahedron Letters
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First stereospecific total synthesis of (ꢀ)-affinisine oxindole as well as
facile entry into the C(7)-diastereomeric chitosenine stereochemistry
a
a
a
b
a,
⇑
German O. Fonseca , Zhi-Jian Wang , Ojas A. Namjoshi , Jeffrey R. Deschamps , James M. Cook
a
Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI 53211, USA
Center for Biomolecular Science and Engineering, Naval Research Laboratory, Code 6930, Washington, D.C. 20375, USA
b
a r t i c l e i n f o
a b s t r a c t
Article history:
The first synthesis of (ꢀ)-affinisine oxindole was completed in an enantiospecific fashion from commer-
cially available -(+)-tryptophan in 10% overall yield. The asymmetric Pictet–Spengler reaction, diastereo-
specific oxidative-rearrangement of tetrahydro-b-carboline, and stereospecific enolate-mediated
palladium-catalyzed cross coupling process were key steps in the sequence. This represents the first
example of a total synthesis via stereospecific entry into either the alstonisine related or epimeric chitos-
Received 15 October 2014
Revised 6 November 2014
Accepted 7 November 2014
Available online xxxx
D
a
b
enine related oxindole stereochemistry depending on the presence or absence of an N -benzyl protecting
group.
Keywords:
Affinisine oxindole
Oxindoles
Ó 2014 Elsevier Ltd. All rights reserved.
Oxindole-rearrangement
Palladium-catalyzed cross coupling
Tetrahydro-b-carbolines
Alkaloids are an important group of diversely distributed, chem-
and the geometry of the C(19),C(20)-double bond was determined
1
ically, biologically, and commercially significant natural products.
to be (E) from the NOE interaction observed between H(18)
0
5
The spiro[pyrrolidine-3,3 -oxindole] ring system 2 (Fig. 1) is the key
(methyl group) and H(15).
structural fragment in a large group of bioactive natural products
which are also attractive targets for chemical synthesis.2
Oxindole alkaloids are often associated with significant phar-
Herein we report the first enantiospecific total synthesis of
(ꢀ)-affinisine oxindole 1, which confirmed the absolute configura-
5
tion at C(7) and C(16) proposed by Kam et al. This stereospecific
3
macological activity. The Gardneria sarpagine-oxindole termed
approach will provide entry into either the spirocyclic oxindole
of the chitosenine-series 3 or the opposite configuration at C(7)
in the alstonisine-series 4 (Fig. 1).
As shown in the retrosynthetic analysis (Scheme 1), it was
envisaged that disconnection (a) between C(16) and C(17) of 1
‘
alkaloid I’ and closely related gardnerine as well as other gardnu-
tine alkaloids exhibited short-lived inhibitory activity of ganglionic
transmission in vivo in both rats and rabbits.3e In this regard, an
iodine-containing sarpagine oxindole alkaloid, prepared by Sakai
et al. from gardneramine has been employed in a formulation
would provide the a-methylalcohol from the ketone 5 via a simple
known to inhibit ulcers.4
a,b
Although various alkaloids isolated
homologation sequence involving a series of 3 reactions (a Wittig
reaction followed by hydrolysis of the enol ether and subsequent
epimerization and reduction of the corresponding aldehyde). The
D-ring could be formed by an intramolecular enolate-driven palla-
dium-cross coupling process with the corresponding vinyl-iodide
from Alstonia angustifolia were reported to possess potent antima-
4
c,d
larial activity,
none of the Alstonia macroline-related oxindoles
have been evaluated, biologically, in detail, due to the paucity of
isolable material.
The sarpagine-related (ꢀ)-affinisine oxindole 1 (Fig. 1) was first
isolated from the leaf extract of Alstonia angustifolia var. latifolia by
Kam et al. and its structure was assigned in 2004.5 The original
structure and relative configuration of this alkaloid were estab-
(disc. b) which would be introduced through N
b
-alkylation of the
pyrrolidine-N nitrogen atom in 6 with an allylic bromide (disc.
b
c). The spiro junction would be constructed via stereospecific oxida-
tion/rearrangement of a b-carboline precursor 7 (disc. d). Finally,
tetracyclic ketone 7 would be made from available D-(+)-trypto-
5
lished via analysis by IR, UV/VIS, NMR, and mass spectroscopy.
The configuration of the spirocyclic center was determined to be
phan 9 through an asymmetric Pictet–Spengler (disc. f)/Dieck-
mann-condensation (disc. e) sequence, as developed earlier.6
The asymmetry of the target molecule at C(3) and C(5) was
constructed by means of the modified Pictet–Spengler reaction
followed by a Dieckmann cyclization (Scheme 2), in a two-pot
,7
(R) from the NOE interaction observed between H(9) and H(16)
⇑
Corresponding author.
E-mail address: capncook@uwm.edu (J.M. Cook).
http://dx.doi.org/10.1016/j.tetlet.2014.11.036
040-4039/Ó 2014 Elsevier Ltd. All rights reserved.
0
Please cite this article in press as: Fonseca, G. O.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.11.036

2
G. O. Fonseca et al. / Tetrahedron Letters xxx (2014) xxx–xxx
H
H
16
15
1
0
H
H
10
CO Me
2
9
16
OH
1
1
17
9
D
14
3
CO2H 1 pot
NH2
8
6
5
1
1
8
NH
A
N
Ph
1
2
4
N
C
4
3
21
20
19
N
1
3
7
B
7
2
N
1
5
2
12 13
1
6
H
N1 = Na
N4 = Nb
CO Me
N
15
N
H
2
H
14
Me
O
9
8
O
H
18
H
1
affinisine oxindole
2 spiro[pyrrolidine-3,3'-oxindole]
1
pot
O
N
N
OH
MeO
H
H
H
H
OMe
H
O
Ph
10
OH
H
N
N
H
Scheme 2. Synthesis of N -H, N -benzyl tetracyclicketone 10 (see Refs. 1 and 6).
a b
7
O
MeO
7
H
H
O
N
H
N
H
Me
O
THF/rt/24 h]6c failed to provide the desired iodide 5. The starting
material 12 was recovered even after treating the system at reflux
for 24 h (Table 1, entries 1 and 2). It is well known that the N
3
chitosenine
4
alstonisine
b
-nitro-
Figure 1.
gen function of oxindoles in the alstonisine-series is severely
1
0
hindered to attack. Interestingly, when oxindole 12 was treated
with allylic bromide 13 (1.1 equiv)/diisopropylethylamine (DIEA)
process to provide N
a b
-H, N -benzyl tetracyclic ketone 10 on three
hundred gram scale in high yield with greater than 98% ee, as
1
2
(
3
1.1 equiv) in CH CN at reflux for 12 h, a mixture of diastereomeric
1
,6
oxindoles at C(7) (see 5 and 14) in a 1:1 ratio (80% yield) was
obtained (entry 3). When the period of heating was extended, this
generated diastereomer 14 in 90% yield and 95% de (entry 4). It
was clear oxindole 14 was the thermodynamically more stable
oxindoleundertheseconditions. Thepolarityof thesolventwasthen
altered in order to study the diastereomeric ratio of oxindoles 5 and
reported earlier.
The core of this general approach to sarpagine/macroline oxin-
doles is based on the earlier discovery by Yu.7 Diastereospecific
entry into either oxindole at C(7) was realized when N
tetrahydro-b-carboline 10 or N -H tetrahydro-b-carboline 7 was
reacted under a sequence of oxidation/rearrangement conditions
with tBuOCl/Et N/0 °C, followed by treatment with AcOH/MeOH at
reflux (Scheme 3.) The presence or absence of the N -benzyl protect-
b
-benzyl
b
1
4 in the process (entries 5–7).
Tetracyclic oxindole 5 was first obtained as the major diastereo-
3
b
mer with iodide 13 in a CH
moderate yield and 92% de. However, very little alkylation of 12
occurred when the percentage of CH Cl was elevated further
entries 6 and 7). Finally, oxindole intermediate 5 was synthesized
as the sole diastereomer in high yield when 12 was heated at
0 °C under solvent-free conditions with 8 equiv of iodobutane
3/2.5 equiv of base (entry 8). Careful selection of the experimental
b
conditions permitted control of the steric outcome of the N -alkyl-
3 2 2
CN–CH Cl (9:1) mixture (entry 5) in
ing group in ketones 10 and 7 respectively, permitted access into
either the chitosenine series or the alstonisine series in diastereo-
specific fashion and high yield.7
2
2
(
In this vein, the N
ketone 10 under reductive conditions with hydrogen on Pd/C to
furnish the N -H tetracyclic ketone 7 in 88% yield. The key oxida-
b
-benzyl group was readily removed from
5
1
b
tion/rearrangement sequence was then executed to afford the
oxindole 6 with the desired configuration at C(7) in diastereospec-
ific fashion in 80% yield.7
ation as regards the configuration of the oxindole at C(7). This
significant result provided an alternative route to access the chitos-
The N
a b
-H, N -H substituted oxindole 6 was chemospecifically
8
enine series or alstonisine series through an N
rearrangement sequence. According to observations made during
the progress of the N -alkylation (analysis by TLC and NMR), oxin-
b
-alkylation/oxindole-
methylated at the indole N
a
-position [pK
-H ꢁ 44 ] with NaH in THF at 0 °C to effect complete conver-
sion of the N -unsubstituted oxindole into the corresponding
sodium oxindolyl which was then treated with MeI in THF at
°C to provide the N -methylated oxindole 12 in 80% yield
a
(DMSO): N
a
-H ꢁ 18;
9
for N
b
b
a
dole 14 formed only after oxindole 5 had been observed in the reac-
tion; importantly no diastereomer of starting oxindole 12 at C(7)
was observed at any time under these conditions. Epimerization
at C(3) had been observed in related oxindole systems; however,
since the C/D ring fusion in 5 was cis, in the azabicyclo[3.2.1] system,
isomerization was not favorable and the epimer at C(3) was not
observed. Isomerization of related spiro-oxindole alkaloids was first
0
(
a
1
0
Scheme 4).
Alkylation of oxindole 12 at the N
-bromo-2-iodo-2-butene 13 which had been prepared in an
b
-position required the use of Z-
1
improved, 3-step procedure, which began with trans-but-2-enal,
b
-alkylate oxindole
2 under the conditions successfully employed for the parent sys-
1
1
as reported previously. Initial attempts to N
1
3a
reported by Wenkert et al. in 1959
generally to provide structural proof of diastereomeric oxindoles
and has been employed
1
tem [(indole system), bromide 13 (1.1 equiv)/K
2
CO
3
(1.1 equiv)/
H
H
H
H
a
O
c
O
OH
d
N
N
NH
H
I
N
H
H
N
N
H
Me
O
H b
O
O
Me
1
affinisine oxindole
5
6
H
CO Me
H
2
CO H
2
f
O
e
H
N
Ph
NH2
N
H
N
N
N
H
H
CO Me
H
9
D-(+)-tryptophan
8
2
7
Scheme 1. Retrosynthetic analysis.
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G. O. Fonseca et al. / Tetrahedron Letters xxx (2014) xxx–xxx
3
H
O
H
tBuOCl, Et3N
O
CH Cl , rt, 5h;
N
2
2
chitosenine
series
N
aq AcOH/MeOH
N
5
H
H
H
0
N
H
Ph
O
reflux, 2h, 93%
Ph
1
1
1
% HCl, EtOH;
H2/Pd (on C),
EtOH, rt, 88%
H
O
H
tBuOCl, Et3N
CH2Cl2, rt, 5h;
aq AcOH/MeOH
NH
O
alstonisine
series
NH
N
H
N
H
O
H
H
reflux, 2h, 80%
7
6
Scheme 3. Stereospecific construction of spirocyclic oxindoles (see Ref. 7).
H
H
O
O
o
NaH, THF, 0 C;
I
Br
o
NH
NH
CH I, THF, 0 C-rt,
3
1
3
N
N
N
H
conditions:
see Table 1
H
80%
Me
O
O
O
O
12
H
6
5
H
H
O
N
N
+
+
12
I
I
N
H
H
Me
Me
O
14
Scheme 4. Synthesis of N
b
-allyl oxindole 5.
Table 1
Reaction conditions for N
b
-alkylation of 12a
Entry
Solvent
Base (equiv)
Temp (°C)/time (h)
5 (%)
14 (%)
12 (%)
1
2
3
4
5
6
7
8
THF
THF
K
K
2
CO
CO
3
3
(1.1)
(1.1)
Rt/24
0
0
40
5
60
5
0
0
0
40
90
5
0
0
0
98
98
15
5
20
95
98
<5
2
Reflux/24
Reflux/12
Reflux/48
Reflux/8
Reflux/24
Reflux/24
50/10
CH
3
CH
3
CH
3
CH
3
CH
2
CN
CN
CN-CH
CN-CH
Cl
DIEA (1.1)
DIEA (1.1)
DIEA (1.1)
DIEA (1.1)
DIEA (1.1)
DIEA (2.5)
2
Cl
Cl
2
(9:1)
(1:1)
2
2
2
Neat
90
The bold is meant to the conditions that provided product 5 without the formation of its epimer and in excellent yield.
a
Entries 1–7: (1.1 equiv) of 13, entry 8: (8 equiv) of 13.
[
at C(7)] isolated as natural products. Recently, rigorous kinetic
To complete the synthesis of (ꢀ)-affinisine oxindole 1, ketone 5
was converted into the desired pentacyclic ketone 17 in 65% yield
(Scheme 6) via an intramolecular palladium-catalyzed (enolate
13b,c
studies on this process were reported by Laus et al.
As part of ongoing efforts to synthesize chitosenine-related
oxindole alkaloids and as part of the structural proof of 5 and 14,
diastereomer 14 was synthesized from oxindole 11 using the chem-
istry earlier described in Scheme 3. Application of the oxidation/
rearrangement conditions on the N
system in 10, afforded the chitosenine-related 11 (Scheme 3),
which was successively methylated at the indole N -position with
NaH/MeI to yield diastereomeric oxindole 15 (Scheme 5) in 87%
yield. Reductive debenzylation was not successful; however, deb-
enzylation of 15 under oxidative conditions with ceric ammonium
3 4
mediated) cross-coupling reaction with (10 mol %) Pd(PPh ) /
1
5
PhONaꢂ3H
2
O (2.5 equiv)/THF/reflux/2 h. The steric outcome of
this reaction for 17 was again confirmed by X-ray analysis. The
Wittig reaction with (methoxymethyl)triphenyl-phosphonium
chloride and anhydrous tBuOK in benzene with oxindole 17 pro-
vided a mixture of enol ethers represented by 18. The mixture of
enol ethers was hydrolyzed under acidic conditions to afford the
a b
-H, N -benzyl tetracyclic ketone
a
thermodynamically more stable a-epimeric aldehyde 19 as the sole
diastereomer. Several attempts to purify aldehyde 19 by chroma-
tography (using silica gel, as well as basic or neutral alumina) were
unsuccessful. Consequently, the crude product was treated with
nitrate (CAN)/CH
6
3
CN–H
2
O (5:1)/rt14 afforded N
b
-H-oxindole 16 in
b
-pyrrolidine nitrogen function with
0% yield. Alkylation of the N
allylic bromide 13 under solvent free conditions depicted in
Scheme 5, provided oxindole 14 in 91% yield. The structures of both
oxindoles, 5 and 14, were now unequivocally confirmed by X-ray
NaBH
4
in EtOH, to obtain affinisine oxindole 1 in 34% overall yield
from ketone 17 (attempts to increase the yield are underway).
The spectral (IR, H and C NMR, HRMS) data and optical rotation
are in excellent agreement with the published values. NOE studies
1
13
7
,13
5
crystallography and were diastereomeric at C(7) as expected.
Please cite this article in press as: Fonseca, G. O.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.11.036

4
G. O. Fonseca et al. / Tetrahedron Letters xxx (2014) xxx–xxx
H
O
H
O
o
NaH, THF, 0 C;
ceric ammonium nitrate,
CH CN-H O (5:1), rt,
o
N
MeI, THF, 0 C-rt,
N
3
2
H
87%
H
60%
N
N
N
O
Ph
O
O
Ph
H
Me
1
1
1
6
15
H
H
O
I
Br
13
NH
N
(
8 eq)
DIEA (2 eq)
H
I
H
N
O
O
o
4
91%
0-55 C,
Me
Me
14
Scheme 5. Synthesis of chitosenine series intermediate 14.
H
H
O
O
H
[
MeOCH PPh ]Cl,
Pd(PPh3)4,
PhONa 3H2O,
2
3
tBuOK,
N
.
N
N
benzene/THF, 24h
H
I THF, reflux,
N
H
N
O
2h, 65%
O
17
H
Me
Me
5
H
H
OMe HCl (2N)-THF,
CHO
N
N
o
5
5 C, 5h
H
H
N
O
H
O
H
Me
Me
18
19
H
H
OH
(-)-affinisine oxindole
NaBH ,
4
N
EtOH, rt, 8h
4% combined
yield from 17
1
H
O
3
N
H
Me
Scheme 6. Synthesis of affinisine oxindole 1 (see Ref. 16 for experimental data of synthetic 1).
of our synthetic material confirmed the configuration of the spiro-
cyclic center, the configuration at C(16), and the geometry of the
C(19),C(20)-double bond to be the same as the ones reported by
2. (a) Le Quesne, P. W.; Garnick, R. L. J. Am. Chem. Soc. 1978, 100, 4213; (b) Da
Silva, J. F. M.; Garden, S. J.; Pinto, A. C. J. Braz. Chem. Soc. 2001, 12, 273; (c) Lin,
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5
Kam et al. In conclusion, the first stereospecific total synthesis of
4
6, 5489; (g) Galliford, C. V.; Scheidt, K. A. Angew. Chem., Int. Ed. 2007, 46, 8748;
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(
h) Kitaima, M. J. Nat. Med. 2007, 61, 14; (i) Takayama, H.; Kitajima, M.; Kogure,
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1
0% overall yield from commercially available D-(+)-tryptophan 9.
Further application of this method toward the synthesis of the
chitosenine-series of oxindole alkaloids is currently in progress.
(
n) Hart, D. J.; Magomedov, N. J. Am. Chem. Soc. 2001, 123, 5892.
(a) Shi, J. S.; Lui, G. X.; Wu, Q.; Huang, Y. P.; Zhang, X. D. Acta Pharmacol. Sinica
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Phytochemistry 1996, 41, 313; (e) Harada, M.; Ozaki, Y. Chem. Pharm. Bull. 1978,
26, 48.
(a) Sakai, S.; Aimi, N.; Kubo, A.; Kitagawa, M.; Hanasawa, M.; Katano, K.;
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3
4
.
.
1
Acknowledgments
This work was supported in part by NIMH and the Lynde and
Harry Bradley Foundation. X-ray crystallographic studies were sup-
ported by NIDA-NRL Interagency Agreement Number Y1-DA1101.
This Letter is dedicated to Professor Harry Wasserman, a scholar
and a gentleman.
5
6
.
.
Kam, T.; Choo, Y. Phytochemistry 2004, 65, 603.
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Please cite this article in press as: Fonseca, G. O.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.11.036

G. O. Fonseca et al. / Tetrahedron Letters xxx (2014) xxx–xxx
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1
2. Soloshonok, V. A.; Moore, J. L.; Taylor, S. M. ARKIVOC 2005, vi, 287.
3. (a) Wenkert, E.; Udelhofen, J. H.; Bhattacharyya, N. K. J. Am. Chem. Soc. 1959, 81,
J = 8, 1 Hz, 1H), 6.83 (br d, J = 8 Hz, 1H), 5.32 (qt, J = 7, 2 Hz, 1H), 3.78 (m, 2H),
3.62 (m, 2H), 3.37 (dd, J = 10, 2 Hz, 1H), 3.31 (dd, J = 6, 3 Hz, 1H), 3.21 (s, 3H), 2.88
(br s, 1H), 2.77 (dd, J = 13, 6 Hz, 1H), 2.18 (ddd, J = 14, 4, 2 Hz, 1H), 2.05 (m, 1H),
1.82 (d, J = 13 Hz, 1H), 1.61 (dt, J = 7, 2 Hz, 3H), 1.56 (ddd, J = 14, 10, 2 Hz, 1H);
3
1
763; (b) Laus, G.; Brössner, D.; Senn, G.; Wurst, K. J. Chem. Soc., Perkin Trans. 2
996, 1931; (c) Laus, G. J. Chem. Soc., Perkin Trans. 2 1998, 315.
13
1
4. Bull, S. D.; Davies, S. G.; Fenton, G.; Mulvaney, A. W.; Prasad, R. S.; Smith, A. D. J.
Chem. Soc., Perkin Trans. 1 2000, 3765.
C NMR (75.5 MHz, CDCl
126.6 (CH), 121.5 (CH), 114.8 (CH), 107.8 (CH), 65.7 (CH
56.7 (C), 48.8 (CH ), 47.9 (CH), 44.6 (CH ), 28.8 (CH ), 26.5 (CH
(CH ); HRMS (ESI, m/z, relative intensity) calcd for
(M+H) = 325.1916, found 325. 1927.
3
) d 181.8 (C), 144.4 (C), 136.0 (C), 130.4 (C), 128.1 (CH),
), 62.8 (CH), 59.1 (CH),
), 26.1 (CH), 12.4
2
1
1
5. Solé, D.; Urbaneja, X.; Bonjoch, J. Adv. Synth. Catal. 2004, 346, 1646.
2
2
2
3
5
6. Synthetic affinisine oxindole (1) (see Ref. for natural affinisine oxindole data):
3
20 24 2 2
C H N O
2
3
ꢀ1
1
+
[
(
a]
D
ꢀ66.0 (c 0.3, CHCl
3
); IR (KBr) 3375, 2933, 1711, 1610, 1470 cm
; H NMR
300 MHz, CDCl ) d 7.37 (br d, J = 8 Hz, 1H), 7.31 (td, J = 8, 1 Hz, 1H), 7.09 (td,
3
Please cite this article in press as: Fonseca, G. O.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.11.036