Efficient synthesis of (±)-horsfiline through the MgI2-catalyzed ring- expansion reaction of a spiro[cyclopropane-1,3'-indol]-2'-one

Article abstract of DOI:10.1002/1522-2675(20000607)83:6<1175::AID-HLCA1175>3.0.CO;2-D

We report a short synthetic route to (±)-horsfiline that provides the racemate in five steps from commercially available, substituted isatin in 41% overall yield. Efficient entry into the spiro[oxindole-pyrrolidine] ring system is possible through the application of the cyclopropane opening/ring expansion chemistry we have described with MgI₂ as a bifunctional catalyst.

Full text of DOI:10.1002/1522-2675(20000607)83:6<1175::AID-HLCA1175>3.0.CO;2-D

Helvetica Chimica Acta ± Vol. 83 (2000)
1175
Efficient Synthesis of (Æ)-Horsfiline through the MgI2-Catalyzed
Ring-Expansion Reaction of a Spiro[cyclopropane-1,3'-indol]-2'-one
by Christian Fischer1), Christiane Meyers, and Erick M. Carreira*
Laboratorium für Organische Chemie der Eidgenössischen Technischen Hochschule Zürich,
Universitätstrasse 16, ETH-Zentrum, CH-8092 Zürich
Â
Dedicated to Prof. Dr. Jose Barluenga on the occasion of his 60th birthday
We report a short synthetic route to (Æ)-horsfiline that provides the racemate in five steps from
commercially available, substituted isatin in 41% overall yield. Efficient entry into the spiro[oxindole-
pyrrolidine] ring system is possible through the application of the cyclopropane opening/ring expansion
chemistry we have described with MgI2 as a bifunctional catalyst.
1. Introduction. ± The spiro[indole-pyrrolidine] nucleus is a key structural
component found in a number of pharmacologically important natural products such
as vinblastine and vincristine. These compounds are cell-cycle-specific cytostatic agents
that arrest mitosis at metaphase by acting as spindle poisons. Because they
disproportionately affect proliferating cells, they have become of prime importance
in cancer chemotherapy [1]. The related spiro[indole-pyrrolidin]-2-one ring system has
been identified in a number of other cytostatic alkaloids of potential interest to human
medicine, such as spirotryprostatin A and strychnophylline [2]. These natural products
embody stereochemical and structural complexities that provide a challenge in the
evolution of modern synthetic chemistry [3][4]. In combination, these factors provide
an impetus for the development of novel, versatile, and efficient reaction methods and
strategies aimed at the synthesis of the spiro[indole-pyrrolidin]-2-one moiety, as
exemplified recently in the elegant total synthesis of spirotryprostatin A by
Danishefsky and co-workers [5].
As part of our interest in developing novel approaches for the stereoselective
synthesis of alkaloids, we have recently reported a number of useful strategies [6]. In
this regard, we have documented a new approach to spiro[indole-pyrrolidines],
involving the reaction of spiro[cyclopropane-indol]-2'-one 1 and N-alkyl- as well as N-
arylsulfonyl aldimines 2 (Scheme 1) [7]. The successful implementation of this
cyclopropane ring-expansion strategy resulted from the unique properties of MgI2 as
a bifunctional catalyst wherein the electrophilic metal center (MgII) and nucleophilicity
of the counterion (IÀ) appear to operate synergistically, leading to the formation of a
reactive g-iodo enolate 32). The ambiphilic character of this intermediate allows for
1
)
)
Part of the Diploma Thesis of C.F., ETH-Zürich, 2000.
MgI2 has been observed to function as a uniquely effective catalyst in asymmetric Diels-Alder and aldol
addition reactions. Its superiority has been attributed to the facile dissociation of IÀ from L2MgI2 [8].
2

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Helvetica Chimica Acta ± Vol. 83 (2000)
efficient reaction with imines, leading to the formation of spiro[indole-pyrrolidin]-2-
ones. Our preliminary work in this area has been focussed primarily on the use of N-
tosyl and N-allyl imines derived from aromatic and aliphatic aldimines derived from
propionaldehyde, isobutyraldehyde, and a,b-unsaturated aldehydes.
Scheme 1
The successful application of this methodology to structures typified by horsfiline 5
necessitates that the methodology we have delineated be successfully executed with
formaldehyde-derived aldimines. In this regard, we initiated a project aimed at the total
synthesis of (Æ)-horsfiline (5) with the dual goals of expanding the methodology to
include N-methylmethanimine, or its equivalent, and of applying the method to an
efficient synthesis strategy for a spiro[indole-pyrrolidin]-2-one.
Background. ± Horsfiline (5) is one of the structurally simpler oxindole alkaloids
isolated in 1991 by Bodo and co-workers from Horsfieldia superba, a tree from
Malaysia, whose extracts are commonly employed in local medicine [9]. In the context
of confirming the proposed structure, these workers carried out a synthesis of the
racemate through oxidative rearrangement reaction of 1,2,3,4-tetrahydro-N-methyl-6-
methoxy-b-carboline. Subsequent to the isolation work, additional syntheses have been
reported of the natural product, employing a variety of strategies [10 ± 14]. The most
general approach to the installation of the requisite spirocyclic core such as that found
in (À)-horsfiline ((À)-5) is typified by an annulation sequence wherein a tryptamine
derivative is subjected to a Pictet-Spengler condensation to afford the corresponding
tetrahydrocarbolines followed by oxidative rearrangement [15][16].
In our retrosynthetic analysis, we envisioned a different approach to such ring
systems wherein 5 is disconnected to synthon 6 and aldimine 7 (Scheme 2). The
dissonant charge-affinity pattern manifest in 6 is congruent with that of spiro[cyclo-
propane-indol]-2'-one 8. Indeed, this pattern is manifest in the well-known reactivity of

Helvetica Chimica Acta ± Vol. 83 (2000)
1177
cyclopropanes, when substituted with electron-withdrawing groups3), to serve as
homo-Michael acceptors [17][18]. The strategy plan we had envisioned for the
synthesis of horsfiline would necessitate the nucleophilic ring opening of a singly
activated cyclopropane ring. As a way of implementing the synthetic plan, we
speculated that the use of a catalyst exhibiting dual electrophilic and nucleophilic
activation would furnish an intermediate possessing the ambiphilic reactivity (i.e., 3),
which could be intercepted by the imine, thus enabling the desired reaction [8]. It is
important to note, however, that the use of such a strategy would lead to the desired
spiro[indole-pyrrolidin]-2-ones, provided competitive self-immolative consumption of
the intermediate species via intramolecular O-alkylation is precluded. In this regard,
the fact that the horsfiline synthesis would employ the aldimine derived from
formaldehyde, i.e., methanimine, posed a potential problem. Because methanimines
typically are handled as the corresponding trimeric triazines, the success of the
annulation strategy would depend on the stability of reactive intermediate 3, in light of
potential intramolecular O-alkylation, under the thermal conditions prescribed for the
triazine fragmentation reaction to give methanimine.
Scheme 2
Results and Discussion. ± The synthesis route commenced with the N-benzylation
of the commercially available 5-methoxyisatin 10 to furnish 11 as a red crystalline solid
(m.p. 117 ± 1188) in 74% yield (Scheme 3). Subsequent subjection of 11 to the Wolff-
Kishner reduction (NH2NH2 ´ H2O, reflux) afforded oxindole 12 (91%). The success of
the strategy outlined above depends on the availability of the spiro[cyclopropane-
indol]-2'-one ring system. In this regard, we were pleased to observed that, as reported,
the Na-enolate derived from 12 underwent clean alkylative cyclization with 1,2-
dibromoethane to afford 13 as a crystalline solid (m.p. 112 ± 1138) in 81% yield.
The stage was set for the key cyclopropane fragmentation/ring-expansion reaction.
Treatment of 13 with 1,3,5-trimethyl-1,3,5-triazinane (9) and 5.5 mol-% MgI2 in THF
at reflux furnished the desired spiro[indole-pyrrolidin]-2-one 14 in 83% yield. Removal
3
)
The reactivity of cyclopropanes towards nucleophiles is typically limited to those activated by two electron-
withdrawing groups or those that are highly strained. Exceptions to this generalization occur with strong
nucleophiles such as metal selenides and Ni-catalyzed additions of organoaluminums (see [18]).

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Scheme 3
a) NaH, BnBr, DMF, 238. b) N2H4 ´ H2O, reflux. c) 1,2-Dibromoethane, NaH, DMF, 238. d) MgI2 (5.5 mol-%),
1,3,5-trimethyl-1,3,5-triazinane (9), THF, 1258. e) Na/NH3, À 788.
of the N-Bn protecting group was effected by subjecting 14 to dissolving metal
reduction (Na/NH3), affording (Æ)-horsfiline (5) in 91% yield. The racemic horsfiline
obtained from the synthetic sequence displayed spectroscopic properties (1H-NMR,
13C-NMR, IR, MS) identical in all respects with that reported for the authentic
material.
In the synthesis of (Æ)-horsfiline (5) reported herein, we have demonstrated the use
of 1,3,5-trimethyl-1,3,5-triazinane as an equivalent for N-methylmethanimine under
the conditions of the ring-expansion reaction of spiro[cyclopropane-indol]-2'-ones. The
conversion of 1,3,5-trimethyl-1,3,5-triazinane to N-methyl methanimine has been
reported to take place at T> 2508 under conditions of flash-vacuum-pyrolysis [19][20].
These conditions are considerably harsher than those we utilized in the construction
of the spiro[indole-pyrrolidin]-2-one. At least two putative mechanistic pathways for
the annulation reaction can be envisioned: reaction of free N-methyl methanimine
with 16, directly affording iminium 17, or alkylation of the triazinane to give
cationic quaternized amine 18 (Scheme 4). This latter intermediate could subsequently
undergo fragmentation to 17. Although it is not possible at this time to differen-
tiate between mechanistic alternatives involving reaction of free N-methylmethan-
imine vs. 1,3,5-trimethyl-1,3,5 triazinane itself, we favor the latter mechanism, as it is
unlikely that in refluxing a significant quantitity of N-methyl methanimine is generated
(Scheme 4).
Conclusion. ± We have reported a short synthetic route to (Æ)-horsfiline with which
the natural product can be accessed as its racemate in five steps from commercially
available substituted isatin in 41% overall yield. Efficient entry into the spiro[indole-
pyrrolidin]-2-one ring system is possible through the application of the cyclopropane
opening/ring expansion chemistry we have described with MgI2 as a bifunctional
catalyst. This synthesis thus demonstrates the viability of the process to generate
adducts formally derived from N-alkyl methanimines. Additional studies of this process
are ongoing, particularly as it pertains to asymmetric induction, and these will be
reported as they become available.

Helvetica Chimica Acta ± Vol. 83 (2000)
1179
Scheme 4
We are grateful for financial support from the Swiss National Science Foundation and F. Hoffmann La
Roche AG, Basel.
Experimental Part
General. All reactions were carried out in oven-dried glassware under an atmosphere or Ar or N2. The
solvents used for reactions were reagent grade and purchased from commercial suppliers; THF was degassed
with Ar, then passed through two 4 Â 36 inch columns of anh. neutral A-2 alumina (8 Â 14 mesh; La Roche
Chemicals; activated under a flow of Ar at 3508 for 3 h) to remove H2O. For chromatography, technical-grade
solvents, distilled prior to use, were used. All chemicals were purchased from Fluka or Aldrich in purum or
higher quality, 5-methoxyisatin (> 99.8%) was purchased from Spectrum Laboratory Products, Gardena, CA,
USA. Chromatographic purification was performed as flash chromatography using Fluka silica gel 60 (40 ±
63 mm) or neutral Merck silica 60 (40 ± 63 mm), with 0.2 ± 0.4 bar N2 pressure. TLC: Merck silica gel 60 F254 TLC
glass plates; visualized with UV light or ceric ammonium molybdate (CAM stain; 500 ml of 10% H2SO4 soln.,
25 g of (NH4)Mo7O24 ´ 6H2O, 1 g of Ce(SO4)2). M.p.: Büchi 510 with open glass capillaries; uncorrected. IR:
Perkin Elmer Spectrum RX-I FT-IR spectrophotometer as KBr pellets. NMR: Varian-Mercury-300 or Varian-
Gemini-300 (1H: 300 MHz, 13C: 75 MHz) in CDCl3, with the internal CHCl3 signal as reference (1H: 7.27 ppm,
13C: 77.0 ppm). MS: VG ZAB2-SEQ spectrometer (FAB: bombardment with 35 keV Cs-atoms (3-nitrobenzyl-
alcohol (NOBA) matrix)); in m/z (rel. %). Elemental analyses were conducted by the Microanalytical
Laboratory of the Laboratorium für Organische Chemie, ETH-Zürich.
1-Benzyl-5-methoxy-1H-indol-2,3-one (11). 5-Methoxy-1H-indole-2,3-dione (10; 1.000 g, 5.645 mmol) was
placed in a two-neck flask, and dry DMF (10 ml, over 4-Š molecular sieves) was added. NaH (142 mg,
5.92 mmol) was added portionwise to the brown soln., which changed color to dark blue. After the H2 evolution
had ceased, BnBr (771 ml, 6.49 mmol) was added dropwise via a syringe, the color changed back to brown-red.
After stirring for 1 h at 238, H2O (30 ml) was added, and a red sticky solid was observed to precipitate. The aq.
layer was extracted with AcOEt (8 Â 40 ml), and the combined org. layers were dried (anh. Na2SO4). The
solvent was evaporated in vacuo. The remaining residual DMF was removed under high vacuum/608. The sticky
red solid was purified by chromatography on silica gel (hexane/AcOEt 2 :1), and 140 mg of 10 and 1.114 g
(74%) of 11 as red solid were obtained. Recrystallization from hexane afforded a pure sample as red needles.
M.p. 117 ± 1188. IR: 1723s, 1621m, 1602m, 1494s, 1472w, 1437w, 1349w, 1336m, 1313w, 1271w, 1238w, 1175m,
1
1145w, 1080w, 1047w, 1018w, 836m, 773m, 695m, 473w. H-NMR: 7.37 ± 7.31 (m, 5 arom. H); 7.16 (d, J ˆ 2.8, 1
arom. H); 7.03 (dd, J ˆ 8.4, 2.8, 1 arom. H); 6.68 (d, J ˆ 8.4, 1 arom. H); 4.91 (s, CH2N); 3.78 (s, MeO).
13C-NMR: 183.8; 158.5; 156.6; 144.6; 134.6; 129.1; 128.1; 127.4; 124.7; 118.1; 112.0; 109.6; 56.0; 44.1. MS: 269.1
‡
‡
‡
(30.4, [M ‡ 2 H] ), 268.1(100.0, [M ‡ H] ), 267.0 (32.7, M ). Anal. calc. for C16H13NO3 (267.30): C 71.90,
H 4.90, N 5.24; found: C 71.84, H 5.09, N 5.25.

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1-Benzyl-2,3-dihydro-1H-indol-2-one (12). Compound 11 (702 mg, 2.63 mmol) was dissolved in N2H4 ´ H2O
(5 ml) and the soln. heated to reflux. After 45 min., the mixture was allowed to cool to 238, and a greenish yellow
oil separated. The mixture was diluted with H2O (40 ml) and extracted with Et2O (30 ml). The org. layer was
dried (anh. Na2SO4) and the solvent evaporated in vacuo. Crude 12 (647 mg, 97%) was obtained as a yellow oil
and used without further purification. A pure sample (91%) could be obtained by chromatography on silica gel
(hexane/AcOEt 3 :1). IR: 1708s, 1602w, 1494s, 1454w, 1436w, 1359w, 1345w, 1289w, 1220w, 1180m, 1142w, 1037w,
806w, 746w, 705w, 676w, 621w. 1H-NMR: 7.33 ± 7.25 (m, 5 arom. H); 6.90 ± 6.89 (m, 1 arom. H); 6.72 ± 6.68 (m, 1
arom. H); 6.62 ± 6.59 (m, 1 arom. H); 4.90 (s, CH2N); 3.76 (s, MeO); 3.61 (s, CH2(3)). 13C-NMR: 175.0; 156.0;
‡
‡
136.1; 128.8; 127.7; 127.4; 125.9; 112.2; 112.0; 109.4; 55.7; 43.7; 36.0. HR-MS: 253.1104 (MH , C16H16NO2 ; calc.
253.1103).
5'-Methoxy-1',3'-dihydrospiro-[cyclopropane-1,3'-indol]-2'-one (13). A soln. of 12 (402 mg, 1.59 mmol) in
Et2O was concentrated in a two-neck flask and dried under high vacuum. After the addition of DMF (2 ml, over
4 Š molecular sieves) and 1,2-dibromoethane (0.15 ml, 1.7 mmol), the mixture was cooled to 08, NaH (114 mg,
5.75 mmol) was portionwise added, and the color of the mixture turned from yellow to orange to red to brown-
red upon addition. After 3 h, H2O (40 ml) was added, and the aq. layer was extracted with AcOEt (2 Â 25 ml).
The combined org. layers were washed with H2O (4 Â 20 ml) and brine, dried (anh. Na2SO4), and the solvent was
evaporated in vacuo. The brown-red oil obtained was purified by chromatography on silica gel (hexane/AcOEt
9 :1 ! 8 :1) to yield 358 mg (81%) of 13. Colorless, slightly yellowish crystals. Recrystallization from hexane/
AcOEt gave colorless crystals. M.p. 112 ± 1138. IR: 3060w, 3037w, 3009w, 2916w, 2838w, 1692s, 1602m, 1491s,
1475m, 1454m, 1438m, 1382s, 1350m, 1334m, 1286w, 1239s, 1077w, 1056w, 1031m, 1003w, 954w, 892w, 882m,
1
806m, 745m, 732w, 698m, 652w, 596m, 558w, 458w. H-NMR: 7.34 ± 7.24 (m, 5 arom. H); 6.67 (m, 2 arom. H);
6.47 ± 6.46 (m, 1 arom. H); 4.98 (s, CH2N); 3.75 (s, MeO); 1.84 ± 1.80 (m, 2 cyclopropyl H); 1.55 ± 1.51 (m, 2
cyclopropyl H). 13C-NMR: 177.1; 156.0; 136.4; 132.4; 128.8; 127.6; 127.4; 111.1; 111.0; 109.3; 106.1; 55.8; 44.1;
‡
‡
‡
27.3; 19.4. MS 281.1 (23.6, [M ‡ 2 H] ), 280.1 (71.3, [M ‡ H] ), 279.1 (100.0, M ). Anal. calc. for C18H17NO2
(279.34): C 77.40, H 6.13, N 5.01; found: C 77.31, H 6.30, N 4.96.
1-Benzyl-5-methoxy-1'-methylspiro[1H-indole-3,3'-pyrrolidin]-2-one (14). A 10-ml sealed tube was charg-
ed with 13 (50 mg, 0.18 mmol) and anh. MgI2 (2.5 mg, 9.0 mmol). The tube was closed, evacuated, and back-
filled with Ar. 1,3,5-Trimethyl-1,3,5-triazinane (26 ml, 0.18 mmol) and THF (0.3 ml) were added, and the tube
was sealed, before it was submerged in a preheated oil bath at 1258. The mixture turned pale orange, and, after a
few min, a colorless solid was observed to precipitate. After 60 h, the mixture was allowed to cool to 238 and was
then further cooled in an ice bath. H2O (1 ml), a single crystal of Na2S2O3, and AcOEt (2 ml) were added,
whereupon more of the precipitate was formed. The reaction vessel was decanted and extracted with AcOEt
(3 Â 10 ml), the layers were separated, and the combined org. layers were washed with brine, dried (anh.
Na2SO4), and concentrated in vacuo. Purification of the yellow oil by chromatography on silica gel (AcOEt/
acetone 4 :1) afforded 48 mg (83%) of 14 as a colorless, slightly yellowish oil. Repeated purification by
chromatography on silica gel (AcOEt/acetone 4 :1) yielded a pure sample as a colorless, viscous oil. IR: 2944w,
2836w, 2789w, 1707s, 1603w, 1496s, 1456m, 1436m, 1359w, 1346m, 1303w, 1282w, 1176m, 1030w, 807w, 739w, 697w,
668m. 1H-NMR: 7.34 ± 7.22 (m, 5 arom. H); 7.10 (d, J ˆ 2.5, 1 arom. H); 6.67 (dd, J ˆ 8.4, 2.5, 1 arom. H); 7.10 (d,
J ˆ 8.4, 1 arom. H); 4.89 (s, CH2N); 3.77 (s, MeO); 3.14 ± 3.07 (m, HÀC(5')); 2.96 (d, J ˆ 9.3, HÀC(2')); 2.88 (d,
J ˆ 9.3, HÀC(2')); 2.81 ± 2.72 (m, HÀC(5')); 2.49 (s, MeN); 2.47 ± 2.39 (m, HÀC(4')); 2.18 ± 2.08 (m, HÀC(4')).
13C-NMR: 180.3; 156.5; 138.9; 136.2; 135.5; 128.8; 127.6; 127.3; 112.1; 110.4; 109.1; 66.4; 56.6; 55.8; 53.7; 43.8;
‡
‡
‡
41.8; 38.1. MS: 324.1 (29.9, [M ‡ 2 H] ), 323.1 (100.0, [M ‡ H] ), 322.1 (26.3, M ). Anal. calc. for C20H22N2O2
(322.41): C 74.51, H 6.88, N 8.69; found: C 74.36, H 6.62, N 8.45.
(Æ)-Horsfiline (5). NH3 (ca. 5 ml) was condensed at À788, and Na was added with vigorous stirring at À428,
until the blue color persisted. Compound 14 (32 mg, 0.10 mmol) was added in THF (0.5 ml). After 13 min, H2O
(25 ml) and a small amount of NH4Cl were added. Then, the pH of the mixture was adjusted to pH 11 with 6n
HCl. The mixture was extracted with CH2Cl2 (6 Â 20 ml) and washed with brine. The combined org. layers were
dried (anh. Na2SO4), and the solvent was evaporated in vacuo. Recrystallization from hexane yielded 21 mg
(91%) of 5 as a colorless solid. M.p. 1518. IR: 3173w, 2785w, 1702s, 1638w, 1619w, 1602w, 1480m, 1442w, 1319w,
1279w, 1258w, 1229w, 1210w, 1183w, 1161w, 1138w, 1058w, 1036w, 907w, 883w, 791w, 681w, 668w, 641w. 1H-NMR:
8.9 (br. s, NH); 7.02 (d, J ˆ 2.5, 1 arom. H); 6.82 (d, J ˆ 8.3, 1 arom. H); 6.72 (dd, J ˆ 8.3, 2.5, 1 arom. H); 3.79 (s,
MeO); 3.04 ± 2.97 (m, HÀC(5')); 2.89 (d, J ˆ 9.3, HÀC(2')); 2.84 (d, J ˆ 9.3, HÀC(2')); 2.81 ± 2.73 (m,
HÀC(5')); 2.46 (s, MeN); 2.43 ± 2.37 (m, HÀC(4')); 2.13 ± 2.04 (m, HÀC(4')). 13C-NMR: 183.3; 156.3; 137.8;
‡
‡
133.7; 112.4; 110.3; 110.0; 66.3; 56.7; 55.8; 54.1; 41.7; 37.9. MS: 234.1 (20.4, [M ‡ 2 H] ), 233.1 (100.0, [M ‡ H] ),
‡
232.1 (24.0, [M] ). Anal. calc. for C13H16N2O2 (232.28): C 67.22, H 6.94, N 12.06; found: C 67.37, H 6.94, N 11.86.

Helvetica Chimica Acta ± Vol. 83 (2000)
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Received April 1, 2000