Domino Pd-catalyzed heck cyclization and bismuth-catalyzed hydroamination: Formal synthesis of elacomine and isoelacomine

Article abstract of DOI:10.1002/chem.201002287

The formal synthesis of hemiterpene spirooxindole alkaloids elacomine (1) and isoelacomine (2) is described. Heck reaction of protected iodoanilines with 5,6-dihydro-2H-pyran-2-one or six-membered unsaturated lactams was investigated. The coupling product

Full text of DOI:10.1002/chem.201002287

DOI: 10.1002/chem.201002287
Domino Pd-Catalyzed Heck Cyclization and Bismuth-Catalyzed
Hydroamination: Formal Synthesis of Elacomine and Isoelacomine
Haruhi Kamisaki, Takeshi Nanjo, Chihiro Tsukano, and Yoshiji Takemoto*[a]
Abstract: The formal synthesis of hem-
iterpene spirooxindole alkaloids elaco-
mine (1) and isoelacomine (2) is de-
scribed. Heck reaction of protected io-
doanilines with 5,6-dihydro-2H-pyran-
2-one or six-membered unsaturated
lactams was investigated. The coupling
product was readily converted to a car-
bamoyl chloride with an incorporated
diene unit. The spiro(pyrrolidine-3,3’-
oxindole) skeleton, which corresponds
to the carbon skeleton of 1 and 2, was
efficiently constructed from this inter-
mediate by using a domino palladium-
catalyzed Heck reaction and bismuth-
catalyzed hydroamination. An isolated
byproduct of the reaction could also be
converted to the spirooxindole skele-
ton.
Keywords:
bismuth
·
domino
reactions
·
formal synthesis
·
palladium · spiro compounds
Introduction
chosen as starting materials and construction of the spiro
center was a key reaction.
Elacomine (1) was originally isolated from the shrub Elaea-
guns commutate by Slywka in 1969.[1] The relative stereo-
chemistry of the hemiterpene spirooxindole alkaloid was un-
ambiguously determined by X-ray analysis of a racemic nat-
ural sample.[2] The first enantioselective total synthesis of 1
was achieved by Borschberg et al., through an oxidative re-
arrangement of b-carboline, and 1 was revealed to isomerize
to isoelacomine (2) under mild conditions.[3] It was also con-
firmed that 1 and 2 occur naturally in racemic form by re-
isolation. Although neither 1 nor 2 exhibit any biological ac-
tivities, these molecules have continued to attract much at-
tention as synthetic targets because they possess a simple
spiro(pyrrolidine-3,3’-oxindole) skeleton, which has been
found in bioactive natural products.[4] Horne et al. reported
the total synthesis of 1 and 2 based on a stereoselective in-
tramolecular iminium ion spirocyclization methodology.[5]
Recently White et al. developed a tandem intramolecular
photocycloaddition and retro-Mannich fragmentation strat-
egy and applied it to the diastereoselective synthesis of 1.[6]
In all three total syntheses, tryptamine derivatives were
In the course of our studies on the synthesis of 3,3-disub-
stituted oxindoles through Pd-catalyzed intramolecular cycli-
zation,[7] we have become interested in Pd-catalyzed double
cyclization for the construction of spiro structures. Several
groups have developed elegant double cyclization strategies
for the construction of these structures.[8–12] Overman and
Rosen achieved the total synthesis of spirotryprostatin B
through stereoselective construction of a spirooxindole, by
using a sequential Heck cyclization and h3-allyl palladium
trapping reaction of trienyl anilide.[8] Recently, Zhu et al. re-
ported Pd-catalyzed double cyclization initiated by amino-
palladation.[9] Herein, the formal synthesis of 1 and 2 is de-
scribed, with a domino Pd-catalyzed Heck cyclization and
Bi-catalyzed hydroamination of a carbamoyl chloride as a
key step.
[a] H. Kamisaki, T. Nanjo, Dr. C. Tsukano, Prof. Dr. Y. Takemoto
Graduate School of Pharmaceutical Sciences, Kyoto University
Yoshida, Sakyo-ku, Kyoto 606-8501 (Japan)
Fax : (+81)75-753-4532
Results and Discussion
E-mail: takemoto@pharm.kyoto-u.ac.jp
We recently reported domino Pd-catalyzed spirooxindole
formation from carbamoyl chlorides tethered to terminal
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201002287.
626
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Chem. Eur. J. 2011, 17, 626 – 633

FULL PAPER
1,3-diene units.[7] If this domino reaction could be applied to
an internal 1,3-diene, a spirooxindole skeleton with the com-
plete carbon skeleton of 1 and 2 would be constructed effi-
ciently. Thus, carbamoyl chloride 5 was envisioned as a cycli-
zation precursor (Scheme 1). The Pd0-catalyzed reaction of
Table 1. Investigation of the Heck reaction of 7a and 8.
Entry
Ligand
Additive[a]
Yield [%]
1
2
3
4
5
6
7
8
PPh3
–
–
–
–
42
15
29
24
0[c]
0
DPPE[b]
P
P
–
U
–
PPh3
PPh3
PPh3
Ag3PO4 (2)
nBu4NCl (1)
nBu4NBr (1)
41
64
[a] Number of equiv is given in parentheses. [b] 5 mol% of ligand was
employed. [c] Complex mixture.
of the desired product (Table 1, entries 2–4). In the absence
of phosphine ligands the reaction gave a complex mixture
(Table 1, entry 5). Addition of halide scavengers, such as
Ag3PO4, produced no desired product (Table 1, entry 6).
When K2CO3 was employed, instead of the amine base, the
reaction afforded only a trace
amount of the desired product.
Addition of tetrabutylammoni-
Scheme 1. Retrosynthetic analysis of 1 and 2.
um salts[16] suppressed the pro-
duction of deiodinated aniline
5 would give p-allyl palladium complex 4 upon formation of
an oxindole. Subsequent intramolecular nucleophilic addi-
tion of the nitrogen atom might produce either protected
elacomine or isoelacomine 3 diastereoselectively, depending
on the configuration of the diene moiety. On the basis of
our previous results, N-methylcarbamate was selected as a
nitrogen nucleophile because of its appropriate nucleophilic-
ity and feasibility of deprotection. We envisioned the prepa-
ration of carbamoyl chloride 5 via lactone 6, which was to
be obtained by Heck reaction of iodoaniline 7 and dihydro-
pyranone 8. There have been several reports of intermolecu-
lar Heck reactions with cyclic enones such as 2-cyclohexen-
1-one,[13,14] whereas the same reaction of a,b-unsaturated
lactones has not been reported.[15] This prompted us to ex-
plore the intermolecular Heck reaction of a,b-unsaturated
lactones and lactams.
and use of Bu4NBr gave the
best yield (Table 1, entries 7
and 8).
To explore the generality of this method, the optimal con-
ditions were applied to several lactone and lactam sub-
strates. When Boc, 2-trimethylsilylethoxymethyl (SEM), car-
bobenzyloxy (Cbz), and benzyl (Bn) groups were used for
iodoaniline protection, the reaction proceeded to give the
coupling products 6b–d in 41–59% yield, along with small
quantities of byproduct 9 (Table 2, entries 1–3). Interesting-
ly, lactams 10a[17] and 10b[18] could be successfully employed
in place of lactone 8 in the reaction, to give compounds 6e
and 6 f, respectively (Table 2, entries 4 and 5). It should be
1
noted that broadened peaks were observed in the H NMR
spectra of the coupling products 6a and 6c–f, presumably
because of the presence of rotamers.
The Heck reaction of tert-butoxycarbonyl (Boc)-protected
iodoaniline 7a[7b] with commercially available 5,6-dihydro-
2H-pyran-2-one (8) was selected for the optimization of the
We applied the established conditions for the coupling of
7 and 8 to the synthesis of carbamoyl chloride 17 from 7e
and 8. This was followed by acid-catalyzed deprotection of
the Boc group to give lactone 11 in 52% yield over two
steps (Scheme 2). The E-diene moiety of 12 was installed by
subjecting 11 to diisobutylaluminum hydride (DIBAL-H) re-
duction, followed by Wittig olefination. The secondary
amine of compound 12 was selectively protected as a tri-
fluoroacetamide, in two steps, to give primary alcohol 13,
which was then converted to azide 14 by mesylation. Reduc-
tion of the azido group and protection of the resultant pri-
mary amine as a methyl carbamate gave compound 15. This
reaction conditions. Treatment of 7a and 8 with PdACTHNUTRGNEUNG(OAc)2
(5 mol%), PPh3 (10 mol%), and iPr2NEt in DMF at 1008C
gave the coupling product 6a in 42% yield. The major by-
products were the deiodinated aniline and the saturated lac-
tone 9 (R1 =Me, R2 =Boc), which arose from the O-enolate
of palladium (Table 1, entry 1). The use of other phosphine
ligands, such as bidentate ligands (1,2-bis(diphenylphosphi-
no)ethane (DPPE)), bulky ligands (PACTHUNGTRENNNUG
electron-donating ligands (PACHTNUGTRENNUNG
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627

Y. Takemoto et al.
Table 2. Heck reaction of protected iodoanilines with unsaturated lac-
tones and lactams.
of nucleophilic addition of the nitrogen atom to give the de-
sired spirooxindole 18. To promote the latter reaction, sever-
al additives and ligands were examined. Whereas the reac-
tions with 1,1’-bis(diphenylphosphino)ferrocene (DPPF) or
Bu4NPF6 only gave product 19, addition of Bu4NI produced
the desired product 18 as a minor product, together with 19
(Table 3, entries 2–4). We initially expected that the domino
cyclization of 17 would occur diastereoselectively to give an
elacomine-type diastereomer, but the product 18 was ob-
tained with no diastereoselectivity. This may be caused by
an inversion of the p-allyl palladium intermediate prior to
the nucleophilic addition of the nitrogen atom. The reaction
without Cs2CO3 took place smoothly to give the desired spi-
rooxindole 18 as a major product (Table 3, entry 5). The b-
elimination process might be suppressed under acidic condi-
Entry
R
R1
R2
Olefin
Product
Yield [%]
1
2
3
4
5
7b
7c
7d
7e
7 f
H
H
OMe
OMe
OMe
Boc
Boc
Cbz
Boc
Boc
Boc
SEM
Bn
Bn
Me
8
8
8
10a
10b
6b
6c
6d
6e
6 f
41
42
59
49[a]
39[b]
[a] Yield obtained after deprotection of the Boc group with TFA in
CH2Cl2. [b] Yield based on recovered starting material.
tions so several acids, which included TfOH, HfCAHTUNGTRENNNUG
[19]
BiACHTUGNTRENNNUG
was treated with potassium hydroxide to remove the tri-
fluoroacetyl group and yield secondary amine 16, which was
treated with triphosgene and pyridine in CH2Cl2 at ꢀ788C
to give cyclization precursor 17.
With the desired internal E-diene-containing carbamoyl
chloride 17 in hand, we investigated the domino Pd-cata-
lyzed spirooxindole formation. Treatment of 17 with Pd-
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
(10 mol%) provided spirooxindole 18 in 52% yield with no
contamination by diene 19. The diastereoselectivity achieved
at the C-2’ position remained low (diastereomeric ratio
(d.r.)=5:4[20]).
(OAc)2 and Cs2CO3 in xylene at 1308C (previously reported
To clarify the effect of the additives on the Pd0-catalyzed
domino cyclization, intramolecular hydroamination of diene
19 with Lewis acid catalysts was next investigated. We first
best conditions)[7] did not provide the desired product 18; in-
stead, compound 19 was obtained in 86% yield (Table 3,
entry 1). Compound 19 was probably produced by b-elimi-
nation of the intermediate p-allyl palladium complex instead
selected the conditions of a Bi
xylene at 1308C, which were the same conditions employed
ACHUTGTNERN(GUN OTf)3 or HfCAHTUNGTREN(NNGU OTf)4 catalyst in
Scheme 2. Synthesis of carbamoyl chloride 17. TFA=trifluoroacetic acid, DIBAL-H=diisobutylaluminum hydride, KHMDS=potassium hexamethyldisi-
lazide, TFAA=trifluoroacetic anhydride, DMAP=4-dimethylaminopyridine, Ms=methanesulfonyl.
628
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ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 626 – 633

Synthesis of Elacomine and Isoelacomine
FULL PAPER
Table 3. Domino Pd-catalyzed spirooxindole formation.
Entry
Reagents
18 [%][a]
19 [%]
1
2
3
4
5
6
7
8
PPh3, Cs2CO3
0
0
86
66
28
84
0
0
0
0
PPh3, Cs2CO3, Bu4NPF6
PPh3, Cs2CO3, Bu4NI
DPPF, Cs2CO3
DPPF
11 (1:1)
0
37 (1:1)
17 (1:1)
33 (5:4)
52 (5:4)
DPPF, TfOH[b]
[c]
DPPF, Hf
N
[c,d]
DPPF, Bi(OTf)3
C
Scheme 3. Formal syntheses of 1 and 2.
[a] Diastereomeric ratios given in parentheses. [b] 50 mol% was used.
[c] 10 mol% was used. [d] Pd(TFA)2 was used instead of Pd(OAc)2.
N
ACHTUNGTRENNUNG
of the yield of cyclized product (Table 4, entry 4). In sharp
contrast, Zn(OTf)2 did not give any of the desired spirooxin-
dole 18 (Table 4, entry 7). Therefore, it was found that inter-
mediate 19, which arose from b-elimination, could be con-
in the domino Pd-catalyzed spirooxindole formation with
the exclusion of the palladium catalyst and ligand. Under
these conditions, the hydroamination proceeded smoothly to
give the desired spirooxindole 18 in moderate yields, as a
3:1 or 2:1 diastereomeric mixture[20] (Table 4, entries 1 and
ACHTUNGTRENNUNG
verted into 18 by BiACTHNUTRGNE(UNG OTf)3-catalyzed hydroamination. Fur-
thermore, the spirooxindole 18 was synthesized from carba-
moyl chloride 17 in better yield and with better diastereose-
lectivity by stepwise Pd0-catalyzed Heck reaction and
ꢀ
2). Under Shibasakiꢁs conditions[21] (PF6 salt and borderline
metals, according to the hard and soft acids and bases princi-
ple,[22] such as Bi
(OTf)3, Hf
E
N
BiACHTUNTGRENNUNG
ical yields of 18 significantly increased; compound 18 was af-
forded in 57–83% yield with the same levels of diastereose-
lectivity (Table 4, entries 3–6). The combined use of Bi-
thus, our attention turned to the completion of their formal
syntheses. After hydrogenation of 18 under high-pressure
conditions, diastereomers 20a and 20b were separated by
silica gel column chromatography (Scheme 3). The benzyl
groups of 20a and 20b were removed efficiently with lithi-
um 4,4’-di-tert-butylbiphenyl (LiDBB),[23] and afforded the
desired products 21a and 21b, respectively, in good yields.
These compounds were shown to have identical stereochem-
istry relative to authentic samples by comparison of their
spectral data. Compounds 21a and 21b have previously
been transformed into 1 and 2 by Horne and co-workers
and we have, therefore, achieved the formal synthesis of 1
and 2 from iodoaniline 7e and dihydropyranone 8.[5]
ACHTUNGTRENNUNG(OTf)3 and KACHTUNGTRENNUNG[PF6] in dioxane gave the best results in terms
Table 4. Hydroamination of diene 19.
Entry
Conditions
Bi(OTf)3, xylene, 1308C
Hf(OTf)4, xylene, 1308C
Bi(OTf)3, [Cu(CH3CN)4]
Bi(OTf)3, K[PF6], 1,4-dioxane, 508C
Hf(OTf)4, K[PF6], 1,4-dioxane, 508C
Sc(OTf)3, K[PF6], 1,4-dioxane, 508C
Zn(OTf)2, K[PF6], 1,4-dioxane, 508C
Yield [%]
1
2
3
4
5
6
7
G
49
41[a]
66
83
57
58
0
ACHTUNGTRENNUNG
Conclusion
E
T
ACHTUNGTREN[NUGN PF6], 1,4-dioxone, 508C
N
ACHTUNGTRENNUNG
The intermolecular Heck reaction of iodoanilines with 5,6-
dihydro-2H-pyran-2-one has been developed and the estab-
lished conditions were successfully extended to the coupling
of six-membered unsaturated lactams. To the best of our
A
ACHTUNGTRENNUNG
G
ACHTUNGTRENNUNG
N
ACHTUNGTRENNUNG
[a] 2:1 diastereomeric mixture
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629

Y. Takemoto et al.
to give 6e as a yellow solid (992 mg, 49% over 2 steps). M.p. 132.5–
132.98C; 1H NMR (500 MHz, CDCl3): d=7.38–7.30 (m, 4H), 7.30–7.26
(m, 1H), 7.03 (d, J=8.5 Hz, 1H), 6.30 (dd, J=8.5, 2.0 Hz, 1H), 6.26 (s,
1H), 6.20 (d, J=2.0 Hz, 1H), 4.60 (brs, 1H), 4.05 (t, 2H, J=6.5 Hz), 4.33
(s, 2H), 3.89 (s, 3H), 3.73 (s, 3H), 2.76 ppm (t, J=6.5 Hz, 2H); 13C NMR
(126 MHz, CDCl3): d=163.9, 161.9, 154.8, 154.7, 146.4, 138.4, 129.3,
128.8, 127.4, 127.1, 121.6, 116.6, 102.5, 98.0, 55.1, 53.9, 48.3, 44.0,
29.6 ppm; IR (ATR): n˜ =3389, 1718, 1678 cmꢀ1; MS (FAB): m/z: 367
[M+H]+; HRMS (FAB): m/z: calcd for C21H23N2O4: 367.1613 [M+H+];
found: 367.1641.
knowledge, this is the first example of the intermolecular
Heck reaction with unsaturated lactams. The domino cycli-
zation of carbamoyl chloride 17 into spiro(pyrrolidine-3,3’-
oxindole) 18 was efficiently performed with two metal cata-
lysts, PdACHTUNGTRENNUNG(OAc)2 and BiACHUTNGTREN(NUGN OTf)3, in the absence of any base.
Furthermore, the spirooxindole products obtained were suc-
cessfully converted into Horneꢁs synthetic intermediates of
elacomine (1) and isoelacomine (2), to accomplish the
formal synthesis of these natural products.
Lactone 11: PdACTHNUTRGNE(UNG OAc)2 (85.7 mg, 0.382 mmol), PPh3 (241 mg,
0.916 mmol), tetra-n-butylammonium bromide (2.46 g, 7.63 mmol), and
iPr2NEt (5.32 mL, 30.5 mmol) were added to a stirred solution of 7e
(3.30 g, 7.63 mmol) in DMF (25 mL) at RT and the reaction mixture was
warmed to 1008C. After stirring overnight, the mixture was neutralized
by the addition of a saturated aqueous solution of NH4Cl and filtered
through a Celite pad. The filtrate was extracted with Et2O then the com-
bined organic layers were washed with H2O and brine, dried over
Na2SO4, and concentrated under reduced pressure. TFA (5.66 mL,
76.3 mmol) was added to a solution of the crude lactone in CH2Cl2
(25 mL) at 08C. After stirring overnight, the reaction mixture was con-
centrated under reduced pressure. The residue was diluted with CHCl3,
basified with a saturated aqueous solution of NaHCO3 and extracted
with CHCl3. The combined organic layers were washed with brine, dried
over Na2SO4, and concentrated under reduced pressure. The obtained
residue was purified by silica gel column chromatography (hexane/
EtOAc=8:2!7:3) to give 11 as yellow crystals (1.52 g, 52% over 2
steps). M.p. 165.5–166.18C (hexane/EtOAc); 1H NMR (400 MHz,
CDCl3): d=7.37–7.29 (m, 5H), 7.04 (d, J=8.8 Hz, 1H), 6.31 (dd, J=8.8,
2.4 Hz, 1H), 6.29 (s, 1H), 6.20 (d, J=2.4 Hz, 1H), 4.68 (brs, 1H), 4.48 (t,
J=5.8 Hz, 2H), 4.34 (s, 2H), 3.73 (s, 3H), 2.78 ppm (t, J=5.8 Hz, 2H);
13C NMR (100 MHz, CDCl3): d=165.0, 162.2, 156.2, 146.7, 138.5, 129.3,
128.9, 127.5, 127.2, 116.4, 116.2, 102.7, 98.1, 66.1, 55.1, 48.3, 28.8 ppm; IR
(ATR): n˜ =1702 cmꢀ1; MS (FAB): m/z: 310 [M+H+]; elemental analysis
calcd (%) for C19H19NO3: C 73.77, H 6.19, N 4.53; found: C 73.83, H
6.13, N 4.51.
Experimental Section
General: Unless otherwise noted, all reactions were performed under an
argon atmosphere. Analytical TLC was performed with Merck silica gel
60 F254 glass plates. Silica gel column chromatography was performed
1
with Kanto silica gel 60 (particle size, 63–210 mm). H NMR spectra were
recorded on Bruker DMX 600, JEOL JNM-LA 500, or JEOL JNM-AL
400 spectrometers at 600, 500, and 400 MHz, respectively. Chemical shifts
are reported relative to Me4Si (d=0.00 ppm). Multiplicity is indicated by
one or more of the following: s (singlet); d (doublet); t (triplet); q (quar-
tet); sep (septet); m (multiplet); br (broad). 13C NMR spectra were re-
corded on Bruker DMX 600, JEOL JNM-LA 500, or JEOL JNM-AL
400 spectrometers at 150, 126, and 100 MHz, respectively. Chemical shifts
are reported relative to CDCl3 (d=77.0 ppm). Attenuated total reflec-
tance (ATR) infrared spectra were recorded on a FT/IR-410 spectrome-
ter (JASCO). Low and high resolution mass spectra (LRMS and HRMS)
were recorded on JEOL JMS-700 and HX-110 mass spectrometers under
fast atom bombardment (FAB) conditions in m-nitrobenzyl alcohol or
glycerol.
Typical procedure for Heck reaction of 7 and 8 (or 10): PdACTHNUTRGNEUNG(OAc)2
(3.4 mg, 0.015 mmol), PPh3 (9.4 mg, 0.036 mmol), tetra-n-butylammonium
bromide (96 mg, 0.298 mmol), and iPr2NEt (0.238 mL, 1.20 mmol) were
added to a stirred solution of 7a (100 mg, 0.299 mmol) and 8 (0.030 mL,
0.346 mmol) in DMF (2 mL) at RT and the reaction mixture was heated
to 1008C. After stirring for 9 h, the mixture was neutralized by the addi-
tion of a saturated aqueous solution of NH4Cl and filtered through a
Celite pad. The filtrate was extracted with EtOAc then the combined or-
ganic layers were washed with H2O and brine, dried over Na2SO4, and
concentrated under reduced pressure. The obtained residue was purified
by silica gel column chromatography (hexane/EtOAc=8:2!9:1) to give
Dienylalcohol 12: DIBAL-H (1.04m solution in hexane, 5.73 mL,
5.80 mmol) was added over 30 min to a stirred solution of 11 (1.28 g,
4.14 mmol) in CH2Cl2 (45 mL) at ꢀ788C and the mixture was stirred for
10 min at the same temperature. A saturated aqueous solution of potassi-
um sodium tartrate was added and the reaction mixture was stirred at
RT. After stirring for 30 min, the mixture was extracted with CHCl3. The
combined organic layers were dried over Na2SO4 and concentrated under
reduced pressure. The obtained residue was purified by silica gel column
chromatography (hexane/EtOAc=7:3!1:1) to give the lactol as a yellow
solid (1.26 g, 98%). KHMDS (0.5m in toluene, 37.1 mL, 8.10 mmol) was
added to a suspension of isopropyltriphenylphosphonium iodide (3.86 g,
8.94 mmol) in THF (25 mL) at 08C. After stirring at 08C for 30 min, a so-
lution of the lactol (1.26 g, 4.04 mmol) in THF (10 mL) was added at
ꢀ408C. The reaction mixture was warmed to 08C overnight. After con-
centration under reduced pressure, the obtained residue was purified by
silica gel column chromatography (hexane/EtOAc=9:1!8:2) to give 12
as a colorless oil (938 mg, 69%). 1H NMR (400 MHz, CDCl3): d=7.33–
7.24 (m, 5H), 6.90 (d, J=8.3 Hz, 1H), 6.39 (d, J=11.5 Hz, 1H), 6.26 (d,
J=8.3 Hz, 1H), 6.21–6.18 (m, 2H), 4.30 (s, 2H), 3.73 (s, 3H), 3.62 (t, J=
6.3 Hz, 2H), 2.76 (t, J=6.3 Hz, 2H), 1.84 (s, 3H), 1.74 ppm (s, 3H);
13C NMR (100 MHz, CDCl3): d=160.1, 146.4, 139.3, 137.1, 133.2, 129.7,
129.0, 128.7, 127.3, 127.2, 123.2, 120.8, 101.4, 97.9, 61.2, 55.0, 48.2, 34.9,
26.4, 18.2 ppm; IR (ATR): n˜ =3410, 2339 cmꢀ1; MS (FAB): m/z: 338
[M+H+]; elemental analysis calcd (%) for C22H27NO2: C 78.30, H 8.06, N
4.15; found: C 78.05, H 8.25, N 4.09.
1
coupling product 6a as an oil (58 mg, 64%). H NMR (500 MHz, CDCl3,
408C): d=7.39 (ddd, J=7.2, 7.2, 2.1 Hz, 1H), 7.31–7.19 (m, 3H), 6.03
(br, 1H), 4.47 (t, J=6.0 Hz, 2H), 3.17 (s, 3H), 2.74 (br, 2H), 1.39 ppm
(br, 9H); 13C NMR (126 MHz, CDCl3, 408C): d=164.2, 157.0, 154.5,
141.0, 136.5, 130.3, 128.0, 127.3, 118.7, 117.5, 80.8, 66.5, 37.8, 28.2 (ꢂ3),
28.0 ppm; IR (ATR): n˜ =2977, 1718, 1697, 1366, 1158 cmꢀ1
;
HRMS
(FAB): m/z: calcd for C17H22NO4: 304.1549 [M+H+]; found: 304.1538.
Heck reaction of 7e and 10a: Pd(OAc)2 (126 mg, 0.561 mmol), PPh3
(318 mg, 1.21 mmol), tetra-n-butylammonium bromide (1.78 g,
AHCTUNGTRENNUNG
5.52 mmol), and iPr2NEt (3.8 mL, 22.1 mmol) were added to a stirred so-
lution of 7e (2.66 g, 6.06 mmol) and 10a (854 mg 5.51 mmol) in DMF
(50 mL) at RT and the reaction mixture was warmed to 1008C. After stir-
ring overnight, the mixture was neutralized by the addition of a saturated
aqueous solution of NH4Cl and filtered through a Celite pad. The filtrate
was extracted with Et2O then the combined organic layers were washed
with H2O and brine, dried over Na2SO4, and concentrated under reduced
pressure. The obtained residue was dissolved in CHCl3 and filtered
through a silica gel pad to give coupling product 6e. TFA (2.5 mL,
33.7 mmol) was added to a solution of the crude lactam 6e in CH2Cl2
(30 mL) at 08C. After stirring overnight, the reaction mixture was con-
centrated under reduced pressure. The residue was diluted with CHCl3
and basified with saturated aqueous NaHCO3 solution. The combined or-
ganic layers were extracted with CHCl3, washed with brine, dried over
Na2SO4, and concentrated under reduced pressure. The obtained residue
was purified by silica gel column chromatography (hexane/EtOAc=6:4)
Dienylalcohol 13: DMAP (catalytic amount), pyridine (1.18 mL,
14.6 mmol) and trifluoroacetic anhydride (1.62 mL, 11.7 mmol) were
added to a stirred solution of 12 (1.64 g, 4.86 mmol) in CH2Cl2 (16 mL) at
08C. The mixture was stirred at RT for 1 h, then neutralized by the addi-
tion of a saturated aqueous solution of NH4Cl at 08C and extracted with
CHCl3. The combined organic extracts were washed with a saturated
aqueous solution of NH4Cl and brine, dried over Na2SO4, and concentrat-
630
www.chemeurj.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 626 – 633

Synthesis of Elacomine and Isoelacomine
FULL PAPER
ed under reduced pressure. K2CO3 (67.2 mg, 0.486 mmol) was added to a
solution of the crude material in MeOH (16 mL) at 08C. The reaction
mixture was stirred for 10 min, then neutralized by the addition of a satu-
rated aqueous solution of NH4Cl at 08C and extracted with EtOAc. The
combined organic extracts were washed with H2O and brine, dried over
Na2SO4, and concentrated under reduced pressure. The obtained residue
was purified by silica gel column chromatography (hexane/EtOAc=7:3)
Carbamate 16: KOH (921 mg, 16.4 mmol) was added to a stirred solution
of 15 (1.61 g, 3.28 mmol) in DMF (30 mL) and H2O (5.0 mL) at 08C.
After stirring for 1 h at the same temperature, the mixture was diluted
with Et2O at 08C and extracted with Et2O. The combined organic ex-
tracts were washed with brine, dried over Na2SO4, and concentrated
under reduced pressure. The obtained residue was purified by silica gel
column chromatography (hexane/EtOAc=8:2) to give 16 as a colorless
oil (1.28 g, 99% over 2 steps). 1H NMR (400 MHz, CDCl3): d=7.31–7.20
(m, 5H), 6.86 (d, J=8.3 Hz, 1H), 6.34 (d, J=11.4 Hz, 1H), 6.24 (dd, J=
8.3, 2.4 Hz, 1H), 6.19 (d, J=2.4 Hz, 1H), 6.13 (d, J=11.4 Hz, 1H), 4.35
(brs, 1H), 4.27 (s, 3H), 4.09 (brs, 1H), 3.72 (s, 3H), 3.07 (td, J=6.1,
6.1 Hz, 2H), 2.62 (t, J=6.1 Hz, 2H), 1.82 (s, 3H), 1.72 ppm (s, 3H);
13C NMR (100 MHz, CDCl3): d=160.1, 158.0, 146.2, 139.3, 137.2, 133.7,
129.7, 128.7, 128.5, 127.4, 127.3, 123.0, 120.7, 101.2, 97.8, 55.0, 48.1, 39.3,
31.8, 26.4, 18.2 ppm; IR (ATR): n˜ =1705 cmꢀ1; MS (FAB): m/z: 395
[M+H+]; elemental analysis calcd (%) for C24H10N2O3: C 73.07, H 7.66,
N 7.10; found: C 72.81, H 7.63, N 7.00.
to give 13 as
a colorless oil (2.08 g, 99% over 2
steps). 1H NMR
(400 MHz, CDCl3): d=7.26–7.11 (m, 4H), 7.13–7.11 (m, 2H), 6.87 (dd,
J=8.6, 2.7 Hz, 1H), 6.41 (d, J=11.2 Hz, 1H), 6.22 (d, J=11.2 Hz, 1H),
6.16 (d, J=2.7 Hz, 1H), 5.52 (d, J=13.9 Hz, 1H), 4.11 (d, J=13.9 Hz,
1H), 3.74–3.60 (m, 5H), 2.96 (ddd, J=14.2, 7.6, 7.6 Hz, 1H), 2.62 (ddd,
J=12.0, 7.6, 7.6 Hz, 1H), 1.88 (s, 3H), 1.78 ppm (s, 3H); 13C NMR
(100 MHz, CDCl3): d=158.4, 157.8, 157.4, 138.9, 136.8, 135.4, 132.9,
131.7, 131.6, 129.7, 129.4, 128.5, 128.1, 120.8, 115.9, 114.9, 61.3, 55.3, 53.4,
34.1, 26.5, 18.2 ppm; IR (ATR): n˜ =3727, 1695 cmꢀ1
.
Azide 14: Et3N (0.851 mL, 6.06 mmol) and methanesulfonyl chloride
(0.432 mL, 5.59 mmol) were added to a stirred solution of 13 (2.02 g,
4.66 mmol) in CH2Cl2 (50 mL) at 08C. The mixture was stirred at RT for
2 h, neutralized by the addition of a saturated aqueous solution of NH4Cl
at 08C and extracted with CHCl3. The combined organic extracts were
washed with brine, dried over Na2SO4, and concentrated under reduced
pressure. NaN3 (908 mg, 14.0 mmol) and tetra-n-butylammonium iodide
(172 mg, 0.466 mmol) were added to a solution of the mesylated alcohol
in DMF (50 mL) at RT then the mixture was warmed to 808C. After stir-
ring for 2 h, H2O was added at 08C and the mixture was extracted with
Et2O. The combined organic extracts were washed with H2O and brine,
dried over Na2SO4, and concentrated under reduced pressure. The ob-
tained residue was purified by silica gel column chromatography
(hexane/EtOAc=9:1) to give 14 as a colorless oil (1.81 g, 85% over 2
steps). 1H NMR (500 MHz, [D7]DMF, *=signals of minor rotamer): d=
7.42 (d, J=8.6 Hz, 1H), 7.37–7.20 (m, 5H), 7.07 (dd, J=8.6, 2.3 Hz, 1H),
6.92* (dd, J=8.6, 2.3 Hz), 6.60* (d, J=2.3 Hz), 6.45 (d, J=11.5 Hz, 1H),
6.42 (d, J=2.3 Hz, 1H), 6.34 (d, J=11.5 Hz, 1H), 5.46 (d, J=14.3 Hz,
1H), 5.18* (d, J=16.1 Hz), 4.59* (d, J=16.1 Hz), 4.25 (d, J=14.3 Hz,
1H), 3.69 (s, 3H), 3.55–3.34 (m, 3H), 3.05 (ddd, J=14.3, 7.3, 7.3 Hz, 1H),
1.89 (s, 3H), 1.79 ppm (s, 3H); 13C NMR (126 MHz, [D7]DMF, major
rotamer only): d=162.7, 159.1, 139.2, 137.6, 136.2, 132.63, 132.55, 132.0,
130.0, 129.6, 129.2, 128.7, 121.5, 116.8, 115.2, 106.6, 55.9, 54.1, 50.5, 34.1,
26.5, 18.2 ppm; IR (ATR): n˜ =1688 cmꢀ1; elemental analysis calcd (%)
for C24H25F3N4O2: C 62.87, H 5.50, N 12.22; found: C 63.00, H 5.52, N
12.14.
Chloroformamide 17: At ꢀ788C, pyridine (0.104 mL, 1.30 mmol) was
added to a solution of 16 (425 mg, 1.08 mmol) in CH2Cl2 (10 mL), fol-
lowed by triphosgene (319 mg, 1.08 mmol). The reaction mixture was
warmed to RT, diluted with CHCl3, and washed with 1m HCl and brine.
The organic phase was dried over Na2SO4, filtered, and concentrated
under reduced pressure. The obtained residue was purified by silica gel
column chromatography (hexane/EtOAc=7:3) to give 17 as a colorless
oil (485 mg, 98%). 1H NMR (500 MHz, [D7]DMF): d=7.40–7.27 (m,
6H), 7.02 (dd, J=8.6, 2.6 Hz, 1H), 6.49–6.47 (m, 2H), 6.35 (d, J=
11.1 Hz, 1H), 5.26 (d, J=14.6 Hz, 1H), 4.25 (d, J=14.6 Hz, 1H), 3.69 (s,
3H), 3.56 (s, 3H), 3.23–3.19 (m, 2H), 2.88–2.84 (m, 1H), 2.71–2.68 (m,
1H), 1.88 (s, 3H), 1.81 ppm (s, 3H); 13C NMR (126 MHz, [D7]DMF): d=
159.2, 157.8, 150.0, 140.1, 138.0, 136.5, 134.1, 132.9, 132.0, 129.5, 129.2,
129.0, 128.7, 122.0, 117.1, 115.2, 56.2, 55.8, 51.7, 41.1, 32.5, 26.6, 18.3 ppm;
IR (ATR): n˜ =1719 cmꢀ1; HRMS (FAB): m/z: calcd for C25H29ClN2O4:
457.1894 [M+H+]; found: 457.1898.
Diene 19: A solution of chloroformamide 17 (47.9 mg, 0.105 mmol), Pd-
AHCTUNTGRENGUN(N OAc)2 (2.35 mg, 0.0105 mmol), PPh3 (5.51 mg, 0.0210 mmol), and
Cs2CO3 (41.1 mg, 0.126 mmol) in xylene (1.0 mL) was stirred at 1308C
for 1 h. The reaction mixture was cooled to RT, diluted with H2O, and ex-
tracted with CHCl3. The organic phase was dried over Na2SO4, filtered,
and concentrated under reduced pressure. The obtained residue was puri-
fied by silica gel column chromatography (hexane/EtOAc=8:2!7:3) to
give 19 as a colorless oil (38.1 mg, 86%). 1H NMR (500 MHz, CDCl3):
d=7.31–7.23 (m, 5H), 7.16 (d, J=8.0 Hz, 1H), 6.60 (dd, J=8.0, 2.3 Hz,
1H), 6.34 (d, J=2.3 Hz, 1H), 6.12 (d, J=15.8 Hz, 1H), 5.80 (d, J=
15.8 Hz, 1H), 4.95 (s, 1H), 4.88 (s, 1H), 4.87 (s, 2H), 4.78 (brs, 1H), 3.74
(s, 3H), 3.60 (s, 3H), 3.11–2.98 (m, 2H), 2.29–2.14 (m, 2H), 1.83 ppm (s,
3H); 13C NMR (126 MHz, CDCl3): d=178.4, 160.1, 156.7, 143.5, 141.2,
135.7, 133.3, 129.2, 128.9, 128.8, 127.6, 127.1, 125.0, 117.4, 106.6, 97.7,
Carbamate 15: PPh3 (3.61 g, 13.7 mmol) was added to a stirred solution
of 14 (2.10 g, 4.58 mmol) in THF (35 mL) and H2O (10 mL) at RT. After
stirring for 30 min at 508C, H2O was added at RT and the mixture was
extracted with CHCl3. The combined organic extracts were washed with
brine, dried over Na2SO4, and concentrated under reduced pressure.
DMAP (catalytic amount), Et3N (1.28 mL, 9.16 mmol) and methyl chlor-
oformate (0.425 mL, 5.50 mmol) were added to a solution of the crude
amine in CH2Cl2 (45 mL) at 08C. After stirring for 2 h at RT, the reaction
mixture was neutralized by the addition of a saturated aqueous solution
of NH4Cl at 08C and extracted with CHCl3. The combined organic ex-
tracts were washed with H2O and brine, dried over Na2SO4, and concen-
trated under reduced pressure. The obtained residue was purified by
silica gel column chromatography (hexane/EtOAc=8:2!7:3) to give 15
55.4, 53.0, 51.9, 43.8, 37.24, 37.20, 18.6 ppm; IR (ATR): n˜ =1701 cmꢀ1
Hydroamination of diene 19: Bi(OTf)3 (170 mg, 0.259 mmol) and K[PF6]
.
A
ACHTUNGTRENNUNG
(47.7 mg, 0.259 mmol) were added to a solution of diene 19 (1.09 g,
2.59 mmol) in 1,4-dioxane (25 mL) at RT. The solution was stirred at
508C for 10 h and quenched with water at 08C. The resultant mixture
was extracted with EtOAc (ꢂ3). The combined organic layers were dried
over Na2SO4, filtered, and concentrated under reduced pressure. The res-
idue was purified by silica gel column chromatography (hexane/EtOAc=
7:3) to give 18 as a colorless oil (905 mg, 83%, d.r.=1:3). 1H NMR
(600 MHz, CDCl3): d=7.31–7.19 (m, 5H), 7.12 (d, J=8.2 Hz, 0.25H),
7.08 (d, J=8.2 Hz, 0.75H), 6.53 (dd, J=8.2, 2.0 Hz, 0.25H), 6.50 (dd, J=
8.2, 2.0 Hz, 0.75H), 6.28 (d, J=2.0 Hz, 0.75H), 6.23 (br, 0.25H), 5.25 (d,
J=7.7 Hz, 0.25H), 5.15 (d, J=15.5 Hz, 0.25H), 5.04 (d, J=15.8 Hz,
0.75H), 4.95 (d, J=8.2 Hz, 0.75H), 4.80 (d, J=8.2 Hz, 0.75H), 4.75 (br,
0.25H), 4.71 (d, J=15.8 Hz, 0.75H), 4.52 (d, J=15.5 Hz, 0.25H), 4.08 (br,
0.25H), 4.01 (br, 0.75H), 3.79–3.74 (m, 1H), 3.72 (s, 2.25H), 3.71 (s,
0.75H), 3.71 (br, 3H), 2.36 (ddd, J=12.6, 7.5, 7.5 Hz, 0.75H), 2.26 (br,
0.25H), 2.20 (br, 0.25H), 2.11 (ddd, J=12.6, 6.9, 5.8 Hz, 0.75H), 1.63 (s,
0.75H), 1.59 (s, 2.25H), 1.38 (s, 2.25H), 1.28 ppm (s, 0.75H); 13C NMR
(150 MHz, CDCl3, *=signals of minor diastereomer): d=178.2, 160.2*,
160.0, 155.9 (br), 155.5* (br), 143.8, 136.1, 135.7*, 135.6, 128.74*, 128.72,
as
a colorless oil (1.88 g, 84% over 2
steps). 1H NMR (500 MHz,
[D7]DMF, major rotamer): d=7.44 (d, J=8.6 Hz, 1H), 7.32–7.15 (m,
5H), 7.05 (dd, J=8.6, 2.3 Hz, 1H), 6.41–6.37 (m, 3H), 5.49 (d, J=
14.4 Hz, 1H), 4.19 (d, J=14.4 Hz, 1H), 3.68 (s, 3H), 3.57 (s, 3H), 3.21
(ddd, J=7.5, 7.5, 6.3 Hz, 2H), 2.86 (m, 1H), 2.66 (ddd, J=13.2, 7.5,
7.5 Hz, 1H), 1.88 (s, 3H), 1.78 ppm (s, 3H); 13C NMR (126 MHz,
[D7]DMF, *=peaks of minor rotamer): d=159.0, 157.8, 157.5*, 138.2,
137.5, 136.2, 133.5, 132.9, 132.4, 131.4, 129.6, 129.3, 129.2, 128.6, 128.3*,
121.9, 118.5, 116.5, 116.2*, 115.1, 114.9*, 55.8, 55.7*, 54.3, 51.7, 40.9, 32.4,
25.6, 18.2 ppm; IR (ATR): n˜ =1686 cmꢀ1; elemental analysis calcd (%)
for C26H29F3N2O4: C 63.66, H 5.96, N 5.71; found: C 63.36, H 6.20, N
5.51.
Chem. Eur. J. 2011, 17, 626 – 633
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
631

Y. Takemoto et al.
127.53, 127.48*, 127.1, 126.9, 125.4, 123.1*, 121.8 (br), 120.9* (br), 106.3*,
105.9, 97.1*, 97.0, 63.4* (br), 61.7 (br), 56.7*, 56.6, 55.4*, 55.3, 52.3, 45.9*,
45.6, 43.5*, 43.6, 34.8*, 34.2, 25.6*, 25.7, 17.9 ppm; IR (ATR): n˜ =2952,
0.0249 mmol) in THF (2.0 mL) at ꢀ788C, until a deep-blue color persist-
ed, and the mixture was stirred for 30 min. A saturated aqueous solution
of NH4Cl was added and the reaction mixture was extracted with EtOAc.
The organic layer was washed with water and brine, dried over Na2SO4,
filtered, and concentrated under reduced pressure. The resultant residue
was purified by silica gel column chromatography (hexane/EtOAc=
9:1!8:2) to give 21b as a colorless solid (5.2 mg, 64%). 1H NMR
(500 MHz, CDCl3): d=7.13 (d, J=8.0 Hz, 1H), 6.55 (dd, J=8.0, 2.3 Hz,
1H), 6.45 (d, J=2.3 Hz, 1H), 4.16 (br, 1H), 3.99 (br, 1H), 3.84 (s, 3H),
3.73 (s, 3H), 3.59 (ddd, J=10.6, 7.8, 7.8 Hz, 1H), 2.24 (ddd, J=12.1, 7.8,
7.8 Hz, 1H), 1.99 (m, 1H), 1.72 (br, 1H), 1.31 (m, 1H), 1.17 (m, 1H),
0.83 (d, J=6.3 Hz, 3H), 0.63 ppm (d, J=6.3 Hz, 3H); 13C NMR
(126 MHz, CDCl3): d=179.0, 160.1, 156.2, 144.8, 125.3, 121.2, 105.2, 97.1,
61.5 (br), 55.7 (br), 55.4, 52.3, 45.4 (br), 40.7 (br), 35.7, 25.7, 23.0,
1704, 1625, 1376 cmꢀ1
421.2127 [M+H+]; found: 421.2108.
; HRMS (FAB): m/z: calcd for C25H29N2O4:
Spirooxindole 18:
0.0875 mmol), PdACHTUNGTRENNUNG
0.018 mmol), and BiACHTUNGTRENNUNG
A
solution of chloroformamide 17 (40.0 mg,
(TFA)2 (2.9 mg, 0.0088 mmol), DPPF (9.7 mg,
(OTf)3 (5.7 mg, 0.0088 mmol) in xylene (1.0 mL) was
stirred at 1308C for 17 h. The reaction mixture was cooled to RT and pu-
rified directly by silica gel column chromatography (hexane/EtOAc=
8:2!7:3) to give 18 as a colorless oil (19.0 mg, 52%, d.r.=4:5).
Spirooxindoles 20a and 20b: A solution of spirooxindole 18 (9.0 mg,
0.021 mmol) and Pd/C (6.3 mg, 0.011 mmol) in EtOH (1.0 mL) was
stirred at RT under H2 pressure (400 kPa) for 4 days. The reaction mix-
ture was filtered through a Celite pad, and concentrated under reduced
pressure. The obtained residue was purified by silica gel column chroma-
tography (hexane/CHCl3/EtOAc=8:1:2) to give 20a (3.9 mg, 43%) as a
colorless solid and 20b (3.9 mg, 43%) as a colorless oil.
21.9 ppm; IR (ATR): n˜ =2925, 1703, 1623, 1446, 1377 cmꢀ1
; HRMS
(FAB): m/z: calcd for C18H25N2O4: 333.1814 [M+H+]; found: 333.1801.
Spirooxindole 20a: 1H NMR (500 MHz, CDCl3, 508C): d=7.31–7.23 (m,
5H), 6.96 (brd, J=8.3 Hz, 1H), 6.50 (dd, J=8.3, 2.0 Hz, 1H), 6.35 (d, J=
2.0 Hz, 1H), 4.97 (d, J=15.5 Hz, 1H), 4.77 (d, J=15.5 Hz, 1H), 4.03 (br,
1H), 3.88–3.78 (br, 2H), 3.72 (s, 6H), 2.46 (br, 1H), 2.02 (ddd, J=13.2,
6.6, 6.6 Hz, 1H), 1.82 (br, 1H), 1.62 (br, 1H), 1.25 (br, 1H), 0.77 ppm (d,
J=6.3 Hz, 6H); 13C NMR (126 MHz, CDCl3, 508C): d=176.8, 160.1,
155.6, 142.8, 135.8, 128.7, 127.6, 127.3, 125.5 (br), 122.8, 106.6, 97,3, 63.9,
55.4, 55.0, 52.2, 44.6, 43.9, 40.0, 35.7 (br), 25.1, 22.8, 22.0 ppm; IR (ATR):
[1] G. W. A. Slywka, Ph.D. Thesis, The University of Alberta, Edmon-
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[2] M. N. G. James, G. J. B. Williams, Can. J. Chem. 1972, 50, 2407.
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n˜ =2954, 1699, 1624, 1376 cmꢀ1
; HRMS (FAB): m/z: calcd for
C25H31N2O4: 423.2284 [M+H+]; found: 423.2266.
Spirooxindole 20b: 1H NMR (400 MHz, CDCl3): d=7.33–7.23 (m, 5H),
7.12 (d, J=8.3 Hz, 1H), 6.53 (dd, J=8.3, 2.4 Hz, 1H), 6.38 (d, J=2.4 Hz,
1H), 4.95 (d, J=15.6 Hz, 1H), 4.79 (d, J=15.6 Hz, 1H), 4.30–4.13 (br,
1H), 4.11–3.93 (br, 1H), 3.75 (s, 3H), 3.74 (s, 3H), 3.61 (ddd, J=11.0,
8.0, 7.6 Hz, 1H), 2.32 (ddd, J=12.7, 8.0, 8.0 Hz, 1H), 2.07–2.01 (m, 1H),
1.87–1.63 (br, 1H), 1.34–1.24 (m, 1H), 1.04–0.87 (br, 1H), 0.82 (d, J=
6.1 Hz, 3H), 0.58 ppm (d, J=6.1 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d=178.9, 160.1, 156.3, 143.9, 135.7, 128.8, 127.7, 127.5, 125.4, 121.0, 105.9,
97.4, 61.6, 55.4, 52.4, 45.5, 43.9, 35.8, 30.9, 24.7, 23.0, 21.9, ꢀ0.02 ppm; IR
ˇ
12, 952; h) I. Allous, S. Comesse, D. Berkes, A. Alkyat, A. Daꢃch,
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P. W. L. Quesne, J. R. Deschamps, J. M. Cook, J. Nat. Prod. 2008, 71,
1431.
(ATR): n˜ =1703 cmꢀ1
; HRMS (FAB): m/z: calcd for C25H31N2O4:
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423.2284 [M+H+]; found: 423.2270.
Spirooxindole 21a: A LiDBB solution was prepared by addition of lithi-
um (17.9 mg, 2.58 mmol) to
a solution of 4,4’-di-tert-butylbiphenyl
(291.5 mg, 1.09 mmol) in THF, which was then sonicated for 30 min. The
LiDBB solution was added to a solution of 20a (43.2 mg, 0.102 mmol) in
THF (2.0 mL) at ꢀ788C, until a deep-blue color persisted, and the mix-
ture was stirred for 30 min. A saturated aqueous solution of NH4Cl was
added and the mixture was extracted with EtOAc. The organic layer was
washed with water and brine, dried over Na2SO4, filtered, and concen-
trated under reduced pressure. The resultant residue was purified by
silica gel column chromatography (hexane/EtOAc=9:1!7:3) to give 21a
1
as a colorless solid (20.8 mg, 61%). H NMR (500 MHz, CDCl3): d=8.53
(br, 1H), 6.96 (br, 1H), 6.54 (d, J=8.0 Hz, 1H), 6.50 (s, 1H), 4.11–3.65
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I. W. Davies, Angew. Chem. 2008, 120, 4789; Angew. Chem. Int. Ed.
2008, 47, 4711.
(m, 3H), 3.80 (s, 6H), 2.46 (m, 1H), 2.03 (m, 1H), 1.83 (br, 1H), 1.51–
1
1.26 (m, 2H), 0.82 ppm (br, 6H); H NMR (500 MHz, CDCl3, 508C): d=
8.11 (br, 1H), 6.94 (d, J=8.3 Hz, 1H), 6.53 (dd, J=8.3, 2.3 Hz, 1H), 6.47
(d, J=2.3 Hz, 1H), 4.03 (br, 1H), 3.83 (br, 1H), 3.74 (s, 3H), 3.76 (br,
1H), 3.73 (s, 3H), 2.45 (br, 1H), 2.01 (ddd, J=13.2, 6.9, 6.9 Hz, 1H), 1.82
(m, 1H), 1.62 (br, 1H), 1.34 (m, 1H), 0.81 (d, J=6.3 Hz, 3H), 0.80 ppm
(d, J=6.3 Hz, 3H); 13C NMR (126 MHz, CDCl3): d=179.3 (br), 160.1,
155.6, 140.5 (br), 125.8 (br), 123.2, 107.4, 97.3, 63.8, 55.5, 55.3, 52.4, 44.5
(br), 40.2 (br), 34.1 (br), 25.2, 23.3 (br), 22.4 ppm (br); 13C NMR
(126 MHz, CDCl3, 508C): d=178.8 (br), 160.2, 155.6, 140.6, 126.1 (br),
123.3, 107.5, 97.3, 64.0, 55.5, 55.4, 52.3, 44.5, 40.1, 35.3 (br), 25.3, 23.0,
22.2 ppm; IR (ATR): n˜ =3242, 2955, 1703, 1634 cmꢀ1; HRMS (FAB): m/
z: calcd for C18H25N2O4: 333.1814 [M+H+]; found: 333.1805.
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Spirooxindole 21b: A LiDBB solution was prepared by addition of lithi-
um (30 mg, 4.3 mmol) to
a solution of 4,4’-di-tert-butylbiphenyl
(221.0 mg, 0.83 mmol) in THF (3 mL), which was then sonicated for
20 min. The LiDBB solution was added to a solution of 20b (10.5 mg,
632
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ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 626 – 633

Synthesis of Elacomine and Isoelacomine
FULL PAPER
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[15] During this study, one example of a Heck reaction with a six-mem-
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D. J. Jenkins, E. J. Trybulski, A. Fensome, US Pat. Appl. Publ. 2009,
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[20] The major diastereomer had the same stereochemistry of isoelaco-
mine.
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[18] Compound 10b was prepared by nosylation (oNsCl, nBuLi, THF,
ꢀ788C, 71%) of 5,6-dihydropyridine-2(1H)-one.
Received: August 10, 2010
Published online: November 16, 2010
Chem. Eur. J. 2011, 17, 626 – 633
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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