Synthesis of (±)-strychnofoline via a highly convergent selective annulation reaction

Article abstract of DOI:10.1002/chem.200600957

Studies aimed at preparing (±)-strychnofoline by total synthesis are detailed. The route described makes use of a recently developed MgI ₂-mediated ring-expansion reaction of spiro[cyclopropan-1,3′- oxindole] with a cyclic disubstituted aldimin

Full text of DOI:10.1002/chem.200600957

FULL PAPER
DOI: 10.1002/chem.200600957
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FULL PAPER
Synthesis of (Æ)-Strychnofoline viaaHighly Convergent Selective
Annulation Reaction
Andreas Lerchner and Erick M. Carreira*[a]
Abstract: Studies aimed at preparing
(Æ)-strychnofoline by total synthesis
are detailed. The route described
makes use of a recently developed
MgI2-mediated ring-expansion reaction
The ring-expansion product was
formed as a single diastereoisomer in
55% yield, possessing the same stereo-
chemical pattern found in strychnofo-
line. In addition, our synthetic effort
has led to the development of new re-
action methodology to access 3,4-disub-
stituted cyclic aldimines.
Keywords: alkaloids
·
cyclopro-
of
spiro[cyclopropan-1,3’-oxindole]
panes · spirocycles · total synthesis
with a cyclic disubstituted aldimine.
Introduction
termediates.[14] Usambaridine Br (15) has been isolated from
the leaves of Strychnos usambarensis, together with strych-
In 1978, Angenot and co-workers disclosed the isolation and
characterization of strychnofoline (1),[1] which belongs to a
class of natural products isolated from the leaves of Strych-
nos usambarensis.[2] The compound was shown to inhibit mi-
tosis[3] in a number of cancer cell lines, including mouse mel-
anoma B16, Ehrlich, and Hepatom HW165. A prominent
structural feature of the oxindole alkaloids of the Strychnos
family and related natural products is the presence of a spi-
ro[pyrrolidin-3,3’-oxindole] core (Figure 1). Additional oxin-
dole alkaloids have been isolated from other plant sources,
exemplified by spirotryprostatin B (3),[4] rhynchophylline
(4),[5] formosanine (5),[6] voachalotine oxindole (6),[7] (À)-
horsfiline (7),[8] and gelsemine (8),[9] containing similar struc-
tural features.
The biosynthesis of strychnofoline has not been specifical-
ly investigated, but the general biosynthetic pathways en
route to such alkaloids in the Corynanthe/Strychnos group
have been established[10] and may also be valid for strychno-
foline (1) (Scheme 1). The biosynthesis of commences with
the conversion of geraniol (9) to loganin (10),[11] and there-
after proceeds from loganin (10) to secologanin (11).[12] Se-
cologanin is believed to undergo Pictet–Spengler reaction
with tryptamine 12, furnishing strictosidine (13).[13] Corynan-
theal (14) is likely to be the last of the Corynanthe-type in-
[a] A. Lerchner, Prof. Dr. E. M. Carreira
Laboratorium für Organische Chemie
ETH Zürich, HCIH335, 8093 Zürich (Schweiz)
Fax : (+41)1-632-1328
Figure 1. Collection of natural products incorporating the spiro[pyrroli-
E-mail: carreira@org.chem.ethz.ch
din-3,3’-oxindole] core.
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E. M. Carreira and A. Lerchner
at developing and studying efficient strategies toward their
preparation. In this context a methodological study was un-
dertaken, leading to the development of a novel ring-expan-
sion reaction of a spiro[cyclopropan-1,3’-oxindole] (17) with
a range of simple, unfunctionalized imines (18) to furnish
spiro[pyrrolidin-3,3’-oxindoles] (19), whose core structure is
identical to the core structure of many oxindole alkaloids
(Scheme 2).[19] It was our intention to apply this novel MgI2-
mediated ring-expansion reaction as a key step to the first
total synthesis of (Æ)-strychnofoline (1). Within the context
of such a target-specific synthesis program, we aimed to ad-
dress a key issue, namely, whether a cyclic imine could be
used in the annulation reaction and whether previously ex-
isting stereocenters in such an imine could effect control
over the stereochemical course of the annulation process,
leading to the formation of the desired relative configura-
tion found in strychnofoline.
Our working hypothesis with respect to the mechanism of
the reaction is that the iodide participates in nucleophilic
opening of the cyclopropyl ring in the spiro[cyclopropan-
Scheme 1. Putative biosynthetic pathway to strychnofoline.
1,3’-oxindole] to furnish
a putative iodo enolate 23
nofoline.[1] Usambaridine Br
(15) is likely converted to
strychnofoline (1) by an oxida-
tive rearrangement, a sequence
which is probably responsible
for the origin of all oxindole al-
kaloids
of the Strychnos
family.[15]
Within the context of com-
plex molecule syntheses, the
successful preparation of spiro[-
perhydroindolizine-oxindoles]
Scheme 2. Annulation reaction of imines and cyclopropylspirooxindoles.
has been effected following
four general strategies. The first
was reported for the total synthesis of related antineoplas-
tics,[16] wherein condensation of a 2-oxytryptamine with an
aldehyde afforded an intermediate imine that subsequently
participated in an intramolecular Mannich reaction. In a
second complementary approach, the oxidative rearrange-
ment of yohimbinoids provided access to oxindole alka-
loids.[15] The third approach reported to date is exemplified
by the elegant total synthesis of pseudotabersonine, wherein
the analogous spirofused quinolizidine-oxindole ring system
is formed by aza Diels–Alder reaction of an imine and
diene.[17] We have recently introduced a fourth method in-
volving the annulation reaction of imines and cyclopropyl-
spirooxindoles described below.[18]
(Scheme 3). A number of several distinct reaction pathways
to the end-product are available from this intermediate,
which possesses both nucleophilic and electrophilic charac-
ter. This dual characteristic could also be viewed as a cause
Results and Discussion
Because of the biological activity of the oxindole alkaloids
as well as the synthetic challenges presented by their com-
plex architecture we have embarked on a program that aims
Scheme 3. Working mechanistic model of the annulation process.
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(Æ)-Strychnofoline
FULL PAPER
of some concern, as the iodo enolate could participate in an
intramolecular alkylation forming the corresponding furano-
fused indolyl ring system. However, if it was sufficiently
long-lived, nucleophilic substitution of the iodide with the
aldimine could lead to the formation of a putative aldimini-
um 24 which could undergo Mannich cyclization to form
pyrrolidine 19. We have circumstantial evidence that lends
credence to this pathway; thus when MgBr2 was used as a
catalyst, the reaction proceeds at a significantly slower pace,
and when Mg(OTf)2 was used, the ring-expansion reaction
A
did not proceed at all.[19] Moreover, the corresponding io-
doethyl oxindole could be isolated from the MgI2-mediated
ring-expansion reaction in the absence of added imine.[21]
One key issue that would have to be addressed for the
successful execution of the strategy is the preparation of the
requisite disubstituted cyclic aldimine. A significant problem
was the fact that unsubstituted cyclic aldimines (i.e., 25)
readily suffer self-condensation (Scheme 4). This can be best
Scheme 5. Synthesis of imide intermediate. a) LiBH4, THF, 238C, 88%
yield; b) Na, NH3, THF, tBuOH, À408C, 10 min, 75% yield; c) imida-
zole, DMF, TBDPSCl, 238C, 91% yield; d) DMAP, NEt3, CH2Cl2,
Boc2O, 23 8C, 88% yield; e) LHMDS, THF, PhSeCl, À788C, then
EtOAc, H2O2, 238C, 80% yield; f) allylMgCl, CuBr·SMe2, THF, À788C,
75% yield for both diastereoisomers.
1
Scheme 4. Formation of tetrahydroanabasin from tetrahydropyridine as
reported by Schçpf.
veniently assayed by integration of the H NMR signals at d
2.26 (dd, 1H, J1 =15.8, J2 =8.8 Hz) for the major diaster-
eoisomer and d 2.34 (dd, 1H, J1 =17.7, J2 =8.1 Hz) for the
minor diastereoisomer. At this stage, it was assumed with a
reasonable level of confidence that the major diastereoisom-
er corresponded to the trans-disubstituted product; this
appreciated in the work of Schçpf who investigated the for-
mation of tetrahydroanabasin (26) from tetrahydropyridine
25.[22] In line with these studies, the large number of the
stable isolable cyclic imines possess a,a-disubstitution; pre-
cluding the formation of the corresponding enamine and
subsequent oligomerisation.
1
could later be confirmed by H NMR NOE studies of the
ring annulation product 47 as shown in Figure 2. In the
course of the studies of this Mi-
chael addition reaction, we had
observed that reactions in THF
gave improved yields over
those conducted in Et2O, and
the addition of allylMgCl led to
a higher yield than when al-
lylMgBr was employed.[26,27]
The synthesis of strychnofoline commences with the prep-
aration of lactam 34 through a convenient sequence from
propiolic acid 27 (Scheme 5).[24] Ester 28 was reduced with
LiBH4 in THF at room temperature to give alcohol 29 in a
yield of 89%. Debenzylation of 29 (Na in NH3,THF, tert-bu-
tanol, À408C) provided lactam 30 in 75% yield. Deprotec-
tion of the N-benzyl group by hydrogenation with Pd/C was
not found to be a viable option, consistent with findings in
literature.[25] The alcohol in 30 was protected with
TBDPSCl, (imidazole, DMAP, DMF) to afford 31 (91%
yield). Subsequent N-protection was effected by treatment
of 31 with Boc2O (NEt3, DMAP, CH2Cl2/DMF) to afford 32
in 88% yield. Deprotonation of lactam 32 with LHMDS at
À788C in THF was followed by the slow addition of PhSeCl
in THF at À788C via cannula to furnish the a-selenylated
derivative. Subsequent treatment of the selenylated product
with H2O2 in EtOAc afforded unsaturated lactam 33 in 80%
yield.
Conversion of disubstituted
lactam 34 to the desired imine
Figure 2. 1H NMR NOE stud-
ies of the ring annulation prod-
commenced with reduction of uct 47.
34 with DIBALH (THF/
hexane, À788C) to afford lacta-
mol 35 (Scheme 6). Treatment of a solution of 35 in CH2Cl2
with 1m aq HCl and subsequent stirring of the biphasic reac-
tion mixture at room temperature for 5 min provided the
Boc-protected enamine 36 in a yield of 75%.[29] Enamine 36
was treated with TMSOTf and NEt3 in CH2Cl2 at À208C to
afford cyclic aldimine 38, which was used directly in the
ring-expansion reaction.[28] It is worth noting that the selec-
tion of N-Boc protection strategy was made, as we were cog-
nizant of the instability of the cyclic imine. Thus, it was par-
ticularly appealing that N-Boc deprotection could be carried
out under mild conditions and would lead to co-products
Unsaturated lactam 33 underwent Michael addition with
allylMgCl in the presence of CuBr·SMe2 and TMSCl
(À788C, THF) to give 34 in 75% yield as a diastereomeric
mixture of 5:1 in favor of the desired product. This was con-
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E. M. Carreira and A. Lerchner
Scheme 6. Conversion of imide to the key imine intermediate. a) DIBAL,
THF, hexane, À788C; b) aqueous HCl in CH2Cl2, 238C, 75% yield from
34; c) TMSOTf, NEt3, then aqueous NaHCO3.
that were volatile or readily soluble in aqueous media, and
thus permit convenient purification and isolation of the
imine.
Scheme 7. Synthesis of the spirocyclic cyclopropane. a) NaH, BnBr,
DMF, À788C to 258C, 72% yield; b) hydrazine hydrate, EtOH, 1008C,
90% yield; c) BBr3, CH2Cl2, 08C, 92% yield; d) TBDMSCl, imidazole,
DMF, 88% yield; e) dibromoethane, DMF, NaH, 08C, then MeOH, À78
to 258C, 86% yield; f) BnBr, NaH, DMF, 08C, 87% yield.
Spiro[cyclopropan-1,3’-oxindole] (46), necessary for the
synthesis of strychnofoline, was prepared from 6-methoxyi-
satine (41), which itself is conveniently prepared in two
steps from m-anisidine (39) (Scheme 7). Because the cleav-
age of the O-methyl ether would involve the use of harsh
conditions that might not be compatible with an advanced
intermediate later in the synthetic sequence, the methyl
ether was exchanged early on in the synthesis for an O-
benzyl protecting group. Although isatines 40 and 41 did not
withstand the reaction conditions for the removal of the
methyl group with BBr3, oxindole 42 proved sufficiently
robust. Thus, oxindole 42 was treated with BBr3 in CH2Cl2
at 08C to give 43 in 92% yield. Subsequent attempted O-
benzylation of 43 by treatment with K2CO3 and BnBr in
DMF at 608C gave a complex mixture including products
from O-benzylation of the phenol as well as C-alkylation of
a putative indole enolate. This problem was dealt with at
the expense of an additional step in the synthesis of the spi-
ro[cyclopropan-1,3’-oxindole]. In this respect the phenol in
43 was silylated with TBSCl and imidazole in DMF to give
silyl ether 44 in a yield of 88%. Oxindole 44 was C-dialky-
lated using dibromoethane and NaH in DMF at 08C to give
cyclopropylspirooxindole 45. Once installation of the cyclo-
propane was deemed complete by thin layer chromatogra-
phy, the reaction mixture was cooled to À788C and treated
with MeOH. Given the slight excess of base employed in
the preceding reaction, the residual MeONa effected desily-
lation of the phenol to provide
46 in hand, the MgI2-mediated ring-expansion reaction
could be investigated. Because of the inherent instability of
cyclic aldimine 38, it was employed without purification in
the annulation reaction (Scheme 8).
The annulation reaction was carried out by charging a
sealable tube with MgI2 and spiro[cyclopropan-1,3’-oxin-
dole] (46) and cyclic aldimine 38 in THF. The sealed tube
was placed into a preheated oil bath at 808C, and the reac-
tion mixture was heated for 16 h at 808C. Upon cooling, spi-
rooxindole 47 was isolated as a single diastereoisomer in a
yield of 55% over two reaction steps, namely, imine forma-
tion and annulation. The optimal concentration for the an-
nulation proved to be 0.3m. Moreover, we observed that
substoichiometric amounts of MgI2 could be employed, thus,
with 50 mol% of MgI2 the product could be isolated in
roughly similar yield. The assignment of the relative stereo-
chemistry in 47 was effected by 1H NMR NOE studies
(Figure 2). Thus, the axial proton at C-14 was shown to be
in close proximity to the aromatic proton at C-9: irradiation
of the proton at C-9 produces an enhancement at the reso-
nance corresponding to HRe-C(14) of 3%. Irradiation of the
spiro[cyclopropan-1,3’-oxindole]
(45) in 86% yield. Spiroindole
45 was treated with BnBr and
NaH at 08C to afford spiro[cy-
clopropan-1,3’-oxindole]
46
(87% yield).
With cyclic aldimine 38 and
Scheme 8. The critical annulation reaction. a) 1 equiv MgI2, THF, 808C, 55% (combined yield of the imine
spiro[cyclopropan-1,3’-oxindole] forming reaction and the ring-expansion reaction).
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(Æ)-Strychnofoline
FULL PAPER
axial proton at HRe-C-14 resulted in a NOE enhancement at
the axial proton at C-20 of 2%. The axial protons at C-3, C-
1
15 and C-21 are also spatially close: the observed H NMR
NOE enhancement of H-C(15) upon irradiation of H-C(3)
1
is 4% and the H NOE enhancement of H-C(15) upon irra-
diation of HRe-C(21) is 4%. Thus, from these studies it can
be concluded that the product possesses the stereochemical
pattern commonly found in the pyrrolidinospirooxindole
family of natural products and specifically that of strychno-
foline.
Because four different diastereoisomers could have been
formed in the described MgI2-mediated ring-expansion reac-
tion, an explanation for the high diastereoselectivity seems
called for. In principle, the oxindole alkaloids can exist as
mixture of four distinct diastereomers on the basis of the
spiro-fusion that are readily interconvertible. These have
been classified (Figure 3) into various groups: normal A and
Figure 4. The effect of acidity of the medium on the diastereomer popula-
tion in the pyrrolidinospirooxindole family of natural products.
A, the formation of a comparable hydrogen bond is preclud-
ed. This effect is manifest in the difference of the acidity for
the two stereoisomers: the pKa value for conjugate acid of
type normal A are usually by one unit lower than the pKa
value for the conjugate acid of type normal B. It is worth
noting that further analysis of these structures reveals an
electrostatic repulsion between the nitrogen lone pair and
carbonyl lone pairs which is destabilizing. Such a destabiliz-
ing interaction is absent in type normal A. In summary, we
assume that the product of the MgI2-mediated ring-expan-
sion reaction is the thermodynamically most stable diaster-
eoisomer in aprotic medium. Thus, the diastereoselectivity
of the product isolated from the MgI2-mediated annulation
reaction is at present best accommodated by thermodynam-
ics of the product formed.[32]
Since the MgI2-mediated ring-expansion reaction had pro-
vided access to the core structure of strychnofoline, we
could focus on the conversion of the allyl group at C-15 into
a carbolinylmethyl group and the conversion of the silyloxy-
methyl group at C-20 into a vinyl group (Scheme 9).[33] The
olefin in spiroindole 47 was oxidized with OsO4 and NMO
(tBuOH/water/dioxane) to afford an intermediate diol,
which was cleaved directly with NaIO4 to give aldehyde 48
in 86% yield. Aldehyde 48 was treated with p-TsOH,
Figure 3. Classification of the diastereomer patterns in pyrrolidinospiro-
oxindole family of natural products.
B along with pseudo A and B.[31] Type pseudo A and pseudo
B have not been detected in oxindole alkaloids. It has been
suggested that they are thermodynamically less stable than
the diastereoisomers of the type normal A and B due to un-
favorable diaxial steric interactions between the substituents
of the piperidine ring. In the case of the stereoisomers of
the type normal A and B, the substituents on the piperidine
ring are all equatorially poised. Oxindole alkaloids with the
stereochemical pattern of type normal B appear in nature as
often as oxindole alkaloids of type normal A. These two
types are known to be interconverted via an intramolecular
retro-Mannich/Mannich reaction sequence in refluxing pyri-
dine or refluxing acetic acid. Interestingly the position of
this equilibrium is correlated to the protonation state of the
alkaloid. In acidic medium the stereoisomer of the type
normal B dominates; by contrast under alkaline conditions
the stereoisomer of the type normal A is predominant
(Figure 4). It has been argued that the protonated form of
type normal B diastereomer, a stabilizing interaction ensues
through the formation of a hydrogen bond to the oxindole
carbonyl acceptor. For diastereoisomer of the type normal
MeOH, and CH(OMe)3 to provide acetal 49 (93%). The
A
TBDPS-silyl ether was removed by treatment of 49 with
TBAF in THF to provide alcohol 50 (86%). Alcohol 50 was
oxidized by IBX in DMSO to afford aldehyde 51 in 88%
yield. Aldehyde 51 was subjected to Wittig olefination
(PPh3MeBr, tBuOK, THF) at room temperature to provide
olefin 52 in a yield of 87%. A crystal structure of 52 could
be obtained; analytically useful crystals were formed over
two days at À208C in a solvent mixture of EtOAc and
hexane. The crystal structure of 52 confirmed the NOE stud-
ies for 47; the MgI2-mediated ring-expansion reaction had
provided a diastereoisomer of type normal A (Figure 5).[32,33]
Acetal 52 was treated with aqueous HCl in acetone to give
aldehyde 53 in a yield of 94% (Scheme 10). Aldehyde 53
and N-methyltryptamine[35] were stirred in toluene and
acetic acid at 808C for 2 h to provide 54 in 38% yield and
desired 55 in 26% yield. The deprotection of the two benzyl
groups in 55 by Na in a solvent mixture of ammonia,
tBuOH, and THF from À78 to À458C for 10 min provided
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E. M. Carreira and A. Lerchner
Scheme 10. End steps. a) HCl (10% in H2O), acetone, 238C, 94% yield;
b) AcOH, toluene, Nw-methyltryptamine, 808C, 38% yield for 55 and
26% yield for 54; c) Na in NH3, tBuOH, THF, À78 to À458C, 82%
yield.
ly work with a spiro[cyclopropan-1,3’-oxindole] and a disub-
stituted cyclic aldimine to provide the corresponding spiro[-
perhydroindolizine-oxindole] in good yield over two steps
and excellent diastereoselectivity. The stereochemical pat-
tern produced in annulation reaction was identical with the
pattern found in strychnofoline. In the context of the total
synthesis of strychnofoline, useful, mild method leading to
the formation of cyclic aldimines has been established,
which may in turn lead to new access to this class of reactive
building blocks. The large number of oxindole alkaloids and
their promising biological activity makes them an interesting
target in academic and industrial chemistry. Thus, the results
presented substantively contribute to the development of
stereocontrolled synthesis of this important class of natural
products.
Scheme 9. Synthetic elaboration of 47. a) i) OsO4, NMO, THF, tBuOH,
H2O, 23 8C ii) NaIO4, THF, tBuOH, H2O, 23 8C, 86% yield over 2 steps;
b) p-TsOH, MeOH, CH(OMe)3, 238C, 93% yield; c) TBAF, THF, 238C,
A
86% yield; d) IBX, DMSO, 238C, 88% yield; e) PPh3MeBr, tBuOK,
THF, 238C, 87% yield.
Experimental Section
All non-aqueous reactions were carried out using glassware that had
been dried by heating for 5 min to 3008C under high vacuum. THF,
Et2O, toluene and CH2Cl2 were purified by distillation and dried by pas-
sage over activated alumina under an argon atmosphere (H2O content
< 30 ppm, Karl-Fischer titration). Triethylamine and HMDS were distil-
led prior to use. Radial chromatography was performed with a Cyclo-
Graph chromatodron using 1 mm or 2.5 mm CaSO4-bound silica gel
plates at a flow rate of 5–7 mLminÀ1. NMR spectra were recorded on a
Bruker DRX500 spectrometer operating at 500 MHz and 125 MHz for
1H and 13C acquisitions, respectively. IR: Perkin Elmer spectrum RXI
FT-IR spectrophotometer. Mass spectra (m/z [amu] (% base peak)):
MALDI; IonSpec Ultima Fourier Transform Mass Spectrometer.
Figure 5. X-ray crystal structure of 52.
strychnofoline (1) in 82% yield. It could be observed that
the benzyl protected aromatic hydroxyl group was depro-
tected at À788C, whereas the benzyl group on the amide
moiety was only deprotected at À458C. The synthetic mate-
rial isolated was identical in all respects with the material
from natural sources by TLC, mass spectrometry, 13C NMR
N-Benzyl-5-hydroxymethyl-2-piperidinone
(29):
LiBH4
(1.23 g,
56.6 mmol, 2.00 equiv) was added in one portion at 08C to a solution of
ester 28 (7.00 g, 28.3 mmol, 1.00 equiv) in THF (270 mL). The reaction
mixture was stirred at room temperature for 24 h and then cooled to
08C. The reaction was quenched by H2O (250 mL), followed by the addi-
tion of HCl (10% in H2O). The combined organic solvents were washed
with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concen-
trated under reduced pressure. Purification by flash chromatography on
silica gel (CH2Cl2/MeOH 20:1) provided alcohol 29 (5.53 g, 89%) as a
thick oil. 1H NMR (500 MHz, CDCl3): d = 7.19–7.32 (m, 5H), 4.60 (d,
1H, J=14.6 Hz), 4.53 (d, 1H, J=14.6 Hz), 3.55 (dd, 1H, J1 =10.7, J2 =
5.6 Hz), 3.45 (dd, 1H, J1 =10.7, J2 =7.1 Hz), 3.31 (ddd, 1H, J1 =12.2, J2 =
5.2, J3 =1.7 Hz), 3.00 (dd, 1H, J1 =12.2, J2 =10.0 Hz), 2.50–2.56 (m, 1H),
1
and H NMR spectroscopy.
Conclusion
In summary, we have described the first total synthesis of
(Æ)-strychnofoline with the use of a highly selective MgI2-
mediated annulation reaction, which was shown to effective-
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(Æ)-Strychnofoline
FULL PAPER
2.35–2.46 (m, 1H), 1.95–2.06 (m, 1H), 1.84–1.90 (m, 1H), 1.45–1.55 (m,
1H); 13C NMR (125 MHz, CDCl3): d = 170.1, 137.0, 128.6, 128.0, 127.4,
64.4, 50.4, 49.8, 36.4, 31.2, 23.8; FTIR (neat): n˜ = 3392 (m), 1619 (s, C=
O), 1498 (m), 913 (m), 743 cmÀ1 (m); HRMS (MALDI): m/z: calcd for
C13H18NO2: 220.1332; found: 220.1333 [M+H]+.
was stirred at À788C for 1 h. The reaction was quenched at À788C by
the addition of saturated aqueous NaHCO3 (20 mL). The combined or-
ganic solvents were washed with saturated aqueous NaHCO3 (10 mL)
and brine (10 mL), dried over anhydrous Na2SO4, filtered, and concen-
trated under reduced pressure to provide a residue. This residue was dis-
solved in EtOAc (40 mL), and aqueous H2O2 (30% in H2O, 8 mL) was
added at 08C. The ice bath was removed and the reaction mixture was
stirred at room temperature for 1 h. The organic layer was separated,
washed with brine (2”10 mL) and saturated aqueous NaHCO3 (4”
10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure to provide unsaturated lactam 33 (2.79 g, 80%) as a
thick oil. 1H NMR (500 MHz, CDCl3): d = 7.62–7.65 (m, 4H), 7.38–7.47
(m, 6H), 6.60 (dd, 1H, J1 =9.8, J2 =3.7 Hz), 5.95 (dd, 1H, J1 =9.8, J2 =
1.9 Hz), 3.98 (ddd, 1H, J1 =12.9, J2 =5.1, J3 =0.6 Hz), 3.84 (dd, 1H, J1 =
12.9, J2 =7.9 Hz), 3.61–3.68 (m, 2H), 2.70–2.75 (m, 1H), 1.55 (s, 9H), 1.06
5-Hydroxymethyl-2-piperidinone (30): Alcohol 29 (4.20 g, 19.2 mmol,
1.00 equiv) in THF (5 mL) was added at À458C to a homogeneous solu-
tion of Na (1.77 g, 76.8 mmol, 4.00 equiv) in NH3 (70 mL), THF (5 mL),
and tBuOH (5 mL). The reaction mixture was stirred at À458C for
10 min and then cooled to À788C. The reaction was quenched by the ad-
dition of NH4Cl (13 g) and diluted with THF (60 mL). NH3 was allowed
to evaporate slowly at À308C over 3 h. The slurry was filtered and
washed with THF (3”5 mL) and CH2Cl2 (20 mL). The filtrate was con-
centrated under reduced pressure to give lactam 30 (1.85 g, 75%) as a
thick oil. 1H NMR (500 MHz, CDCl3): d = 6.60 (s, 1H), 3.63 (dd, 1H,
J1 =10.7, J2 =5.6 Hz), 3.54 (dd, 1H, J1 =10.7, J2 =7.4 Hz), 3.42–3.46 (m,
1H), 3.09 (dd, 1H, J1 =10.9, J2 =10.3 Hz), 2.42 (ddd, 1H, J1 =18.0, J2 =
6.2, J3 =3.8 Hz), 2.33 (ddd, 1H, J1 =18.0, J2 =10.6, J3 =6.6 Hz), 1.98–2.08
(m, 1H), 1.86–1.96 (m, 1H), 1.51–1.59 (m, 1H); 13C NMR (125 MHz,
CDCl3): d = 172.8, 64.2, 44.7, 35.7, 30.2, 23.4; FTIR (neat): n˜ = 3299
(m), 1644 (m, C=O), 913 (s), 744 cmÀ1 (s); HRMS (MALDI): m/z: calcd
for C6H18NO2: 130.0863; found: 130.0865 [M+H]+.
(s, 9H); 13C NMR (125 MHz, CDCl3): d
= 163.7, 152.5, 144.2, 135.5,
133.0, 132.9, 130.0, 129.9, 127.9, 126.8, 83.0, 63.3, 45.8, 37.9, 28.1, 26.8,
19.3; FTIR (neat): n˜ = 1770 (s, C=O), 1760 (s, C=O), 1714 (m, C=O),
1246 (s), 913 (m), 743 cmÀ1 (m); HRMS (MALDI): m/z: calcd for
C27H35NO4SiNa: 488.2228; found: 488.2236 [M+Na]+.
(4S,5R)-4-Allyl-5-[[[(1,1-dimethylethyl)diphenylsilyl]oxy]methyl]-2-oxo-
1-piperidine carboxylic acid 1,1-dimethylethyl ester (34): Allylmagnesium
chloride (2m in THF, 13.4 mL, 26.9 mmol, 5.00 equiv) was added at
À788C to a suspension of CuBr·SMe2 (5.53 g, 26.9 mmol, 5.00 equiv) in
THF (50 mL). The reaction mixture was stirred at À788C for 1 h. A solu-
tion of TMSCl (1.34 mL, 10.8 mmol, 2.01 equiv) and unsaturated lactam
33 (2.50 g, 5.38 mmol, 1.00 equiv) in THF (80 mL) at À788C was added
via cannula into the reaction mixture over 5 min. After stirring at À788C
for 1 h, the reaction mixture was quenched by saturated aqueous NH4Cl
(10 mL). NH3 (25% in H2O, 5 mL), H2O (20 mL), and EtOAc (50 mL)
were added. The organic layer was separated, washed with saturated
aqueous NH4Cl (3”10 mL) and brine (10 mL), dried over anhydrous
Na2SO4, filtered, and concentrated under reduced pressure. Purification
by flash chromatography on silica gel (EtOAc/hexane 1:5) provided
lactam 34 (2.05 g, 75%) as a thick oil as a diastereomeric mixture in the
ratio of 5:1 as determined by integration of d 2.26 (dd, 1H, J1 =15.8, J2 =
8.8 Hz) for the major diastereoisomer and d 2.34 (dd, 1H, J1 =17.7, J2 =
8.1 Hz) for the minor diastereoisomer in 1H NMR. 1H NMR (500 MHz,
CDCl3): d = 7.62–7.66 (m, 4H), 7.37–7.46 (m, 6H), 5.53–5.67 (m, 1H),
4.97–5.01 (m, 2H), 3.78–3.87 (m, 2H), 3.62 (dd, 1H, J1 =10.4, J2 =
4.6 Hz), 3.55 (dd, 1H, J1 =10.4, J2 =7.9 Hz), 2.52 (dd, 1H, J1 =15.8, J2 =
6.0 Hz), 2.26 (dd, 1H, J1 =15.8, J2 =8.8 Hz), 2.06–2.16 (m, 1H), 1.93–1.99
(m, 1H), 1.78–1.85 (m, 1H), 1.67–1.74 (m, 1H), 1.53 (s, 9H), 1.06 (s,
9H); 13C NMR (125 MHz, CDCl3): d = 171.7, 151.8, 135.5, 134.7, 133.2,
129.8, 127.8, 117.8, 82.9, 64.0, 45.9, 41.0, 39.3, 39.1, 32.6, 28.0, 26.8, 19.2;
FTIR (neat): n˜ = 1770 (s, C=O), 1759 (s, C=O), 1246 (m), 914 (m),
744 cmÀ1 (m); HRMS (MALDI): m/z: calcd for C30H41NO4SiNa:
530.2697; found: 530.2709 [M+Na]+.
5-[[[(1,1-Dimethylethyl)diphenylsilyl]oxy]methyl]-2-piperidinone
(31):
Imidazole (3.27 g, 48.0 mmol, 3.43 equiv) and TBDPSCl (6.60 mL,
25.0 mmol, 1.79 equiv) were added to a solution of alcohol 30 (1.80 g,
14.0 mmol, 1.00 equiv) in DMF (14 mL). The reaction mixture was stirred
at room temperature for 12 h and then quenched with saturated aqueous
NaHCO3 at 08C. The combined organic solvents were washed with brine
(10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure. Purification by flash chromatography on silica gel
(CH2Cl2/MeOH 20:1) provided silyl ether 31 (4.69 g, 91%) as white crys-
tals. 1H NMR (500 MHz, CDCl3): d = 7.62–7.65 (m, 4H), 7.37–7.46 (m,
6H), 6.39 (s, 1H), 3.65 (dd, 1H, J1 =10.2, J2 =5.4 Hz), 3.56 (dd, 1H, J1 =
10.2, J2 =7.2 Hz), 3.43–3.48 (m, 1H), 3.11 (dd, 1H, J1 =11.0, J2 =10.9 Hz),
2.41 (ddd, 1H, J1 =17.9, J2 =6.2, J3 =3.5 Hz), 2.31 (ddd, 1H, J1 =17.9, J2 =
11.0, J3 =6.4 Hz), 2.00–2.11 (m, 1H), 1.80–1.87 (m, 1H), 1.49–1.60 (m,
1H), 1.05 (s, 1H); 13C NMR (125 MHz, CDCl3): d = 172.4, 135.5, 133.3,
129.8, 127.7, 65.5, 44.8, 35.8, 30.4, 26.8, 23.5, 19.2; FTIR (neat): n˜ = 2931
(m), 2858 (m), 1667 (s, C=O), 1427 (m), 1113 (s), 772 (s), 702 cmÀ1 (s);
HRMS (MALDI): m/z: calcd for C22H29NO2SiNa: 390.1860, found
390.1859 [M+Na]+.
5-[[[(1,1-Dimethylethyl)diphenylsilyl]oxy]methyl]-2-oxo-1-piperidinecar-
boxylic acid 1,1-dimethylethyl ester (32): NEt3 (667 mL, 5.44 mmol,
1.00 equiv) and DMAP (665 mg, 5.44 mmol, 1.00 equiv) were added to a
solution of lactam 31 (2.00 g, 5.44 mmol, 1.00 equiv) in CH2Cl2 (10 mL)
and DMF (0.5 mL). Boc2O (2.37 g, 10.9 mmol, 2.00 equiv) was dissolved
in CH2Cl2 (5 mL) and added slowly. The reaction mixture was stirred for
12 h at room temperature. The reaction mixture was concentrated to a
volume of 5 mL and purified by flash chromatography on silica gel
(EtOAc/pentane 1:4) to afford lactam 32 (2.24 g, 88%) as a thick oil.
1H NMR (500 MHz, CDCl3): d = 7.63–7.65 (m, 4H), 7.36–7.47 (m, 6H),
3.96 (ddd, 1H, J1 =12.8, J2 =5.0, J3 =1.2 Hz), 3.63 (dd, 1H, J1 =10.2, J2 =
5.2 Hz), 3.55 (dd, 1H, J1 =10.2, J2 =7.2 Hz), 3.42 (dd, 1H, J1 =12.8, J2 =
9.7 Hz), 2.39–2.61 (m, 2H), 2.05–2.17 (m, 1H), 1.80–1.89 (m, 1H), 1.44–
1.57 (m, 1H), 1.53 (s, 9H), 1.06 (s, 9H); 13C NMR (125 MHz, CDCl3): d
= 171.5, 152.3, 135.5, 133.2, 129.8, 127.7, 82.8, 65.4, 48.0, 36.0, 33.8, 28.0,
A
dihydro-1(2H)-pyridinecarboxylic acid 1,1-dimethylethyl ester (36):
DIBAL (1.00m in hexane, 4.73 mL, 4.73 mmol, 2.99 equiv) was added at
À788C to a solution of lactam 34 (800 mg, 1.58 mmol, 1.00 equiv) in THF
(20 mL). The reaction mixture was stirred at À788C for 2 h. The reaction
was quenched by the addition of saturated aqueous Na/K tartrate
(20 mL). The mixture was diluted with Et2O (40 mL) and stirred over
night. The organic layer was separated, washed with brine (10 mL), dried
over anhydrous Na2SO4, filtered, and concentrated under reduced pres-
sure to provide the lactamol as an oil, which was diluted with CH2Cl2
(200 mL). Aqueous HCl (1m in H2O, 5 mL) was added and the reaction
mixture was stirred for 5 min. The organic layer was separated and
washed with saturated aqueous NaHCO3 (10 mL) and brine (10 mL),
dried over anhydrous Na2SO4, filtered, and concentrated under reduced
pressure. Purification by flash chromatography on silica gel (EtOAc/
26.8, 22.6, 19.2; FTIR (neat): n˜
= 1771 (s, C=O), 1717 (s, C=O),
1247 cmÀ1 (s); HRMS (MALDI): m/z: calcd for C27H37NO4SiNa:
490.2384; found: 490.2395 [M+Na]+.
5-[[[(1,1-Dimethylethyl)diphenylsilyl]oxy]methyl]-5,6-dihydro-2-oxo-
1(2H)-pyridine carboxylic acid 1,1-dimethylethyl ester (33): BuLi (1.60m
in hexane, 10.8 mL, 17.2 mmol, 2.30 equiv) was added at À788C to a solu-
tion of freshly distilled HMDS (3.75 mL, 18.0 mmol, 2.40 equiv) in THF
(30 mL). After stirring the reaction mixture at À788C for 1 h, lactam 32
(3.50 g, 7.49 mmol, 1.00 equiv) in THF (30 mL) was added dropwise over
10 min. The reaction mixture was stirred at À788C for 1 h. PhSeCl
(1.72 g, 8.98 mmol, 1.20 equiv) in THF (40 mL) at À788C was transferred
via cannula into the reaction mixture within 30 s. The reaction mixture
1
hexane 1:20) provided enamine 36 (697 mg, 90%) as a thick oil. H NMR
(500 MHz, CDCl3): d = 7.63–7.68 (m, 4H), 7.35–7.44 (m, 6H), 6.77 (dd,
1H, J1 =57.4, J2 =7.9 Hz), 5.61–5.80 (m, 1H), 4.95–5.0 (m, 2H), 4.66–4.80
(m, 1H), 3.48–3.73 (m, 4H), 1.90–2.21 (m, 3H), 1.78–1.90 (m, 1H), 1.49
(s, 9H), 1.06 (s, 9H); 13C NMR (125 MHz, CDCl3): d
=
153.1/152.3,
136.0/136.1, 135.6, 133.6, 133.5, 129.7, 127.7, 124.7/124.9, 116.6, 108.3/
Chem. Eur. J. 2006, 12, 8208 – 8219
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8215

E. M. Carreira and A. Lerchner
108.1, 80.6, 64.1/63.8, 41.6/41.4, 39.4/39.0, 38.5, 32.9/32.6, 28.3, 26.9, 19.3;
FTIR (neat): n˜ 1770 (s, C=O), 1759 (s, C=O), 1706 (m, C=O),
anhydrous Na2SO4, filtered, and concentrated under reduced pressure.
Purification by flash chromatography on silica gel (EtOAc/hexane 1:4)
provided silyl ether 44 (1.30 g, 88%) as a thick oil. 1H NMR (500 MHz,
CDCl3): d = 7.19–7.30 (m, 5H), 7.02 (ddd, 1H, J1 =8.0, J2 =1.0, J3 =
0.9 Hz), 6.43 (dd, 1H, J1 =8.0, J2 =2.2 Hz), 6.19 (d, 1H, J=2.2 Hz), 4.84
(s, 2H), 3.50 (d, 2H, J=1.0 Hz), 0.88 (s, 9H), 0.05 (s, 6H); 13C NMR
(125 MHz, CDCl3): d = 175.8, 155.6, 145.1, 135.8, 128.7, 127.5, 127.3,
124.7, 116.7, 113.4, 102.5, 43.7, 35.2, 25.6, 18.1, À4.6; FTIR (neat): n˜ =
2930 (m), 2858 (m), 1717 (s, C=O), 1622 (s), 1499 (s), 1373 (s), 1266 (m),
1190 (m), 1163 (m), 955 (m), 839 cmÀ1 (m); HRMS (MALDI): m/z: calcd
for C21H28NO2Si: 354.1884; found 354.1881 [M+H]+.
=
1246 cmÀ1 (s); HRMS (MALDI): m/z: calcd for C30H41NO3SiNa:
514.2748; found: 514.2763 [M+Na]+. “First number/second number” in
the 13C NMR spectrum of 36 means that there are two small peaks be-
longing to one C, due to a slow equilibrium of rotamers during the meas-
urement because of the Boc-protecting group on the lactam moiety.
1-Benzyl-6-methoxy-1H-indole-2,3-dione (41): NaH (1.34 g, 56.0 mmol,
1.99 equiv) was added at À788C to a solution of isatine 40 (5.00 g,
28.2 mmol, 1.00 equiv) in DMF (60 mL). After stirring for 5 min, BnBr
(4.99 mL, 42.0 mmol, 1.49 equiv) was added dropwise. The reaction mix-
ture was allowed to warm to room temperature over 30 min. At À208C
the reaction mixture turned from orange to black, and gas formation
could be observed. The reaction mixture was stirred for 30 min at room
temperature and was then cooled to À788C. MeOH (15 mL) was added,
followed by saturated aqueous NaHCO3 (15 mL). After dilution with
Et2O (150 mL) and H2O (100 mL), the combined organic solvents were
filtered through a plug of silica gel. The filtrate was separated, washed
with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concen-
trated under reduced pressure. Purification by flash chromatography on
silica gel (EtOAc/hexane 1:3) provided isatine 41 (5.42 g, 72%) as orange
crystals. 1H NMR (500 MHz, CDCl3): d = 7.57 (d, 1H, J=8.5 Hz), 7.27–
7.39 (m, 5H), 6.52 (dd, 1H, J1 =8.1, J2 =2.1 Hz), 6.26 (d, 1H, J=2.1 Hz),
4.89 (s, 2H), 3.82 (s, 2H); 13C NMR (125 MHz, CDCl3): d = 180.6, 168.2,
159.7, 153.2, 134.7, 129.0, 128.1, 128.0, 127.4, 111.4, 108.0, 98.3, 56.0, 44.0;
1-Benzyl-6-hydroxy-3,3-spirocyclopropyl-1,3-dihydroindol-2-one (45): Di-
bromoethane (367 mL, 4.26 mmol, 1.51 equiv) was added to a solution of
oxindole 44 (1.00 g, 2.83 mmol, 1.00 equiv) in DMF (8 mL). The reaction
mixture was cooled to 08C. NaH (205 mg, 8.52 mmol, 3.01 equiv) was
added portionwise. After stirring for 1 h at 08C, the reaction mixture was
cooled to À788C. MeOH (10 mL) was added to the reaction mixture at
À788C. After warming to 08C, the mixture was diluted with H2O
(15 mL) and Et2O (50 mL). The combined organic solvents were washed
with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concen-
trated under reduced pressure. Purification by flash chromatography on
silica gel (EtOAc/hexane 1:2) provided spiroindole 45 (650 mg, 86%) as
white crystals. 1H NMR (500 MHz, CDCl3): d = 7.20–7.30 (m, 5H), 6.65
(d, 1H, J=8.0 Hz), 6.46 (dd, 1H, J1 =8.0, J2 =2.2 Hz), 6.29 (d, 1H, J=
2.2 Hz), 5.86 (brs, 1H), 4.92 (s, 2H), 1.73 (dd, 2H, J1 =7.9, J2 =4.1 Hz),
1.47 (dd, 2H, J1 =7.9, J2 =4.1 Hz); 13C NMR (125 MHz, CDCl3): d
=
FTIR (neat): n˜
= 1728 (m, C=O), 1612 (m), 1376 (m), 1221 (m),
772 cmÀ1 (s); HRMS (MALDI): m/z: calcd for C16H14NO3: 268.0968,
found 268.0967 [M+H]+.
178.3, 155.5, 143.7, 136.0, 128.8, 127.6, 127.3, 122.3, 119.0, 108.6, 98.1,
44.2, 26.7, 19.0; FTIR (neat): n˜ = 3180 (m), 1672 (s, C=O), 1629 (s), 1605
(s), 1479 (m), 1390 (s), 1166 (s), 772 cmÀ1 (s); HRMS (MALDI): m/z:
calcd for C17H16NO2: 266.1176; found: 266.1175 [M+H]+.
1-Benzyl-1,3-dihydro-6-methoxy-2H-indol-2-one (42): Isatine 41 (1 g,
3.74 mmol, 1.00 equiv) was dissolved in EtOH (15 mL) and
NH2NH2·H2O (15 mL). The reaction mixture was refluxed for 12 h. After
dilution with brine (30 mL) and Et2O (100 mL), the combined organic
solvents were washed with brine (10 mL), dried over anhydrous Na2SO4,
filtered, and concentrated under reduced pressure. Purification by flash
chromatography on silica gel (Et2O/pentane 2:3) provided oxindole 42
1-Benzyl-6-(phenylmethoxy)-3,3-spirocyclopropyl-3,3-spirocyclopropyl-
1,3-dihydroindol-2-one (46): NaH (149 mg, 6.23 mmol, 1.50 equiv) was
added in portions at À458C to
a solution of alcohol 45 (1.10 g,
4.15 mmol, 1.00 equiv) in DMF (7 mL). Benzylbromide (739 mL,
6.23 mmol, 1.50 equiv) was added to the reaction mixture at À458C. The
reaction mixture was allowed to warm to 08C within 30 min and was stir-
red for 1 h at 08C. The reaction was quenched at À458C with aqueous sa-
turated NaHCO3 (15 mL).The combined organic solvents were separated,
washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and
concentrated under reduced pressure. Purification by flash chromatogra-
phy on silica gel (EtOAc/hexane 1:3) provided benzyl ether 46 (1.28 g,
87%) as white crystals. 1H NMR (500 MHz, CDCl3): d = 7.24–7.37 (m,
10H), 6.72 (d, 1H, J=8.2 Hz), 6.57 (dd, 1H, J1 =8.2, J2 =2.2 Hz), 6.48 (d,
1H, J=2.2 Hz), 4.97 (s, 2H), 4.93 (s, 2H), 1.74 (dd, 2H, J1 =7.7, J2 =
3.9 Hz), 1.47 (dd, 2H, J1 =7.7, J2 =3.9 Hz); 13C NMR (125 MHz, CDCl3):
d = 177.8, 158.4, 143.8, 136.8, 136.1, 128.7, 128.6, 128.0, 127.5, 127.4,
1
(850 mg, 90%) as yellow crystals. H NMR (500 MHz, CDCl3): d = 7.22–
7.30 (m, 5H), 7.05 (ddd, 1H, J1 =8.1, J2 =1.1, J3 =0.8 Hz), 6.50 (dd, 1H,
J1 =8.1, J2 =2.2 Hz), 6.32 (d, 1H, J=2.2 Hz), 4.88 (s, 2H), 3.72 (s, 3H),
3.55 (d, 2H, J=1.1 Hz); 13C NMR (125 MHz, CDCl3): d = 174.9, 158.8,
144.5, 134.8, 127.7, 126.6, 126.3, 123.8, 115.3, 105.1, 96.3, 54.4, 42.8, 34.1;
FTIR (neat): n˜ = 1714 (s, C=O), 1628 (s), 1503 (s), 1374 (s), 1196 (m),
1162 (m), 1030 (m), 699 (m); HRMS (MALDI): m/z: calcd for
C16H16NO2: 254.1176, found 254.1178 [M+H]+.
1-Benzyl-1,3-dihydro-6-hydroxy-2H-indol-2-one (43): A solution of BBr3
(0.160m in CH2Cl2, 57.0 mL, 9.12 mmol, 1.92 equiv) was added at À788C
to a solution of oxindole 42 (1.20 g, 4.74 mmol, 1.00 equiv) in CH2Cl2
(60 mL). The reaction mixture was stirred at 08C for 5 h and then cooled
to À788C. The reaction was quenched with saturated aqueous NaHCO3
(50 mL). After dilution with EtOAc (50 mL), the combined organic sol-
vents were washed with brine (10 mL), dried over anhydrous Na2SO4, fil-
tered, and concentrated under reduced pressure. Purification by flash
chromatography on silica gel (EtOAc/hexane 1:2) provided alcohol 43
(1.05 g, 92%) as slightly yellow crystals. 1H NMR (500 MHz, CDCl3): d
= 7.22–7.30 (m, 5H), 7.05 (ddd, 1H, J1 =8.0, J2 =1.1, J3 =0.8 Hz), 6.45
(dd, 1H, J1 =8.0, J2 =2.2 Hz), 6.29 (d, 1H, J=2.2 Hz), 4.86 (s, 2H), 3.53
(d, 2H, J=1.1 Hz), 1.65 (brs, 1H); 13C NMR (125 MHz, CDCl3): d =
176.3, 156.0, 145.5, 135.7, 128.8, 127.7, 127.3, 125.0, 116.0, 108.8, 98.0,
43.9, 35.2; FTIR (neat): n˜ = 3254 (m), 1682 (s, C=O), 1604 (s), 1375 (m),
1220 (s), 773 cmÀ1 (s); HRMS (MALDI): m/z: calcd for C15H14NO2:
240.1019, found: 240.1017 [M+H]+.
127.3, 123.0, 118.8, 107.2, 98.2, 70.4, 44.1, 26.6, 18.9; FTIR (neat): n˜
=
1710 (s, C=O), 1630 (m), 1501 (m), 1387 (m), 1165 (s), 913 (s), 743 cmÀ1
(s); HRMS (MALDI): m/z: calcd for C24H22NO2: 356.1645; found:
356.1648 [M+H]+.
(1’R*,6’R*,7’R*,8’aS*)-7’-Allyl-1-benzyl-6’-(tert-butyldiphenylsilyloxy-
methyl)-2’,3’,6’,7’,8’,8’a-hexahydro-6-phenylmethoxy-spiro[3H-indole-3,1’-
A
was added to a solution of enamine 37 (700 mg, 1.42 mmol, 1.00 equiv) in
CH2Cl2 (20 mL). The reaction mixture was cooled to À788C. TMSOTf
(1.85 mL, 10.2 mmol, 7.18 equiv) was added slowly. The reaction mixture
was allowed to warm to À208C and was stirred for 2 h at À208C. After
cooling to À788C, the reaction was quenched by saturated aqueous
NaHCO3 (15 mL). After warming to room temperature, the organic layer
was separated, washed with saturated aqueous NaHCO3 (10 mL) and
brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated
under reduced pressure to afford the cyclic aldimine as a residue. MgI2
(397 mg, 1.43 mmol, 1.01 equiv) and spiroindole 46 (508 mg, 1.43 mmol,
1.01 equiv) were charged into a sealable tube. The aldimine was dissolved
in THF (4 mL) and added into the sealable tube, which was sealed and
put into the preheated oil bath at 808C. The reaction mixture was re-
fluxed for 16 h at 808C. The reaction mixture was allowed to cool to
room temperature and was diluted with Et2O (30 mL) and H2O (10 mL).
1-Benzyl-1,3-dihydro-6-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-2H-indol-
2-one (44): Imidazole (570 mg, 8.37 mmol, 2.00 equiv) and TBDMSCl
(941 mg, 6.27 mmol, 1.50 equiv) were added to a solution of alcohol 43
(1.00 g, 4.18 mmol, 1.00 equiv) in DMF (12 mL). The reaction mixture
was stirred at room temperature for 3 h and then cooled to 08C. The re-
action was quenched with saturated aqueous NaHCO3 (15 mL). After di-
lution with Et2O (50 mL) and H2O (30 mL), the combined organic sol-
vents were washed with saturated aqueous NaHCO3 (10 mL), dried over
8216
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 8208 – 8219

(Æ)-Strychnofoline
FULL PAPER
The organic layer was washed with brine, dried over anhydrous Na2SO4,
filtered, and concentrated under reduced pressure. Purification by flash
chromatography on silica gel (EtOAc/hexane 1:5) provided spiroindole
47 (588 mg, 55%) as a thick oil. 1H NMR (500 MHz, CDCl3): d = 7.63–
7.67 (m, 4H), 7.20–7.45 (m, 17H), 6.61 (dd, 1H, J1 =8.2, J2 =2.3 Hz), 6.35
(d, 1H, J=2.3 Hz), 5.47–5.55 (m, 1H), 5.03 (d, 1H, J=15.8 Hz), 4.96 (s,
2H), 4.85 (d, 1H, J=10.1 Hz), 4.76 (d, 1H, J=17.1 Hz), 4.71 (d, 1H, J=
15.8 Hz), 3.71 (dd, 1H, J1 =10.3, J2 =3.1 Hz), 3.55 (dd, 1H, J1 =10.3, J2 =
6.5 Hz), 3.36 (dd, 1H, J1 =10.8, J2 =3.8 Hz), 3.32 (ddd, 1H, J1 =8.6, J2 =
8.6, J3 =2.4 Hz), 2.52 (ddd, 1H, J1 =8.8, J2 =8.6, J3 =8.4 Hz), 2.46 (dd,
1H, J1 =11.2, J2 =2.4 Hz), 2.39–2.44 (m, 1H), 2.07–2.14 (m, 2H), 1.98–
2.05 (m, 1H), 1.57–1.63 (m, 1H), 1.46–1.52 (m, 1H), 1.34–1.42 (m, 1H),
1.22–1.30 (m, 1H), 1.06 (s, 9H), 0.64 (ddd, 1H, J1 =11.8, J2 =11.8, J3 =
11.7 Hz); 13C NMR (125 MHz, CDCl3): d = 180.2, 158.8, 143.3, 136.8,
136.3, 136.0, 135.6, 133.7, 129.6, 128.7, 128.6, 128.1, 127.6, 127.5, 127.0,
125.8, 125.3, 116.1, 107.1, 97.6, 72.0, 70.3, 64.2, 56.7, 56.1, 53.9, 43.8, 42.7,
37.0, 36.2, 35.4, 31.1, 26.9, 19.3; FTIR (neat): n˜ = 1770 (s, C=O), 1753 (s,
C=O), 1712 (w, C=O), 1246 (s), 913 (m), 743 cmÀ1 (m); HRMS
(MALDI): m/z: calcd for C49H55N2O3Si: 747.3982; found: 747.3977
[M+H]+.
2H), 1.26–1.31 (m, 1H), 1.06 (s, 9H), 0.99–1.05 (m, 1H), 0.66 (ddd, 1H,
J1 =12.0, J2 =11.8, J3 =11.6 Hz); 13C NMR (125 MHz, CDCl3): d = 180.2,
158.8, 143.3, 136.8, 136.1, 135.7, 135.6, 133.6, 129.6, 128.8, 128.6, 128.1,
127.6, 127.5, 127.2, 125.7, 125.3, 107.1, 102.1, 97.6, 71.7, 70.3, 64.4, 56.8,
56.0, 54.0, 52.6, 51.6, 43.8, 43.4, 35.5, 35.4, 32.7, 31.7, 26.9, 19.3; FTIR
(neat): n˜ = 1738 (s, C=O), 1723 (s, C=O), 1366 (m), 1217 (m), 913 (m),
744 cmÀ1 (m); HRMS (MALDI): m/z: calcd for C50H59N2O5Si: 795.4188;
found: 795.4159 [M+H]+.
(1’R*,6’R*,7’R*,8’aS*)-1-Benzyl-7’-(2,2-dimethoxyethyl)-2’,3’,6’,7’,8’,8’a-
hexahydro-6’-hydroxymethyl-6-phenylmethoxy-spiro[3H-indole-3,1’(5’H)-
R
indolizin]-2(1H)-one (50): TBAF (1.00m in THF, 0.57 mL, 570 mmol,
3.02 equiv) was added at 08C to a solution of silyl ether 49 (150 mg,
189 mmol, 1.00 equiv) in THF (5 mL). The reaction mixture was stirred
for 5 h and was then transferred onto a column with silica gel (diameter
3.5 cm, length 15 cm). Elution with EtOAc/hexane 1:4 followed by
CH2Cl2/MeOH 15:1 afforded alcohol 50 (90 mg, 86%) as a thick oil.
1H NMR (500 MHz, CDCl3): d = 7.22–7.40 (m, 11H), 6.60 (dd, 1H, J1 =
8.2, J2 =2.3 Hz), 6.39 (d, 1H, J=2.3 Hz), 4.98 (d, 1H, J=15.6 Hz), 4.97
(s, 2H), 4.75 (d, 1H, J=15.6 Hz), 4.24 (dd, 1H, J1 =7.7, J2 =3.7 Hz),
3.63–3.65 (m, 2H), 3.24–3.32 (m, 2H), 3.25 (s, 3H), 3.23 (s, 3H), 2.38–
2.55 (m, 3H), 1.97–2.12 (m, 3H), 1.85 (ddd, 1H, J1 =14.2, J2 =7.7, J3 =
2.7 Hz), 1.33–1.49 (m, 1H), 1.24–1.32 (m, 1H), 1.15–1.24 (m, 1H), 0.74
(ddd, 1H, J1 =11.5, J2 =11.5, J3 =11.5 Hz); 13C NMR (125 MHz, CDCl3):
d = 180.1, 158.9, 143.4, 136.8, 136.1, 128.8, 128.6, 128.1, 127.6, 127.2,
125.6, 125.3, 107.2, 103.0, 97.6, 71.6, 70.3, 63.3, 56.4, 55.9, 53.8, 52.9, 52.8,
43.9, 43.3, 35.7, 35.4, 32.6, 32.3; FTIR (neat): n˜ = 1770 (s, C=O), 1759 (s,
C=O), 1246 cmÀ1 (s); HRMS (MALDI): m/z: calcd for C34H41N2O5:
557.3021; found: 557.3025 [M+H]+.
(1’R*,6’R*,7’R*,8’aS*)-1-Benzyl-6’-(tert-butyldiphenylsilyloxymethyl)-
2’,3’,6’,7’,8’,8’a-hexahydro-6-phenylmethoxy-7’-(2-oxoethyl)-spiro[3H-
indole-3,1’(5’H)-indolizin]-2-(1H)-one (48): NMO (94.1 mg, 803 mmol,
A
2.97 equiv) in H2O (1 mL) was added to a solution of olefin 47 (200 mg,
268 mmol, 1.00 equiv) in tBuOH (8 mL), H2O (9 mL), and dioxane
(20 mL). OsO4 (3% in H2O, 227 mL, 26.9 mmol, 10.0 mol%) was added
dropwise to the homogeneous reaction mixture. After stirring at room
temperature for 4 h, the reaction mixture was diluted with H2O and
Et2O. The organic layer was separated, washed with brine and saturated
aqueous NaHSO3 (4”10 mL), dried over anhydrous Na2SO4, filtered,
and concentrated under reduced pressure to afford the diol as a thick oil.
NaIO4 (300 mg, 1.403 mmol, 5.24 equiv) in H2O (1 mL) was added drop-
wise to the diol in a mixture of dioxane (10 mL), water (5 mL), and
tBuOH. The reaction mixture was stirred for 2 h at room temperature
and was then diluted with EtOAc (100 mL) and H2O (20 mL). The or-
ganic layer was separated and washed with saturated aqueous NH4Cl (3”
10 mL) and brine (10 mL), dried over anhydrous Na2SO4, filtered, and
concentrated under reduced pressure to give aldehyde 48 (172 mg, 86%)
as a thick oil. 1H NMR (500 MHz, CDCl3): d = 9.46 (dd, 1H, J1 =2.7,
J2 =1.1 Hz), 7.58–7.61 (m, 4H), 7.16–7.42 (m, 17H), 6.55 (dd, 1H, J1 =
8.2, J2 =2.3 Hz), 6.32 (d, 1H, J=2.3 Hz), 4.92 (d, 1H, J=15.7 Hz), 4.91
(s, 2H), 4.71 (d, 1H, J=15.7 Hz), 3.59 (dd, 1H, J1 =10.6, J2 =3.5 Hz),
3.51 (dd, 1H, J1 =10.6, J2 =5.6 Hz), 3.22–3.26 (m, 2H), 2.46–2.53 (m,
2H), 2.29–2.42 (m, 2H), 2.10 (dd, 1H, J1 =11.0, J2 =10.9 Hz), 1.94–2.01
(m, 1H), 1.84–1.91 (m, 2H), 1.41–1.52 (m, 1H), 1.16–1.26 (m, 1H), 1.03
(s, 9H), 0.68 (ddd, 1H, J1 =11.7, J2 =11.7, J3 =11.6 Hz); 13C NMR
(125 MHz, CDCl3): d = 201.9, 180.0, 158.9, 143.4, 136.8, 135.9, 135.6,
133.4, 133.3, 129.8, 128.8, 128.6, 128.1, 127.8, 127.7, 127.6, 127.1, 125.4,
125.2, 107.3, 97.7, 71.5, 70.3, 64.2, 56.4, 55.9, 53.9, 47.4, 43.8, 42.8, 35.3,
32.3, 31.7, 26.9, 19.3; FTIR (neat): n˜ = 1716 (s, C=O), 1625 (m, C=O),
1499 (m), 1382 (m), 1164 (m), 1112 (m), 913 (m), 745 (s), 701 cmÀ1 (s);
HRMS (MALDI): m/z: calcd for C48H53N2O4Si: 749.3775; found:
749.3773 [M+H]+.
(1’R*,6’R*,7’R*,8’aS*)-1-Benzyl-7’-(2,2-dimethoxyethyl)-6’-formyl-
2’,3’,6’,7’,8’,8’a-hexahydro-6-phenylmethoxy-spiro[3H-indole-3,1’(5’H)-in-
E
dolizin]-2(1H)-one (51): IBX (655 mg, 2.34 mmol, 10.0 equiv) was added
to a solution of alcohol 50 (130 mg, 234 mmol, 1.00 equiv) in DMSO
(9 mL). The reaction mixture was stirred at room temperature for 12 h.
After dilution with Et2O (100 mL) and H2O (15 mL), the combined or-
ganic solvents were washed with saturated aqueous Na2CO3 (4”10 mL),
dried over anhydrous Na2SO4, filtered, and concentrated under reduced
pressure to give aldehyde 51 (114 mg, 88%) as a thick oil. 1H NMR
(500 MHz, CDCl3): d = 9.63 (d, 1H, J=3.2 Hz), 7.22–7.40 (m, 11H),
6.61 (dd, 1H, J1 =8.2, J2 =2.3 Hz), 6.39 (d, 1H, J=2.3 Hz), 4.99 (d, 1H,
J=15.6 Hz), 4.98 (s, 2H), 4.74 (d, 1H, J=15.6 Hz), 4.24 (dd, 1H, J1 =7.4,
J2 =4.2 Hz), 3.48–3.50 (m, 1H), 3.26–3.37 (m, 2H), 3.20 (s, 3H), 3.19 (s,
3H), 2.50–2.63 (m, 2H), 2.40–2.46 (m, 1H), 2.28–2.39 (m, 1H), 2.13 (dd,
1H, J1 =11.1, J2 =11.2 Hz), 1.97–2.07 (m, 1H), 1.79–1.88 (m, 1H), 1.69–
1.79 (m, 1H), 1.33–1.37 (m, 1H), 0.70 (ddd, 1H, J1 =11.8, J2 =11.7, J3 =
11.7 Hz); 13C NMR (125 MHz, CDCl3): d = 203.2, 179.7, 159.0, 143.4,
136.7, 136.0, 128.8, 128.6, 128.1, 127.7, 127.6, 127.2, 125.3, 125.2, 107.3,
101.6, 97.8, 70.8, 70.3, 55.9, 54.3, 53.6, 52.8, 52.2, 51.8, 43.9, 36.5, 35.2,
31.7, 31.2; FTIR (neat): n˜ = 1712 (m, C=O), 1625 (m, C=O), 1499 (m),
1381 (m), 1220 (m), 772 cmÀ1 (s); HRMS (MALDI): m/z: calcd for
C34H39N2O5: 555.2854; found: 555.2859 [M+H]+.
(1’R*,6’R*,7’R*,8’aS*)-1-Benzyl-7’-(2,2-dimethoxyethyl)-6’-ethenyl-
2’,3’,6’,7’,8’,8’a-hexahydro-6-phenylmethoxy-spiro[3H-indole-3,1’
dolizin]-2(1H)-one (52): tBuOK (97.0 mg, 866 mmol, 3.99 equiv) was
added at 08C to suspension of Ph3PMeBr (387 mg, 1.08 mmol,
A
(1’R*,6’R*,7’R*,8’aS*)-1-Benzyl-6’-(tert-butyldiphenylsilyloxymethyl)-7’-
(2,2-dimethoxyethyl)-2’,3’,6’,7’,8’,8’a-hexahydro-6-phenylmethoxy-
a
4.98 equiv) in THF (3 mL). The ice bath was removed and the yellow re-
action mixture was stirred at room temperature for 2 h. Aldehyde 51
(120 mg, 217 mmol, 1.00 equiv) in THF (4 mL) and added dropwise. The
reaction mixture was stirred at room temperature for 6 h and then cooled
to À788C. The reaction was quenched by the addition of acetone
(10 mL). The mixture was warmed to room temperature and stirred for
20 min. After dilution with Et2O (100 mL) and H2O (15 mL), the com-
bined organic solvents were washed with brine (10 mL), dried over anhy-
drous Na2SO4, filtered, and concentrated under reduced pressure. Purifi-
cation by flash chromatography on silica gel (EtOAc/pentane 2:5) pro-
vided olefin 52 (105 mg, 87%) as a white solid. 1H NMR (500 MHz,
CDCl3): d = 7.21–7.40 (m, 11H), 6.61 (dd, 1H, J1 =8.2, J2 =2.3 Hz), 6.38
(d, 1H, J=2.3 Hz), 5.51–5.58 (m, 1H), 5.05–5.10 (m, 2H), 5.01 (d, 1H,
J=15.6 Hz), 4.97 (s, 2H), 4.73 (d, 1H, J=15.6 Hz), 4.24 (dd, 1H, J1 =8.0,
spiro[3H-indole-3,1’
1.07 mmol, 4.65 equiv) was added to a solution of aldehyde 48 (172 mg,
230 mmol, 1.00 equiv) in MeOH (20 mL) and CH(OMe)3 (20 mL). The
A
reaction mixture was stirred at room temperature for 12 h. Saturated
aqueous NaHCO3 (10 mL) was added to quench the reaction. After dilu-
tion with EtOAc (100 mL) and H2O (30 mL), the combined organic sol-
vents were washed with brine, dried over anhydrous Na2SO4, filtered,
and concentrated under reduced pressure to give 49 (170 mg, 93%) as a
thick oil. 1H NMR (500 MHz, CDCl3): d = 7.64–7.67 (m, 4H), 7.23–7.45
(m, 17H), 6.61 (dd, 1H, J1 =8.2, J2 =2.3 Hz), 6.37 (d, 1H, J=2.3 Hz),
5.01 (d, 1H, J=15.7 Hz), 4.97 (s, 2H), 4.72 (d, 1H, J=15.7 Hz), 4.18 (dd,
1H, J1 =7.7, J2 =4.0 Hz), 3.69 (dd, 1H, J1 =10.4, J2 =3.1 Hz), 3.54 (dd,
1H, J1 =10.4, J2 =6.5 Hz), 3.30–3.35 (m, 2H), 3.13 (s, 3H), 3.10 (s, 3H),
2.39–2.52 (m, 3H), 1.99–2.07 (m, 2H), 1.75–1.80 (m, 1H), 1.35–1.49 (m,
Chem. Eur. J. 2006, 12, 8208 – 8219
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8217

E. M. Carreira and A. Lerchner
J2 =4.0 Hz), 3.28 (ddd, 1H, J1 =8.6, J2 =8.5, J3 =2.3 Hz), 3.19 (s, 3H),
3.16 (s, 3H), 3.10 (dd, 1H, J1 =10.7, J2 =3.8 Hz), 2.47–2.52 (m, 2H), 2.38–
2.43 (m, 1H), 1.99 (dd, 1H, J1 =10.7, J2 =10.7 Hz), 1.98–2.03 (m, 1H),
1.83–1.95 (m, 2H), 1.22–1.33 (m, 2H), 0.99–1.05 (m, 1H), 0.65 (ddd, 1H,
J1 =11.9, J2 =11.5, J3 =11.4 Hz); 13C NMR (125 MHz, CDCl3): d = 180.1,
158.9, 143.4, 139.8, 136.8, 136.1, 128.8, 128.6, 128.1, 127.6, 127.2, 125.7,
125.3, 116.9, 107.2, 102.1, 97.7, 71.6, 70.4, 58.8, 56.0, 53.8, 52.8, 51.4, 47.2,
43.9, 36.0, 35.6, 35.3, 31.6; FTIR (neat): n˜ = 1770 (s, C=O), 1753 (s, C=
O), 1382 (m), 1246 (s), 1056 (m), 913 (m), 744 cmÀ1 (m); HRMS
(MALDI): m/z: calcd for C35H41N2O4: 553.3061; found: 553.3064
[M+H]+.
15.6 Hz), 4.97–5.05 (m, 2H), 5.00 (s, 2H), 4.61 (d, 1H, J=15.6 Hz), 3.29–
3.35 (m, 2H), 3.02–3.12 (m, 2H), 2.77–2.82 (m, 2H), 2.60 (d, 1H, J=
9.4 Hz), 2.50–2.55 (m, 2H), 2.41–2.47 (m, 1H), 2.33 (s, 3H), 1.91–2.06 (m,
4H), 1.54–1.59 (m, 1H), 1.42–1.47 (m, 1H), 1.04–1.09 (m, 1H), 0.67 (ddd,
1H, J1 =11.3, J2 =11.7, J3 =11.7 Hz); 13C NMR (125 MHz, CDCl3): d =
180.0, 158.9, 143.5, 140.0, 136.7, 136.2, 135.6, 132.2, 132.1, 132.0, 131.9,
128.7, 128.7, 128.6, 128.5, 128.4, 128.2, 127.7, 127.3, 127.2, 125.5, 121.3,
119.2, 118.0, 116.8, 110.6, 107.1, 97.6, 71.5, 70.4, 58.7, 56.1, 56.0, 53.7, 47.3,
46.0, 43.9, 41.2, 38.4, 36.0, 35.3, 31.5, 16.8; FTIR (neat): n˜ = 3405 (w),
2925 (s), 1714 (s, C=O), 1622 (s), 1497(s), 1455 (s), 1380 (s), 1167 (s), 734
(s), 697 cmÀ1 (s); HRMS (MALDI): m/z: calcd for C44H47N4O2: 663.3694;
found: 663.3688 [M+H]+.
(1’R*,6’R*,7’R*,8’aS*)-1-Benzyl-6’-ethenyl-2’,3’,6’,7’,8’,8’a-hexahydro-7’-
AHCTREUNG
(2-oxoethyl)-6-phenylmethoxy-spiro[3H-indole-3,1’(5’H)-indolizin]-
G
a
2(1H)-one (53): Aqueous HCl (10% in H2O, 15 mL) was added to 52
(100 mg, 181 mmol, 1.00 equiv) in acetone (100 mL). The reaction mixture
was stirred at room temperature for 12 h and was then diluted with Et2O
(100 mL) and H2O (20 mL). The combined organic solvents were washed
with saturated aqueous NaHCO3 (10 mL), dried over Na2SO4, filtered,
and concentrated under reduced pressure. The residue was diluted with
H2O (10 mL) and Et2O (50 mL). The combined organic solvents were
washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and
concentrated under reduced pressure to afford aldehyde 53 (86 mg,
94%) as an oil. 1H NMR (500 MHz, CDCl3): d = 9.59 (dd, 1H, J1 =2.6,
J2 =1.1 Hz), 7.20–7.39 (m, 11H), 6.59 (dd, 1H, J1 =8.3, J2 =2.3 Hz), 6.36
(d, 1H, J=2.3 Hz), 5.48–5.57 (m, 1H), 5.08–5.13 (m, 2H), 4.96 (s, 2H),
4.96 (d, 1H, J=15.6 Hz), 4.75 (d, 1H, J=15.6 Hz), 3.29 (ddd, 1H, J1 =
8.6, J2 =8.5, J3 =2.3 Hz), 3.14 (dd, 1H, J1 =10.4, J2 =3.3 Hz), 2.50–2.58
(m, 3H), 2.33–2.45 (m, 1H), 1.95–2.08 (m, 4H), 1.75–1.84 (m, 1H), 1.26–
1.31 (m, 1H), 0.72 (ddd, 1H, J1 =11.6, J2 =11.6, J3 =11.3 Hz); 13C NMR
(125 MHz, CDCl3): d = 202.0, 179.9, 159.0, 143.4, 139.1, 136.8, 135.9,
128.8, 128.6, 128.1, 127.6, 127.1, 125.4, 125.2, 117.7, 107.3, 97.7, 71.4, 70.4,
58.4, 55.9, 53.7, 48.1, 46.8, 43.9, 35.2, 34.7, 32.1; FTIR (neat): n˜ = 1715
(m, C=O), 1625 (m, C=O), 1276 (s), 1261 (s), 913 (s), 749 cmÀ1 (s);
HRMS (MALDI): m/z: calcd for C33H35N2O3: 507.2642; found: 507.2637
[M+H]+.
1.74 mmol, 11.6 equiv) in a mixture of NH3 (3 mL), tBuOH (0.3 mL) and
THF (0.3 mL). The reaction mixture was stirred for 5 min at À788C and
was warmed then to À458C. After stirring at À458C for 10 min, the reac-
tion mixture was cooled to À788C. The reaction was quenched by the ad-
dition of saturated aqueous NH4Cl (5 mL). The mixture was allowed to
slowly warm to room temperature, and was then diluted with H2O
(20 mL) and CH2Cl2 (100 mL). The combined organic solvents were
washed with brine, dried over anhydrous Na2SO4, filtered, and concen-
trated under reduced pressure. Purification by flash chromatography on
silica gel [MeOH/CH2Cl2/NH3 (25% in H2O) 30:169:1] provided strych-
1
nofoline 1 (6 mg, 82%) as an oil. H NMR (500 MHz, [D6]-acetone): d =
9.60 (s, 1H), 8.90 (s, 1H), 8.17 (brs, 1H), 7.34 (ddd, 1H, J1 =8.0, J2 =0.8,
J3 =0.5 Hz), 7.16 (ddd, 1H, J1 =8.0, J2 =1.0, J3 =0.5 Hz), 7.07 (d, 1H, J=
7.9 Hz), 7.00 (ddd, 1H, J1 =8.0, J2 =7.2, J3 =1.0 Hz), 6.93 (ddd, 1H, J1 =
8.0, J2 =7.2, J3 =0.8 Hz), 6.40 (dd, 1H, J1 =7.9, J2 =2.3 Hz), 6.28 (d, 1H,
J=2.3 Hz), 5.63–5.71 (m, 1H), 5.12 (ddd, 1H, J1 =17.2, J2 =2.1, J3 =
0.6 Hz), 5.03 (dd, 1H, J1 =10.3, J2 =2.1 Hz), 3.51–3.54 (m, 1H), 3.20–3.26
(m, 1H), 3.00–3.06 (m, 2H), 2.67–2.78 (m, 2H), 2.49–2.54 (m, 1H), 2.32
(s, 3H), 2.19–2.34 (m, 3H), 2.00–2.08 (m, 1H), 1.82–2.00 (m, 3H), 1.58–
1.64 (m, 1H), 1.41–1.51 (m, 1H), 1.20–1.23 (m, 1H), 0.69 (ddd, 1H, J1 =
11.9, J2 =11.9, J3 =11.9 Hz); 13C NMR (125 MHz, [D6]-acetone): d
=
181.4, 158.0, 143.3, 142.0, 137.2, 136.7, 128.1, 126.0, 125.4, 121.4, 119.3,
118.2, 116.6, 111.7, 108.7, 107.1, 98.4, 72.5, 59.9, 58.8, 56.9, 54.4, 48.7, 48.6,
41.9, 38.6, 37.5, 35.7, 32.5, 18.8; FTIR (neat): n˜ 1738 (s, C=O), 1366 (m),
1229 (m), 1217 cmÀ1 (m); HRMS (MALDI): n˜ = calcd for C30H35N4O2:
483.2755; found: 483.2758 [M+H]+.
(1’R*,6’R*,7’R*,8’aS*)-1-Benzyl-6’-ethenyl-2’,3’,6’,7’,8’,8’a-hexahydro-6-
phenylmethoxy-7’-[[(1S)-2,3,4,9-tetrahydro-2-methyl-1H-pyrido
A
b]indol-1-yl]methyl]-spiro-[3H-indole-3,1’(5’H)-indolizin]-2(1H)-one
AHCTREUNG
(54): AcOH (3 mL) was added to a solution of aldehyde 53 (90 mg,
177 mmol, 1.00 equiv) and N-methyl tryptamine (80 mg, 460 mmol,
2.6 equiv) in toluene (30 mL). The reaction mixture was heated to 808C
for 2 h and was then diluted with Et2O (50 mL) and H2O (10 mL). The
organic layer was separated and washed with saturated aqueous Na2CO3
(10 mL) and brine (10 mL), dried over anhydrous Na2SO4, filtered, and
concentrated under reduced pressure. Purification by chromatotron (iso-
propanol/hexane 1:4) provided 55 (44 mg, 38%) and 54 (30 mg, 26%) as
an oil. 1H NMR (500 MHz, CDCl3): d = 7.65–7.70 (m, 2H), 7.53–7.57
(m, 1H), 7.32–7.48 (m, 8H), 7.09–7.26 (m, 4H), 6.56 (dd, 1H, J1 =8.2,
J2 =2.3 Hz), 6.16 (s, 1H), 5.56–5.63 (m, 1H), 5.13 (dd, 1H, J1 =16.9, J2 =
1.9 Hz), 5.08 (dd, 1H, J1 =10.2, J2 =1.9 Hz), 4.95 (s, 2H), 4.74 (d, 1H, J=
15.6 Hz), 4.36 (d, 1H, J=15.6 Hz), 3.35–3.41 (m, 1H), 3.25–3.29 (m, 1H),
3.03–3.11 (m, 2H), 2.68–2.76 (m, 2H), 2.61–2.65 (m, 1H), 2.44–2.50 (m,
2H), 2.36–2.41 (m, 1H), 2.33 (s, 3H), 1.96–2.05 (m, 4H), 1.45–1.54 (m,
1H), 1.25–1.35 (m, 1H), 1.05 (d, 1H, J=11.8 Hz), 0.50 (ddd, 1H, J1 =
Acknowledgements
We are grateful to Prof. Luc Angenot for his assistance in comparing the
synthesized and natural products, to Dr. B. Schweizer for X-ray analysis
and Prof. B. Jaun for NMR studies. Support has been provided by a grant
from the Swiss National Science Foundation, F. Hoffmann-La Roche, Eli
Lilly, Merck, and in part by an INIT grant from ETH-Zürich.
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ACHTREUNG
b]indol-1-yl]methyl]-spiro-[3H-indole-3,1’
ACHTREUNG
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1H), 7.33- 7.48 (m, 8H), 7.04–7.27 (m, 4H), 6.66 (dd, 1H, J1 =8.2, J2 =
2.3 Hz), 6.44 (d, 1H, J=2.3 Hz), 5.50–5.56 (m, 1H), 5.12 (d, 1H, J=
8218
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 8208 – 8219

(Æ)-Strychnofoline
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Received: July 5, 2006
Published online: October 2, 2006
Chem. Eur. J. 2006, 12, 8208 – 8219
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8219