Total synthesis of horsfiline: A palladium-catalyzed domino Heck-cyanation strategy

Article abstract of DOI:10.1055/s-0029-1218004

A total synthesis of horsfiline has been accomplished featuring a key intramolecular palladium-catalyzed domino Heck-cyanation sequence for the formation of the 3,3′-disubstituted oxindole. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1218004

LETTER
2997
Total Synthesis of Horsfiline: A Palladium-Catalyzed Domino
Heck-Cyanation Strategy
Total
S
ynthesi
t
s
of
H
o
é
rsfiline phanie Jaegli,a Jean-Pierre Vors,b Luc Neuville,*a Jieping Zhu*a
a
Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette Cedex, France
Fax +33(1)69077247; E-mail: zhu@icsn.cnrs-gif.fr; E-mail: neuville@icsn.cnrs-gif.fr
b
Bayer CropScience SA, 14-20 Rue Pierre Baizet, 69009 Lyon, France
Received 20 July 2009
to illustrate the power of novel synthetic methodologies/
strategies and indeed a number of total synthesis have
been accomplished to date.8
Abstract: A total synthesis of horsfiline has been accomplished
featuring a key intramolecular palladium-catalyzed domino Heck–
cyanation sequence for the formation of the 3,3¢-disubstituted oxin-
dole.
As part of our interest in developing novel approaches to
Key words: domino reaction, palladium, Heck, cyanation, oxin- indolinones
based
on
transition-metal-catalyzed
transformations9 and domino processes,10,11 we have re-
cently reported a facile access to functionalized 3-alkyl-3-
cyanomethyl-2-oxindole 6 by a palladium-catalyzed dom-
ino intramolecular Heck–cyanation process.12 In this
transformation, the nontoxic potassium ferro(II)cyanide,
K4[Fe(CN)6], was used as a cyanide source to trap the s-
alkylpalladium intermediate.13 This strategy allowed us to
develop a concise total synthesis of physostigmine (5).
Based on the same strategy, we report herein a total syn-
thesis of horsfiline (4).
dole, horsfiline
The spiropyrrolidinyloxindole skeleton is present in a
growing number of natural products presenting various
biological activities.1 This class of compound can be as
simple as elacomine (1)2 or present additional structural
complexity as in spirotryprostatine A (2)3 or alstonisine
(3)4 (Figure 1). The stereogenic quaternary spiro center is
usually well defined, but some natural compounds have
been isolated as racemate.5 It has also been established
that both enantiomers of some synthetic analogues of 2
presented biological activities with equal potency.6
Our synthesis began with the preparation of protected a-
hydroxymethylacrylate 9. The Baylis–Hillman reaction
between acrylate and formaldehyde was initially exam-
ined for the synthesis of hydroxymethylacrylate 8.14 How-
ever, the yield of 8 never exceeded 35%. Alternatively,
reaction of triethyl phosphonoacetate with formaldehyde
in the presence of potassium carbonate following a proce-
dure described by Villieras et al. provided 8 in a reliable
74% yield.15 Hydrolysis of the ester (LiOH, THF–H2O)
followed by protection of the primary alcohol as a tert-
butyldimethylsilyl ether afforded compound 9 in 72%
yield. On the other hand, double deprotonation of N-Boc
p-anisidine 11, prepared in 92% yield from p-anisidine
(10), with t-BuLi followed by addition of 1,2-diiodo-
ethane and removal of N-Boc under mild acidic conditions
afforded the desired iodide 12 in 67% yield over three
steps.16 Coupling of 9 and 12 was best realized in the pres-
ence of Mukaiyama’s reagent (2-chloro-N-methyl pyri-
dinium iodide, tributylamine in refluxing toluene)17 to
afford the desired amide 13 in 74% yield. Finally, protec-
tion of the secondary amide 13 with SEM group afforded
the ortho-iodoanilide 14 in 84% yield (Scheme 1).
MeOC
H
N
O
H
H
H
O
O
NH
N
NH
H
H
O
O
O
N
N
N
H
H
H
elacomine (1)
spirotryprostatine A (2)
alstonisine (3)
O
NMe
Me
R2
CN
NMe
O
Me
O
O
R2
O
NMe
N
N
H
N
Me
R1
H
horsfiline (4)
physostigmine (5)
6
Figure 1 Examples of naturally occurring spiroxoindoles
With the properly functionalized amide in hand, we set
out to examine the pivotal domino Heck–cyanation reac-
tion. When ortho-iodoanilide 14 was submitted to previ-
ously established reaction conditions {Pd(OAc)2 (1.5
mol%), K4[Fe(CN)6] (0.22 equiv), Na2CO3 (1 equiv),
DMF, 120 °C}, we were delighted to isolate the desired
oxindole 15 in 60% yield (Scheme 2).18 Three points de-
served further comment regarding this transformation: 1)
by-product 16, which could be easily separated from 15,
Horsfiline (4) is an oxindole alkaloid isolated from the
roots of Horsfieldia superba by Bodo and co-workers.7
Due to its structural simplicity, it has often been targeted
SYNLETT 2009, No. 18, pp 2997–2999
x
x
.x
x
.2
0
0
9
Advanced online publication: 08.10.2009
DOI: 10.1055/s-0029-1218004; Art ID: G23709ST
© Georg Thieme Verlag Stuttgart · New York

2998
Jaegli et al.
LETTER
1) LiOH,
conditions afforded 18. Treatment of 18 with methane-
sulfonyl chloride (MsCl, Et3N, CH2Cl2) afforded the cor-
responding mesylate, which without purification was
cyclized upon treatment with NaH in THF to afford the
spirooxindole 19 in 95% yield. This advanced intermedi-
ate has been converted by Murphy et al. to horsfiline in
three steps with 41% overall yield.8m However, removal
of the Boc protecting group (the first step) was low yield-
ing in their synthesis. We therefore slightly modified the
reaction sequence. Removal of the N-SEM group (TBAF
in DMF–ethylenediamine at 110 °C, 24 h) followed by
deprotection of the N-Boc function afforded compound 20
in 85% yield. To complete the synthesis, a selective meth-
ylation of the secondary amine over the amide functional-
ity had to be effected. This reaction proved to be more
difficult than expected. After having examined a variety
of methylation conditions, it was finally realized in two
steps. Treatment of 20 with an excess of formaldehyde in
acetic acid in the presence of NaBH3CN furnished 21
(88% yield) in which the secondary amine was N-methy-
lated whereas the secondary amide was hydroxymethylat-
ed. Hydrolysis of the hemiaminal function under basic
reaction condition (Et3N, MeOH) afforded the horsfiline
(4) in 85% yield (Scheme 3). Thus, we were able to con-
vert the compound 19 into 4 in 64% overall yield which
appears to be more efficient than the literature procedure.
OH
K2CO3,
OTBS
O
THF–H2O, 40 °C
CH2O (aq)
EtO2C
HO2C
(EtO)2P
2) TBDMSCl,
imidazole, DMF
r.t., 72%
40 °C, 74%
CO2Et
8
9
7
OMe
OMe
OMe
1) t-BuLi, Et2O, –20 °C
then ICH2CH2I, –78 °C to r.t.
Boc2O,
THF
2) TFA–CH2Cl2, r.t.
73%
r.t., 92%
I
NH2
NHBoc
11
NH2
12
10
OTBS
OTBS
NaH
SEMCl
THF
n-Bu3N
toluene
90 °C
MeO
MeO
9
+
N
O
N
H
O
0 °C to r.t.
84%
SEM
72%
N+ Cl
12
I
I
14
I–
13
Scheme 1 Synthesis of ortho-iodoanilide 14
was isolated in 20% yield. This compound probably arises
from the reduction of the intermediate s-alkylpalladium.19
It is well known that DMF decomposes to some extent un-
der thermal conditions furnishing dimethylamine, which
could then reduce the s-alkylpalladium intermediate.20 2)
Protection of the hydroxyl group was mandatory in this
transformation as extensive degradation was observed
otherwise. 3) Attempted enantioselective Heck–cyanation
of 14 under our previously established conditions
[Pd(dba)2 (0.05 equiv), (S)-difluorophos (0.12 equiv),
Ag3PO4 (2.0 equiv), K2CO3 (1.0 equiv), K4[Fe(CN)6]
(0.22 equiv)] afforded 15 in low yield and negligible ee. It
is interesting to note that the related N-methyl anilide cy-
clized to afford the oxindole in 78% yield with 72% ee.12
The presence of chelating N-SEM group had apparently
negative impact on the reaction outcome under these con-
ditions.
H2N
TBSO
a) HCl (12 N),
MeOH, r.t.
CoCl2⋅6H2O, NaBH4 MeO
15
O
b) Boc2O, THF, r.t.
83%
MeOH, r.t., 78%
N
SEM
17
MsCl, Et3N,
Boc
N
BocHN
HO
MeO
MeO
CH2Cl2, 0 °C to r.t.
O
O
then NaH, THF, r.t.
95%
N
N
SEM
SEM
18
19
H
N
OTBS
CN
TBSO
TBAF,
MeO
Pd(OAc)2 (1.5 mol%)
K4[Fe(CN)6] (0.22 equiv)
MeO
DMF–ethylenediamine
(v/v = 2.3:1), 110 °C
aqueous HCHO
NaBH3CN, AcOH, r.t.
MeO
O
O
N
O
N
Na2CO3 (1 equiv)
DMF, 120 °C
60%
then TFA, CH2Cl2, r.t.
85%
88%
SEM
SEM
N
15
I
H
14
20
Me
N
TBSO
Me
N
MeO
O
MeO
Et3N–MeOH (1:3)
reflux, 85%
MeO
N
O
16
SEM
O
N
N
H
Scheme 2 Palladium-catalyzed domino Heck–cyanation for the
construction of oxindole
HO
21
horsfiline 4
Scheme 3 Total synthesis of horsfiline
Construction of the pyrrolidine ring was next undertaken.
Selective reduction of the nitrile function in 15
(CoCl2·6H2O, NaBH4, MeOH, r.t.)21 afforded amine 17 in
78% yield. Removal of O-TBS protecting group from 17
under acidic conditions afforded the amino alcohol in
quantitative yield. Direct cyclization of this amino alcohol
using Appel’s conditions (CBr4, PPh3)22 was sluggish and
we therefore adopted a three-step sequence. A tert-butyl-
oxycarbonylation of the primary amine under standard
In conclusion, we have reported a total synthesis of
horsfiline featuring a key palladium-catalyzed domino
intramolecular Heck–cyanation sequence. This work fur-
ther demonstrated the synthetic potential of oxindole of
general structure 6 which is readily prepared in one step
from simple anilides by a palladium-catalyzed domino se-
quence.
Synlett 2009, No. 18, 2997–2999 © Thieme Stuttgart · New York

LETTER
Total Synthesis of Horsfiline
2999
Zewge, D.; Chen, C. J. Org. Chem. 2005, 70, 1508.
Supporting Information for this article is available online at
(c) Gelman, D.; Grossman, O. Org. Lett. 2006, 8, 1189.
(d) Li, L. H.; Pan, Z.-L.; Liang, Y.-M. Synlett 2006, 2094.
(e) Schareina, T.; Zapf, A.; Magerlein, W.; Muller, N.;
Beller, M. Tetrahedron Lett. 2007, 48, 1087. (f) For related
domino palladium-catalyzed cyanation process, see:
Mariampillai, B.; Alliot, J.; Li, M.; Lautens, M. J. Am.
Chem. Soc. 2007, 129, 15372. (g) Cheng, Y.-N.; Duan, Z.;
Yu, L.; Li, Z.; Zhu, Y.; Wu, Y. Org. Lett. 2008, 10, 901.
(h) For a general review on palladium-catalyzed cross-
coupling involving metal cyanides, see: Takagi, K. In
Handbook of Organopalladium Chemistry for Organic
Synthesis, Vol.1; Negishi, E.; de Meijere, A., Eds.; Wiley:
New York, 2002, 657–672.
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
Financial support from the CNRS and the Bayer CropScience (Doc-
toral fellowship to S.J.) is gratefully acknowledged.
References and Notes
(1) For reviews, see: (a) Marti, C.; Carreira, E. M. Eur. J. Org.
Chem. 2003, 2209. (b) Galliford, C. V.; Sheidt, K. A.
Angew. Chem. Int. Ed. 2007, 46, 8748.
(14) (a) Byun, H. S.; Reddy, K. C.; Bittman, R. Tetrahedron Lett.
1994, 35, 1371. (b) Yu, C.; Liu, B.; Hu, L. J. Org. Chem.
2001, 66, 5413. For reviews, see: (c) Basavaiah, D.; Rao,
A. J.; Satyanarayana, T. Chem. Rev. 2003, 103, 811.
(d) Masson, G.; Housseman, C.; Zhu, J. Angew. Chem. Int.
Ed. 2007, 46, 4614.
(15) (a) Villieras, J.; Rambaud, M. Synthesis 1982, 924.
(b) Villieras, J.; Rambaud, M. Org. Synth. 1988, 66, 220.
(16) Kondo, Y.; Kojima, S.; Sakamoto, T. J. Org. Chem. 1997,
62, 6507.
(2) James, M. N. G.; Williams, G. J. B. Can. J. Chem. 1972, 50,
2407.
(3) (a) Cui, C. B.; Kakeya, H.; Osada, H. J. Antibiot. 1996, 49,
832. (b) Cui, C.-B.; Kakeya, H.; Ckada, H. Tetrahedron
1996, 52, 12651.
(4) Elderfield, R. C.; Gilman, R. E. Phytochemistry 1972, 11,
339.
(5) Pellegrin, C.; Weber, M.; Borschberg, H.-J. Helv. Chim.
Acta 1996, 79, 151; and references therein.
(6) Edmondson, S.; Danishefsky, S. J.; Sepp-Lorenzino, L.;
(17) Bald, E.; Saigo, K.; Mukaiyama, T. Chem. Lett. 1975, 4,
1163.
Rosen, N. J. Am. Chem. Soc. 1999, 121, 2147.
(7) Jossang, A.; Jossang, P.; Hadi, H. A.; Sevenet, T.; Bodo, B.
J. Org. Chem. 1991, 56, 6527.
(18) Experimental Procedure: To a degassed solution of
iodoanilide 14 (1.90 g, 3.29 mmol, 1.0 equiv) in DMF (16
mL) were added K4Fe(CN)6·3H2O (306.0 mg, 0.72 mmol,
0.22 equiv), Na2CO3 (350.0 mg, 3.30 mmol, 1.0 equiv) and
Pd(OAc)2 (22.0 mg, 0.1 mmol, 0.03 equiv). After being
stirred at 120 °C under an argon atmosphere for 3 h, the
reaction mixture was quenched with H2O and extracted with
EtOAc. The combined organic layers were washed with
brine, dried (Na2SO4) and concentrated. The residue was
purified by flash chromatography (SiO2, heptane–EtOAc,
95:5 → 90:10) to give the corresponding oxindole 15 (0.94
g, 60%) as a light orange solid.
(8) (a) Jones, K.; Wilkinson, J. Chem. Commun. 1992, 1767.
(b) Bascop, S.; Sapi, J.; Laronze, J.; Levy, J. Heterocycles
1994, 38, 725. (c) Pellegrini, C.; Strässler, C.; Weber, M.;
Borschberg, H. Tetrahedron: Asymmetry 1994, 5, 1979.
(d) Palmisano, G.; Annunziata, R.; Papeo, G.; Sisti, M.
Tetrahedron: Asymmetry 1996, 7, 1. (e) Lakshmaiah, G.;
Kawabata, T.; Shang, M.; Fuji, K. J. Org. Chem. 1999, 64,
1699. (f) Fischer, C.; Meyers, C.; Carreira, E. M. Helv.
Chim. Acta 2000, 83, 1175. (g) Cravotto, G.; Giovenzana,
G.; Pilati, T.; Sisti, M.; Palmisano, G. J. Org. Chem. 2001,
66, 8447. (h) Kumar, U. K. S.; Illa, H.; Junjappa, H. Org.
Lett. 2001, 3, 4193. (i) Lizos, D.; Tripoli, R.; Murphy, J. A.
Chem. Commun. 2001, 2732. (j) Selvakumar, N.; Azhagan,
A. M.; Srinivas, D.; Krishna, G. G. Tetrahedron Lett. 2002,
43, 9175. (k) Lizos, D. E.; Murphy, J. A. Org. Biomol.
Chem. 2003, 1, 117. (l) Chang, M. Y.; Pai, C.-L.; Kung,
Y.-H. Tetrahedron Lett. 2005, 46, 8463. (m) Murphy, J. A.;
Tripoli, R.; Khan, T. A.; Mali, U. W. Org. Lett. 2005, 7,
3287. (n) Trost, B. M.; Brennan, M. K. Org. Lett. 2006, 8,
2027.
(9) (a) Bonnaterre, F.; Bois-Choussy, M.; Zhu, J. Org. Lett.
2006, 8, 4351. (b) Salcedo, A.; Neuville, L.; Zhu, J. J. Org.
Chem. 2008, 73, 3600. (c) Erb, W.; Neuville, L.; Zhu, J.
J. Org. Chem. 2009, 74, 3109.
(10) (a) Pinto, A.; Neuville, L.; Retailleau, P.; Zhu, J. Org. Lett.
2006, 8, 4927. (b) Pinto, A.; Neuville, L.; Retailleau, P.;
Zhu, J. Angew. Chem. Int. Ed. 2007, 46, 3291. (c) Pinto, A.;
Neuville, L.; Zhu, J. Tetrahedron Lett. 2009, 50, 3602.
(11) For general reviews on the domino process, see: (a) Tietze,
L. F. Chem. Rev. 1996, 96, 115. (b) Nicolaou, K. C.;
Edmonds, D. J.; Bulger, P. G. Angew. Chem. Int. Ed. 2006,
45, 7134. (c) For a recent book, see: Domino Reactions in
Organic Synthesis; Tietze, L. F.; Brasche, G.; Gericke, K.,
Eds.; Wiley-VCH: Weinheim, 2006.
Compound 15: 1H NMR (500 MHz, CDCl3): d = 7.06 (d, J =
2.6 Hz, 1 H), 7.02 (d, J = 8.6 Hz, 1 H), 6.88 (dd, J = 8.6, 2.6
Hz, 1 H), 5.17 (d, J = 11.0 Hz, 1 H), 5.11 (d, J = 11.0 Hz, 1
H), 3.92 (d, J = 9.7 Hz, 1 H), 3.80 (s, 3 H), 3.73 (d, J = 9.7
Hz, 1 H), 3.62–3.51 (m, 2 H), 3.02 (d, J = 16.7 Hz, 1 H), 2.79
(d, J = 16.7 Hz, 1 H), 0.92 (t, J = 8.2 Hz, 2 H), 0.84 (s, 9 H),
0.00 (s, 3 H), –0.01 (s, 3 H), –0.03 (s, 9 H). 13C NMR (75
MHz, CDCl3): d = 175.4, 156.4, 135.4, 129.1, 116.2, 114.3,
111.2, 110.6, 69.9, 66.5, 66.1, 55.8, 51.9, 25.7, 21.7, 18.1,
17.7, –1.4, –5.6, –5.7. HRMS (ES+): m/z [M + Na]+ calcd for
C24H40N2O4Si2Na: 499.2424; found: 499.2415.
(19) Such reduction product has been reported in a related
domino Heck reaction recently: Ruck, R. T.; Huffman,
M. A.; Kim, M. K.; Shevlin, M.; Kandur, W. V.; Davies,
I. W. Angew. Chem. Int. Ed. 2008, 47, 4711.
(20) Zawisza, A. M.; Muzart, J. Tetrahedron Lett. 2007, 48,
6738; and references cited herein.
(21) (a) Satoh, T.; Suzuki, S.; Suzuki, Y.; Miyagi, Y.; Imai, Z.
Tetrahedron Lett. 1969, 4555. (b) Osby, J. O.; Heinzman,
S. W.; Ganem, B. J. Am. Chem. Soc. 1986, 108, 67.
(c) Caddick, S.; Haynes, A. K. de K.; Judd, D. B.; Williams,
M. R. V. Tetrahedron Lett. 2000, 41, 3513.
(22) (a) Appel, R. Angew. Chem. Int. Ed. 1976, 14, 801.
(b) Shishido, Y.; Kibayashi, C. J. Org. Chem. 1992, 57,
2876. (c) Wittenberger, S. J.; McLaughlin, M. A.
Tetrahedron Lett. 1999, 40, 7175. (d) Harris, J. M.; Padwa,
A. J. Org. Chem. 2003, 68, 4371.
(12) Pinto, A.; Jia, X.; Neuville, L.; Zhu, J. Chem. Eur. J. 2007,
13, 961.
(13) For the seminal use of K4[Fe(CN)6] in palladium-mediated
cyanation, see: (a) Schareina, T.; Zapf, A.; Beller, M. Chem.
Commun. 2004, 1388. See also: (b) Weissman, S. A.;
Synlett 2009, No. 18, 2997–2999 © Thieme Stuttgart · New York

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